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Report for Clinical Trial NCT01339442

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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 Estrogen Receptor-positive Breast Cancer Recurrent Breast Cancer Stage IV Breast Cancer
MeSH: Breast Neoplasms
HPO: Breast carcinoma Neoplasm of the breast

3 Interventions

Name: BKM120

Type: Drug

Cohort C Dose Level 1 - Phase 1A Dose Level 2 - Phase IA Phase IB

Name: Fulvestrant

Type: Drug

Cohort C Dose Level 1 - Phase 1A Dose Level 2 - Phase IA Phase IB

Name: biopsy

Description: Correlative studies

Type: Procedure

Cohort C Dose Level 1 - Phase 1A Dose Level 2 - Phase IA Phase IB


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

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There is one SNP

SNPs


1 P13K

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 ---



HPO Nodes


HPO:
Breast carcinoma
Genes 95
TP53 PPM1D CTNNB1 TP53 COL14A1 AKT1 AKT1 OPCML MDM2 BRCA1 SLC22A18 POLE BRCA2 BRCA1 SDHC NTHL1 PTEN XRCC3 MSH6 IDH1 RAD51C RAD51C CASP8 RB1CC1 PIK3CA PALLD KRAS PIK3CA CHEK2 BRIP1 MRE11 NTHL1 ATM TP53 RAD51D STK11 PRKN ESR1 PIK3CA KLLN MSH2 SDHD KRAS SEC23B HMMR PTEN POLD1 PIK3CA IDH2 BRCA1 PALB2 BRIP1 TP53 RAD51 RNF43 BARD1 BARD1 AAGAB AKT1 SMAD4 RAD50 STK11 CHEK2 RAD54L NBN CDKN2A SEC23B CDH1 WRN NQO2 PALB2 ATR PALB2 TWIST1 SDHB MSH2 BRCA2 BRCA1 RAD51 CHEK2 MLH1 BRCA1 FGFR2 TP53 PHB BRCA2 CDH1 PTEN BRCA2 CHEK2 CDKN2A APC MLH1 AKT1 APC
Neoplasm of the breast
Genes 123
PPM1D CTNNB1 PTEN MGMT AKT1 BRCA1 SLC22A18 BRCA1 SDHC NTHL1 XRCC3 APC IDH1 LMNA RAD51C CDKN2B PIK3CA PALLD CHEK2 NTHL1 ATM RAD51D ESR1 GNAS APC PIK3CA RASGRP1 SDHD PRKCD KRAS BAP1 IDH2 PALB2 FAS RAD51 RNF43 PRLR AKT1 CHEK2 CDKN2A CDH1 CDK4 RELA BRCA2 BRCA1 TERF2IP CHEK2 MLH1 BRCA1 PRKAR1A POT1 BRCA2 CDH1 TERT APC MLH1 AKT1 TP53 CASP10 TP53 COL14A1 AKT1 OPCML MDM2 POLE BRCA2 PTEN MSH6 RAD51C CASP8 RB1CC1 KRAS ACD PIK3CA BRIP1 MRE11 TP53 STK11 PRKN KLLN MSH2 SEC23B HMMR PTEN POLD1 PIK3CA BRCA1 MITF FAS BRIP1 TP53 BARD1 BARD1 AAGAB SMAD4 RAD50 STK11 RAD54L NBN C11ORF95 SEC23B WRN PTEN NQO2 PTEN PALB2 ATR PALB2 CDKN2A TWIST1 SDHB MSH2 MC1R FASLG RAD51 FGFR2 TP53 PHB PTEN BRCA2 CHEK2 CDKN2A APC