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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation P13K

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There are 39 clinical trials

Clinical Trials


1 A Phase I Trial of Irinotecan and BKM120 in Previously Treated Advanced Colorectal Cancer

This phase I trial will use the combination of irinotecan and BKM120 in patients with advanced colorectal cancer who have failed on or have become intolerant of at least one line of therapy for advanced colorectal cancer and who are candidates for irinotecan therapy.

NCT01304602
Conditions
  1. Colorectal Cancer
Interventions
  1. Drug: Irinotecan
  2. Drug: BKM120
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates - Clinical manifestation of diabetes mellitus or steroid-induced diabetes mellitus - Impairment of GI function or disease that may significantly alter the absorption of BKM120; diarrhea ≥ grade 2 - Major surgery ≤ 4 weeks prior to starting study drug - Prior treatment with a P13K inhibitor; any hematopoietic colony-stimulating growth factors ≤ 2 weeks prior to starting study drug; corticosteroids ≤ 2 weeks prior to starting study drug; chemotherapy or targeted anticancer therapy ≤4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug; small molecule therapeutics (excluding monoclonal antibodies) ≤5 effective half-lives prior to starting study drug - Currently receiving medication that has the potential to prolong the QT interval or inducing Torsades de Pointes - chronic treatment with steroids or another immunosuppressive agent. --- P13K ---

Primary Outcomes

Description: The maximum tolerated dose will be defined as the dose level prior to the dose level in which dose-escalation was stopped based on dose-limiting toxicities (DLTs). DLTs are based on specific adverse events specified in the study protocol. DLTs will be assessed during the first two cycles of treatment (28 days total).

Measure: Maximum tolerated dose

Time: 28 days

Secondary Outcomes

Description: Blood samples will be collected at cycle 1/day 1 and cycle 2/day 1 to determine the AUC of irinotecan in the presence and absence of BKM120.

Measure: area under the plasma concentration versus time curve (AUC) of irinotecan

Time: up to 25.5 hours post dose of irinotecan

Description: Disease will be assessed at baseline and then every four cycles (8 weeks) by CT or MRI. Response will be assessed following RECIST criteria. Patients will be categorized as complete response, partial response, progressive disease, stable disease, or unknown.

Measure: Change in tumor size

Time: baseline, and every 8 weeks

Description: Blood samples will be collected at cycle 1/day 1 and cycle 2/day 1 to determine the AUC of irinotecan in the presence and absence of BKM120.

Measure: Peak Plasma Concentration (Cmax) of irinotecan

Time: up to 25.5 hours post-dose of irinotecan

Description: Blood samples will be collected at cycle 1/day 1 and cycle 2/day 1 to determine the AUC of irinotecan in the presence and absence of BKM120.

Measure: biological half-life of irinotecan

Time: up to 25.5 hours post dose of irinotecan

Description: The Cmax of BKM120 will be measured at Cycle 2/Day 1 for pharmacokinetic characterization of BKM120.

Measure: Peak Plasma Concentration (Cmax) of BKM120

Time: up to 25.5 hours post-dose of irinotecan

Description: The AUC of BKM120 will be measured at Cycle 2/Day 1 for pharmacokinetic characterization of BKM120.

Measure: area under the plasma concentration versus time curve (AUC) of BKM120

Time: up to 25.5 hours post dose of irinotecan

Description: The biological half life of BKM120 will be measured at Cycle 2/Day 1 for pharmacokinetic characterization of BKM120.

Measure: Biological half life of BKM120

Time: up to 25.5 hours post dose of irinotecan

2 A Phase II Study of BKM 120 for Patients With Recurrent Glioblastoma and Activated PI3K Pathway

BKM120 is a newly discovered drug that has been used in other research studies. Information from those other research studies suggests that BKM120 may help to slow or stop the growth of malignant gliomas. The purpose of this study is to see how well BKM120 works in patients with malignant gliomas. Patients on this study will be treated in two groups: patients who are going to receive surgery and those who will not receive surgery. This study is trying to determine how effective BKM120 is in stopping cancer cells from growing. For patients receiving surgery the research will also try to determine if an effective level of BKM120 can penetrate the brain before surgery.

NCT01339052
Conditions
  1. Glioblastoma
Interventions
  1. Drug: BKM120
  2. Procedure: Surgery
MeSH:Glioblastoma
HPO:Glioblastoma multiforme

Exclusion Criteria: - Participants who have received prior treatment with a P13K inhibitor, AKT inhibitor, mTOR inhibitor (e.g. --- P13K ---

Primary Outcomes

Description: pAKT response was determined by pathologist-performed semi-quantitative IHC scoring for pAKT using previously established methods for glioblastoma (GBM) patients. Sample staining scored for intensity on a 0-2+ scale (0 none, 1+ weak positive, 2+ strong positive). Change in pAKT IHC score was the difference in score from baseline to surgery. Participants were classified into 3 groups: a reduction of staining score of one degree or more (considered a response), an increase in score and no change in score.

Measure: Change in pAKT (S473) Immunohistochemistry (IHC) Score From Baseline to Surgery [Cohort 1]

Time: Samples were collected at baseline and at surgery (resected surgical tumor specimen) which occurred after up to 12 days of BKM120 treatment.

Description: PFS6 is the proportion of participants remaining alive and progression-free at 6-months from cycle 1 day 1 of BKM120 treatment. Progressive disease is defined using RANO (Response Assessment in Neuro-Oncology) criteria (Wen et al JCO 2010), which takes modified Macdonald Criteria and adds assessment of non-enhancing lesions. Per RANO, progressive disease (PD) is defined either as > 25% increase in sum of the products of perpendicular diameters of enhancing lesions on stable or increasing doses of corticosteroids, or one or more of the of the following: 1) Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids steroids not due to co-morbid events; 2) Any new lesion; 3) Clear clinical deterioration not attributable to other causes apart from the tumor; or 4) Failure to return for evaluation due to death or deteriorating condition.

Measure: 6-Month Progression-Free Survival (PFS6) [Cohort 2]

Time: Participants were assessed radiologically every other cycle on treatment; Relevant for this outcome is up to month 6 evaluation.

Description: Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry. BKM120 tumor-to-plasma ratio at time of surgery was calculated based on these levels.

Measure: BKM120 Brain-to-Plasma Ratio at Time of Surgery [Cohort 1]

Time: Samples were collected at surgery (surgical tumor specimen and plasma sample) which occurred after up to 12 days of BKM120 treatment.

Description: Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry.

Measure: BKM120 Tumor Tissue Concentration at Time of Surgery [Cohort 1]

Time: Samples were collected at surgery (resected surgical tumor specimen) which occurred after up to 12 days of BKM120 treatment.

Description: Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry.

Measure: BKM120 Plasma Concentration at Time of Surgery [Cohort 1]

Time: Samples were collected at surgery which occurred after up to 12 days of BKM120 treatment.

Secondary Outcomes

Description: Tumor cell proliferation and tumor cell death was using immunohistochemistry for Ki-67 based on established methods. Percent reduction was based on Ki-67 levels at baseline and at surgery.

Measure: % Ki-67 Reduction Using Immunohistochemistry (IHC) [Cohort 1]

Time: Samples were collected at baseline (archival tumor specimen) and at surgery (surgical tumor specimen) which occurred after up to 12 days of BTK120 treatment.

Description: Radiographic response was based on RANO (Response Assessment in Neuro-Oncology) criteria. Per RANO, complete response (CR): 1) Complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks, 2) No new lesions, 3) All lesions assessed using the same techniques as baseline, 4) No steroid use (or on physiologic replacement doses only), 5) Stable or improved non-enhancing (T2/FLAIR) lesions and 6) Stable or improved clinically; partial response (PR): 1) >/= 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions (sum LD) sustained for at least 4 weeks and 2) No progression; progressive disease (PD): 1) > 25% increase sum LD and/or 2) significant increase in T2/FLAIR, 3) any new lesion, 4) clear clinical deterioration; stable disease (SD): none of the above.

Measure: Radiographic Response [Cohort 2]

Time: Participants were assessed radiologically every other cycle on treatment. Cohort 2 participants were on treatment up to 9.2 months.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. NOTE: This outcome measure was previously titled: "Investigate Pharmacokinetics of BKM120 in This Population by Comparing Maximum Plasma Concentrations (Cmax) From Day 1 to Day 8"

Measure: Maximum Observed Plasma Concentrations (Cmax) of BKM120 Day 1 and Day 8 [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. The accumulation ratio is day 8/day 1.

Measure: Cmax Accumulation Ratio of BKM120 Day 1 and Day 8 Ratio [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. NOTE: This outcome measure was previously titled: "Investigate Pharmacokinetics of BKM120 in This Population by Comparing the Drug Exposure Area Under the Curve (AUC0-5h) From Day 1 to Day 8"

Measure: Area Under the Concentration Curve From Time 0 to Last Concentration (AUC0-5h) of BKM120 Day 1 and Day 8 [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. The accumulation ratio is day 8/day 1.

Measure: AUC0-5h Accumulation Ratio of BKM120 Day 1 and Day 8 [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods.

Measure: Time to Maximum Observed Plasma Concentration (Tmax) of BKM120 Day 1 and Day 8 [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Overall survival is defined as the time from date of first dose to death or date last known alive and estimated using Kaplan-Meier (KM) methods.

Measure: Overall Survival (OS) [Cohort 2]

Time: Participants were followed long-term for survival via medical record review. Cohort 2 participants were followed for survival up to 52 months in this study cohort.

Description: PFS is defined as the time from first dose to the earliest documentation of disease progression or death. Participants alive without evidence of PD were censored at the date of last disease assessment. Progressive disease was established based on Response Assessment in Neuro-Oncology (RANO) criteria (Wen et al JCO 2010). See outcome measure #2.

Measure: Progression-Free Survival (PFS) [Cohort 2]

Time: Participants were assessed radiologically every other cycle on treatment and off-treatment via medical record review until death. Cohort 2 participants were followed for progression-free survival up to 12 months in this study cohort.

Description: The percentage of patients who experienced any grade 3-5 treatment-related adverse event based on CTCAEv4 as reported on case report forms.

Measure: Grade 3-5 Treatment-Related Toxicity Rate

Time: Adverse events experienced by participants are collected and reported throughout treatment with study drug (from initiation of study medication until 30 days after the last dose of BKM120), maximum timeframe was 2 years.

3 A Phase 1 Trial of BKM 120, a Novel Oral Selective Phosphatidylinositol-3-kinase (PI3K) Inhibitor, in Combination With Fulvestrant in Postmenopausal Women With Estrogen Receptor Positive Metastatic Breast Cancer

This phase I trial will determine the Maximum Tolerated Dose (MTD) of BKM120 when given together with fulvestrant in treating postmenopausal patients with estrogen receptor-positive (ER+) stage IV breast cancer. The toxicity profile of this combination therapy will also be described. Inhibition of PI3K by BKM120 may enhance programmed cell death (apoptosis) in estrogen receptor positive (ER+) breast cancer cells. Giving fulvestrant together with BKM 120 may enhance this apoptotic effect, providing a novel therapeutic strategy for patients with metastatic ER+ breast cancer.

NCT01339442
Conditions
  1. Estrogen Receptor-positive Breast Cancer
  2. Recurrent Breast Cancer
  3. Stage IV Breast Cancer
Interventions
  1. Drug: BKM120
  2. Drug: Fulvestrant
  3. Procedure: biopsy
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

Inclusion Criteria: - Patient must be ≥ 18 years of age - Patient must be a postmenopausal woman, defined by one of the following criteria: - Women ≥ 60 years - Women aged 45-59 years with spontaneous cessation of menses ≥ 12 months prior to registration - Women aged 45-59 years with cessation of menses of duration < 12 months or secondary to hysterectomy AND an follicle-stimulating hormone (FSH) level in the postmenopausal range according to institutional standards (or > 34.4 IU/L if institutional range is not available) prior to registration - Women aged 45-59 years on hormonal replacement therapy who have discontinued hormonal therapy AND an FSH level in the postmenopausal range according to institutional standards (or > 34.4 IU/L if institutional range is not available) prior to registration - Status post bilateral surgical oophorectomy - Patient must have a negative serum pregnancy test within 48 hours before starting study treatment (if a woman of childbearing potential) - Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 - Patient must have histologically or cytologically confirmed invasive breast cancer that is stage IV or metastatic (histologic/cytologic confirmation of recurrence preferred, but not required) - Patient must have a representative tumor tissue specimen available; archival tissue is allowed - Either the primary or the metastatic tumor must be positive for estrogen receptor (>= 1% tumor cell staining by immunohistochemistry or an Allred Score of >= 3 by immunohistochemistry) - Patient must have at least one site of measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria - Patient must have had no more than 3 lines of systemic therapy (including endocrine therapy) for metastatic disease to be eligible for phase IB and the last 10 patients of Cohort C; there is no limitation on the numbers of prior systemic therapies for phase IA and the first 2 patients of Cohort C - Patients who are currently taking fulvestrant without disease progression are eligible - Patient must have a life expectancy of >= 12 weeks - Patient must have adequate oran function as defined as: - Absolute neutrophil count (ANC) >= 1500/uL - Platelet count >= 100,000/uL - Hemoglobin >= 9 g/dL - Serum creatinine =< 1.5 x upper limit of normal (ULN) - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or =< 3.0 x ULN if liver metastases are present) - Serum bilirubin =< ULN (or =< 1.5 x ULN if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) - Serum amylase =< ULN - Serum lipase =< ULN - Magnesium >= the lower limit of normal - Potassium within normal limits for the institution - Patient must have international normalized ratio (INR) =< 2 - Patient must have fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - Patient must have total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed) - Patient must be able and willing to sign the consent form Exclusion Criteria: - Patient must not have received prior treatment with a P13K inhibitor - Patient must not have a known hypersensitivity to BKM120 or to its excipients - Patient must not have untreated brain metastases; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial if the patient is: - 4 weeks from therapy completion (including radiation and/or surgery) - Clinically stable at the time of study entry - Not receiving corticosteroid therapy - Patient must not have acute or chronic liver disease, renal disease, or pancreatitis - Patient must not have any of the following mood disorders as judged by the Investigator or a Psychiatrist - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - Greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety - Patient must not meet the cut-off score of >= 10 in the Patient Health Questionnaire (PHQ-9) or a cut-off of >= 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or select a positive response of 1, 2, or 3 to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Patient must not have >= grade 2 diarrhea - Patient must not have active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO) - QTc > 480 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Angina pectoris that requires the use of anti-anginal medication - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Valvular disease with document compromise in cardiac function - Symptomatic pericarditis - Patient must not have a history of cardiac dysfunction including any of the following: - Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification III-IV) - Documented cardiomyopathy - Patient must not have poorly controlled diabetes mellitus or steroid-induced diabetes mellitus (defined by fasting glucose >120 mg/dL or hemoglobin [Hb] A1c > 7%) - Patient must not have any other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol - Patient must not have significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes; diffusion capacity of carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates - Patient must not have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Patient must not have been treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF]) =< 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued - Patient must not have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to: St. Johns wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng; fruits include the CYP3A inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits - Patient must not be currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes unless the treatment can either be discontinued or switched to a different medication prior to starting study drug; please refer to Table 5-2 for a list of prohibited QT prolonging drugs with risk of Torsades de Pointes - Patient must not be receiving chronic treatment with steroids or another immunosuppressive agent; Note: topical applications (e.g. --- P13K ---

dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible - Patient must not be currently treated with drugs known to be moderate or strong inhibitors or inducers of isoenzyme cytochrome P450, family 3, subfamily A (CYP3A) unless the treatment can be discontinued or switched to a different medication prior to starting study drug (please note that co-treatment with weak inhibitors of CYP3A is allowed) - Patient must not have received chemotherapy or targeted anticancer therapy =< 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug - Patient with any residual toxicities may not be enrolled unless all toxicities recover to =< grade 1 before starting the trial - Patient must not have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) =< 5 effective half lives prior to starting study drug; patient must have recovered from side effects of such therapy - Patient must not have received wide field radiotherapy =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to starting study drug; patient must have recovered from side effects of such therapy - Patient must not have undergone major surgery =< 2 weeks prior to starting study drug; patient must have recovered from side effects of such therapy - Patient must not be currently taking therapeutic doses of warfarin sodium or any other Coumadin-derivative anticoagulant - Patient must not have a known diagnosis of human immunodeficiency virus (HIV) infection - Patient must not have a history of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix Inclusion Criteria: - Patient must be ≥ 18 years of age - Patient must be a postmenopausal woman, defined by one of the following criteria: - Women ≥ 60 years - Women aged 45-59 years with spontaneous cessation of menses ≥ 12 months prior to registration - Women aged 45-59 years with cessation of menses of duration < 12 months or secondary to hysterectomy AND an follicle-stimulating hormone (FSH) level in the postmenopausal range according to institutional standards (or > 34.4 IU/L if institutional range is not available) prior to registration - Women aged 45-59 years on hormonal replacement therapy who have discontinued hormonal therapy AND an FSH level in the postmenopausal range according to institutional standards (or > 34.4 IU/L if institutional range is not available) prior to registration - Status post bilateral surgical oophorectomy - Patient must have a negative serum pregnancy test within 48 hours before starting study treatment (if a woman of childbearing potential) - Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 - Patient must have histologically or cytologically confirmed invasive breast cancer that is stage IV or metastatic (histologic/cytologic confirmation of recurrence preferred, but not required) - Patient must have a representative tumor tissue specimen available; archival tissue is allowed - Either the primary or the metastatic tumor must be positive for estrogen receptor (>= 1% tumor cell staining by immunohistochemistry or an Allred Score of >= 3 by immunohistochemistry) - Patient must have at least one site of measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria - Patient must have had no more than 3 lines of systemic therapy (including endocrine therapy) for metastatic disease to be eligible for phase IB and the last 10 patients of Cohort C; there is no limitation on the numbers of prior systemic therapies for phase IA and the first 2 patients of Cohort C - Patients who are currently taking fulvestrant without disease progression are eligible - Patient must have a life expectancy of >= 12 weeks - Patient must have adequate oran function as defined as: - Absolute neutrophil count (ANC) >= 1500/uL - Platelet count >= 100,000/uL - Hemoglobin >= 9 g/dL - Serum creatinine =< 1.5 x upper limit of normal (ULN) - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or =< 3.0 x ULN if liver metastases are present) - Serum bilirubin =< ULN (or =< 1.5 x ULN if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) - Serum amylase =< ULN - Serum lipase =< ULN - Magnesium >= the lower limit of normal - Potassium within normal limits for the institution - Patient must have international normalized ratio (INR) =< 2 - Patient must have fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - Patient must have total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed) - Patient must be able and willing to sign the consent form Exclusion Criteria: - Patient must not have received prior treatment with a P13K inhibitor - Patient must not have a known hypersensitivity to BKM120 or to its excipients - Patient must not have untreated brain metastases; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial if the patient is: - 4 weeks from therapy completion (including radiation and/or surgery) - Clinically stable at the time of study entry - Not receiving corticosteroid therapy - Patient must not have acute or chronic liver disease, renal disease, or pancreatitis - Patient must not have any of the following mood disorders as judged by the Investigator or a Psychiatrist - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - Greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety - Patient must not meet the cut-off score of >= 10 in the Patient Health Questionnaire (PHQ-9) or a cut-off of >= 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or select a positive response of 1, 2, or 3 to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Patient must not have >= grade 2 diarrhea - Patient must not have active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO) - QTc > 480 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Angina pectoris that requires the use of anti-anginal medication - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Valvular disease with document compromise in cardiac function - Symptomatic pericarditis - Patient must not have a history of cardiac dysfunction including any of the following: - Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification III-IV) - Documented cardiomyopathy - Patient must not have poorly controlled diabetes mellitus or steroid-induced diabetes mellitus (defined by fasting glucose >120 mg/dL or hemoglobin [Hb] A1c > 7%) - Patient must not have any other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol - Patient must not have significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes; diffusion capacity of carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates - Patient must not have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Patient must not have been treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF]) =< 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued - Patient must not have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to: St. Johns wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng; fruits include the CYP3A inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits - Patient must not be currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes unless the treatment can either be discontinued or switched to a different medication prior to starting study drug; please refer to Table 5-2 for a list of prohibited QT prolonging drugs with risk of Torsades de Pointes - Patient must not be receiving chronic treatment with steroids or another immunosuppressive agent; Note: topical applications (e.g. --- P13K ---

Primary Outcomes

Description: Highest dose level at which no more than 1 of 6 patients develops a dose-limiting toxicity

Measure: MTD of BKM120 in combination with fulvestrant

Time: 28 days (completion of cycle 1)

Measure: Number of participants with adverse events after treatment with BKM120 in combination with fulvestrant

Time: 28 days after completion of treatment

Secondary Outcomes

Measure: Anti-tumor effect (PR, CR, SD and PD) of BKM120 in combination with fulvestrant

Time: End of treatment (approximately 3 months)

Measure: Steady state blood concentration of BKM120

Time: Baseline, Cycle 2 Day 1, Cycle 3 Day 1

Measure: Tumor PI3K pathway abnormalities in tissue from previous biopsy or collected at baseline

Time: Baseline

Measure: Effects of study therapy on blood levels of fasting C-peptide

Time: Baseline, Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1

Measure: Effects of study therapy on blood levels of glucose

Time: Baseline, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, End of Treatment

Measure: Samples will be analyzed for markers of PI3K signaling (including pAKT, pS6, Cyclin D1, subcellular localization of FOXO3a, phosphoproteomics), tumor cell proliferation (Ki67) and apoptosis (cleaved caspase 3 or TUNEL staining).

Time: Baseline

Measure: Examine the PIK3CA mutation status in circulating DNA at baseline thru last treatment

Time: Baseline or Cycle 1 Day 1 and Day 1 of each subsequent cycle

Other Outcomes

Description: To obtain preliminary pilot data to evaluate the effect of BKM120 on tumor cell proliferation, as measured by FLT-PET/CT

Measure: FLT-PET/CT effect of BKM120 on tumor cell proliferation

Time: 18 days

4 A Phase 1a/1b, Multicenter, Open Label, Dosefinding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the Dual Dna-pk and Tor Kinase Inhibitor, Cc-115, Administered Orally to Subjects With Advanced Solid Tumors and Hematologic Malignancies

The main purpose of this first human study with CC-115 is to assess the safety and action of a new class of experimental drug (dual DNA-PK and TOR kinase inhibitors) in patients with advanced tumors unresponsive to standard therapies and to determine the appropriate dose and tumor types for later-stage clinical trials. The bioavailability of tablet and capsule formulations under fasting and fed conditions will also be evaluated in some patients.

NCT01353625
Conditions
  1. Glioblastoma Multiforme
  2. Squamous Cell Carcinoma of Head and Neck
  3. Prostate Cancer
  4. Ewing's Osteosarcoma
  5. Chronic Lymphocytic Leukemia
  6. Neoplasm Metastasis
Interventions
  1. Drug: CC-115
MeSH:Prostatic Neoplasms Neoplasms Neoplasm Metastasis Glioblastoma Leukemia, Lymphocytic, Chronic, B-Cell Hematologic Neoplasms Osteosarcoma Squamous Cell Carcinoma of Head and Neck
HPO:Chronic lymphatic leukemia Glioblastoma multiforme Hematological neoplasm Leukemia Neoplasm Osteosarcoma Prostate cancer Prostate neoplasm

Prior treatment with some drugs targeting mTOR, P13K and related pathways is now permitted. --- P13K ---

Primary Outcomes

Measure: Dose-Limiting Toxicity

Time: Continuously for 28 days after starting treatment

Measure: Non-Tolerated Dose

Time: Continuously for 28 days after starting treatment

Measure: Maximum Tolerated Dose

Time: Continuously for 28 days after starting treatment

Measure: Maximum Observed Concentration in Plasma of CC-115

Time: Days 1, 2, 15, 16 of treatment

Measure: Area Under the Concentration-Time Curve for CC-115

Time: Days 1, 2, 15 and 16 of treatment

Measure: Time to Maximum Concentration of CC-115

Time: Days 1, 2, 15, and 16 of treatment

Measure: Terminal Half-Life for CC-115

Time: Days 1, 2, 15, and 16 of treatment

Measure: Apparent Total Body Clearance of CC-115

Time: Days 1, 2, 15 and 16 of treatment

Measure: Apparent Volume of Distribution of CC-115

Time: Days 1, 2, 15, and 16 of treatment

Measure: Accumulation Index of CC-115

Time: Days 1, 2, 15 and 16 of treatment

Secondary Outcomes

Description: Phosphorylation inhibition determined by changes in the levels of multiple biomarkers including S6 and, 4EBP (for mTORC1), AKT (for mTORC2) and other appropriate biomarkers in circulating granulocytes and tumor tissue (when available).

Measure: Pharmacodynamics

Time: Screening (within 28 days prior to first dose of study drug) and Days 1, 2, 8, 15, 22, 28, 155, and end of treatment

Description: Tumor response rates using appropriate objective criteria for various malignancies

Measure: Anti-Tumor Efficacy

Time: Every 2-3 months until proof of tumor progression

5 A Phase II Trial of Adjuvant Paclitaxel and Trastuzumab for Node-Negative HER2-Positive Breast Cancer

The purpose of this study is to find out what effect the postoperative combination of therapies: trastuzumab (herceptin) and paclitaxel (taxol) will have on breast cancer recurrence. A combination of trastuzuamb and chemotherapy has been used in women with node positive and high risk node negative disease. This tests utilizes a well tolerated regimen of weekly paclitaxel and trastuzumab in women with T1, node negative tumors that are HER2 positive. We would like to determine how effective this drug combination is when used in women with early stage breast cancer, as well as to better define the side effects of this treatment.

NCT00542451
Conditions
  1. Breast Cancer
  2. Carcinoma of the Breast
Interventions
  1. Drug: Paclitaxel
  2. Drug: Trastuzumab
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

Evaluate P13K mutations and PTEN alterations in a subset of patients and correlate events with the presence or absence of these mutations/alterations. --- P13K ---

Primary Outcomes

Measure: Evaluate disease free survival (DFS) rate in patients with node-negative HER2-positive breast cancer with tumors less than or equal to 3cm treated with adjuvant trastuzumab and paclitaxel

Time: 3 years

Secondary Outcomes

Measure: Describe DFS in patient groups defined by tumor size and hormone receptor status.

Time: 3 years

Measure: Evaluate the incidence of grade III/IV cardiac left ventricular dysfunction from adjuvant trastuzumab and paclitaxel

Time: 3 years

Measure: Evaluate the incidence of grade III/IV neurotoxicity associated with adjuvant paclitaxel

Time: 3 years

Measure: Evaluate Topoisomerase II, cMYC, and p53 expression, and correlate with event rate

Time: 3 years

Measure: Evaluate P13K mutations and PTEN alterations in a subset of patients and correlate events with the presence or absence of these mutations/alterations

Time: 3 Years

6 Phase I/II Study of the Combination of BKM120 and Bevacizumab in Patients With Refractory Solid Tumors (Phase I) and Relapsed/Refractory Glioblastoma Multiforme (Phase II)

In this phase I/II study,investigators are evaluating the feasibility and efficacy of the combination of BKM120, an oral inhibitor of PI3 kinase, and bevacizumab in the treatment of patients with relapsed/refractory GBM. In the Phase I part of the trial, the optimal BKM120 dose to be administered with a standard dose of bevacizumab will be determined in patients with refractory solid tumors. Although it is unlikely that the concurrent administration of bevacizumab will alter the pharmacokinetics of BKM120, limited pharmacokinetic sampling will be performed on all patients treated during the Phase II portion of the study. Assuming this combination is feasible, the Phase II portion of the study will proceed, using the doses determined in the Phase I portion. In the phase II portion, eligible patients will be limited to those with recurrent/progressive GBM following 1st line combined modality therapy.

NCT01349660
Conditions
  1. Glioblastoma Multiforme
Interventions
  1. Drug: Bevacizumab
  2. Drug: BKM120
MeSH:Glioblastoma
HPO:Glioblastoma multiforme

- Patients who have received prior treatment with a P13K inhibitor. --- P13K ---

Primary Outcomes

Description: The optimal dose of BKM120 to administer in combination with standard dose bevacizumab determined as the dose at which ≤1 of 6 patients experiences a DLT assessed using NCI CTCAE v4.03 during Cycle 1 (28 days). The optimal dose of BKM120 was determined to be 60 mg by mouth (PO), once a day for each 28 day cycle along with bevacizumab, administered 10 mg/kg intravenously (IV) on Day 1 and Day 15 of each 28 day cycle.

Measure: Number of Phase I Patients Receiving 60mg or 80mg BKM120 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage

Time: Collected from day of first dose to the end of the first treatment cycle, up to 28 days

Description: Two groups of patients in the Phase II trial will be considered separately, 1) participants who have not received previous bevacizumab and 2) participants who have received bevacizumab as part of first-line treatment. PFS is measured from the date of first protocol treatment until date of disease progression or death occurs, or date of last adequate tumor assessment using RANO or McDonald criteria. McDonald disease progression criteria: a 25% or greater increase in sum of the diameters of lesions, new lesions, or clinical deterioration (McDonald et al, 1990). RANO disease progression criteria: a 25% or greater increase in the enhancing lesions sum compared with smallest tumor measurement, significant increase in T2/FLAIR nonenhancing lesion on stable or increasing corticosteroids, new lesions, or clinical deterioration (Wen et al 2010)

Measure: Median Progression-Free Survival (PFS) in Phase II Participants - Prior Bevacizumab and Bevacizumab Naive

Time: every 8 weeks for up to 33 months

Secondary Outcomes

Description: Two groups of participants in the Phase II trial will be considered separately, 1) those who have not received previous bevacizumab and 2) those who have received bevacizumab as part of first-line treatment. Overall Response (OR) = number of patients with complete or partial responses (CR or PR) per McDonald or RANO criteria. McDonald: CR as disappearance of all disease for at least four weeks, no new lesions, no steroids; PR as 50% or greater decrease in the sum of all lesions compared with baseline for at least four weeks, no new lesions, stable or reduced steroids (McDonald 1990). RANO: CR as disappearance of all disease for at least 4 weeks, no new lesions, stable or improved nonenhancing lesions, and no steroid usage; and PR as a 50% or greater decrease in the sum of all lesions compared with baseline measurement for at least four weeks, no new lesions, stable or improved nonenhancing lesions on same or lower steroid dose compared to baseline (Wen 2010).

Measure: Overall Response (CR or PR) of Phase II Participants - Prior Bevacizumab and Bevacizumab Naive

Time: every 8 weeks, projected 24 months

Description: Two groups of patients in the Phase II trial will be considered separately, 1) participants who have not received previous bevacizumab and 2) participants who have received bevacizumab as part of first-line treatment. Overall survival is measured as the interval from first study treatment until date of death, or date last known alive.

Measure: Median Overall Survival (OS) in Phase II Participants - Prior Bevacizumab and Bevacizumab Naive

Time: every 12 weeks for up to 60 months

Description: Defined as the number of participants with treatment-emergent grade 3/4/5 adverse events/serious adverse events utilizing the National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.03

Measure: Number of Participants With Grade 3/4/5 Serious Adverse Events and Adverse Events as a Measure of Safety and Tolerability

Time: every 4 weeks for up to 5.2 years

7 A Phase I Study of BKM120 and Everolimus in Advanced Solid Malignancies

This study will assess the safety of combining two agents (everolimus and BKM120) for the treatment of advanced cancer arising from solid organ in patients who are no longer benefiting from or unable to withstand standard treatment of these conditions.

NCT01470209
Conditions
  1. Solid Tumors
  2. Lung Cancer
Interventions
  1. Drug: BKM120
  2. Drug: Everolimus
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Ability and willingness to undergo repeat tumor biopsies (the biopsy is optional and only applicable to subjects considered for the expansion cohort stage of the study) Exclusion Criteria: 1. Patients who have received prior treatment with a phosphatidylinositol 3-kinase (P13K) inhibitor or RAD001 (if discontinued for toxicity) 2. Patients with a known hypersensitivity to BKM120, RAD001 (including other rapalogs) or their excipients 3. Patients with untreated symptomatic brain metastases are excluded. --- P13K ---

Primary Outcomes

Description: i. Grade 4 hematologic toxicity (excluding anemia) lasting more than 7 days ii. Grade 3 anemia lasting more than 7 days or requiring blood transfusion iii. Grade 4 anemia iv. Grade ≥ 3 febrile neutropenia of any duration v. Grade ≥ 3 nausea and or vomiting lasting more than 72 hours in spite of standard supportive therapy vi. Grade ≥ 3 non-hematologic toxicity (excluding alopecia)

Measure: Dose limiting toxicity

Time: During the first cycle of treatment; approximately 4 weeks

Secondary Outcomes

Description: Sum of complete response, partial response and stable disease

Measure: Clinical benefit rate

Time: During the entire duration of therapy estimated to be an average of 6 months for each patient

8 Phase I Trial of Cisplatin and Etoposide Plus BKM120 in Advanced Solid Tumors, With an Emphasis on Small Cell Lung Cancer

This phase I trial studies the side effects and the best dose of PI3K inhibitor BKM120 when given together with cisplatin and etoposide in treating patients with advanced solid tumors or small cell lung cancer. Drugs used in chemotherapy, such as cisplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing , or by stopping them from spreading. PI3K inhibitor BKM120 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving PI3K inhibitor BKM120 with cisplatin and etoposide may kill more tumor cells.

NCT02194049
Conditions
  1. Extensive Stage Small Cell Lung Cancer
  2. Unspecified Adult Solid Tumor, Protocol Specific
Interventions
  1. Drug: BKM120
  2. Drug: cisplatin
  3. Drug: etoposide
MeSH:Lung Neoplasms Small Cell Lung Carcinoma
HPO:Neoplasm of the lung Small cell lung carcinoma

Pharmacokinetic analysis will use non-linear curve fitting methods to estimate the mean peak concentration.. Inclusion Criteria: - Histological or cytological proven advanced solid tumors - =< 3 chemotherapy regimens for metastatic disease; any number of prior targeted or biologic therapies is allowed; (in the expansion cohort, patients must be chemo naïve) - ECOG performance status =< 2 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Platelets >= 100 x 10^9/L - Hemoglobin (Hb) > 9 g/dL - Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium >= the lower limit of normal - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or =< 3.0 x upper limit of normal (ULN) if liver metastases are present) - Serum bilirubin within normal range (or =< 1.5 x ULN if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) - Serum creatinine =< 1.5 x ULN or calculated clearance >= 60 mL/min - Serum albumin >= 3 g/dl - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - International normalized ratio (INR) =< 2 - Ability to swallow pills - Negative serum pregnancy test Exclusion Criteria: - Received prior treatment with a P13K inhibitor - Received > 300 mg/m^2 of cisplatin and/or for whom cisplatin would not be beneficial - Prior treatment with any investigational drug within the preceding 3 weeks - Known hypersensitivity to BKM120 or to its excipients - Untreated brain metastases are excluded - Acute or chronic liver, renal disease or pancreatitis - Following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire - Diarrhea >= CTCAE grade 2 - Active cardiac disease - History of cardiac dysfunction - Poorly controlled diabetes mellitus or steroid-induced diabetes mellitus - Other concurrent severe and/or uncontrolled concomitant medical conditions - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Treated with any hematopoietic colony-stimulating growth factors - Currently receiving treatment with medication with a known risk to prolong the QT interval or inducing torsades de pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug - Chronic treatment with steroids or another immunosuppressive agent - Herbal medications and certain fruits within 7 days prior to starting study drug - Treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug - Intravenous chemotherapy or targeted anticancer therapy =< 4 weeks - Any continuous or intermittent oral small molecule therapeutics - Received wide field radiotherapy =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Undergone major surgery =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Currently taking therapeutic doses of warfarin sodium or any other Coumadin-derivative anticoagulant - Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control - Known diagnosis of HIV infection - History of another active malignancy - Unable or unwilling to abide by the study protocol or cooperate fully with the investigator treatments Inclusion Criteria: - Histological or cytological proven advanced solid tumors - =< 3 chemotherapy regimens for metastatic disease; any number of prior targeted or biologic therapies is allowed; (in the expansion cohort, patients must be chemo naïve) - ECOG performance status =< 2 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Platelets >= 100 x 10^9/L - Hemoglobin (Hb) > 9 g/dL - Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium >= the lower limit of normal - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or =< 3.0 x upper limit of normal (ULN) if liver metastases are present) - Serum bilirubin within normal range (or =< 1.5 x ULN if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) - Serum creatinine =< 1.5 x ULN or calculated clearance >= 60 mL/min - Serum albumin >= 3 g/dl - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - International normalized ratio (INR) =< 2 - Ability to swallow pills - Negative serum pregnancy test Exclusion Criteria: - Received prior treatment with a P13K inhibitor - Received > 300 mg/m^2 of cisplatin and/or for whom cisplatin would not be beneficial - Prior treatment with any investigational drug within the preceding 3 weeks - Known hypersensitivity to BKM120 or to its excipients - Untreated brain metastases are excluded - Acute or chronic liver, renal disease or pancreatitis - Following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire - Diarrhea >= CTCAE grade 2 - Active cardiac disease - History of cardiac dysfunction - Poorly controlled diabetes mellitus or steroid-induced diabetes mellitus - Other concurrent severe and/or uncontrolled concomitant medical conditions - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Treated with any hematopoietic colony-stimulating growth factors - Currently receiving treatment with medication with a known risk to prolong the QT interval or inducing torsades de pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug - Chronic treatment with steroids or another immunosuppressive agent - Herbal medications and certain fruits within 7 days prior to starting study drug - Treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug - Intravenous chemotherapy or targeted anticancer therapy =< 4 weeks - Any continuous or intermittent oral small molecule therapeutics - Received wide field radiotherapy =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Undergone major surgery =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Currently taking therapeutic doses of warfarin sodium or any other Coumadin-derivative anticoagulant - Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control - Known diagnosis of HIV infection - History of another active malignancy - Unable or unwilling to abide by the study protocol or cooperate fully with the investigator treatments Extensive Stage Small Cell Lung Cancer Unspecified Adult Solid Tumor, Protocol Specific Lung Neoplasms Small Cell Lung Carcinoma PRIMARY OBJECTIVES: I. To determine the safety and feasibility of combining BKM120 (PI3K inhibitor BKM120) with cisplatin and etoposide in advanced solid tumors, with emphasis on small cell lung cancer (SCLC). --- P13K ---

Pharmacokinetic analysis will use non-linear curve fitting methods to estimate the mean peak concentration.. Inclusion Criteria: - Histological or cytological proven advanced solid tumors - =< 3 chemotherapy regimens for metastatic disease; any number of prior targeted or biologic therapies is allowed; (in the expansion cohort, patients must be chemo naïve) - ECOG performance status =< 2 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Platelets >= 100 x 10^9/L - Hemoglobin (Hb) > 9 g/dL - Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium >= the lower limit of normal - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or =< 3.0 x upper limit of normal (ULN) if liver metastases are present) - Serum bilirubin within normal range (or =< 1.5 x ULN if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) - Serum creatinine =< 1.5 x ULN or calculated clearance >= 60 mL/min - Serum albumin >= 3 g/dl - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - International normalized ratio (INR) =< 2 - Ability to swallow pills - Negative serum pregnancy test Exclusion Criteria: - Received prior treatment with a P13K inhibitor - Received > 300 mg/m^2 of cisplatin and/or for whom cisplatin would not be beneficial - Prior treatment with any investigational drug within the preceding 3 weeks - Known hypersensitivity to BKM120 or to its excipients - Untreated brain metastases are excluded - Acute or chronic liver, renal disease or pancreatitis - Following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire - Diarrhea >= CTCAE grade 2 - Active cardiac disease - History of cardiac dysfunction - Poorly controlled diabetes mellitus or steroid-induced diabetes mellitus - Other concurrent severe and/or uncontrolled concomitant medical conditions - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Treated with any hematopoietic colony-stimulating growth factors - Currently receiving treatment with medication with a known risk to prolong the QT interval or inducing torsades de pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug - Chronic treatment with steroids or another immunosuppressive agent - Herbal medications and certain fruits within 7 days prior to starting study drug - Treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug - Intravenous chemotherapy or targeted anticancer therapy =< 4 weeks - Any continuous or intermittent oral small molecule therapeutics - Received wide field radiotherapy =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Undergone major surgery =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Currently taking therapeutic doses of warfarin sodium or any other Coumadin-derivative anticoagulant - Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control - Known diagnosis of HIV infection - History of another active malignancy - Unable or unwilling to abide by the study protocol or cooperate fully with the investigator treatments Inclusion Criteria: - Histological or cytological proven advanced solid tumors - =< 3 chemotherapy regimens for metastatic disease; any number of prior targeted or biologic therapies is allowed; (in the expansion cohort, patients must be chemo naïve) - ECOG performance status =< 2 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Platelets >= 100 x 10^9/L - Hemoglobin (Hb) > 9 g/dL - Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium >= the lower limit of normal - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or =< 3.0 x upper limit of normal (ULN) if liver metastases are present) - Serum bilirubin within normal range (or =< 1.5 x ULN if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) - Serum creatinine =< 1.5 x ULN or calculated clearance >= 60 mL/min - Serum albumin >= 3 g/dl - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - International normalized ratio (INR) =< 2 - Ability to swallow pills - Negative serum pregnancy test Exclusion Criteria: - Received prior treatment with a P13K inhibitor - Received > 300 mg/m^2 of cisplatin and/or for whom cisplatin would not be beneficial - Prior treatment with any investigational drug within the preceding 3 weeks - Known hypersensitivity to BKM120 or to its excipients - Untreated brain metastases are excluded - Acute or chronic liver, renal disease or pancreatitis - Following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire - Diarrhea >= CTCAE grade 2 - Active cardiac disease - History of cardiac dysfunction - Poorly controlled diabetes mellitus or steroid-induced diabetes mellitus - Other concurrent severe and/or uncontrolled concomitant medical conditions - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Treated with any hematopoietic colony-stimulating growth factors - Currently receiving treatment with medication with a known risk to prolong the QT interval or inducing torsades de pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug - Chronic treatment with steroids or another immunosuppressive agent - Herbal medications and certain fruits within 7 days prior to starting study drug - Treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug - Intravenous chemotherapy or targeted anticancer therapy =< 4 weeks - Any continuous or intermittent oral small molecule therapeutics - Received wide field radiotherapy =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Undergone major surgery =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Currently taking therapeutic doses of warfarin sodium or any other Coumadin-derivative anticoagulant - Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control - Known diagnosis of HIV infection - History of another active malignancy - Unable or unwilling to abide by the study protocol or cooperate fully with the investigator treatments Extensive Stage Small Cell Lung Cancer Unspecified Adult Solid Tumor, Protocol Specific Lung Neoplasms Small Cell Lung Carcinoma PRIMARY OBJECTIVES: I. To determine the safety and feasibility of combining BKM120 (PI3K inhibitor BKM120) with cisplatin and etoposide in advanced solid tumors, with emphasis on small cell lung cancer (SCLC). --- P13K --- --- P13K ---

Primary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity, time of onset (i.e. course number), duration, and reversibility or outcome.

Measure: Incidence of adverse events of combining daily BKM120 with cisplatin and etoposide as graded by the National Cancer Institute (NC) CTCAE version 4.0

Time: Up to 28 days post-treatment

Secondary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity, time of onset (i.e. course number), duration, and reversibility or outcome.

Measure: MTD defined as the highest dose tested in which fewer than 33% of patients experience DLT attributed to the study drugs when at least 6 patients were treated at that dose, as graded by NCI CTCAE version 4.0

Time: 21 days

Description: Response rate among patients with measurable disease will be summarized by exact binomial confidence intervals

Measure: Response rate assessed by computed tomography (CT) scan based on Response Evaluation Criteria In Solid Tumors (RECIST)

Time: Up to 30 days

Description: Survival will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol. Median survival time will be estimated using standard life table methods.

Measure: Overall survival

Time: Up to 30 days

Description: TTP will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol. Median time to progression will be estimated using standard life table methods.

Measure: Time to progression (TTP) based on RECIST

Time: Up to 30 days

Description: Pharmacokinetic analysis will use non-linear curve fitting methods to estimate the mean peak concentration.

Measure: Pharmacokinetic analysis

Time: Baseline, at 1, 2, 4, 6, and 24 hours of day 1 of course 1, baseline day 15 of course 1, and at 1 and 2 hours post-dose on day 1 of course 2

9 An Open-Label Pilot Study to Evaluate the Efficacy and Safety of a Combination Treatment of Sonidegib (LDE225) and Buparlisib (BKM120) For the Treatment of Advanced Basal Cell Carcinomas

This pilot trial studies how well sonidegib and buparlisib work in treating patients with basal cell carcinoma that has spread to other places in the body. Sonidegib and buparlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02303041
Conditions
  1. Carcinoma, Basal Cell
  2. Recurrent Skin Cancer
  3. Skin Neoplasms
  4. Basal Cell Nevus Syndrome
Interventions
  1. Drug: Buparlisib
  2. Drug: Sonidegib
MeSH:Carcinoma Carcinoma, Basal Cell Skin Neoplasms Basal Cell Nevus Syndrome
HPO:Basal cell carcinoma Carcinoma Neoplasm of the skin

The gene expression profiles for Gli-1; Gli-2; "Patched" (Ptch) ; "Suppressor of Fused" (SuFu); "Smoothened" (Smo)"; and phosphatidylinositol-3-kinase (PI3K) were to be correlated to the clinical response to therapeutic therapy.. INCLUSION CRITERIA: - Able to understand and sign informed consent - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 - Metastatic BCC, histologic confirmation of distant BCC metastasis - Metastatic disease, target lesion must be measurable using computed tomography (CT) or magnetic resonance imaging (MRI) - Locally advanced BCC are required to have disease that is considered inoperable due to significant functional compromise or to have a medical contraindication to surgery - Nevoid BCC syndrome (Gorlin syndrome) may enroll in this study but must meet the criteria for locally advanced or metastatic disease listed above - COHORT 2 ONLY: A Smoothened inhibitor must have been previously administered as monotherapy - Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L - Platelets ≥ 80 x10^9/L - Hemoglobin (Hb) > 9 g/dL or values ≥ lower limit of normal (LLN) for site-specific lab - Total calcium (corrected for serum albumin) within normal limits (biphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium ≥ the lower limit of normal - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range [or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present] - Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well-documented Gilbert Syndrome) - Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min - Serum amylase ≤ ULN - Serum lipase ≤ ULN - Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) - Negative serum pregnancy test within 72 hours before starting study treatment in women with childbearing potential - International normalized ratio (INR) ≤ 2 EXCLUSION CRITERIA: - Prior treatment with a P13K inhibitor - Known hypersensitivity to buparlisib or to its excipients - Untreated brain metastases are excluded; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (including radiation and/or surgery), is clinically stable at the time of study entry and is not receiving corticosteroid therapy - Acute or chronic liver, renal disease or pancreatitis - Baseline creatinine kinase (CK) > ULN - The following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire: - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety - Meets the cut-off score of ≥ 12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of ≥ 15 in the Generalized Anxiety Disorder 7-item (GAD-7) mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Diarrhea ≥ CTCAE grade 2 - Active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) - QTc > 450 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Angina pectoris that requires the use of anti-anginal medication - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Valvular disease with document compromise in cardiac function - Symptomatic pericarditis - Patient has a history of cardiac dysfunction including any of the following: - Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification 3-4) - Documented cardiomyopathy - Patient has poorly controlled diabetes mellitus [defined as hemoglobin A1C (HgA1c) > ULN], steroid-induced diabetes mellitus, or insulin dependent diabetes mellitus - Other concurrent severe and/or uncontrolled concomitant medical conditions (eg, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol - Significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, diffusing capacity of the lung for carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of buparlisib (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Patients who have been treated with any hematopoietic colony-stimulating growth factors (eg, filgrastim (granulocyte-colony stimulating factor, G-CSF), sargramostim (granulocyte-macrophage colony-stimulating factor, GM-CSF) ≤ 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued - Patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug - Patients receiving chronic treatment with steroids or another immunosuppressive agent - Note: topical applications (eg, rash), inhaled sprays (eg, obstructive airways diseases), eye drops or local injections (eg, intr-articular) are allowed; patients with previously treated brain metastases, who are on stable low dose corticosteroids treatment (eg, dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible - Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to St. John's Wort, Kava, ephedra (ma huang), dehydroepiandrosterone (DHEA), gingko biloba, yohimbe, saw palmetto, and ginseng; fruits include the cytochrome P450, family 3, subfamily A (CYP3A) inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits - Patients who are currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug; please note that co-treatment with weak inhibitors of CYP3A is allowed - Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a grade 1 before starting the trial - Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy - Use of statin drugs or other medications known to associate with rhabdomyolysis; these drugs must be discontinued at enrollment - Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant; low molecular weight heparin is allowed - Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control; double barrier contraceptives must be used through the trial by both sexes; oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study; women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 72 hours prior to initiating treatment - Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL (for US only: and estradiol < 20 pg/mL) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential - Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through 20 months after the final dose of study treatment; for males with partners with childbearing potential, highly effective contraception is required for 6 months; the highly effective contraception is defined as either: - True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient - Use of a combination of any two of the following (a+b): - a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) - b. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - Oral contraception, injected or implanted hormonal methods are not allowed - Fertile males, must use highly effective (double barrier) methods of contraception (eg, spermicidal gel plus condom) for the entire duration of the study, and continuing using contraception and refrain from fathering a child for 6 months following the study drug; a condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the study treatment via seminal fluid; female partner of male study subject should use highly effective contraception during dosing of any study agent and for 16 weeks after final dose of study therapy - Note: hormonal contraception methods (eg, oral, injected, implanted) are not allowed - Note: woman are considered post-menopausal and not child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential - Known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C - History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix - Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator INCLUSION CRITERIA: - Able to understand and sign informed consent - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 - Metastatic BCC, histologic confirmation of distant BCC metastasis - Metastatic disease, target lesion must be measurable using computed tomography (CT) or magnetic resonance imaging (MRI) - Locally advanced BCC are required to have disease that is considered inoperable due to significant functional compromise or to have a medical contraindication to surgery - Nevoid BCC syndrome (Gorlin syndrome) may enroll in this study but must meet the criteria for locally advanced or metastatic disease listed above - COHORT 2 ONLY: A Smoothened inhibitor must have been previously administered as monotherapy - Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L - Platelets ≥ 80 x10^9/L - Hemoglobin (Hb) > 9 g/dL or values ≥ lower limit of normal (LLN) for site-specific lab - Total calcium (corrected for serum albumin) within normal limits (biphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium ≥ the lower limit of normal - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range [or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present] - Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well-documented Gilbert Syndrome) - Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min - Serum amylase ≤ ULN - Serum lipase ≤ ULN - Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) - Negative serum pregnancy test within 72 hours before starting study treatment in women with childbearing potential - International normalized ratio (INR) ≤ 2 EXCLUSION CRITERIA: - Prior treatment with a P13K inhibitor - Known hypersensitivity to buparlisib or to its excipients - Untreated brain metastases are excluded; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (including radiation and/or surgery), is clinically stable at the time of study entry and is not receiving corticosteroid therapy - Acute or chronic liver, renal disease or pancreatitis - Baseline creatinine kinase (CK) > ULN - The following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire: - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety - Meets the cut-off score of ≥ 12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of ≥ 15 in the Generalized Anxiety Disorder 7-item (GAD-7) mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Diarrhea ≥ CTCAE grade 2 - Active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) - QTc > 450 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Angina pectoris that requires the use of anti-anginal medication - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Valvular disease with document compromise in cardiac function - Symptomatic pericarditis - Patient has a history of cardiac dysfunction including any of the following: - Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification 3-4) - Documented cardiomyopathy - Patient has poorly controlled diabetes mellitus [defined as hemoglobin A1C (HgA1c) > ULN], steroid-induced diabetes mellitus, or insulin dependent diabetes mellitus - Other concurrent severe and/or uncontrolled concomitant medical conditions (eg, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol - Significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, diffusing capacity of the lung for carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of buparlisib (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Patients who have been treated with any hematopoietic colony-stimulating growth factors (eg, filgrastim (granulocyte-colony stimulating factor, G-CSF), sargramostim (granulocyte-macrophage colony-stimulating factor, GM-CSF) ≤ 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued - Patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug - Patients receiving chronic treatment with steroids or another immunosuppressive agent - Note: topical applications (eg, rash), inhaled sprays (eg, obstructive airways diseases), eye drops or local injections (eg, intr-articular) are allowed; patients with previously treated brain metastases, who are on stable low dose corticosteroids treatment (eg, dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible - Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to St. John's Wort, Kava, ephedra (ma huang), dehydroepiandrosterone (DHEA), gingko biloba, yohimbe, saw palmetto, and ginseng; fruits include the cytochrome P450, family 3, subfamily A (CYP3A) inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits - Patients who are currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug; please note that co-treatment with weak inhibitors of CYP3A is allowed - Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a grade 1 before starting the trial - Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy - Use of statin drugs or other medications known to associate with rhabdomyolysis; these drugs must be discontinued at enrollment - Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant; low molecular weight heparin is allowed - Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control; double barrier contraceptives must be used through the trial by both sexes; oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study; women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 72 hours prior to initiating treatment - Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL (for US only: and estradiol < 20 pg/mL) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential - Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through 20 months after the final dose of study treatment; for males with partners with childbearing potential, highly effective contraception is required for 6 months; the highly effective contraception is defined as either: - True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient - Use of a combination of any two of the following (a+b): - a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) - b. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - Oral contraception, injected or implanted hormonal methods are not allowed - Fertile males, must use highly effective (double barrier) methods of contraception (eg, spermicidal gel plus condom) for the entire duration of the study, and continuing using contraception and refrain from fathering a child for 6 months following the study drug; a condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the study treatment via seminal fluid; female partner of male study subject should use highly effective contraception during dosing of any study agent and for 16 weeks after final dose of study therapy - Note: hormonal contraception methods (eg, oral, injected, implanted) are not allowed - Note: woman are considered post-menopausal and not child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential - Known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C - History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix - Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator Carcinoma, Basal Cell Recurrent Skin Cancer Skin Neoplasms Basal Cell Nevus Syndrome Carcinoma Carcinoma, Basal Cell Skin Neoplasms Basal Cell Nevus Syndrome PRIMARY OBJECTIVES: Estimate the overall response rate (ORR) of sonidegib (erismodegib) in combination with buparlisib (hereby referred to as "LB therapy") for patients with locally advanced or metastatic basal cell carcinoma (BCC) in Smoothened inhibitor-naive patients (Cohort 1) and those whose disease is refractory or relapsed on Smoothened inhibitor monotherapy (Cohort 2). --- P13K ---

The gene expression profiles for Gli-1; Gli-2; "Patched" (Ptch) ; "Suppressor of Fused" (SuFu); "Smoothened" (Smo)"; and phosphatidylinositol-3-kinase (PI3K) were to be correlated to the clinical response to therapeutic therapy.. INCLUSION CRITERIA: - Able to understand and sign informed consent - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 - Metastatic BCC, histologic confirmation of distant BCC metastasis - Metastatic disease, target lesion must be measurable using computed tomography (CT) or magnetic resonance imaging (MRI) - Locally advanced BCC are required to have disease that is considered inoperable due to significant functional compromise or to have a medical contraindication to surgery - Nevoid BCC syndrome (Gorlin syndrome) may enroll in this study but must meet the criteria for locally advanced or metastatic disease listed above - COHORT 2 ONLY: A Smoothened inhibitor must have been previously administered as monotherapy - Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L - Platelets ≥ 80 x10^9/L - Hemoglobin (Hb) > 9 g/dL or values ≥ lower limit of normal (LLN) for site-specific lab - Total calcium (corrected for serum albumin) within normal limits (biphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium ≥ the lower limit of normal - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range [or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present] - Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well-documented Gilbert Syndrome) - Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min - Serum amylase ≤ ULN - Serum lipase ≤ ULN - Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) - Negative serum pregnancy test within 72 hours before starting study treatment in women with childbearing potential - International normalized ratio (INR) ≤ 2 EXCLUSION CRITERIA: - Prior treatment with a P13K inhibitor - Known hypersensitivity to buparlisib or to its excipients - Untreated brain metastases are excluded; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (including radiation and/or surgery), is clinically stable at the time of study entry and is not receiving corticosteroid therapy - Acute or chronic liver, renal disease or pancreatitis - Baseline creatinine kinase (CK) > ULN - The following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire: - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety - Meets the cut-off score of ≥ 12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of ≥ 15 in the Generalized Anxiety Disorder 7-item (GAD-7) mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Diarrhea ≥ CTCAE grade 2 - Active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) - QTc > 450 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Angina pectoris that requires the use of anti-anginal medication - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Valvular disease with document compromise in cardiac function - Symptomatic pericarditis - Patient has a history of cardiac dysfunction including any of the following: - Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification 3-4) - Documented cardiomyopathy - Patient has poorly controlled diabetes mellitus [defined as hemoglobin A1C (HgA1c) > ULN], steroid-induced diabetes mellitus, or insulin dependent diabetes mellitus - Other concurrent severe and/or uncontrolled concomitant medical conditions (eg, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol - Significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, diffusing capacity of the lung for carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of buparlisib (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Patients who have been treated with any hematopoietic colony-stimulating growth factors (eg, filgrastim (granulocyte-colony stimulating factor, G-CSF), sargramostim (granulocyte-macrophage colony-stimulating factor, GM-CSF) ≤ 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued - Patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug - Patients receiving chronic treatment with steroids or another immunosuppressive agent - Note: topical applications (eg, rash), inhaled sprays (eg, obstructive airways diseases), eye drops or local injections (eg, intr-articular) are allowed; patients with previously treated brain metastases, who are on stable low dose corticosteroids treatment (eg, dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible - Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to St. John's Wort, Kava, ephedra (ma huang), dehydroepiandrosterone (DHEA), gingko biloba, yohimbe, saw palmetto, and ginseng; fruits include the cytochrome P450, family 3, subfamily A (CYP3A) inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits - Patients who are currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug; please note that co-treatment with weak inhibitors of CYP3A is allowed - Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a grade 1 before starting the trial - Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy - Use of statin drugs or other medications known to associate with rhabdomyolysis; these drugs must be discontinued at enrollment - Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant; low molecular weight heparin is allowed - Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control; double barrier contraceptives must be used through the trial by both sexes; oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study; women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 72 hours prior to initiating treatment - Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL (for US only: and estradiol < 20 pg/mL) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential - Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through 20 months after the final dose of study treatment; for males with partners with childbearing potential, highly effective contraception is required for 6 months; the highly effective contraception is defined as either: - True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient - Use of a combination of any two of the following (a+b): - a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) - b. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - Oral contraception, injected or implanted hormonal methods are not allowed - Fertile males, must use highly effective (double barrier) methods of contraception (eg, spermicidal gel plus condom) for the entire duration of the study, and continuing using contraception and refrain from fathering a child for 6 months following the study drug; a condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the study treatment via seminal fluid; female partner of male study subject should use highly effective contraception during dosing of any study agent and for 16 weeks after final dose of study therapy - Note: hormonal contraception methods (eg, oral, injected, implanted) are not allowed - Note: woman are considered post-menopausal and not child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential - Known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C - History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix - Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator INCLUSION CRITERIA: - Able to understand and sign informed consent - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 - Metastatic BCC, histologic confirmation of distant BCC metastasis - Metastatic disease, target lesion must be measurable using computed tomography (CT) or magnetic resonance imaging (MRI) - Locally advanced BCC are required to have disease that is considered inoperable due to significant functional compromise or to have a medical contraindication to surgery - Nevoid BCC syndrome (Gorlin syndrome) may enroll in this study but must meet the criteria for locally advanced or metastatic disease listed above - COHORT 2 ONLY: A Smoothened inhibitor must have been previously administered as monotherapy - Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L - Platelets ≥ 80 x10^9/L - Hemoglobin (Hb) > 9 g/dL or values ≥ lower limit of normal (LLN) for site-specific lab - Total calcium (corrected for serum albumin) within normal limits (biphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium ≥ the lower limit of normal - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range [or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present] - Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well-documented Gilbert Syndrome) - Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min - Serum amylase ≤ ULN - Serum lipase ≤ ULN - Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) - Negative serum pregnancy test within 72 hours before starting study treatment in women with childbearing potential - International normalized ratio (INR) ≤ 2 EXCLUSION CRITERIA: - Prior treatment with a P13K inhibitor - Known hypersensitivity to buparlisib or to its excipients - Untreated brain metastases are excluded; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (including radiation and/or surgery), is clinically stable at the time of study entry and is not receiving corticosteroid therapy - Acute or chronic liver, renal disease or pancreatitis - Baseline creatinine kinase (CK) > ULN - The following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire: - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety - Meets the cut-off score of ≥ 12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of ≥ 15 in the Generalized Anxiety Disorder 7-item (GAD-7) mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Diarrhea ≥ CTCAE grade 2 - Active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) - QTc > 450 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Angina pectoris that requires the use of anti-anginal medication - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Valvular disease with document compromise in cardiac function - Symptomatic pericarditis - Patient has a history of cardiac dysfunction including any of the following: - Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification 3-4) - Documented cardiomyopathy - Patient has poorly controlled diabetes mellitus [defined as hemoglobin A1C (HgA1c) > ULN], steroid-induced diabetes mellitus, or insulin dependent diabetes mellitus - Other concurrent severe and/or uncontrolled concomitant medical conditions (eg, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol - Significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, diffusing capacity of the lung for carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of buparlisib (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Patients who have been treated with any hematopoietic colony-stimulating growth factors (eg, filgrastim (granulocyte-colony stimulating factor, G-CSF), sargramostim (granulocyte-macrophage colony-stimulating factor, GM-CSF) ≤ 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued - Patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug - Patients receiving chronic treatment with steroids or another immunosuppressive agent - Note: topical applications (eg, rash), inhaled sprays (eg, obstructive airways diseases), eye drops or local injections (eg, intr-articular) are allowed; patients with previously treated brain metastases, who are on stable low dose corticosteroids treatment (eg, dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible - Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to St. John's Wort, Kava, ephedra (ma huang), dehydroepiandrosterone (DHEA), gingko biloba, yohimbe, saw palmetto, and ginseng; fruits include the cytochrome P450, family 3, subfamily A (CYP3A) inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits - Patients who are currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug; please note that co-treatment with weak inhibitors of CYP3A is allowed - Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a grade 1 before starting the trial - Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy - Use of statin drugs or other medications known to associate with rhabdomyolysis; these drugs must be discontinued at enrollment - Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant; low molecular weight heparin is allowed - Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control; double barrier contraceptives must be used through the trial by both sexes; oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study; women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 72 hours prior to initiating treatment - Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL (for US only: and estradiol < 20 pg/mL) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential - Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through 20 months after the final dose of study treatment; for males with partners with childbearing potential, highly effective contraception is required for 6 months; the highly effective contraception is defined as either: - True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient - Use of a combination of any two of the following (a+b): - a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) - b. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - Oral contraception, injected or implanted hormonal methods are not allowed - Fertile males, must use highly effective (double barrier) methods of contraception (eg, spermicidal gel plus condom) for the entire duration of the study, and continuing using contraception and refrain from fathering a child for 6 months following the study drug; a condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the study treatment via seminal fluid; female partner of male study subject should use highly effective contraception during dosing of any study agent and for 16 weeks after final dose of study therapy - Note: hormonal contraception methods (eg, oral, injected, implanted) are not allowed - Note: woman are considered post-menopausal and not child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential - Known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C - History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix - Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator Carcinoma, Basal Cell Recurrent Skin Cancer Skin Neoplasms Basal Cell Nevus Syndrome Carcinoma Carcinoma, Basal Cell Skin Neoplasms Basal Cell Nevus Syndrome PRIMARY OBJECTIVES: Estimate the overall response rate (ORR) of sonidegib (erismodegib) in combination with buparlisib (hereby referred to as "LB therapy") for patients with locally advanced or metastatic basal cell carcinoma (BCC) in Smoothened inhibitor-naive patients (Cohort 1) and those whose disease is refractory or relapsed on Smoothened inhibitor monotherapy (Cohort 2). --- P13K --- --- P13K ---

Primary Outcomes

Description: Response was assessed by the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 criteria, and reported as overall response rate (ORR), comprised of the sum of complete response (CR) rate and partial response (PR) rate. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Overall Response (OR) = CR + PR

Measure: Overall Response Rate (ORR)

Time: Up to 2 years

Secondary Outcomes

Description: Response per the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 criteria was monitored for duration of response (DOR) Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Overall Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions Stable disease (SD) = Small changes that do not meet any of the above criteria

Measure: Median Duration of Response

Time: up to 12 weeks

Description: Adverse events, graded according to the National Cancer Institute CTCAE version 3.0, are reported by treatment arm in total and by Grade 1 to 5.

Measure: Adverse Event Frequency

Time: Up to 30 days post-treatment

Description: Immunostaining for the Gli-1; Gli-2; "Patched" (Ptch) ; "Suppressor of Fused" (SuFu); "Smoothened" (Smo)"; and phosphatidylinositol-3-kinase (PI3K) cellular biomarkers were to be contacted at baseline and after 12 weeks of treatment.

Measure: Changes in Gene Expression Profiles of BCCs Including Hedgehog Pathway and PI3K Pathways

Time: Baseline to 2 years

Description: The gene expression profiles for Gli-1; Gli-2; "Patched" (Ptch) ; "Suppressor of Fused" (SuFu); "Smoothened" (Smo)"; and phosphatidylinositol-3-kinase (PI3K) were to be correlated to the clinical response to therapeutic therapy.

Measure: Gene Expression Profiles (Correlation of Particular Gene Expression Profiles and Response to LB Therapy Will be Assessed.)

Time: up to 2 years post-treatment

10 Phase I/II Clinical Trial of Copanlisib and Ibrutinib in Mantle Cell Lymphoma

The purpose of this study is to test the safety and any good and bad side effects of combining 2 study drugs, copanlisib and ibrutinib. This combination of drugs could shrink your Mantle Cell Lymphoma (MCL), but it could also cause side effects. Both these drugs have been given to people before, but this is the first time that they are being given together.

NCT03877055
Conditions
  1. Mantle Cell Lymphoma (MCL)
Interventions
  1. Drug: Copanlisib
  2. Drug: Ibrutinib
MeSH:Lymphoma Lymphoma, Mantle-Cell
HPO:Lymphoma

Inclusion Criteria: - Patient is ≥ 18 years of age at the time of signing Informed Consent - Patient is able and willing to adhere to the study visit schedule and other protocol requirements - Patient has histologically confirmed diagnosis of R/R mantle cell lymphoma who has received at least 1 line of therapy °Autologous stem cell transplant recipients must have adequate bone marrow recovery and transfusion independent - Patients may have been previously treated with BTK or PI3K inhibitors: °If BTK/P13K inhibitors were part of their last treatment, patients must have had a best response of stable disease or better - Patient has at least one measurable lesion (≥ 2 cm) according to RECIL criteria[37] - Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 - Patient has adequate bone marrow and organ function by: - Absolute neutrophil count (ANC) ≥ 1 x 10^9/L , independent of growth factor support for 14 days unless there is bone marrow involvement. --- P13K ---

- Lipase ≤ 1.5x ULN - LVEF ≥ 50% - Hemoglobin A1c ≤ 8.5% Exclusion Criteria: - Patient has a history of non-compliance to medical regimen or inability to grant consent - Patient is concurrently using other approved or investigational antineoplastic agent with the exception of BTK or Pi3K inhibitors in patients who had these agents as the last line of treatment °Patient on BTK or P13K inhibitors will be continued on therapy as they transition to protocol therapy - Patient has not recovered to Grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy - Patient has had major surgery or a wound that has not fully healed within 4 weeks of starting study drugs. --- P13K ---

Primary Outcomes

Description: using the RECIL criteria

Measure: complete response (Phase II)

Time: 2 years

11 The Impact of Activated p-AKT Expression on Clinical Outcomes in Malignant Lymphoma : A Clinicopathological Study

PI3K(phosphatidylinositol 3-kinase)/AKT pathway is an important oncogenic signaling pathway. However, clinical information about the significance of p-AKT expression in malignant lymphoma is not fully understood yet. In this study, we investigated the overexpression of p-AKT and its prognostic implication in malignant lymphoma.

NCT01789060
Conditions
  1. Malignant Lymphoma
  2. P13K-AKT Pathway Deregulation
Interventions
  1. Other: p-AKT immunohistochemical staining
MeSH:Lymphoma
HPO:Lymphoma

Primary central nervous system lymphoma was excluded in this study Malignant Lymphoma P13K-AKT Pathway Deregulation Lymphoma Recently, among diverse oncogenic signaling pathways, a number of studies have focused on the significance of oncogenic PI3K/AKT (phophatidylinositol 3-kinase/serine-threonine kinase, also known as protein kinase B [PKB]) pathway. --- P13K ---

Primary Outcomes

Measure: Difference of overall survival according to p-AKT status in malignant lymphoma

Time: study entry

Secondary Outcomes

Measure: Subgroup analysis of overall survival according to histologic subtypes (GCB vs non GCB)

Time: study entry

Other Outcomes

Measure: Subgroup analysis of overall survival according to International Prognostic Index risk groups

Time: study entry

12 An Open Label, Phase II Trial of BKM120 in Cancers With PIK3CA Activating Mutations

In people whos cancers have a PIK3CA mutation, this trial will be evaluating the drug BKM120 as a possible treatment. BKM120 works by blocking the phosphatidylinositol-3-kinase (PI3K)pathway, thereby inhibiting tumor growth and survival. The purpose of this study is to learn if the study drug BKM120 can shrink or slow the growth of your tumor. The safety of BKM120 will also be studied. Your physical state, symptoms, change in the size of your tumor, and laboratory findings obtained while you are on study will help the research team decide if BKM120 is safe and effective in patients with advanced cancers.

NCT01501604
Conditions
  1. Lung Cancer
  2. Breast Cancer
  3. Colorectal Cancer
  4. Cholangiocarcinoma
  5. Solid Tumors
Interventions
  1. Drug: BKM120
MeSH:Cholangiocarcinoma
HPO:Cholangiocarcinoma

The PIK3CA mutation must be documented in a CLIA approved laboratory Exclusion Criteria: - Prior treatment with a P13K inhibitor - Known hypersensitivity to BKM120 or its excipients - Untreated brain metastases - Acute or chronic liver, renal disease or pancreatitis - Currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A - Diarrhea >/= CTCAE grade 2 - Any concurrent severe and/or uncontrolled medical condition - Active cardiac disease - History of cardiac dysfunction - Poorly controlled diabetes mellitus or steroid-induced diabetes mellitus - Significant symptomatic deterioration of lung function - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKDM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) - Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant - Pregnant or breast-feeding - Known diagnosis of HIV infection - History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix - Unable to swallow the medication in its prescribed form Inclusion Criteria: - At least 1 site of measurable disease - Life expectancy >/= 12 weeks - Adequate marrow and organ function - Diagnosis of lung cancer, breast cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer, esophageal cancer, or head and neck cancer - Pathologically documented, definitively diagnosed, advanced solid tuor that is refractory to standard treatment, for which no standard therapy is available, or the subject refuses standard therapy - Cancer must have at least one of the following PIK3CA mutations: E542K, E545K, H1047R, H1047L. --- P13K ---

The PIK3CA mutation must be documented in a CLIA approved laboratory Exclusion Criteria: - Prior treatment with a P13K inhibitor - Known hypersensitivity to BKM120 or its excipients - Untreated brain metastases - Acute or chronic liver, renal disease or pancreatitis - Currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A - Diarrhea >/= CTCAE grade 2 - Any concurrent severe and/or uncontrolled medical condition - Active cardiac disease - History of cardiac dysfunction - Poorly controlled diabetes mellitus or steroid-induced diabetes mellitus - Significant symptomatic deterioration of lung function - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKDM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) - Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant - Pregnant or breast-feeding - Known diagnosis of HIV infection - History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix - Unable to swallow the medication in its prescribed form Lung Cancer Breast Cancer Colorectal Cancer Cholangiocarcinoma Solid Tumors Cholangiocarcinoma Subjects enrolled in this study will receive BKM120 once daily, orally, in cycles of 28 days. --- P13K ---

Primary Outcomes

Description: Objective Response Rate (CR or PR) by RECIST 1.1 criteria

Measure: Response Rate

Time: 2 years

Secondary Outcomes

Description: Clinical Benefit Rate (CR, PR, or SD) by RECIST 1.1 criteria

Measure: Clinical Benefit Rate

Time: 2 years

Description: Progression Free Survival (PFS)

Measure: Survival

Time: 2 years

Description: Determine if the presence of specific co-existing mutations may influence clinical benefit from BKM120

Measure: Clinical Benefit

Time: 2 years

13 Phase I, Pharmacokinetic and Pharmacodynamic Study of BAY 43-9006 (Sorafenib) in Combination With CCI-779 (Temsirolimus) in Advanced Solid Malignancies

This phase I trial is studying the side effects and best dose of temsirolimus when given together with sorafenib in treating patients with unresectable or metastatic solid tumors. Sorafenib and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with temsirolimus may kill more tumor cells.

NCT00255658
Conditions
  1. Unspecified Adult Solid Tumor, Protocol Specific
Interventions
  1. Drug: sorafenib tosylate
  2. Drug: temsirolimus
  3. Other: laboratory biomarker analysis

To analyze the biologic effects of BAY 43-9006 and CCI-779 on downstream targets of the P13K/Akt/mTOR and Raf signaling pathways. --- P13K ---

Primary Outcomes

Measure: Maximum tolerable dose (MTD) and recommended dose for phase II determined by dose-limiting toxicities (DLT) graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0

Time: 4 weeks

14 A Phase 1b/2 Study of BEZ235 in Patients With Advanced Renal Cell Carcinoma (RCC)

This study tests a new medication for treatment of kidney cancer, called BEZ235. This medication works by blocking several mechanisms that the cancer needs to grow and survive. By blocking these mechanisms, the medication can thus suppress further growth of the cancer, possibly kill cancer cells. Older kidney cancer medications (such as temsirolimus [Torisel®] or everolimus [Afinitor®]) typically only block one mechanism in cancer cells, so the investigators think that BEZ235 may work even better against kidney cancer. The purpose of the first part of this study is to test the safety of giving BEZ235 at different doses. The investigators are trying to find a safe dose of BEZ235 and want to find out what effects, good and/or bad, it has on the patient and the cancer.

NCT01453595
Conditions
  1. Renal Cancer
Interventions
  1. Drug: BEZ235
MeSH:Carcinoma Carcinoma, Renal Cell Kidney Neoplasms
HPO:Carcinoma Clear cell renal cell carcinoma Papillary renal cell carcinoma Renal cell carcinoma Renal neoplasm

Exclusion Criteria: - Patients who have received prior treatment with a P13K inhibitor (Phase 2 portion only). --- P13K ---

Primary Outcomes

Description: In patients with advanced clear cell RCC, progressing after prior first-line or second-line mTOR therapy. The determination of antitumor efficacy will be based on objective tumor assessments made according to the RECIST1.1.

Measure: Objective Response Rate (ORR)

Time: 1 year

15 Evaluation of PI3K/AKT/mTOR Signaling Pathway Using BKM120 in Early Breast Cancer

BKM120 is a potent and highly specific oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, currently under investigation in a first-in-man study in patients with advanced solid tumors (wild type and PIK3CA-mutated). Consistent, dose-dependent pharmacodynamic activity has been demonstrated and clear signs of anti-tumor activity have been seen with BKM120.

NCT01513356
Conditions
  1. Breast Cancer
Interventions
  1. Drug: BKM120
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

- Patients must meet the following laboratory criteria within 7 days prior to start the study treatment: - Hematology - Neutrophil count of > 1200/mm3 - Platelet count of > 100,000/ mm3 - Hemoglobin > 90g/L - Biochemistry - AST/SGOT and ALT/SGPT < 2.5 x upper limit of normal (ULN) or < 5.0 x ULN if the transaminase elevation is due to liver metastases - Total bilirubin < 1.5 x ULN [Patients with Gilbert Syndrome must have total bilirubin < 3 ULN] - Cholesterol < ULN - 7.75 mmol/L and Triglycerides < ULN - 2.5 x ULN (with lipid-lowering drugs permitted) - Serum creatinine < 1.5 x ULN or 24-hour creatinine clearance > 60 mL/min - Serum albumin > LLN or > 30 g/L - Fasting plasma glucose ≤ 140 mg/dL (7.8 mmol/L) Exclusion Criteria: - Patients who have received prior treatment with a P13K inhibitor - Patients with a known hypersensitivity to BKM120 or to its excipients - Patients with a history of photosensitivity reactions to other drugs - Patients with the following mood disorders as judged by the Investigator or a psychiatrist, or as result of patient's mood assessment questionnaire: - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - ≥ CTCAE grade 3 anxiety The psychiatric judgment overrules the mood assessment questionnaire result/investigators judgment. --- P13K ---

Primary Outcomes

Description: Biomarkers assessments must be performed at baseline and at the end of study treatment. The following biomarkers will be assessed: PI3K, KRAS, pAkt and -RPS6p

Measure: - To determine the grade of inhibition of PI3K/mTOR pathways, in pre-surgery setting with BKM120

Time: 28 days

Secondary Outcomes

Measure: Number, grade and relationship of adverse events with BKM120

Time: 28 days

Measure: Potential predictive biomarkers (PI3K mutation, KRAS, pAkt and RPS6p) for a pathologic complete response relating to BKM120

Time: 28 days

16 A Study of BKM120 as a Single Agent in First Line Therapy in Advanced, Metastatic, or Recurrent Endometrial Cancers

This is a phase II open label fixed dose study in subjects with advanced, metastatic, or refractory endometrial or ovarian, fallopian tube, or primary peritoneal cancer with PI3 kinase pathway activation as demonstrated by PIK3CA gene mutation, PTEN gene mutation, or PTEN null/low protein expression.

NCT01550380
Conditions
  1. Endometrial Cancer
Interventions
  1. Drug: BKM120
MeSH:Endometrial Neoplasms
HPO:Endometrial carcinoma

Exclusion Criteria: - Patients who have received prior treatment with a P13K inhibitor. --- P13K ---

Primary Outcomes

Description: To assess response rate in patients with endometrial cancer treated with first line BKM120. To assess response rate in patients with ovarian, fallopian tube, and primary peritoneal cancer treated with first line BKM120.

Measure: Response Rates of BKM120

Time: Up to 20 months

Secondary Outcomes

Description: To determine the progression free survival (PFS) in patients with endometrial cancer treated with first line BKM120. To document the non-progression rate at 12 weeks in patients with endometrial cancer treated with first line BKM120. To determine the progression free survival (PFS) in patients with ovarian, fallopian tube, and primary peritoneal cancer treated with first line BKM120. To document the non-progression rate at 12 weeks in patients with ovarian, fallopian tube, and primary peritoneal cancer treated with first line BKM120.

Measure: Progression Free Survival (PFS)

Time: Up to 20 months

17 Phase II Study of Buparlisib in Metastatic Transitional Cell Carcinoma of the Urothelium

The purpose of this study is to learn what effects, good and/or bad, Buparlisib has on advanced urothelial cancer. Buparlisib is a pill that works by shutting down some of the signals in cancer cells that make tumors grow. It is being tested in patients in research studies such as this one. As of 2010, more than 80 patients with various types of cancer have received treatment with Buparlisib in research studies. This clinical research study is divided into two parts. The goal of the first part of this study is to learn if the study drug Buparlisib can shrink or slow the growth of cancer in patients with urothelial tumors. The goal of the second part of this study is to learn if the study drug Buparlisib can shrink or slow the growth of urothelial tumors in patients known to have certain genetic alterations that cause these types of tumors. The study doctor will inform the patient which part of the study is currently enrolling participants. Participants in both parts of the study will receive the same treatment and tests. The safety of this drug will also be studied in both parts. The physical state, changes in the size of the tumor, and laboratory findings taken while on-study will help us decide if Buparlisib is safe and effective.

NCT01551030
Conditions
  1. Metastatic Transitional Cell Carcinoma of the Urothelium
Interventions
  1. Drug: Buparlisib
MeSH:Carcinoma Carcinoma, Transitional Cell
HPO:Carcinoma

- Life expectancy of ≥ 12 weeks - Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, - Hemoglobin >9 g/dL - Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed) - Corrected Calcium = (0.8 * (Normal Albumin - Pt's Albumin)) + Serum Ca - Potassium and magnesium within normal limits - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range [or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present] - Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with welldocumented Gilbert syndrome) - Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min - INR ≤ 2 - Serum amylase and lipase ≤ ULN - Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) - Ability to swallow oral medication Exclusion Criteria: - Patients who have received prior treatment with a P13K inhibitor. --- P13K ---

Primary Outcomes

Description: at 2 months for the pan-class I selective PI3K inhibitor Buparlisib in patients with metastatic urothelial cancer that has progressed on prior cytotoxic chemotherapy. Response and progression will be evaluated in this study using the international criteria by the Response Evaluation Criteria in Solid Tumors (RECIST).

Measure: progression free survival (PFS) in the Phase II Cohort

Time: 2 months

Measure: progression free survival (PFS) in the Expansion Cohort

Time: 2 months

Secondary Outcomes

Description: as determined by RECIST v1.1 for Buparlisib in patients with progressive metastatic urothelial cancer who have received prior cytotoxic chemotherapy

Measure: response rate in the Phase II Cohort

Time: 2 months

Description: in patients with an activated PI3K pathway.Response and progression will be evaluated in this study using the international criteria by the Response Evaluation Criteria in Solid Tumors (RECIST).

Measure: overall response rate (ORR) in the Phase II Cohort

Time: 2 months

Description: To establish the safety and toxicity of Buparlisib, the frequency of toxicity will be tabulated according to the NCI Common Toxicity Criteria, version 4.0.

Measure: safety in the Phase II Cohort

Time: 2 years

Description: To establish the safety and toxicity of Buparlisib , the frequency of toxicity will be tabulated according to the NCI Common Toxicity Criteria, version 4.0.

Measure: toxicity in the Phase II Cohort

Time: 2 years

Description: Patient samples will be sequenced for mutations in PTEN and PIK3CA as well as for reduced or absent PTEN expression. Patients will be categorized on the basis of PTEN expression levels into three categories: no expression, low expression, or high expression. PTEN levels and PTEN and PIK3CA mutation status (present/absent) will be correlated with PFS using a log rank test, and with response to treatment (complete response/partial response versus no response) using Fisher's exact test.

Measure: To assess markers of activated PI3K pathway

Time: 2 years

Description: as determined by RECIST v1.1

Measure: response rate in Expansion Cohort

Time: 2 months

Description: To establish the safety and toxicity of Buparlisib, the frequency of toxicity will be tabulated according to the NCI Common Toxicity Criteria, version 4.0.

Measure: safety in Expansion Cohort

Time: 2 years

Description: To establish the safety and toxicity of Buparlisib , the frequency of toxicity will be tabulated according to the NCI Common Toxicity Criteria, version 4.0.

Measure: toxicity in the Expansion Cohort

Time: 2 years

18 A Phase II Study of BKM120 (Buparlisib) in Relapsed or Refractory Thymomas

Thymic tumors are rare tumors, but represent the most common tumors of the anterior mediastinum. Thymoma has an indolent course in advanced disease and has the propensity to spread to the pleura. In first line therapy, combination chemotherapy produces responses in approximately 80% of patients. A number of single agents have activity in recurrent disease, but none are curable. Patients with recurrent thymoma have limited treatment options, and thus novel target modalities are needed. At the Indiana University Simon Cancer Center (IUSCC), more patients with advance thymoma are seen than any other institution in the country. Our main hypothesis is the PI3K pathway is an important driver for growth and metastasis of thymoma and that inhibition of the PI3K pathway is expected to produce clinically meaningful response in patients with recurrent thymoma.

NCT02220855
Conditions
  1. Thymoma
Interventions
  1. Drug: BKM120
MeSH:Thymoma Thymus Neoplasms
HPO:Neoplasm of the thymus Thymoma

Signed informed consent 22. INR ≤ 2 Exclusion Criteria: 1. Patients who have received prior treatment with a P13K inhibitor. --- P13K ---

Primary Outcomes

Description: Percent of patients with Objective response and the Binomial Exact 95% confidence interval. Objective response is defined as having a best response of Complete Response (defined as disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to <10mm) or Partial Response (defined as at least a 30% decrease in the sum of diameters of target lesions from the baseline sum diameters) by RECIST v1.1 criteria.

Measure: Percent of Patients With Objective Response

Time: up to three years

Secondary Outcomes

Description: Number of unique patients who had a treatment related (possible, probable or definite) adverse events with grade >= 3.

Measure: Treatment Related Adverse Events Grade 3 or Above

Time: up to three years

Description: Duration of time from the start of treatment to time of documented progression or death. Patients who do not progress or die will be censored on their last evaluation date. Kaplan-Meier methods will be used and the median and 95% confidence intervals will be calculated.

Measure: Progression-free Survival Rate

Time: up to three years

Description: Percent of patients achieving disease control and the Binomial Exact 95% confidence interval. Disease control is defined as having a best response of Complete Response (defined as disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to <10mm) or Partial Response (defined as at least a 30% decrease in the sum of diameters of target lesions from the baseline sum diameters) or Stable Disease for at least 4 months (defined by neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progression) by RECIST v1.1 criteria.

Measure: Percent of Patients Achieving Disease Control

Time: up to three years

Description: Duration of time from the start of treatment to time of death due to any causes. Patients who do not die will be censored on their last known alive date. Kaplan-Meier methods will be used and the median and 95% confidence intervals will be calculated.

Measure: Overall Survival Rate

Time: up to three years

19 Phase I/II Trial of ZD1839 (Iressa®), Trastuzumab (Herceptin®), and Docetaxel (Taxotere®) in Patients With erbB-2 (HER-2) Overexpressing, Stage IV Breast Carcinoma

RATIONALE: Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining gefitinib and trastuzumab with docetaxel may kill more tumor cells. PURPOSE: This phase I/II trial is studying the best dose of docetaxel when given together with gefitinib and trastuzumab in treating patients with metastatic breast cancer.

NCT00086957
Conditions
  1. Breast Cancer
Interventions
  1. Biological: trastuzumab
  2. Drug: docetaxel
  3. Drug: gefitinib
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

- Correlate expression and/or degree of phosphorylation of epidermal growth factor receptor, HER2/neu, c-fos, Akt, ERK½, P13K, p53, p21, and p27 with outcome in patients treated with this regimen. --- P13K ---

Primary Outcomes

Description: Dose Limiting Toxicity (DLT) defined as any treatment-related grade 3 or greater except for hematological toxicities which must be grade 4. Interstitial Lung Disease (ILD) related to treatment should be considered as a DLT regardless of the grade.

Measure: Number of Participants With at Least One Dose Limiting Toxicity in Phase I

Time: 4 weeks from start of treatment, up to 2 years

Description: The maximum tolerated dose (MTD): subjects received gefitinib 250 mg orally daily, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 75 mg/m^2 intravenously every 3 weeks. This was to serve as the phase II dose if no dose-limiting toxicities (DLTs) occurred in the first three subjects. If one DLT occurred in the first three subjects, another three subjects where to be enrolled at this dose, whereas if two DLTs occurred in the first three subjects, the docetaxel dose was to be decreased to 60 mg/m^2. The study would then be continued only if no more than one patient had a DLT at this dose. Once the dose of docetaxel was established, all further subjects were to be treated at the phase II MTD dose.

Measure: Recommended Phase II Dose

Time: 4 weeks from start of treatment, up to 2 years

Secondary Outcomes

Description: Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.

Measure: Progression-free Survival

Time: Until disease progression, up to 5 years.

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response Rate defined as percentage of patients achieving a Best Response of either CR or PR.

Measure: Objective Response Rate

Time: After 3 cycles of treatment, up to 2 years.

Description: Estimated using the product-limit method of Kaplan and Meier.

Measure: Overall Survival

Time: Until death from any cause, up to 5 years.

20 Phase II Evaluation of Cetuximab (C225) Combined With Induction Paclitaxel and Carboplatin Followed by C225, Paclitaxel, Carboplatin, and Radiation for Stage III/IV Operable Squamous Cancer of the Head and Neck

RATIONALE: Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving cetuximab with combination chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving cetuximab after surgery may kill any tumor cells that remain. PURPOSE: This phase II trial is studying how well giving cetuximab together with combination chemotherapy and radiation therapy works in treating patients who are undergoing surgery for stage III or stage IV head and neck cancer.

NCT00089297
Conditions
  1. Head and Neck Cancer
Interventions
  1. Biological: Cetuximab
  2. Drug: Carboplatin
  3. Drug: Paclitaxel
  4. Radiation: Radiation therapy
MeSH:Head and Neck Neoplasms
HPO:Neoplasm of head and neck

- Determine the effect of this treatment regimen on selective biologic pathways, total and phosphorylated epidermal growth factor receptor, ERK/MAPK, and P13K/AKT in these patients. --- P13K ---

Primary Outcomes

Description: Event-free survival rate at 1 year was defined as the proportion of patients who did not have disease progression, primary site surgery, or death after being followed for 1 year.

Measure: Event-free Survival Rate at 1 Year

Time: Assessed at 1 year.

Secondary Outcomes

Description: Per RECIST criteria, Complete response (CR)= disappearance of all target and nontarget lesions Partial response (PR)= >=30% decrease in the sum of the longest diameters of target lesions from baseline, and persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits. Objective response = CR + PR.

Measure: Proportion of Patients With Objective Response by RECIST

Time: Assessed at weeks 7, 14, 18, 20, and then every every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry

Description: Progression-free survival was defined as the time from registration to documented progression or death without progression. Progression is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s) or unequivocal progression of existing nontarget lesions.

Measure: Progression-free Survival

Time: Assessed at weeks 7, 14, 18, 20, and then every every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry

Description: Overall survival is defined as the time from registration to death of any causes.

Measure: Overall Survival

Time: Weekly during treatment, and then every every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry

21 A Phase I Study of the PI3-Kinase Inhibitor BKM120 in Combination With Docetaxel in Patients With Advanced Solid Tumors.

This phase I trial studies the side effects and best dose of PI3K inhibitor BKM120 when given together with docetaxel in treating patients with advanced solid tumor that is locally advanced, cannot be removed by surgery, or metastatic. PI3K inhibitor BKM120 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving PI3K inhibitor BKM120 together with docetaxel may kill more tumor cells.

NCT01540253
Conditions
  1. Unspecified Adult Solid Tumor, Protocol Specific
Interventions
  1. Drug: PI3K inhibitor BKM120
  2. Drug: docetaxel
  3. Other: pharmacological study
  4. Other: questionnaire administration
  5. Other: laboratory biomarker analysis
MeSH:Neoplasms
HPO:Neoplasm

dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible - Patients who are currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug (please note that co-treatment with weak inhibitors of CYP3A is allowed) - Patients who have received chemotherapy or targeted anticancer therapy =< 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a grade 1 before starting the trial - Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) =< 5 effective half-lives prior to starting study drug or who have not recovered from side effects of such therapy - No concurrent intake of valproic acid, rifampin, phenobarbital, phenytoin, or carbamazepine - Patients who are currently taking therapeutic doses of warfarin sodium or any other Coumadin derivative anticoagulant - Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator Unspecified Adult Solid Tumor, Protocol Specific Neoplasms PRIMARY OBJECTIVES: I. To determine the dose-limiting toxicities and identify the recommended phase II dose of the combination of docetaxel and BKM 120 (P13K inhibitor BKM120) in patients with advanced solid tumors. --- P13K ---

Primary Outcomes

Description: Adverse events (AE) will be coded and evaluated for severity using NCI CTCAE, version 4.0 and will be summarized by system organ class and preferred term.

Measure: Maximum tolerated dose (MTD) or recommended phase 2 dose of PI3K inhibitor BKM120

Time: 21 days

Description: AE will be coded and evaluated for severity using NCI CTCAE, version 4.0 and will be summarized by system organ class and preferred term.

Measure: Incidence AE and tolerability of PI3-kinase inhibitor BKM120 in combination with docetaxel

Time: Up to 30 days after completion of treatment

Secondary Outcomes

Description: The ORR will be calculated as the number of patients with a confirmed complete or partial response divided by the total number of patients. Tumor response will be summarized for the evaluable patient population, and the 95% confidence interval for ORR (complete response [CR] + partial response [PR]) will be presented. Response will be evaluated by revised RECIST 1.1 criteria.

Measure: Objective response rate (ORR) as assessed by the proportion of patients with a confirmed complete response (CR) or partial response (PR)

Time: Up to 6 courses

Measure: Progression-free survival (PFS)

Time: Up to 3 years

Measure: PK parameters of PI3-kinase inhibitor BKM120

Time: Baseline, days 1-7 of course 1, and then day 1 of all subsequent courses

22 A Biomarker Driven Pilot Study of the Pan-class I PI3K Inhibitor NVP-BKM120 in Combination With Cetuximab in Patients With Recurrent/Metastatic Head and Neck Cancer

This pilot randomized phase I/II trial studies the side effects and best dose of PI3K inhibitor BKM120 when given together with cetuximab and to see how well it works in treating patients with recurrent or metastatic head and neck cancer. PI3K inhibitor BKM120 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumors to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving PI3K inhibitor BKM120 together with cetuximab may kill more tumor cells

NCT01816984
Conditions
  1. Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma
  2. Recurrent Metastatic Squamous Neck Cancer With Occult Primary
  3. Recurrent Salivary Gland Cancer
  4. Recurrent Squamous Cell Carcinoma of the Hypopharynx
  5. Recurrent Squamous Cell Carcinoma of the Larynx
  6. Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity
  7. Recurrent Squamous Cell Carcinoma of the Nasopharynx
  8. Recurrent Squamous Cell Carcinoma of the Oropharynx
  9. Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  10. Recurrent Verrucous Carcinoma of the Larynx
  11. Recurrent Verrucous Carcinoma of the Oral Cavity
  12. Salivary Gland Squamous Cell Carcinoma
  13. Stage IV Squamous Cell Carcinoma of the Hypopharynx
  14. Stage IV Squamous Cell Carcinoma of the Nasopharynx
  15. St
  16. Stage IVA Salivary Gland Cancer
  17. Stage IVA Squamous Cell Carcinoma of the Larynx
  18. Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity
  19. Stage IVA Squamous Cell Carcinoma of the Oropharynx
  20. Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  21. Stage IVA Verrucous Carcinoma of the Larynx
  22. Stage IVA Verrucous Carcinoma of the Oral Cavity
  23. Stage IVB Salivary Gland Cancer
  24. Stage IVB Squamous Cell Carcinoma of the Larynx
  25. Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity
  26. Stage IVB Squamous Cell Carcinoma of the Oropharynx
  27. Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  28. Stage IVB Verrucous Carcinoma of the Larynx
  29. Stage IVB Verrucous Carcinoma of the Oral Cavity
  30. Stage IVC Salivary Gland Cancer
  31. Stage IVC Squamous Cell Carcinoma of the Larynx
  32. Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity
  33. Stage IVC Squamous Cell Carcinoma of the Oropharynx
  34. Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  35. Stage IVC Verrucous Carcinoma of the Larynx
  36. Stage IVC Verrucous Carcinoma of the Oral Cavity
  37. Tongue Cancer
Interventions
  1. Drug: PI3K inhibitor BKM120
  2. Biological: cetuximab
MeSH:Carcinoma Carcinoma, Squamous Cell Head and Neck Neoplasms Laryngeal Neoplasms Oropharyngeal Neoplasms Carcinoma, Verrucous Salivary Gland Neoplasms Nasopharyngeal Carcinoma Paranasal Sinus Neoplasms Neoplasms, Unknown Primary Tongue Neoplasms Laryngeal Diseases
HPO:Carcinoma Neoplasm of head and neck Neoplasm of the larynx Neoplasm of the tongue Paranasal sinus neoplasm Salivary gland neoplasm Squamous cell carcinoma

cisplatin or carboplatin) in a prior line of therapy, or documented intolerance to such an agent - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 - No more than two lines of prior cytotoxic chemotherapy in the recurrent/metastatic (palliative intent) treatment setting - Prior use of cetuximab or another epidermal growth factor receptor (EGFR) inhibitor is allowable and if used as a single agent should not be considered as a cytotoxic chemotherapy - Patients must have at least one site of measurable disease (if applicable) (per RECIST for solid tumors or the appropriate disease classification/criteria for the target population) - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Platelets >= 100 x 10^9/L - Hemoglobin (Hb) > 9 g/dL - Total calcium (corrected for serum albumin) within normal limits - Magnesium >= the lower limit of normal for the institution - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 1.5 x normal range (or =< 3.0 x upper limit of normal [ULN] if liver metastases are present) - Serum bilirubin within normal range (or =< 1.5 x ULN if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert syndrome) - Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 mL/min - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - Negative serum pregnancy test within 72 hours before starting study treatment in women with childbearing potential - Signed informed consent - International normalized ratio (INR) =< 2.5 Exclusion Criteria: - Patients who have received prior treatment with a P13K inhibitor - No available tumor material for correlative studies - Patients with a known hypersensitivity to BKM120 or to its excipients, or hypersensitivity to cetuximab - More than two prior lines of cytotoxic chemotherapy in the recurrent/metastatic disease setting (palliative treatment intent)(excluding single agent use of an EGFR inhibitor) - Patients with untreated brain metastases are excluded; however, patients with treated brain metastases are eligible if they are > 4 weeks from therapy completion (including radiation and/or surgery), are clinically stable at the time of study entry and are not receiving corticosteroid therapy at the time of study entry - Patients with acute or chronic liver, renal disease or pancreatitis - Patients with the following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire (treating physician to decide on whether to administer questionnaire): - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - >= Common Terminology Criteria for Adverse Events (CTCAE) version 4 (v4) grade 3 anxiety - Meets the cut-off score of >= 10 in the Patient Health Questionnaire 9 (PHQ-9) or a cut-off of >= 15 in the Generalized Anxiety Disorder 7 (GAD-7) mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Patients with diarrhea >= CTCAE v4 grade 2 - Patient has active cardiac disease including any of the following: - History of clinically significant heart failure (previously assessed) with a left ventricular ejection fraction (LVEF) of < 50% as determined by multiple grated acquisition (MUGA) scan or echocardiogram (ECHO) - Corrected QT (QTc) > 480 msec on screening electrocardiogram (ECG) (using the Fridericia QT correction [QTcF] formula) - Angina pectoris that requires the use of anti-anginal medication - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Valvular disease with document compromise in cardiac function - Symptomatic pericarditis - Patient has a history of cardiac dysfunction including any of the following: - Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification III-IV) - Documented cardiomyopathy - Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus (hemoglobin A1C [HbA1C] > 7.5%) - Patients with any history of hyperglycemia (elevated blood glucose level on blood chemistries) should be considered for initiation of Metformin treatment (500mg, PO, twice daily) prior to starting BKM120 - Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol - Significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, diffusing capacity of the lung for carbon monoxide (DLCO), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated - Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF]) =< 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued - Patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug - Patients receiving chronic treatment with steroids or another immunosuppressive agent other than specified in exclusion criterion #4 - Note: Topical applications (e.g. --- P13K ---

Primary Outcomes

Description: Performed using snap frozen tissue samples using the well-established PamGene Kinase array platform available in the Salgia/Seiwert laboratories.

Measure: Compensatory Signaling/Feedback Loop Signaling Evaluated by Measurement of Phosphorylated (p)-EGFR

Time: 1 week

Description: Maximum tolerated dose (MTD) is defined as the dose level preceding the dose in which greater than or equal to 2 out of 3-6 patients experience a dose limiting toxicity (DLT) assessed using CTCAE v4

Measure: Maximum Tolerated Dose (MTD)

Time: 28 days

Secondary Outcomes

Description: Measured by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay on Formalin-Fixed, Paraffin-Embedded (FFPE) sections in a descriptive manner.

Measure: Apoptosis Induction

Time: Up to 28 days

Description: Percentage of patients whose cancer shrinks or disappears after treatment.

Measure: Response Rate Assessed Using RECIST

Time: Up to 28 days

Description: Percentage of patients with prior EGFR failure assessed using RECIST whose cancer shrinks or disappears after treatment.

Measure: Response Rate in Patients With Prior EGFR Failure Assessed Using RECIST

Time: Up to 28 days

Description: Tumor shrinkage will be visualized as a waterfall plot for graphical (qualitative) comparison.

Measure: Tumor Shrinkage

Time: Up to 28 days

Description: Overall survival is defined as the time from study initiation to death due to any reason.

Measure: Overall Survival

Time: 4 years and 3 months

Description: Progression free survival is defined as the time from study initiation to first evidence of progression of disease.

Measure: Progression Free Survival

Time: 4 years and 3 months

23 A Phase 2 Study of Panitumumab in Patients With Cetuximab-refractory Metastatic Colorectal Cancer

The purpose of this study is to assess if panitumumab is active enough to warrant comparative studies in patients with metastatic colorectal cancer that has progressed after treatment with cetuximab.

NCT01801904
Conditions
  1. Metastatic Colorectal Cancer
Interventions
  1. Drug: Panitumumab
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

exploratory analysis of tumor-tissue for biological or genomic determinants of outcome of BRAF and P13K mutation status, EGFR and PTEN expression status. --- P13K ---

Primary Outcomes

Description: progression of disease within 2 months from registration according to RECIST criteria, and death for any cause within 2 months from registration

Measure: number of patients alive and without disease progression

Time: 2 months

Secondary Outcomes

Description: Response assessed per patients at weeks 8,16,24,32,40 and every 3 months thereafter, using RECIST criteria

Measure: response rate

Time: up to 40 weeks

Measure: progression free survival

Time: 9 months

Measure: overall survival

Time: one year

Description: worst grade toxicity (according to Common Terminology Criteria for Adverse Events version 3) per patient

Measure: worst grade toxicity per patient

Time: every 2 weeks for up to 6 months

Other Outcomes

Description: exploratory analysis of tumor-tissue for biological or genomic determinants of outcome of BRAF and P13K mutation status, EGFR and PTEN expression status

Measure: gene expression on tumor tissue

Time: one year

24 A Pilot and Feasibility Neoadjuvant Study of a 2-Week Ketogenic Diet in Combination With Letrozole to Modulate PI3K Signaling in ER+ Breast Cancer

This is a neoadjuvant study to determine the feasibility and tolerability of 2 weeks of a very low carbohydrate ketogenic diet in combination with letrozole for patients with early stage operable ER+disease.

NCT03962647
Conditions
  1. Estrogen Receptor-positive Breast Cancer
Interventions
  1. Dietary Supplement: 2-Week Ketogenic Diet
  2. Drug: Letrozole
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

Reduction in measures of insulin/P13K pathway activation. --- P13K ---

Primary Outcomes

Description: The number of patients who complete the dietary intervention, as well as the reasons for early discontinuation and any adverse events will be reported. The number of of cases where pre- and post-treatment samples could be obtained and successfully analyzed for Ki67 and insulin signaling will also be reported.

Measure: Patients who complete the dietary intervention

Time: After 2 weeks of a ketogenic diet

Secondary Outcomes

Description: Measured by Ki67

Measure: Measure enhanced inhibition of cancer cell proliferation

Time: After 2 weeks of a ketogenic diet

Description: Marks of insulin receptor/PI3K pathway activation in tumors

Measure: Reduction in measures of insulin/P13K pathway activation

Time: After 2 weeks of a ketogenic diet

Description: Waist circumference will be measured

Measure: Measure changes in body composition

Time: After 2 weeks of a ketogenic diet

Description: Weight will be checked

Measure: Measure changes in body composition

Time: After 2 weeks of a ketogenic diet

Description: Height will be checked

Measure: Measure changes in body composition

Time: After 2 weeks of a ketogenic diet

Description: Body mass index will be measured

Measure: Measure changes in body composition

Time: After 2 weeks of a ketogenic diet

Description: Fasting glucose/insulin to measure HOMA-IR

Measure: Measure changes in insulin resistance

Time: After 2 weeks of a ketogenic diet

Description: Rate of ketones production

Measure: Measure effectiveness in inducing a ketogenic state

Time: After 2 weeks of a ketogenic diet

25 Phase I Trial of BKM120 in Combination With Carboplatin and Pemetrexed in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

This phase I trial studies the side effects and best dose of PI3K inhibitor BKM120 when given together with carboplatin and pemetrexed disodium in treating patients with stage IV non-small cell lung cancer. PI3K inhibitor BKM120 and pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving PI3K inhibitor BKM120, carboplatin, and pemetrexed disodium together may kill more tumor cells

NCT01723800
Conditions
  1. Recurrent Non-small Cell Lung Cancer
  2. Stage IV Non-small Cell Lung Cancer
Interventions
  1. Drug: PI3K inhibitor BKM120
  2. Drug: pemetrexed disodium
  3. Drug: carboplatin
  4. Other: laboratory biomarker analysis
  5. Other: pharmacological study
  6. Procedure: quality-of-life assessment
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.. Inclusion Criteria: - Patients who have signed a written informed consent - Patients must have a histologic or cytologic diagnosis of advanced, nonsquamous NSCLC (stage IV by American Joint Committee on Cancer [AJCC] 7th edition [ed.]) - Patients should not have received prior systemic chemotherapy for metastatic disease (prior epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], kinase inhibitor therapy is allowed); prior adjuvant or neoadjuvant therapy for early stage disease is allowed if received >= 12 months prior to study entry - Prior radiation therapy is allowed to < 25% of the bone marrow; prior radiation must be completed at least 2 weeks prior to day 1 of cycle 1, and patients must have recovered from the acute toxic effects - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 - Patients must have at least one site of measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Platelets >= 100 x 10^9/L - Hemoglobin (Hb) > 9 g/dL - Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium >= the lower limit of normal (LLN) - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or =< 3 x upper limit of normal [ULN] if liver metastases are present) - Serum bilirubin within normal range (or =< 1.5 x ULN if liver metastases are present) - Serum creatinine =< 1.5 x ULN or calculated or 24-hour clearance >= 45 mL/min (calculated creatinine clearance based on Cockcroft-Gault formula) - Serum phosphorus >= LLN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - Negative serum pregnancy test within 72 hours before starting study treatment in women with childbearing potential - International normalized ratio (INR) =< 2 Exclusion Criteria: - Patients who have received prior treatment with a P13K inhibitor or mammalian target of rapamycin (mTOR)-directed inhibitor - Patients with a known hypersensitivity of BKM120 or to its excipients - Patients with anaplastic lymphoma kinase (ALK) rearrangement or an activating epidermal growth factor receptor (EGFR) mutation who have not received and progressed on appropriate tyrosine kinase inhibitor therapy - Patients with untreated brain metastases are excluded; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial, if the patient is > 2 weeks from therapy completion (incl. --- P13K ---

age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL (for United States [US] only: and estradiol < 20 pg/mL) or have had surgical bilateral oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential - Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during treatment for 5 T1/2 (8 days) after stopping treatment and for additional 12 weeks (3 months in total after study drug discontinuation); the highly effective contraception is defined as either: - True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male should be the sole partner for that patient - Use of a combination of any two of the following (a + b): - a) Placement of an intrauterine device (IUD) or intrauterine system (IUS) - b) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - Oral contraception, injected or implanted hormonal methods are not allowed - Fertile males, defined as all males physiologically capable of conceiving offspring, must use a condom during treatment, for 5 T1/2 (8 days) after stopping treatment and for an additional 12 weeks (3 months in total after study drug discontinuation) and should not father a child in this period - Known diagnosis of human immunodeficiency virus (HIV) infection - History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix - Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator - Patient has acute viral hepatitis or a history of chronic or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, (typically defined by elevated AST/ALT [persistent or intermittent], high HBV deoxyribonucleic acid [DNA] level hepatitis B virus surface protein antigen [HBsAg] positive, or high HCV ribonucleic acid [RNA] level) (testing not mandatory) Inclusion Criteria: - Patients who have signed a written informed consent - Patients must have a histologic or cytologic diagnosis of advanced, nonsquamous NSCLC (stage IV by American Joint Committee on Cancer [AJCC] 7th edition [ed.]) - Patients should not have received prior systemic chemotherapy for metastatic disease (prior epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], kinase inhibitor therapy is allowed); prior adjuvant or neoadjuvant therapy for early stage disease is allowed if received >= 12 months prior to study entry - Prior radiation therapy is allowed to < 25% of the bone marrow; prior radiation must be completed at least 2 weeks prior to day 1 of cycle 1, and patients must have recovered from the acute toxic effects - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 - Patients must have at least one site of measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Platelets >= 100 x 10^9/L - Hemoglobin (Hb) > 9 g/dL - Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed) - Magnesium >= the lower limit of normal (LLN) - Potassium within normal limits for the institution - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or =< 3 x upper limit of normal [ULN] if liver metastases are present) - Serum bilirubin within normal range (or =< 1.5 x ULN if liver metastases are present) - Serum creatinine =< 1.5 x ULN or calculated or 24-hour clearance >= 45 mL/min (calculated creatinine clearance based on Cockcroft-Gault formula) - Serum phosphorus >= LLN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - Negative serum pregnancy test within 72 hours before starting study treatment in women with childbearing potential - International normalized ratio (INR) =< 2 Exclusion Criteria: - Patients who have received prior treatment with a P13K inhibitor or mammalian target of rapamycin (mTOR)-directed inhibitor - Patients with a known hypersensitivity of BKM120 or to its excipients - Patients with anaplastic lymphoma kinase (ALK) rearrangement or an activating epidermal growth factor receptor (EGFR) mutation who have not received and progressed on appropriate tyrosine kinase inhibitor therapy - Patients with untreated brain metastases are excluded; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial, if the patient is > 2 weeks from therapy completion (incl. --- P13K ---

Primary Outcomes

Measure: Maximum tolerated dose, defined as the highest dose in which fewer than 33% of study participants experience a dose limiting toxicity (DLT), graded according to the National Cancer Institute (NCI) CTCAE version 4.0

Time: 21 days

Description: Tables will be created to summarize all toxicities and side effects by dose, course, organ, and severity.

Measure: Toxicity profile of PI3K inhibitor BKM120, assessed using NCI CTCAE version 4.0

Time: Up to 28 days after completion of study treatment

Secondary Outcomes

Description: Means and 95% confidence intervals will be provided for the PK parameters.

Measure: Pharmacokinetic (PK) parameters of PI3K inhibitor BKM120, carboplatin, and pemetrexed disodium in combination

Time: Days 1 and 8 of course 1

Description: Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.

Measure: Anti-tumor activity (complete response [CR] + partial response [PR]), assessed using RECIST

Time: Up to 28 days after completion of study treatment

Description: Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.

Measure: Disease control rate (CR + PR + stable disease [SD]), assessed using RECIST

Time: Up to 28 days after completion of study treatment

Description: Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.

Measure: Progression free survival

Time: 6 months

Description: Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.

Measure: Overall survival

Time: 1 year

26 A Phase I Trial of BKM120 in Combination With Weekly Nabpaclitaxel (Abraxane®) in Patients With Advanced Solid Tumors Followed by a Dose Expansion Phase in Patients With Recurrent Endometrial or Recurrent Ovarian Cancer

The purpose of the first part of this study or the dose escalation portion of the study is to determine what dose of BKM120 and Abraxane is safe to give when the two drugs are used at the same time in patients who are diagnosed with a solid cancer. A solid cancer is a cancer that does not involve the blood, bone marrow or lymph nodes. Dose escalation determines the least toxic and most effect dose of this drug combination for treatment. Once this dose is established, it will be used for the dose expansion phase of the study where we will determine the effect of BKM120 and Abraxane in women diagnosed with a recurrent endometrial or ovarian cancer. We will see whether the combination of both drugs improves the response and survival of patients treated on the two drug regimen. Also we will try to find out whether there are changes in tumors that can help us determine what patients are more likely to respond to BKM120 and Abraxane.

NCT02117817
Conditions
  1. Ovarian Cancer
  2. Endometrial Cancer
  3. Recurrent Ovarian Cancer
  4. Recurrent Endometrial Cancer
Interventions
  1. Drug: BKM120
  2. Drug: Nabpaclitaxel
MeSH:Ovarian Neoplasms Carcinoma, Ovarian Epithelial Endometrial Neoplasms
HPO:Endometrial carcinoma Ovarian neoplasm

- Ability to sign informed consent - INR ≤ 1.5 Exclusion Criteria: - Patients who have received prior treatment with a P13K inhibitor. --- P13K ---

Primary Outcomes

Measure: Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Time: 2 years

Secondary Outcomes

Measure: Response rate (at the end of the 3 months of therapy)

Time: 2 years

Measure: Time to progressive disease

Time: 2 years

27 A Phase Ib Study of BKM120 With Weekly Cisplatin and Radiotherapy in High Risk Locally Advanced Squamous Cell Cancer of the Head and Neck

This research study is evaluating a drug called buparlisib (BKM120) as a possible treatment for locally advanced head and neck squamous cell cancer.

NCT02113878
Conditions
  1. Carcinoma, Squamous Cell of Head and Neck
  2. HPV Positive Oropharyngeal Squamous Cell Carcinoma
  3. Hypopharyngeal Cancer
  4. Early Invasive Cervical Squamous Cell Carcinoma
  5. Carcinoma of Larynx
  6. Cancer of Nasopharynx
Interventions
  1. Drug: BKM120
  2. Drug: Cisplatin
  3. Radiation: Intensity-modulated radiotherapy (IMRT)
MeSH:Carcinoma Carcinoma, Squamous Cell Neoplasms, Squamous Cell Hypopharyngeal Neoplasms Squamous Cell Carcinoma of Head and Neck Nasopharyngeal Neoplasms Nasopharyngeal Carcinoma
HPO:Carcinoma Neoplasia of the nasopharynx Squamous cell carcinoma

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range - Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) - Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min - Serum amylase ≤ ULN - Serum lipase ≤ ULN - Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) - Signed informed consent - INR ≤ 2 Exclusion Criteria: - Distant metastatic disease - Less than or equal to 10 pack years of tobacco history - Received prior chemotherapy - Received prior radiation to the head and neck or adjacent anatomical site - Received prior treatment with a P13K inhibitor. --- P13K ---

Primary Outcomes

Description: Determine Maximum Tolerated Dose (MTD) of BKM120/cisplatin in combination with radiation therapy in patients with locally advanced squamous cell cancer of the head and neck.

Measure: Determine Maximum Tolerated Dose (MTD) of BKM120/cisplatin combination with radiation therapy

Time: 2 Years

Secondary Outcomes

Measure: Overall Response Rate

Time: 2 Years

Measure: Time to Progression

Time: 2 Years

Measure: Survival

Time: 2 years

Measure: Mood alteration from BKM120

Time: 2 Years

Measure: Activity of BKM120 as single agent in sequential biopsies

Time: 2 Years

28 A Phase 2 Study of Trastuzumab in Combination With BMS-247550 in Women With Metastatic Breast Cancer

This phase II trial is studying how well giving trastuzumab together with ixabepilone works in treating women with HER2-positive metastatic breast cancer. Monoclonal antibodies, such as trastuzumab, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as ixabepilone, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining trastuzumab with ixabepilone may kill more tumor cells.

NCT00079326
Conditions
  1. HER2-positive Breast Cancer
  2. Recurrent Breast Cancer
  3. Stage IV Breast Cancer
Interventions
  1. Biological: trastuzumab
  2. Drug: ixabepilone
  3. Other: laboratory biomarker analysis
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

HER2/phospho-HER2, EGFR/phospho-EGFR, IGRF-I, phospho-MAPK, phospho-P13K, bcl-2, bcl-xL, MDR-1, MRP and β-tubulin) and blood biomarkers (HER2-extracellular domain [ECD], circulating tumor cells) to correlate them with response to treatment. --- P13K ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by computed tomography or magnetic resonance imaging scans: Complete response (CR) is defined as the disappearance of all target lesions; Partial Response is defined by at least a 30% decrease in the sum of the longest diameter of target lesions; Overall Response Rate (ORR) = CR + PR.

Measure: Overall Response Rate

Time: Up to 6 years

Secondary Outcomes

Description: Time to Treatment Failure as determined by RECIST v.1.0 Criteria: is the time from the date of randomization or start of treatment to the earliest date of progression, date of death due to any cause, or date of discontinuation due to reasons of adverse events, abnormal laboratory values, abnormal test procedure results, subject withdraws consent, or date 'Lost to follow up'.

Measure: Time to Treatment Failure (TTF)

Time: up to 6 years

29 A Pilot Study of the PI3K Inhibitor BKM120 in Patients With Relapsed Lymphoma

This pilot clinical trial studies how well buparlisib works in treating patients with non-Hodgkin lymphoma that has returned after a period of improvement or has not responded to previous treatment. Buparlisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

NCT01719250
Conditions
  1. Recurrent Adult Diffuse Large Cell Lymphoma
  2. Recurrent Grade 3 Follicular Lymphoma
  3. Recurrent Mantle Cell Lymphoma
  4. Refractory Mantle Cell Lymphoma
  5. Transformed Recurrent Non-Hodgkin Lymphoma
Interventions
  1. Drug: Buparlisib
  2. Other: Laboratory Biomarker Analysis
  3. Other: Questionnaire Administration
MeSH:Lymphoma Lymphoma, Non-Hodgkin Lymphoma, Mantle-Cell Lymphoma, Large B-Cell, Diffuse
HPO:Lymphoma Non-Hodgkin lymphoma

Will be estimated using the method of Kaplan-Meier.. Inclusion Criteria: - Biopsy-proven relapsed, refractory or residual aggressive B-cell non-Hodgkin lymphoma; NOTE: re-biopsy is necessary unless the patient has had a previous biopsy < 168 days prior to registration on this protocol and there has been no intervening treatment; eligible tumor types are diffuse large B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma, transformed NHL, and follicular grade III - Not a candidate or has declined standard salvage therapy for their disease - Measurable disease as defined by at least ONE of the following: - Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) or the CT portion of the positron emission tomography (PET)/CT: must have at least one lesion that has a single diameter of >= 2 cm or tumor cells in the blood >= 5 x 10^9/L - Skin lesions can be used if the area is >= 2 cm in at least one diameter and photographed with a ruler - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 - Absolute neutrophil count (ANC) >= 1000/uL - Hemoglobin (Hgb) >= 9 g/dl - Platelets (PLT) >= 100,000/uL - Serum bilirubin within normal range (or =< 1.5 x upper limit of normal [ULN] if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert syndrome) - Aspartate aminotransferase (AST) within normal limits or =< 3 x ULN if due to lymphoma - Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 mL/min - Magnesium >= lower limit of normal (LLN) - Potassium >= LLN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - Serum calcium =< 10.9 mg/dL - Negative pregnancy test done =< 72 hours prior to starting drug, for women of childbearing potential only - Provide informed written consent - Willing to return to Mayo Clinic Rochester for follow-up - Willing to provide blood samples for correlative research purposes - Willingness to take BKM120 orally Exclusion Criteria: - Any of the following: - Pregnant women - Nursing women - Women of childbearing potential who are unwilling to employ highly effective contraception during dosing with BKM120 and for 4 weeks after the final dose of treatment; NOTE: women of childbearing potential are defined as all women physiologically capable of becoming pregnant - Men of childbearing potential who are unwilling to employ highly effective contraception during dosing with BKM120 and for 16 weeks after the final dose of treatment and should not a father a child during this time; NOTE: men of childbearing potential are defined as all males physiologically capable of conceiving offspring - NOTE: the highly effective contraception is defined as either: - True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient - Use of a combination of any two of the following (a+b): 1. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 2. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - Oral contraception, injected or implanted hormonal methods are not allowed - Uncontrolled infection - Average baseline of >= 4 stools per day - Therapy with myelosuppressive chemotherapy or biologic therapy < 21 days prior to registration unless the patient has recovered from the nadir of the previous treatment to a level that meets the inclusion eligibility criteria of this protocol - Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) =< 5 effective half-lives prior to registration or who have not recovered from side effects of such therapy - Received wide field radiotherapy =< 28 days or limited field radiation for palliation =< 14 days prior to registration or who have not recovered from side effects of such therapy - Receiving corticosteroids > 10 mg of prednisone per day (or equivalent); NOTE: patients may be receiving stable doses of corticosteroids with a maximum dose of 10 mg of prednisone per day if they are being given for disorders other than lymphoma such as rheumatoid arthritis, polymyalgia rheumatica or adrenal insufficiency, or asthma - Persistent toxicities >= grade 2 from prior chemotherapy or biological therapy regardless of interval since last treatment - Active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 45% as determined by multi gated acquisition (MUGA) scan or echocardiogram (ECHO) - Fridericia's corrected QT interval (QTcF) > 450 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Unstable angina pectoris; patients with unstable angina should have angina controlled before entering the study - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Symptomatic pericarditis - Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification III-IV) - Documented cardiomyopathy - Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) - Known positivity for human immunodeficiency virus (HIV); note: baseline testing for HIV is not required - Active hepatitis B or C with uncontrolled disease; note: a detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients; hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior hepatitis B virus (HBV) infection - Other active malignancy requiring treatment that would interfere with the assessments of response of the lymphoma to protocol treatment - Inability to swallow or impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) that would preclude use of oral medications - Any severe and/or uncontrolled medical conditions such as diabetes, poor lung function, or other conditions that, in the treating physician's opinion, could adversely impact their ability to participate in the study - Patients who have received prior treatment with a P13K inhibitor; patients with prior mammalian target of rapamycin (mTOR) inhibitor therapy are eligible - Using medications that have a strong risk of prolonging the QT interval or inducing torsades de pointes - Major surgery =< 14 days prior to registration or have not recovered from side effects of such therapy - Currently being treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5), (please note that co-treatment with weak inhibitors of cytochrome P450, family 3, subfamily A [CYP3A] is allowed) - Receiving certain fruits or herbal preparations/medications including, but are not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng; fruits include the CYP3A inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits; NOTE: patients should stop using these fruits and herbal medications 7 days prior to first dose of study drug - Primary central nervous system (CNS) lymphoma or active metastases to the CNS; NOTE: active is defined as requiring therapy such as surgery, radiation, or chemotherapy =< 28 days of study registration or ongoing corticosteroid therapy for CNS disease - The following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire: - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - >= Common Terminology Criteria of Adverse Events (CTCAE) grade 3 anxiety - Meets the cut-off score of >= 12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of >= 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF]) =< 2 weeks prior to study registration; NOTE: erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to study registration, may be continued Inclusion Criteria: - Biopsy-proven relapsed, refractory or residual aggressive B-cell non-Hodgkin lymphoma; NOTE: re-biopsy is necessary unless the patient has had a previous biopsy < 168 days prior to registration on this protocol and there has been no intervening treatment; eligible tumor types are diffuse large B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma, transformed NHL, and follicular grade III - Not a candidate or has declined standard salvage therapy for their disease - Measurable disease as defined by at least ONE of the following: - Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) or the CT portion of the positron emission tomography (PET)/CT: must have at least one lesion that has a single diameter of >= 2 cm or tumor cells in the blood >= 5 x 10^9/L - Skin lesions can be used if the area is >= 2 cm in at least one diameter and photographed with a ruler - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 - Absolute neutrophil count (ANC) >= 1000/uL - Hemoglobin (Hgb) >= 9 g/dl - Platelets (PLT) >= 100,000/uL - Serum bilirubin within normal range (or =< 1.5 x upper limit of normal [ULN] if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert syndrome) - Aspartate aminotransferase (AST) within normal limits or =< 3 x ULN if due to lymphoma - Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 mL/min - Magnesium >= lower limit of normal (LLN) - Potassium >= LLN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - Serum calcium =< 10.9 mg/dL - Negative pregnancy test done =< 72 hours prior to starting drug, for women of childbearing potential only - Provide informed written consent - Willing to return to Mayo Clinic Rochester for follow-up - Willing to provide blood samples for correlative research purposes - Willingness to take BKM120 orally Exclusion Criteria: - Any of the following: - Pregnant women - Nursing women - Women of childbearing potential who are unwilling to employ highly effective contraception during dosing with BKM120 and for 4 weeks after the final dose of treatment; NOTE: women of childbearing potential are defined as all women physiologically capable of becoming pregnant - Men of childbearing potential who are unwilling to employ highly effective contraception during dosing with BKM120 and for 16 weeks after the final dose of treatment and should not a father a child during this time; NOTE: men of childbearing potential are defined as all males physiologically capable of conceiving offspring - NOTE: the highly effective contraception is defined as either: - True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient - Use of a combination of any two of the following (a+b): 1. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 2. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - Oral contraception, injected or implanted hormonal methods are not allowed - Uncontrolled infection - Average baseline of >= 4 stools per day - Therapy with myelosuppressive chemotherapy or biologic therapy < 21 days prior to registration unless the patient has recovered from the nadir of the previous treatment to a level that meets the inclusion eligibility criteria of this protocol - Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) =< 5 effective half-lives prior to registration or who have not recovered from side effects of such therapy - Received wide field radiotherapy =< 28 days or limited field radiation for palliation =< 14 days prior to registration or who have not recovered from side effects of such therapy - Receiving corticosteroids > 10 mg of prednisone per day (or equivalent); NOTE: patients may be receiving stable doses of corticosteroids with a maximum dose of 10 mg of prednisone per day if they are being given for disorders other than lymphoma such as rheumatoid arthritis, polymyalgia rheumatica or adrenal insufficiency, or asthma - Persistent toxicities >= grade 2 from prior chemotherapy or biological therapy regardless of interval since last treatment - Active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 45% as determined by multi gated acquisition (MUGA) scan or echocardiogram (ECHO) - Fridericia's corrected QT interval (QTcF) > 450 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Unstable angina pectoris; patients with unstable angina should have angina controlled before entering the study - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Symptomatic pericarditis - Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification III-IV) - Documented cardiomyopathy - Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) - Known positivity for human immunodeficiency virus (HIV); note: baseline testing for HIV is not required - Active hepatitis B or C with uncontrolled disease; note: a detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients; hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior hepatitis B virus (HBV) infection - Other active malignancy requiring treatment that would interfere with the assessments of response of the lymphoma to protocol treatment - Inability to swallow or impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) that would preclude use of oral medications - Any severe and/or uncontrolled medical conditions such as diabetes, poor lung function, or other conditions that, in the treating physician's opinion, could adversely impact their ability to participate in the study - Patients who have received prior treatment with a P13K inhibitor; patients with prior mammalian target of rapamycin (mTOR) inhibitor therapy are eligible - Using medications that have a strong risk of prolonging the QT interval or inducing torsades de pointes - Major surgery =< 14 days prior to registration or have not recovered from side effects of such therapy - Currently being treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5), (please note that co-treatment with weak inhibitors of cytochrome P450, family 3, subfamily A [CYP3A] is allowed) - Receiving certain fruits or herbal preparations/medications including, but are not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng; fruits include the CYP3A inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits; NOTE: patients should stop using these fruits and herbal medications 7 days prior to first dose of study drug - Primary central nervous system (CNS) lymphoma or active metastases to the CNS; NOTE: active is defined as requiring therapy such as surgery, radiation, or chemotherapy =< 28 days of study registration or ongoing corticosteroid therapy for CNS disease - The following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire: - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - >= Common Terminology Criteria of Adverse Events (CTCAE) grade 3 anxiety - Meets the cut-off score of >= 12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of >= 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF]) =< 2 weeks prior to study registration; NOTE: erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to study registration, may be continued Recurrent Adult Diffuse Large Cell Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Mantle Cell Lymphoma Refractory Mantle Cell Lymphoma Transformed Recurrent Non-Hodgkin Lymphoma Lymphoma Lymphoma, Non-Hodgkin Lymphoma, Mantle-Cell Lymphoma, Large B-Cell, Diffuse PRIMARY OBJECTIVES: I. To evaluate the clinical benefit rate (complete response [CR], partial response [PR] or standard disease [SD] >= 6 months) with BKM120 (buparlisib) in patients with relapsed or refractory lymphoma. --- P13K ---

Will be estimated using the method of Kaplan-Meier.. Inclusion Criteria: - Biopsy-proven relapsed, refractory or residual aggressive B-cell non-Hodgkin lymphoma; NOTE: re-biopsy is necessary unless the patient has had a previous biopsy < 168 days prior to registration on this protocol and there has been no intervening treatment; eligible tumor types are diffuse large B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma, transformed NHL, and follicular grade III - Not a candidate or has declined standard salvage therapy for their disease - Measurable disease as defined by at least ONE of the following: - Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) or the CT portion of the positron emission tomography (PET)/CT: must have at least one lesion that has a single diameter of >= 2 cm or tumor cells in the blood >= 5 x 10^9/L - Skin lesions can be used if the area is >= 2 cm in at least one diameter and photographed with a ruler - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 - Absolute neutrophil count (ANC) >= 1000/uL - Hemoglobin (Hgb) >= 9 g/dl - Platelets (PLT) >= 100,000/uL - Serum bilirubin within normal range (or =< 1.5 x upper limit of normal [ULN] if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert syndrome) - Aspartate aminotransferase (AST) within normal limits or =< 3 x ULN if due to lymphoma - Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 mL/min - Magnesium >= lower limit of normal (LLN) - Potassium >= LLN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - Serum calcium =< 10.9 mg/dL - Negative pregnancy test done =< 72 hours prior to starting drug, for women of childbearing potential only - Provide informed written consent - Willing to return to Mayo Clinic Rochester for follow-up - Willing to provide blood samples for correlative research purposes - Willingness to take BKM120 orally Exclusion Criteria: - Any of the following: - Pregnant women - Nursing women - Women of childbearing potential who are unwilling to employ highly effective contraception during dosing with BKM120 and for 4 weeks after the final dose of treatment; NOTE: women of childbearing potential are defined as all women physiologically capable of becoming pregnant - Men of childbearing potential who are unwilling to employ highly effective contraception during dosing with BKM120 and for 16 weeks after the final dose of treatment and should not a father a child during this time; NOTE: men of childbearing potential are defined as all males physiologically capable of conceiving offspring - NOTE: the highly effective contraception is defined as either: - True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient - Use of a combination of any two of the following (a+b): 1. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 2. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - Oral contraception, injected or implanted hormonal methods are not allowed - Uncontrolled infection - Average baseline of >= 4 stools per day - Therapy with myelosuppressive chemotherapy or biologic therapy < 21 days prior to registration unless the patient has recovered from the nadir of the previous treatment to a level that meets the inclusion eligibility criteria of this protocol - Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) =< 5 effective half-lives prior to registration or who have not recovered from side effects of such therapy - Received wide field radiotherapy =< 28 days or limited field radiation for palliation =< 14 days prior to registration or who have not recovered from side effects of such therapy - Receiving corticosteroids > 10 mg of prednisone per day (or equivalent); NOTE: patients may be receiving stable doses of corticosteroids with a maximum dose of 10 mg of prednisone per day if they are being given for disorders other than lymphoma such as rheumatoid arthritis, polymyalgia rheumatica or adrenal insufficiency, or asthma - Persistent toxicities >= grade 2 from prior chemotherapy or biological therapy regardless of interval since last treatment - Active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 45% as determined by multi gated acquisition (MUGA) scan or echocardiogram (ECHO) - Fridericia's corrected QT interval (QTcF) > 450 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Unstable angina pectoris; patients with unstable angina should have angina controlled before entering the study - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Symptomatic pericarditis - Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification III-IV) - Documented cardiomyopathy - Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) - Known positivity for human immunodeficiency virus (HIV); note: baseline testing for HIV is not required - Active hepatitis B or C with uncontrolled disease; note: a detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients; hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior hepatitis B virus (HBV) infection - Other active malignancy requiring treatment that would interfere with the assessments of response of the lymphoma to protocol treatment - Inability to swallow or impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) that would preclude use of oral medications - Any severe and/or uncontrolled medical conditions such as diabetes, poor lung function, or other conditions that, in the treating physician's opinion, could adversely impact their ability to participate in the study - Patients who have received prior treatment with a P13K inhibitor; patients with prior mammalian target of rapamycin (mTOR) inhibitor therapy are eligible - Using medications that have a strong risk of prolonging the QT interval or inducing torsades de pointes - Major surgery =< 14 days prior to registration or have not recovered from side effects of such therapy - Currently being treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5), (please note that co-treatment with weak inhibitors of cytochrome P450, family 3, subfamily A [CYP3A] is allowed) - Receiving certain fruits or herbal preparations/medications including, but are not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng; fruits include the CYP3A inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits; NOTE: patients should stop using these fruits and herbal medications 7 days prior to first dose of study drug - Primary central nervous system (CNS) lymphoma or active metastases to the CNS; NOTE: active is defined as requiring therapy such as surgery, radiation, or chemotherapy =< 28 days of study registration or ongoing corticosteroid therapy for CNS disease - The following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire: - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - >= Common Terminology Criteria of Adverse Events (CTCAE) grade 3 anxiety - Meets the cut-off score of >= 12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of >= 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF]) =< 2 weeks prior to study registration; NOTE: erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to study registration, may be continued Inclusion Criteria: - Biopsy-proven relapsed, refractory or residual aggressive B-cell non-Hodgkin lymphoma; NOTE: re-biopsy is necessary unless the patient has had a previous biopsy < 168 days prior to registration on this protocol and there has been no intervening treatment; eligible tumor types are diffuse large B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma, transformed NHL, and follicular grade III - Not a candidate or has declined standard salvage therapy for their disease - Measurable disease as defined by at least ONE of the following: - Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) or the CT portion of the positron emission tomography (PET)/CT: must have at least one lesion that has a single diameter of >= 2 cm or tumor cells in the blood >= 5 x 10^9/L - Skin lesions can be used if the area is >= 2 cm in at least one diameter and photographed with a ruler - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 - Absolute neutrophil count (ANC) >= 1000/uL - Hemoglobin (Hgb) >= 9 g/dl - Platelets (PLT) >= 100,000/uL - Serum bilirubin within normal range (or =< 1.5 x upper limit of normal [ULN] if liver metastases are present; or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert syndrome) - Aspartate aminotransferase (AST) within normal limits or =< 3 x ULN if due to lymphoma - Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 mL/min - Magnesium >= lower limit of normal (LLN) - Potassium >= LLN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting plasma glucose =< 120 mg/dL (6.7 mmol/L) - Serum calcium =< 10.9 mg/dL - Negative pregnancy test done =< 72 hours prior to starting drug, for women of childbearing potential only - Provide informed written consent - Willing to return to Mayo Clinic Rochester for follow-up - Willing to provide blood samples for correlative research purposes - Willingness to take BKM120 orally Exclusion Criteria: - Any of the following: - Pregnant women - Nursing women - Women of childbearing potential who are unwilling to employ highly effective contraception during dosing with BKM120 and for 4 weeks after the final dose of treatment; NOTE: women of childbearing potential are defined as all women physiologically capable of becoming pregnant - Men of childbearing potential who are unwilling to employ highly effective contraception during dosing with BKM120 and for 16 weeks after the final dose of treatment and should not a father a child during this time; NOTE: men of childbearing potential are defined as all males physiologically capable of conceiving offspring - NOTE: the highly effective contraception is defined as either: - True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient - Use of a combination of any two of the following (a+b): 1. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 2. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - Oral contraception, injected or implanted hormonal methods are not allowed - Uncontrolled infection - Average baseline of >= 4 stools per day - Therapy with myelosuppressive chemotherapy or biologic therapy < 21 days prior to registration unless the patient has recovered from the nadir of the previous treatment to a level that meets the inclusion eligibility criteria of this protocol - Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) =< 5 effective half-lives prior to registration or who have not recovered from side effects of such therapy - Received wide field radiotherapy =< 28 days or limited field radiation for palliation =< 14 days prior to registration or who have not recovered from side effects of such therapy - Receiving corticosteroids > 10 mg of prednisone per day (or equivalent); NOTE: patients may be receiving stable doses of corticosteroids with a maximum dose of 10 mg of prednisone per day if they are being given for disorders other than lymphoma such as rheumatoid arthritis, polymyalgia rheumatica or adrenal insufficiency, or asthma - Persistent toxicities >= grade 2 from prior chemotherapy or biological therapy regardless of interval since last treatment - Active cardiac disease including any of the following: - Left ventricular ejection fraction (LVEF) < 45% as determined by multi gated acquisition (MUGA) scan or echocardiogram (ECHO) - Fridericia's corrected QT interval (QTcF) > 450 msec on screening electrocardiogram (ECG) (using the QTcF formula) - Unstable angina pectoris; patients with unstable angina should have angina controlled before entering the study - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Symptomatic pericarditis - Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification III-IV) - Documented cardiomyopathy - Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) - Known positivity for human immunodeficiency virus (HIV); note: baseline testing for HIV is not required - Active hepatitis B or C with uncontrolled disease; note: a detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients; hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior hepatitis B virus (HBV) infection - Other active malignancy requiring treatment that would interfere with the assessments of response of the lymphoma to protocol treatment - Inability to swallow or impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) that would preclude use of oral medications - Any severe and/or uncontrolled medical conditions such as diabetes, poor lung function, or other conditions that, in the treating physician's opinion, could adversely impact their ability to participate in the study - Patients who have received prior treatment with a P13K inhibitor; patients with prior mammalian target of rapamycin (mTOR) inhibitor therapy are eligible - Using medications that have a strong risk of prolonging the QT interval or inducing torsades de pointes - Major surgery =< 14 days prior to registration or have not recovered from side effects of such therapy - Currently being treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5), (please note that co-treatment with weak inhibitors of cytochrome P450, family 3, subfamily A [CYP3A] is allowed) - Receiving certain fruits or herbal preparations/medications including, but are not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng; fruits include the CYP3A inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits; NOTE: patients should stop using these fruits and herbal medications 7 days prior to first dose of study drug - Primary central nervous system (CNS) lymphoma or active metastases to the CNS; NOTE: active is defined as requiring therapy such as surgery, radiation, or chemotherapy =< 28 days of study registration or ongoing corticosteroid therapy for CNS disease - The following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire: - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - >= Common Terminology Criteria of Adverse Events (CTCAE) grade 3 anxiety - Meets the cut-off score of >= 12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of >= 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) - Treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF]) =< 2 weeks prior to study registration; NOTE: erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to study registration, may be continued Recurrent Adult Diffuse Large Cell Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Mantle Cell Lymphoma Refractory Mantle Cell Lymphoma Transformed Recurrent Non-Hodgkin Lymphoma Lymphoma Lymphoma, Non-Hodgkin Lymphoma, Mantle-Cell Lymphoma, Large B-Cell, Diffuse PRIMARY OBJECTIVES: I. To evaluate the clinical benefit rate (complete response [CR], partial response [PR] or standard disease [SD] >= 6 months) with BKM120 (buparlisib) in patients with relapsed or refractory lymphoma. --- P13K --- --- P13K ---

Primary Outcomes

Description: The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent binomial confidence intervals for the true success proportion will be calculated.

Measure: Clinical benefit defined as a PR or CR as the objective status at any time or an objective status of SD for a duration of greater than 6 months from registration

Time: From 6 months from registration up to 1 year

Secondary Outcomes

Description: If an adequate number of events are seen, the distribution of duration of response will be estimated using the method of Kaplan-Meier. Otherwise, duration of response will be summarized descriptively.

Measure: Duration of response

Time: From the date at which the patient's objective status is first noted to be a CR or PR to the earliest date progression is documented, assessed up to 1 year

Description: Exact binomial 95% confidence intervals for the true overall response rate will be calculated.

Measure: Overall response rate estimated by the number of confirmed responses (PR or CR) observed in the trial divided by the total number of evaluable patients

Time: Up to 1 year

Description: Will be summarized and used to help characterize the types of patients accrued to this trial. These classifications will be correlated with clinical benefit using Fisher's exact or Wilcoxon rank sum tests.

Measure: Prognostic factors for aggressive lymphoma

Time: Up to 1 year

Description: Will be estimated using the method of Kaplan-Meier.

Measure: Progression-free survival time

Time: Time from registration to progression or death due to any cause, assessed up to 1 year

Description: Will be estimated using the method of Kaplan-Meier.

Measure: Survival time

Time: Time from registration to death due to any cause, assessed up to 1 year

30 A Phase 1b Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GS-9820 in Subjects With Lymphoid Malignancies

This study is to determine the appropriate dosing regimen of GS-9820 in subjects with lymphoid malignancies. This is a Phase 1b, open-label, dose-escalation and expansion study evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of GS-9820.

NCT01705847
Conditions
  1. Lymphoid Malignancies
Interventions
  1. Drug: GS-9820
MeSH:Neoplasms
HPO:Neoplasm

Pharmacodynamics to measure changes in the phosphatidylinositol 3-kinase (P13K) delta pathway activation and changes in plasma concentration of disease-associated chemokines and cytokines. --- P13K ---

Primary Outcomes

Description: MTD will be assessed to determine the appropriate dosing regimens for use in future clinical trials of GS-9820 in subjects with lymphoid malignancies.

Measure: Maximum tolerated dose (MTD)

Time: Up to 4 weeks

Secondary Outcomes

Description: Overall safety will be assessed by overall safety profile, enumeration and description of any dose-limiting toxicities, serious adverse events, or adverse events leading to discontinuation of study drug.

Measure: Overall safety

Time: Up to 5 years

Description: Cmax is defined as the maximum concentration of drug Tmax is defined as the time of Cmax Ctrough is defined as the trough concentration AUC is defined as the area under the plasma concentration versus time curve

Measure: Pharmacokinetic parameters of GS-9820 as measured by Cmax, Tmax, Ctrough, and AUC

Time: Baseline to Day 29

Measure: Pharmacodynamics to measure changes in the phosphatidylinositol 3-kinase (P13K) delta pathway activation and changes in plasma concentration of disease-associated chemokines and cytokines

Time: Baseline to Day 29

Description: Tumor control as assessed by overall response rate (ORR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), percent change in lymph node area, lymph node response rate, splenomegaly response rate, ALC response rate, hepatomegaly response rate, platelet response rate, hemoglobin response rate, and neutrophil response rate.

Measure: Tumor control

Time: Up to 5 years

Measure: Patient well-being assessed using changes in baseline in HRQL (health related quality of life questionnaire) domain and symptom scores based on the Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym)

Time: Up to 5 years

Description: Drug administration for GS-9820 as assessed by prescribing records and GS-9820 compliance as assessed by quantification of used and unused drug.

Measure: Drug exposure

Time: Up to 5 years

31 Window of Opportunity Study of Parsaclisib in Subjects With Newly Diagnosed Stage I-IIIC Triple-Negative or HER2-Positive Breast Cancer

The purpose of this research study is to find the lowest dose of the cancer drug parsaclisib that has an effect on the type of breast cancer a participant has. Researchers are looking at how Parsaclisib affects the immune system. They want to learn whether and how it helps the immune system to find cancer cells to fight them. Parsaclisib is an oral drug that limits the effects of a protein called phosphatidylinositol 3-kinase δ (PI3K). By limiting P13K, parsaclisib can block certain cells that prevent the immune cells from working. As a result, it may help the body's immune system to fight tumors. Parsaclisib is being studied in several clinical trials to treat different types of cancers. Parsaclisib has not yet been approved by FDA for the treatment of cancer. Studies have shown that a good way to find out how cancer acts when exposed to anti-cancer drugs is through a pre-operative window study. In this type of study, tissue and blood are collected before treatment. Then subjects receive a study drug for a few weeks before surgery. Blood is drawn during the course of treatment, and leftover tissue is collected during surgery. Comparing the tissue and blood before and after treatment shows the effects the study drug may have had on the tumor. Research shows that cancers differ when you look at the DNA and RNA (genetic codes) that are inside a cancer cell. DNA and RNA carry genetic information that can determine traits in humans (such as eye color, height, reaction to treatment, etc.), as well as the traits of cancer cells. Depending on the genetic profile (particularly DNA and RNA) of the cancer, it may respond differently to parsaclisib. In this study, the investigators will look at the genetic profile of a participant's tumor by studying tissue and blood samples collected before and after receiving treatment.

NCT04142554
Conditions
  1. Breast Cancer
  2. Breast Neoplasms
  3. Triple Negative Breast Cancer
  4. HER2-positive Breast Cancer
Interventions
  1. Drug: Parsaclisib
MeSH:Breast Neoplasms Triple Negative Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

By limiting P13K, parsaclisib can block certain cells that prevent the immune cells from working. --- P13K ---

Primary Outcomes

Description: To determine the minimum dose of parsaclisib, administered once daily for 14 consecutive days, needed in subjects with triple-negative or human epidermal growth factor receptor 2 (HER2) positive breast cancer to result in either a 50% increase in the intratumoral cluster of differentiation 8 (CD8+) Thymus (T) cells/regulatory T cell ratio or a 50% decrease in the percentage of intratumoral regulatory T cells as measured using single cell transcriptomics and/or flow cytometry.

Measure: Minimum effective dose of parsaclisib

Time: At time of surgery (2 weeks after start of parsaclisib)

Secondary Outcomes

Description: To determine the minimum dose of parsaclisib, administered once daily for 14 consecutive days, in subjects with triple-negative or HER2 positive breast cancer resulting in either a 50% increase in the peripheral blood CD8+ T cells/regulatory T-cell ratio or a 50% decrease in the percentage of peripheral blood regulatory T cells as measured using single cell transcriptomics and/or flow cytometry.

Measure: Minimum dose of parsaclisib needed to decrease peripheral blood regulatory T cells

Time: At time of surgery (2 weeks after start of parsaclisib)

Description: To identify changes in the regulatory T cell signature following treatment with parsaclisib in subjects with triple-negative or HER2-positive breast cancer. A regulatory T-cell gene signature expression score is defined as the average of upper quartile normalized and log2 transformed gene expression values of all genes belonging to that gene signature was calculated for each sample. Gene expression values will be determined via RNA-sequencing. A one-sided paired t-test will be used to test for significant pre-post reductions in signature values in each subject, reflecting a decrease in the abundance of intratumoral regulatory T cells.

Measure: Changes in regulatory T cell signature

Time: At time of surgery (2 weeks after start of parsaclisib)

Description: To identify changes in Ki-67 messenger Ribonucleic acid (mRNA) expression following treatment with parsaclisib in subjects with triple-negative or HER2-positive breast cancer. Ki-67 expression pre versus post treatment will be assessed using the average log2 fold change in gene expression between conditions.

Measure: Changes in Ki-67 mRNA expression

Time: At time of surgery (2 weeks after start of parsaclisib)

Description: The reduction in the regulatory T cell signature by dose of parsaclisib (10 mg, 3.0 mg or 1.0 mg) will be measured as Pre and post-treatment levels of regulatory T-cell total abundance (cell count) and relative abundance (percentage of all cells), and change in relative abundance (fold change in % abundance post vs pre-treatment)

Measure: Comparison of reduction in the regulatory T cell signature by dose of parsaclisib

Time: At time of surgery (2 weeks after start of parsaclisib)

32 A Phase I Study of the HER1, HER2 Dual Kinase Inhibitor, Lapatinib Plus the Proteosomal Inhibitor Bortezomib in Patients With Advanced Malignancies

This study is for patients with an advanced type of cancer for which no curative treatment exists. The purpose of this study is to test the safety and efficacy of the combination of the study drugs, lapatinib and bortezomib. Lapatinib is a drug that targets two proteins important for the growth of cancer cells known as HER1 (EGFR) and HER2. By inhibiting these proteins, lapatinib can inhibit cancer cell growth and even lead to their death. Lapatinib is an oral pill given by mouth once every day. Lapatinib is approved by the FDA for patients with breast cancer. Bortezomib is a drug that targets a part of cancer cells known as the proteosome. By inhibiting the proteosome, bortezomib can inhibit cancer cell growth and even lead to their death. Bortezomib is given intravenously, once a week, 2 out of every 3 weeks. Bortezomib is approved by the FDA for patients with multiple myeloma and mantle cell lymphoma. This research is being done because it is not known if the combination of lapatinib and bortezomib will work better than lapatinib or bortezomib alone, although in the lab and in animal studies the combination of the two drugs was much more effective than either drug alone. As part of this study biopsies will be taken of patients' tumors before any treatment, after starting lapatinib alone, and after receiving both lapatinib and bortezomib. Investigators want to study what markers inside tumors may relate to how well these two medications work. These biopsies are required as part of the study.

NCT01497626
Conditions
  1. Advanced Solid Tumors
Interventions
  1. Drug: Lapatinib and bortezomib
MeSH:Neoplasms
HPO:Neoplasm

To assess changes in the following in serial tumor samples: EGFR, HER2, HER3, AKT, Actin, ERK, GSK3a-beta, IGF-1R, MEK 1/2, mTOR, p70S6, P13K, PTEN, SHC Y317, NFKB, IKB, CFK4, CDK2, cyclin D1, cyclin A, Cyclin E, p15, p16, p21, p27, beta-catenin, and ras gene mutation. --- P13K ---

Primary Outcomes

Description: The highest dose at which Measure: Maximum tolerated dose

Time: 18 months

Secondary Outcomes

Description: Adverse events seen during the trial graded using CTCAE version 4

Measure: toxicity

Time: 18 months

Description: complete response and partial response measured by RECIST 1.1

Measure: Response rate

Time: 18 months

Description: stable disease after two cycles+ partial response + complete response as determined by RECIST 1.1 criteria

Measure: Disease control rate

Time: 2 months

Description: To assess changes in the following in serial tumor samples: EGFR, HER2, HER3, AKT, Actin, ERK, GSK3a-beta, IGF-1R, MEK 1/2, mTOR, p70S6, P13K, PTEN, SHC Y317, NFKB, IKB, CFK4, CDK2, cyclin D1, cyclin A, Cyclin E, p15, p16, p21, p27, beta-catenin, and ras gene mutation

Measure: Pharmacodynamics

Time: pre-treatment, after 1 week of therapy and adter 3 weeks of therapy

33 Phase II Multicenter Single-arm Study of BKM120 Plus Capecitabine for Breast Cancer Patients With Brain Metastases

This is a study to determine the safety and effectiveness of BKM120 plus capecitabine in breast cancer patients with brain metastases. Both capecitabine and BMK120 have previously shown activity in patients with breast cancer. Like capecitabine, BMK120 is also effective in crossing the blood brain barrier making it a preferred candidate for its evaluation in patients with metastatic breast cancer (MBC).

NCT02000882
Conditions
  1. Brain Metastases
  2. Breast Cancer
  3. Metastatic Breast Cancer
Interventions
  1. Drug: BKM120
  2. Drug: capecitabine
  3. Drug: Trastuzumab
MeSH:Breast Neoplasms Neoplasm Metastasis Brain Neoplasms
HPO:Brain neoplasm Breast carcinoma Neoplasm of the breast

Patient is able to swallow and retain oral medication 22. Signed most recent patient informed consent form 23. Signed Patient Authorization Form Exclusion Criteria: 1. Patient received prior treatment with a P13K inhibitor. --- P13K ---

Primary Outcomes

Description: To determine the clinical benefit rate (CBR) based on local investigator assessment associated with BKM120 once daily plus capecitabine (1000 mg/m2 PO BID 14 days on/7 days off) in patients with metastatic breast cancer with a brain metastasis at least 5mm in size following whole brain radiation therapy (WBRT) and that has not progressed following WBRT. An exploratory analysis will be conducted of patients enrolled on study who have evidence of disease progression following WBRT. Clinical benefit rate is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) in the CNS lasting at least 24 weeks based on local investigator assessment.

Measure: clinical benefit rate (CBR)

Time: until end of study (4 years)

Secondary Outcomes

Description: To assess ORR associated with BKM120 plus capecitabine in the central nervous system based on local investigator assessment

Measure: Objective Response Rate (ORR)

Time: until end of study (4 years)

Description: To assess median time to progression (TTP) associated with BKM120 plus capecitabine.

Measure: Median time to progression

Time: until end of study (4 years)

Description: To determine median overall survival (OS) associated with BKM120 plus capecitabine.

Measure: Median Overall Survival

Time: until end of study (4 years)

Description: To characterize the safety and tolerability of BKM120 plus capecitabine, with or without trastuzumab

Measure: Number of Adverse Events

Time: until end of study (4 years)

Description: To assess median time to deterioration of neurologic function based on answers to questionnaires.

Measure: Median time to deterioration of neurologic function

Time: until end of study (4 years)

34 A Phase II Study of Sunitinib or Temsirolimus in Patients With Advanced Rare Tumours

This research is being done because there is no treatment that will cure this type of cancer. Although some types of chemotherapy can cause this cancer to shrink for a time, better options are needed.

NCT01396408
Conditions
  1. Advanced Rare Tumours
Interventions
  1. Drug: Sunitinib
  2. Drug: Temsirolimus

Adverse events will be monitored on an ongoing basis by the central office and their frequencies reported annually at investigators' meetings.. Eligibility Criteria - ALL Patients Patients must have histologically or cytologically confirmed diagnosis of a rare tumour as follows: 1. Vascular sarcomas: Angiosarcoma, hemangiosarcoma, hemangiopericytoma, hemangioblastomas; 2. Clear cell carcinomas of the ovary, endometrium; 3. Medullary thyroid carcinoma; 4. Neuroendocrine tumours: paragangliomas and pheochromocytomas only; 5. Adrenocorticocarcinoma; 6. Thymic carcinoma; 7. Fibrolamellar hepatocellular carcinoma; 8. Exploratory genetic cohort for sunitinib: Rare tumours with somatic or germline mutations in sunitinib targets such as VEGFR, PDGFR, KIT, RET; 9. Exploratory genetic cohort for temsirolimus: Rare tumours arising from known or suspected germline mutations in mTOR pathway such as PTEN, TS1/2, LKB1, NF1/2 or somatic mutations in the mTOR pathway such as mutation or amplification of P13K or AKT; 10. --- P13K ---

rifampin phenytoin rifabutin St. John's wort carbamazepine efavirenz phenobarbital tipranavir Eligibility Criteria - ALL Patients Patients must have histologically or cytologically confirmed diagnosis of a rare tumour as follows: 1. Vascular sarcomas: Angiosarcoma, hemangiosarcoma, hemangiopericytoma, hemangioblastomas; 2. Clear cell carcinomas of the ovary, endometrium; 3. Medullary thyroid carcinoma; 4. Neuroendocrine tumours: paragangliomas and pheochromocytomas only; 5. Adrenocorticocarcinoma; 6. Thymic carcinoma; 7. Fibrolamellar hepatocellular carcinoma; 8. Exploratory genetic cohort for sunitinib: Rare tumours with somatic or germline mutations in sunitinib targets such as VEGFR, PDGFR, KIT, RET; 9. Exploratory genetic cohort for temsirolimus: Rare tumours arising from known or suspected germline mutations in mTOR pathway such as PTEN, TS1/2, LKB1, NF1/2 or somatic mutations in the mTOR pathway such as mutation or amplification of P13K or AKT; 10. --- P13K ---

Primary Outcomes

Description: Objective response as assessed by RECIST version 1.1 criteria as a 30% decrease in the sum of the longest diameters of the target lesions (partial response) maintained for at least 4 weeks, or complete disappearance of disease and cancer related symptoms (complete response), also maintained for at least 4 weeks. Early progression is defined as progressive disease at or prior to the first assessment. The 95% confidence interval for response rate will be calculated. The median and range of the duration of response will be assessed

Measure: Objective Response

Time: Every 4 weeks

Secondary Outcomes

Description: Response duration: median and range Time to progression: median, 95% confidence interval Progression free survival: median, 95% confidence interval Overall survival: median, 95% confidence interval Comparison of the time to first and second progression for patients who receive sunitinib and temsirolimus in sequence.

Measure: Efficacy Outcomes

Time: 48 months

Description: Primary tumour tissue specimens and baseline blood samples, will be obtained from all subjects prior to first dose for genetic analysis and other evaluation. In addition, optional for responding patients will be a fresh tumour biopsy at time of progression and also optional for patients entered in the second stage of accrual for any disease cohort will be fresh tumour biopsy at baseline.

Measure: Translational Research

Time: 48 months

Description: Adverse events will be monitored on an ongoing basis by the central office and their frequencies reported annually at investigators' meetings.

Measure: Safety Monitoring

Time: Daily up to an expected average of 4 weeks after treatment

35 A Phase III Randomized Trial of Metformin Versus Placebo on Recurrence and Survival in Early Stage Breast Cancer

This study is looking at whether Metformin, an agent that is commonly used to treat diabetes, can decrease or affect the ability of breast cancer cells to grow and whether Metformin will work with other therapies to keep cancer from recurring. Health Canada has not approved the sale or use of Metformin to treat breast cancer, although they have approved its use in this clinical trial. Although Metformin is approved by the FDA for the treatment of diabetes, its use in breast cancer is considered investigational.

NCT01101438
Conditions
  1. Breast Cancer
Interventions
  1. Drug: metformin hydrochloride
  2. Other: placebo
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

- Concurrent or planned participation in randomized trials of weight loss or exercise interventions or trials targeting insulin, IGF-1 or their receptors, or involving P13K inhibitors (at the time of randomization)*. --- P13K ---

Primary Outcomes

Measure: Invasive disease-free survival in hormone receptor (ER and PgR) negative and positive (ER and/or PgR) sub-groups

Time: 10 years

Secondary Outcomes

Measure: Overall survival

Time: 10 years

Measure: Distant relapse-free survival

Time: 10 years

Measure: Breast cancer-free interval

Time: 10 years

Measure: Long-term clinical and laboratory safety

Time: 10 years

Measure: Relevant medical endpoints (new diabetes, new cardiovascular hospitalizations)

Time: 10 years

Measure: Health-related quality of life, physical activity, and diet

Time: 10 years

Measure: Change in body mass index

Time: 10 years

Measure: Correlative science outcomes

Time: 10 years

36 A Phase II Study of MK-2206 in the Treatment of Recurrent High-Grade Serous Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Akt inhibitor MK2206 is a drug that may stop cancer cells from growing by blocking a protein called protein kinase B (AKT) inside the cell. AKT interacts with other proteins in the cell that are part of the P13K/AKT pathway, a pathway that is know to play a role in the growth of cancer cells. Mutations in P13K or in AKT, or changes in another protein called phosphatase and tensin homolog (PTEN) in this pathway can lead it to become more active than is normal. This study investigates how effective MK-2206 is in treating ovarian, fallopian tube, or primary peritoneal cancer where there are mutations in P13K or AKT or low levels of PTEN.

NCT01283035
Conditions
  1. Ovarian Sarcoma
  2. Recurrent Fallopian Tube Carcinoma
  3. Recurrent Ovarian Carcinoma
  4. Recurrent Primary Peritoneal Carcinoma
Interventions
  1. Drug: Akt Inhibitor MK2206
  2. Other: Laboratory Biomarker Analysis
MeSH:Carcinoma
HPO:Carcinoma

AKT interacts with other proteins in the cell that are part of the P13K/AKT pathway, a pathway that is know to play a role in the growth of cancer cells. --- P13K ---

Mutations in P13K or in AKT, or changes in another protein called phosphatase and tensin homolog (PTEN) in this pathway can lead it to become more active than is normal. --- P13K ---

This study investigates how effective MK-2206 is in treating ovarian, fallopian tube, or primary peritoneal cancer where there are mutations in P13K or AKT or low levels of PTEN. --- P13K ---

Primary Outcomes

Description: If 4 or more of the final set of 29 patients demonstrate a response, then the null hypothesis H0: =< 5% can be rejected in favor of the alternative hypothesis H1: >= 20% with an alpha of 0.05 and beta of 0.20 (i.e., 80% power). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression

Measure: Efficacy (as Measured by Objective Response Rate) of Akt Inhibitor MK2206 in Patients With Recurrent High-grade Platinum-resistant Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Time: Up to 3 years

Secondary Outcomes

Description: The frequency of mutations in the PI3K/AKT and RAS pathways, copy number alterations, and PTEN loss and AKT expression as assessed by IHC will be tabulated. Associations between these markers with clinical outcome such as response rate and duration of PFS will be assessed.

Measure: Association Between Select Biomarkers and Response to Akt Inhibitor MK2206 (as Assessed by Objective Tumor Response, Progression-free Survival, and Overall Survival)

Time: Up to 3 years

Measure: Development of Feedback Loop Activation and Target Inhibition With Akt Inhibitor MK2206 Via Analysis of Pre-treatment and Post-treatment Biopsies in Select Patients Enrolled in the Trial

Time: Up to 3 years

Description: Distributions will be estimated using Kaplan-Meier analysis.

Measure: Duration of Overall Survival Following Initiation of Therapy With Akt Inhibitor MK2206 in the Cohort of Patients Enrolled on This Study

Time: Up to 3 years

Description: Distributions will be estimated using Kaplan-Meier analysis.

Measure: Duration of Progression-free Following Initiation of Therapy With Akt Inhibitor MK2206 in the Cohort of Patients Enrolled on This Study

Time: Up to 3 years

Measure: Toxicities of Akt Inhibitor MK2206, as Assessed by the Active Version of the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Time: Up to 3 years

37 A Phase I Study of Bevacizumab and Escalation Doses of BKM-120 in Patients With Metastatic Renal Cell Carcinoma Who Failed Prior Systemic Therapies

BKM-120 is a drug that may slow the growth of cancer cells. This drug has been used in laboratory experiments and information from those research studies suggests that this drug may help to slow the growth of renal cancer cells. In this research study, the investigators are testing the safety to BKM-120 at different dose levels. The investigators will also be studying how well tolerated BKM-120 is, and how effective BKM-120 can be in the treatment of kidney cancer.

NCT01283048
Conditions
  1. Renal Cell Carcinoma
Interventions
  1. Drug: BKM-120 Bevacizumab
MeSH:Carcinoma Carcinoma, Renal Cell
HPO:Carcinoma Clear cell renal cell carcinoma Papillary renal cell carcinoma Renal cell carcinoma

Inclusion Criteria: - Metastatic RCC with clear cell component or papillary RCC - Life expectancy > 12 weeks - Must have failed at least 1 prior anti-VEGF systemic therapy for metastatic RCC Exclusion Criteria: - Prior treatment with a P13K inhibitor or bevacizumab - Untreated brain metastases - Acute or chronic liver or pancreatic disease - Major mood disorder - Concurrent severe and/or uncontrolled medical condition - Diabetes mellitus - GI disease - Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant - Pregnant or breastfeeding - HIV positive - History of another malignancy within 3 years except cured basal cell carcinoma of the skin or excised in situ carcinoma of the cervix - Uncontrolled hypertension Inclusion Criteria: - Metastatic RCC with clear cell component or papillary RCC - Life expectancy > 12 weeks - Must have failed at least 1 prior anti-VEGF systemic therapy for metastatic RCC Exclusion Criteria: - Prior treatment with a P13K inhibitor or bevacizumab - Untreated brain metastases - Acute or chronic liver or pancreatic disease - Major mood disorder - Concurrent severe and/or uncontrolled medical condition - Diabetes mellitus - GI disease - Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant - Pregnant or breastfeeding - HIV positive - History of another malignancy within 3 years except cured basal cell carcinoma of the skin or excised in situ carcinoma of the cervix - Uncontrolled hypertension Renal Cell Carcinoma Carcinoma Carcinoma, Renal Cell Subjects will receive an intravenous infusion of Avastin on Day 1 and Day 15 of each month (cycle). --- P13K ---

Inclusion Criteria: - Metastatic RCC with clear cell component or papillary RCC - Life expectancy > 12 weeks - Must have failed at least 1 prior anti-VEGF systemic therapy for metastatic RCC Exclusion Criteria: - Prior treatment with a P13K inhibitor or bevacizumab - Untreated brain metastases - Acute or chronic liver or pancreatic disease - Major mood disorder - Concurrent severe and/or uncontrolled medical condition - Diabetes mellitus - GI disease - Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant - Pregnant or breastfeeding - HIV positive - History of another malignancy within 3 years except cured basal cell carcinoma of the skin or excised in situ carcinoma of the cervix - Uncontrolled hypertension Inclusion Criteria: - Metastatic RCC with clear cell component or papillary RCC - Life expectancy > 12 weeks - Must have failed at least 1 prior anti-VEGF systemic therapy for metastatic RCC Exclusion Criteria: - Prior treatment with a P13K inhibitor or bevacizumab - Untreated brain metastases - Acute or chronic liver or pancreatic disease - Major mood disorder - Concurrent severe and/or uncontrolled medical condition - Diabetes mellitus - GI disease - Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant - Pregnant or breastfeeding - HIV positive - History of another malignancy within 3 years except cured basal cell carcinoma of the skin or excised in situ carcinoma of the cervix - Uncontrolled hypertension Renal Cell Carcinoma Carcinoma Carcinoma, Renal Cell Subjects will receive an intravenous infusion of Avastin on Day 1 and Day 15 of each month (cycle). --- P13K --- --- P13K ---

Primary Outcomes

Measure: To determine the maximum tolerated dose and dose limiting toxicities of the combination of BKM-120 and bevacizumab in metastatic renal cell carcinoma

Time: 2 year

Secondary Outcomes

Measure: To determine additional toxicity and safety information from the combination of BKM-120 and bevacizumab in an expanded cohort of patients at the MTD

Time: 2 year

Measure: To determine the objective response proportion, progression-free survival, overall survival of the combination of BKM-120 and bevacizumab

Time: 2 years

Measure: To determine whether the BKM-120 and bevacizumab combination at the MTD is associated with concomitant changes in angiokines and PI3K pathway members in plasma and tumor samples

Time: 2 years

38 A Phase I and Randomized Phase II Trial of Gemcitabine + Erlotinib (NSC-718781) + IMC-A12 (NSC-742460) vs. Gemcitabine + Erlotinib as First-Line Treatment in Patients With Metastatic Pancreatic Cancer

This randomized phase I/II trial is studying the side effects and best dose of monoclonal antibody therapy when given together with gemcitabine hydrochloride and erlotinib hydrochloride and to see how well they work compared with giving gemcitabine hydrochloride and erlotinib hydrochloride alone as first-line therapy in treating patients with metastatic pancreatic cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving erlotinib hydrochloride and gemcitabine hydrochloride together with monoclonal antibody therapy may kill more tumor cells.

NCT00617708
Conditions
  1. Stage IV Pancreatic Cancer
Interventions
  1. Biological: cixutumumab
  2. Drug: erlotinib hydrochloride
  3. Drug: gemcitabine hydrochloride
MeSH:Pancreatic Neoplasms
HPO:Neoplasm of the pancreas

Samples are assessed for the potential relationship between gene expression levels, germline polymorphisms, Ras and P13K mutations and progression-free survival and overall survival. --- P13K ---

Primary Outcomes

Description: Maximum dose of IMC-A12 (in combination with erlotinib and gemcitabine) at which 3/10 or fewer patients have dose-limiting toxicities (DLT). Toxicities graded according to the NCI Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE 3.0). DLT apply only during cycle 1 and should be drug-related (possible, probable, or definite).

Measure: Maximum Tolerated Dose Determination

Time: 28 days

Description: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact.

Measure: Progression-Free Survival

Time: Up to 3 years

Secondary Outcomes

Description: From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.

Measure: Overall Survival

Time: Up to 3 years

Description: Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.

Measure: Response

Time: Up to 3 years

Description: Number of patients with Grade 3 through 5 adverse events that are related to study drug. Only adverse events that are possibly, probably or definitely related to study drug are reported.

Measure: Toxicity

Time: Up to 3 years

39 A Phase I Study of BKM120 + Carboplatin + Paclitaxel for Patients With Advanced Solid Tumors

The purpose of this study is to find out the good and bad effects that occur when BKM120 is added to standard chemotherapy with carboplatin and paclitaxel.

NCT01297452
Conditions
  1. Solid Tumors
Interventions
  1. Drug: BKM120 days 1 - 21 plus paclitaxel + carboplatin
  2. Drug: BKM120 (days 1 - 28, ) plus paclitaxel + carboplatin
  3. Drug: BKM120 (days 1-21) + paclitaxel (day 1) + carboplatin (day 1)
  4. Drug: BKM120, Paclitaxel + Carboplatin
MeSH:Neoplasms
HPO:Neoplasm

Exclusion Criteria: - Patients who have received prior treatment with a P13K inhibitor. --- P13K ---

Primary Outcomes

Description: for patients with advanced solid tumors, BKM120 in combination with two different schedules of paclitaxel and carboplatin.

Measure: To establish the phase II recommended dose of daily oral BKM120

Time: 2 years

Measure: EXPANSION COHORT A:To evaluate the safety and tolerability of daily oral BKM120 (100 mg) + paclitaxel (200 mg/m2) + carboplatin (AUC 6), both given intravenously (IV) on day 1 of a 21-day cycle, with pegfilgrastim support

Time: 2 years

Measure: EXPANSION COHORT B: To obtain a preliminary description of efficacy of the regimen established in Group 1 among patients with tumors harboring PTEN mutation or homozygous deletion.

Time: 2 years

Secondary Outcomes

Description: Patients will be evaluated by MD at weekly clinic visits during Cycle 1, on Day 1 of subsequent cycles, and will have additional evaluations if clinically indicated. Toxicities will be assessed according to NCI common toxicity criteria (CTC) version 4.0

Measure: To describe the safety of BKM120 combined with paclitaxel and carboplatin,

Time: weekly clinic visits during Cycle 1, on Day 1 of subsequent cycles,

Description: when given in combination with carboplatin and paclitaxel. The area under the curve (AUC0→∞), half-life (t½), and maximum concentration (Cmax) for BKM120 will be determined by noncompartmental analysis.(except for Expansion Cohort B)

Measure: To determine the pharmacokinetic profile of daily BKM120.

Time: 2 years

Description: there is insufficient sample size to support a formal analysis of response rate. As such, radiographic response data will be tabulated and presented in descriptive form.

Measure: To describe and tabulate the radiographic response rate of BKM120 in combination with carboplatin and paclitaxel,

Time: 2 years

Description: we will calculate the proportion of cases with positive staining of PTEN along with a 95% confidence interval, using the Clopper and Pearson method for exact small sample inference. For Sequenom Analysis, we will calculate the proportion of cases that are positive for each mutation

Measure: Correlative Tissue Studies

Time: 2 years


HPO Nodes


HP:0002664: Neoplasm
Genes 1522
SF3B1 GFI1B IGF2 FIBP RPS7 WT1 COL7A1 TREX1 HSPG2 CASP8 SLC22A18 MC1R TFE3 KRAS PLAG1 OFD1 BRAF NUMA1 KRT16 PSENEN CTPS1 APC SOX9 FANCM OPCML CDKN2A RPS15A CTNNB1 SDHD EDN3 FCN3 NELFA GJC2 MALT1 HPGD GLI1 CD70 SPINK1 LETM1 PMS1 LRP5 HNF1B EXT1 TCF4 ELMO2 MET ANTXR1 KRT16 KRT10 PAX4 SETBP1 TERT WT1 SMARCB1 GJB6 HRAS STK11 BUB1B GNPTAB MYD88 MCC GJB2 BRCA1 TP63 PDGFRL TARS1 NF1 FGFR3 KARS1 BARD1 BRIP1 GATA2 IL1RN BRAF CD81 TNFRSF13B TYROBP AR LIG4 KLF11 ABL1 MVK BMPR1A PIK3CA B3GALT6 SLC37A4 SOS1 TSC1 FGFR3 ATRX FANCG TET2 KIT SRP72 MPL TP53 SMAD4 EVC2 MAPRE2 DLST BRCA1 DICER1 HRAS AKT1 RNR1 TSC1 TNPO3 XRCC4 DNMT3A NEUROD1 THPO MN1 NOD2 SRSF2 PPM1D FLT4 ATP7A IL7 KRAS GDNF WNT10A EPAS1 COL1A1 IL1B MRAP ADAMTS3 PRKCD SUFU PTCH1 ERCC3 KRT14 CXCR4 HOXD13 IGF2 LIG4 PALB2 BLM NRAS ERCC3 FOXP1 SDHD TP53 PKD2 PDX1 TINF2 ADA2 MYF6 RHBDF2 POU6F2 PHKG2 CDKN2A RUNX1 ERCC2 MAP2K2 WT1 USB1 GATA4 FGFR2 ACD CR2 MUTYH ARL6IP6 FAH MSH2 RASA1 NEK1 SOX6 NR0B1 LIG4 CDKN2B NF1 NF1 POLE RPL35 SRY SDHAF2 FANCL CPLX1 FAS PRKAR1A PHB SDHA CALR PIK3R1 FAN1 TET2 TMEM216 RSPO1 SEMA3D MDM4 SDHD HRAS NUP214 GJA1 PIK3CA CCND1 RNF6 MSH2 C11ORF95 MVK MCM4 FLI1 TINF2 KIAA0753 ECM1 ARSA ERCC2 SOX2 SDHC SLC26A2 MPL VANGL1 PUF60 RAD51D POT1 CR2 ESCO2 FOXE1 PMVK SRY GJB4 TRIM37 KIT EXT2 PDGFB KIF1B FANCF IGF2R MLH1 GDNF PIK3CA ASCC1 ASCL1 TCIRG1 APPL1 RPS19 BCL10 IGF2 NRAS FLT3 STAT1 BCL10 RMRP GNAI3 KRAS GPR101 BAP1 NKX2-1 MAX BMPR1A DDB2 SMARCB1 RAD51 FGFR3 ALX4 BTK MSH6 NOTCH3 DICER1 CXCR4 CCBE1 RET WT1 TP53 PALLD RNASEH2B WT1 ATR CCND1 KCNQ1OT1 SMAD4 AHCY STK11 FANCC TRNK BCL6 SMAD4 SKIV2L HMBS TP53 TERT PHOX2B SNAI2 BRAF TCOF1 FANCI NRAS REST SDHC HBB HFE CREBBP MET SEC23A CEP57 CTLA4 TRIM28 SMAD7 GNAS BRCA2 PALB2 FGF8 SBDS RET ALK GJB2 CPLANE1 GPC3 TCTN3 PTEN RB1 INTU CYP26C1 LEMD3 PRLR CDON NLRP1 GPR101 DHH HNF4A MMEL1 DNASE1L3 RASGRP1 ATRX CHEK2 FANCA SPRED1 DNM2 FLT4 CHEK2 RPS19 KLLN HACE1 HNF1A PTPN11 CDKN1B GAS1 BRCA2 KCNQ1OT1 NPM1 FGFR3 MC1R MINPP1 PTPN11 TSC2 ABCA5 BRCA2 PLCB4 SCN11A HNF1A BRAF RB1 CBL ARHGAP26 SUFU PTPRJ C1S APC IRF5 GNAQ GDNF TERT MYSM1 XPC TMC8 COL4A5 ERBB3 SLC26A4 CD96 NSUN2 PDGFRA FERMT1 TYR DNAJC21 MSH2 SH3GL1 TUBB RET BRAF ESR1 PAX3 RHBDF2 RTL1 WRN DYNC2LI1 ELANE EXOC6B RPS26 EWSR1 VHL PIGA GCGR POU6F2 RNF43 POLE BRAF MNX1 SFTPA2 CDH23 ASCL1 APC ACVR1 PIGL BAX RAG2 RSPO1 MSH3 PGM3 FGF3 FANCE MPL TP53 COL7A1 BUB1 TET2 PALB2 ACTB PNP SDHC EDN3 XPA TMC6 NEK1 GNA11 KAT6B KRT1 RUNX1 PAX7 NOTCH1 ENG CTNNB1 ETV6 MPLKIP PARN CDKN2A PTPN3 STAG3 MDM2 TP53 LAMC2 NBEAL2 VAMP7 GNA14 DCLRE1C CBL GCDH FANCC AXIN2 PYGL SOS1 BLK WRAP53 IDH1 KRAS CCM2 APC ASXL1 ATP7B ERCC3 SF3B1 EP300 BRCA2 MGAT2 NRTN CDKN2A DICER1 PMS1 RPS10 TBC1D24 FAH BRCA2 ASXL1 BCR C2CD3 KRAS IDH1 IGLL1 RASA1 BRCA2 CHEK2 PTCH1 RNF113A BRAF MBTPS2 EDNRB IGHM PDGFRB RAF1 MEN1 FASLG TUBB NDUFAF6 FOXI1 TGFBR1 EPCAM CYLD SDHB APC CYP2D6 TAF1 KRT17 BRCA1 BUB1B BAP1 GDF2 BUB1B ERCC2 TP53 KRT5 GATA2 BRCA1 RAD54B MRE11 STAC3 DNMT3A MLH1 BCHE EDN3 CDKN1B AURKA NRAS FLCN IDH2 EDN1 ESCO2 USF3 IGH POT1 ACVRL1 JAK2 NBN NRAS SQSTM1 TMEM127 ZFPM2 SLC12A3 NTHL1 ADA CHIC2 STAT3 SETBP1 FANCB FIBP STAT3 STK11 MLLT10 SFTPC HDAC4 NUP214 GLI2 SLX4 TSC1 ERCC6 TP53 CLCNKB KLF6 OGG1 JAK2 PAX6 RECQL4 RPL31 MYO1H FH RPGRIP1L SLC45A2 RPL10 RPL10 HMBS GDF5 TNFRSF10B PIK3CA GABRD TP53 BRCA2 SEMA4A BCR PALB2 ASXL1 KRT6B CCDC22 SAMD9 DMPK DCC ERCC5 RPL5 CTNNB1 RPS27 TRNS2 PTCH1 PTEN TFAP2A RPS24 RPL35A RET AXIN1 HNF1B ARMC5 UBE2T SRP54 SSX2 DKC1 ERCC3 JAK2 GNA11 LAMB3 GJB2 NFKB1 KCNQ1 GLI3 PIK3CA KANSL1 CASP8 MYC RECQL4 ACAN CACNA1S BDNF KIF11 MDH2 MSL3 FGFR1 TERF2IP HFE NFKB2 TOP2A GFI1 SRD5A3 PHKA2 MAX POLE MAP2K1 EYA1 RNF43 ALX3 SETD2 ERCC4 CTLA4 SIX3 LEMD3 OCRL CDH23 DZIP1L MSH3 AR CDC73 PDGFRL TWIST1 POU2AF1 DKC1 CALR LIN28B KRT6A GATA1 MC1R DIS3L2 CD28 CDC73 ADA2 UROD CIB1 TSR2 WNT5A TET2 PHOX2B BMPER KIT DLC1 MSTO1 H19-ICR SLC25A13 ADAR TMEM67 BMPR1A MLH3 POLR1C KRT6B FH EFL1 TERC BUB3 FOXC2 NOTCH3 KIT NSD1 FGFR2 SLC6A17 MAP3K1 TRIP13 MEG3 RRAS2 BMPR1A NF1 DPM1 LIG4 PARN RHOH BRCA2 NF1 TAF15 RFWD3 VHL H19 BCR KRAS VANGL2 KRAS SDHD DVL3 BIN1 ABL1 GPC3 HAX1 FANCA GDNF NHP2 IGF2 VHL CCL2 EXTL3 RUNX1 PRKCD BLNK MSH6 SLC22A18 IL2RG PTH1R SDHB AIP WDPCP APC KCNJ10 ASPSCR1 OCA2 TP53 WT1 SPRTN TET2 TAL1 L2HGDH KIT SDHC ERCC4 GPR143 PRKN SMAD4 SEMA3C TRNS1 BRCA1 SHOX PCNA FANCG CREB1 TRNH VHL MYLK BAP1 SUFU ANTXR1 POLD1 NODAL IGH JAK2 MS4A1 MEN1 TSC2 GATA2 DHCR7 TINF2 F13B RB1 COL7A1 SCN4A BMPR1A DDB2 CDKN2A SDHD CYP11B2 IL7 ARID1B KIT FGFR1 RET CDKN2A LAMA3 CHEK2 TBX2 TBX18 HNF4A GPC4 SHH LMNA BMP2 YY1 AKT1 WT1 BAP1 FZD2 SH2B3 BTK GATA1 RAD54L ATM CTBP1 PTEN SRY RYR1 CTHRC1 MFN2 PTEN RAD21 PTEN MYC SLC26A2 TP53 CTNNB1 RAD51C NAB2 NLRP1 SUFU DLL1 PSAP SDHB REST TGFBR2 TRIP13 IGH ABCC8 IL6 CPLANE1 H19 FANCD2 FGFR2 RET PKD1 DNMT3A REST CHEK2 GNAQ MXI1 BRIP1 DYNC2LI1 GNAS TP53 GLI3 DIS3L2 NRAS PICALM WT1 BAP1 MEN1 TXNRD2 MGMT PTEN MYD88 GNAS POT1 AGGF1 BUB1 PTEN PORCN HFE NUTM1 PHOX2B MSX2 PMS2 SLX4 H19 USP9X RPL27 GNAS SEC23B CBL CD28 PKHD1 AXIN2 TRPV3 KLLN SSX1 TSC1 PPOX KRT17 CARD14 HRAS TCF3 RPL11 CC2D2A GREM1 CHEK2 AP2S1 NRAS TRNL1 ALX1 CREBBP TCTN3 TET2 ESCO2 DOCK8 NRAS STK11 GCM2 TTC37 WT1 SMAD4 DAXX MITF BCL2 DIS3L2 POLR1D TDGF1 KRAS TNFRSF13C KIT PHOX2B SF3B1 RPL15 NF1 TERT TNFRSF1B FANCD2 MLH3 IL7R GPC4 H19-ICR SLC17A9 MEN1 MST1R KIT RAD50 TJP2 DNAJC21 PDCD10 MUTYH IL12RB1 SH2D1A FGFR2 NBN KRAS KIT CASR ENPP1 SDHB HRAS IKBKG PNP EXT2 BRD4 SMARCB1 REST COL11A2 TG KIT LIG4 SUFU NBN RSPRY1 CYSLTR2 SDHD AAGAB BLM RAG1 RNF139 RB1CC1 ACD PTPN11 SLC26A2 TREX1 BMPR1B DDR2 ZAP70 MNX1 MAGT1 AIP GATA2 AR STAR IFIH1 IDH2 BRCA1 USP8 RB1 FGFRL1 SMO USP8 RMRP SLC25A11 MLH3 FUZ DOCK8 SUFU NF2 KDR KRAS RPS14 CASP10 SRP54 ZSWIM6 TBXT PTCH2 EWSR1 TNFRSF13C MTAP NQO2 RPL18 DNAJC21 GCK ERCC6 KDM6B EXT1 SBDS CCND1 SDHAF2 KCNH1 CYLD LMOD1 PDGFRA CAT CHRNG TRNQ ADA NRAS TLR2 SHOX FGFR3 BCL10 TYR KRAS COL2A1 PTCH2 SMO GBA MSTO1 TREM2 JAK2 TMEM231 MSH2 ASXL1 RET DHCR7 NBN PIK3CA NSD2 SDHB EIF2AK4 PALB2 KIF7 PTPN11 PIK3CA HLA-DRB1 STIM1 TMC6 KIF1B TNFSF15 RELA AKT1 NPM1 APC SDHA SDHB STAT6 CDKN1C CDC73 PTCH2 KANSL1 ZSWIM6 FLCN HBB LZTS1 FN1 TRAF7 ACP5 CTNNB1 MLH1 EXT2 RNASEL RNASEH2A IL2RG ATP7A CDK4 CYP11B1 MMP1 SDHB ATRX ACTG2 FOXH1 OFD1 NEK9 STS MUC5B PRKCD PTPN11 PTCH2 LRRC8A RPL26 MSH6 NNT LZTR1 CDC73 PTEN AKT1 AKT1 SASH1 HRAS ANAPC1 PTPN12 KCNJ11 TCF4 GATA2 MLH3 ERCC4 GNB1 DISP1 IDH1 BCR GANAB MSH6 NR5A1 TSC2 GFI1 TNFSF12 TRNP MAPK1 IFNG FLT4 MTM1 WWOX HABP2 RPS28 HRAS SLCO2A1 ND5 SDHB CHD7 BRIP1 SLC37A4 MC2R XRCC3 TNFRSF4 NAGS PHF21A ZIC2 PCGF2 SMARCE1 CTNNB1 SRP54 CDH1 CDK4 RPS20 KCNJ10 RAD21 RNF6 COL14A1 SMO CD19 WRN SRGAP1 CDKN2C AXIN2 GPC6 WWOX HSPA9 FOXI1 CPOX RPS17 APC2 MYH8 SERPINA1 ATM LMX1B ENG POLH TGFBR2 DHX37 VEGFC KIF1B KRT17 DDX41 SPIB CBFB HRAS BCL10 PIGL FGFR1 NSD1 F5 KCNN3 BAX PIEZO2 RECQL4 CREBBP KIT PDGFB PDE6D ABCA5 AKT1 KLHDC8B TNFSF12 EPCAM RARA MLH1 GINS1 EVC PIK3CA FANCE WIPF1 NF2 PDGFRA PRKAR1A CDH1 SDHD PRCC TRNF PTCH1 TNFRSF1B WNT10A WWOX MAD1L1 MTOR WDPCP RNASEH2C NSD2 SAMD9L FH LPP NF1 KRIT1 NTHL1 IL12A HNF1A CDH1 SMARCB1 SMARCE1 CD19 FH FDPS TRPS1 ERCC4 SMPD1 SMARCD2 BRCA1 MPL CRKL SEC23A EXT1 PERP ATM FOXE1 CDKN2B CTSC SIX1 FAM149B1 CDH1 RAD51C ALX3 DLST TRIP13 ING1 PDGFRB FLT3 COL18A1 MST1 TGIF1 TMEM107 SRSF2 TRIM28 BAP1 ANTXR2 CD79A PIK3R1 MAP3K1 NOP10 PIK3CA POLD1 KDSR CCND1 TP53 TMC8 ALK MAP2K1 CD79B SDHC ECE1 PALLD CTSA PRDM16 IVNS1ABP CALR FLNA GPR101 BRCA2 ERCC2 DYNC2H1 TFAP2A COL2A1 DVL1 TERT APC TERT TEK EXT2 TERC ALX4 OFD1 LMO1 PDGFRB RPS14 DCC RTEL1 INS TSC2 FAM20C MYH11 GPC3 SCN9A SMAD4 RASGRP1 HBB TGFBR2 RERE NDP PLA2G2A TCF4 MAD2L2 SKI AIP HMMR SDHC SNAI2 PIK3CA LMNA PGM3 ABCB11 TAL2 WT1 VHL PIK3CA TCTN3 SAMD9L ICOS GLI3 RB1 SLC25A13 SDHC DCLRE1C GCM2 VANGL1 SIX6 WT1 PMS2 KCNH1 BARD1 H19-ICR GNAS TERT CIB1 B3GALT6 GJB3 ERBB2 SDHA KRAS CDC73 TNFRSF13B TET2 FGFR3 WAS SEC23B TGFBR2 TP53 NF2 SMARCA4 NF2 SLC26A4 ANTXR2 WRAP53 FAS SAMHD1 TP53 TET2 ATP7A PTEN SH3KBP1 CARMIL2 MVD PDGFB ABCC6 G6PC1 TRNK KRAS GPC3 PTEN NF2 JAK2 DMRT3 GNAQ RAD51 GTF2H5 TMEM127 TERT RUNX1 FAT4 AR HABP2 NR4A3 EP300 MINPP1 OFD1 RASA1 DLEC1 BIRC3 AIP CD27 PHOX2B BMPR1A KCNE3 PLCD1 RAD51 KRT1 MSH3 MITF EPHB2 DHCR24 RABL3 KRT17 XRCC2 NRAS ITK VHL BICC1 RECQL4 SMARCAD1 MYCN RET CTC1 PTCH1 JAK2 SRC SDHB PHOX2B AKT1 KEAP1 JAG1 VHL LETM1 NLRP1 MEN1 BRCA2 FLCN C2CD3 RFWD3 XPA APC APC SDHD FOXO1 MAFA WHCR GPC4 MLH1 ICOS CDKN1B MTMR14 KIT DICER1 EP300 ZFHX3 MMP1 PRKAR1A KRT9 F13A1 CTNNB1 MPL INPP5E NF1 DKC1 TERT DLK1 SCN10A STS RPS29 PTEN FLCN LRBA ELANE GTF2E2 ATM PIK3CA GPR35 CYLD RAD51C CDKN1A WT1 DICER1 PIK3CA TERC PIK3CA SLC25A11 GNAS CEBPA ATP6V1B2 RET XPC EXT1 BRCA2 SH2B3 ERCC3 BRCA2 RTEL1 WASHC5 ERCC2 AKT1 KCNAB2 CYLD STK4 POLH ERCC5 CDH1 CEL XIAP MSR1 TP53 TET2 DHH PRKAR1A
HP:0008069: Neoplasm of the skin
Genes 287
FERMT1 TYR BAP1 TNFRSF4 MSH2 COL7A1 CDK4 RPS20 MC1R TINF2 WRN KRAS SMO COL7A1 DDB2 CDKN2A KRT16 PSENEN IL7 APC LAMA3 POLH VEGFC LMNA KRT17 FCN3 GJC2 MSH3 HPGD RECQL4 CREBBP COL7A1 KIT PDGFB PTEN KRT16 SDHC EPCAM PTEN XPA TMC6 GJB6 MLH1 HRAS SUFU TGFBR2 PTCH1 CTNNB1 TNFRSF1B WNT10A MPLKIP CDKN2A IL6 GJB2 TP53 LAMC2 TARS1 NF1 FH GNA14 DCLRE1C NF1 WRAP53 NTHL1 KRAS SMARCE1 FH BAP1 ERCC3 EP300 FDPS ERCC4 MVK PIK3CA PERP PMS1 CTSC PORCN ALX3 NUTM1 ING1 PMS2 KIT SLX4 IGLL1 SEC23B RASA1 CD28 HRAS TRPV3 KLLN AKT1 TSC1 PTCH1 KRT17 TCF3 RNF113A MBTPS2 IGHM PDGFRB MEN1 CD79A PIK3R1 FASLG KDSR NRAS IL7 CYLD TMC8 CD79B WNT10A KRT17 COL1A1 IVNS1ABP DOCK8 PRKCD PTCH1 NRAS ERCC3 KRT14 CXCR4 KRT5 ERCC2 MLH1 BLM MITF NRAS KRAS KIT APC TERC NF1 FLCN TERT TNFRSF1B CDKN2A DCC ERCC2 TSC2 SLC17A9 USF3 NF1 NTHL1 FAS PRKAR1A KIT SNAI2 PIK3CA LMNA HRAS IKBKG FAN1 BRD4 RSPO1 TP53 SDHC GJA1 BLM RNF6 FH MSH2 SLC45A2 TERT CIB1 GJB3 TNFRSF10B PIK3CA ECM1 ERCC2 SEMA4A KRT6B DMPK SEC23B PMVK ERCC5 GJB4 TGFBR2 SMO NF2 NF2 RMRP FAS MLH1 CARMIL2 MVD PDGFB SUFU NF2 DKC1 ERCC3 NRAS CASP10 STAT1 PTEN LAMB3 GJB2 BAP1 GTF2H5 RECQL4 DDB2 SMARCB1 CYLD FGFR1 MSH6 NOTCH3 CXCR4 BMPR1A TYR PLCD1 PTCH2 CTLA4 OCRL KRT1 MSH3 MSH2 KRT17 NRAS SDHB KRT6A MC1R CD28 CREBBP CIB1 PIK3CA SDHB STIM1 AKT1 TMC6 KEAP1 AKT1 CTLA4 NLRP1 MLH3 PTCH2 APC KRT6B MLH1 LZTS1 GJB2 CDKN1B KIT TRAF7 DICER1 PTEN MMP1 PRKAR1A KRT9 BMPR1A NF1 MMP1 CTNNB1 RASGRP1 NF1 SPRED1 FLT4 SDHD LRRC8A KLLN GTF2E2 PTEN SASH1 BLNK ANAPC1 PIK3CA GNAS XPC BRAF ERCC4 ERCC3 MSH6 ERCC2 OCA2 KIT ERCC4 IFNG APC GPR143 CYLD FLT4 STK4 POLH ERCC5 WWOX HRAS SLCO2A1 XPC TMC8
SNP 0