SNPMiner Trials by Shray Alag


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Report for Mutation P4503A

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 12 clinical trials

Clinical Trials


1 A Phase 2a, Randomized, Double-Blind, Placebo- and Active-Controlled, Parallel-Group, Multicenter Study to Assess the Safety and Efficacy of ADL5859 100 mg BID in Subjects With Neuropathic Pain Associated With Diabetic Peripheral Neuropathy

The purpose of this study is to evaluate the effectiveness of ADL5859 in relieving the pain associated with diabetic peripheral neuropathy (DPN) compared with placebo and duloxetine (a marketed drug approved for the treatment of painful DPN). The pain symptoms of DPN are thought to be due to damage to nerves caused by the diabetes.

NCT00603265 Peripheral Neuropathy Neuropathic Pain Drug: ADL5859 Drug: Duloxetine Drug: Placebo
MeSH:Peripheral Nervous System Diseases Neuralgia
HPO:Abnormal peripheral nervous system morphology Peripheral neuropathy Polyneuropathy

Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.. Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Peripheral Neuropathy Neuropathic Pain Peripheral Nervous System Diseases Neuralgia Participants were permitted to take acetaminophen 650 to 975 mg every 4 to 6 hours (up to a total of 4 grams in 24 hours) as needed for pain relief. --- P4503A ---

Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.. Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Peripheral Neuropathy Neuropathic Pain Peripheral Nervous System Diseases Neuralgia Participants were permitted to take acetaminophen 650 to 975 mg every 4 to 6 hours (up to a total of 4 grams in 24 hours) as needed for pain relief. --- P4503A --- --- P4503A ---

Primary Outcomes

Description: The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained up to 3 times per day over a 7-day period. Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with treatment group as a main factor and baseline NPRS score as a covariate. Change from Baseline = NPRS at baseline - NPRS at Week 4; a positive number in the LS mean indicates a reduction in pain intensity from baseline.

Measure: Change From Baseline in Mean Numeric Pain Rating Scale (NPRS) Score

Time: Baseline, Week 4

Secondary Outcomes

Description: A responder was defined as a participant who showed a reduction in average pain (as measured by NPRS) of at least 30% from baseline to Week 4. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The percentage of participants who qualified as responders is presented per treatment arm.

Measure: Percentage of Responders

Time: Baseline, Week 4

Description: PGIC is a participant-rated instrument that measures the change in the participant's overall status for the previous 2 weeks based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). The number of participants in each category is presented.

Measure: Patient Global Impression of Change (PGIC)

Time: Week 4

Description: Sleep Interference was assessed on an 11-point Numeric Rating Scale where a score of 0 indicated "pain did not interfere with sleep" and a score of 10 indicated "pain completely interfered with sleep". Here, "n" signifies "Number of participants" for Baseline and Month 3 telephone interview whereas "n" signifies "number of observations" for Month 1, 2, and 3 because a participant could have had multiple visits during Month 1, 2, and 3 as this was a non-interventional study with no scheduled study visits, except Baseline visit and the Month 3 telephone interview. LS means were calculated using ANCOVA with treatment group as a main factor and baseline SIS score as a covariate. Change from baseline = SIS score at baseline - SIS score at Week 4.

Measure: Change in Sleep Interference Scale (SIS) From Baseline

Time: Baseline, Week 4

Description: At each of the evening pain assessments, participants assessed their overall pain intensity over the preceding 24 hours using NPRS. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained at Baseline and Week 4. Change from baseline = NPRS at baseline - NPRS at Week 4.

Measure: Change From Baseline in the Evening Assessment of the 24-hour Overall Mean Pain Intensity Score

Time: Baseline, Week 4

Description: The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken while the participant was at rest. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.

Measure: Change From Baseline in NPRS at Rest in the Clinic

Time: Baseline, Week 1, Week 2, Week 3, Week 4

Description: The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken after the participant walked 50 feet in the clinic. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.

Measure: Change From Baseline in NPRS After Walking 50 Feet in the Clinic

Time: Baseline, Week 1, Week 2, Week 3, Week 4

2 Phase I Study Of Vincristine, Doxorubicin, And Dexamethasone (VXD) Plus Ixazomib In Adults With Relapsed Or Refractory Acute Lymphoblastic Leukemia/Lymphoma, Lymphoblastic Lymphoma Or Mixed Phenotype Acute Leukemia

This is a phase I study of vincristine, doxorubicin and dexamethasone (modified VXD) plus MLN9708 in adults with relapsed or refractory acute lymphoblastic leukemia/lymphoma, lymphoblastic lymphoma or mixed phenotype acute leukemia.

NCT01887587 Relapsed or Refractory Acute Lymphoblastic Leukemia Relapsed or Refractory Lymphoblastic Lymphoma Mixed Phenotype Acute Leukemia Drug: MLN9708 Drug: Vincristine Drug: Doxorubicin Drug: Dexamethasone
MeSH:Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Lymphoma, Non-Hodgkin Acute Disea Acute Disease
HPO:Leukemia Lymphoid leukemia Lymphoma Non-Hodgkin lymphoma

- Systemic treatment, within 7 days before study enrollment, with strong inhibitors of cytochrome P450 1A2 (CYP1A2) (e.g., fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P4503A (CYP3A) (e.g., clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort. --- P4503A ---

Primary Outcomes

Description: Safety, tolerability will be assessed by counting the number of participants experiencing adverse events at 8 weeks post treatment.

Measure: Adverse Events.

Time: Baseline to 30 days post treatment; approximately 8 weeks

Description: This measure will be the maximum tolerated dose (MTD) at which no more than 1 Dose Limiting Toxicity (DLT) is observed. The starting dose of MLN9708 will be 2.3 mg orally on days 1, 8 and 15. If no DLT is seen in the first 3 patients, the dose will be increased to 3 mg and then to 4 mg orally on days 1, 8 and 15 in a classic 3 +3 phase I design. We will not attempt to increase the dose beyond 4 mg orally which, if achieved with acceptable toxicity, would be accepted as the recommended phase 2 dose (RP2D). 0 of 3 DLTs would allow escalation to the next dose level. 1 of 3 DLTs will require expanding to six patients; 1 of 6 DLTs will allow escalation again. 2 DLTs will require dose de-escalation.

Measure: Optimal Dose of MLN9708

Time: 8 Weeks

3 Randomized, Multicenter, Phase III, Open-Label Study of Alectinib Versus Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer

This randomized, active controlled, multicenter phase III open-label study is designed to evaluate the efficacy and safety of alectinib compared with crizotinib treatment in participants with treatment-naive anaplastic lymphoma kinase-positive (ALK-positive) advanced non-small cell lung cancer (NSCLC). Participants will be randomized in a 1:1 ratio to receive either alectinib, 600 milligrams (mg) orally twice daily (BID), or crizotinib, 250 mg orally BID. Participants will receive treatment until disease progression, unacceptable toxicity, consent withdrawal or death. The study is expected to last approximately 42 months.

NCT02075840 Non-Small Cell Lung Cancer Drug: Alectinib Drug: Crizotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A higher score on the global health and functioning subscales is indicative of better functioning.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- P4503A ---

A higher score on the global health and functioning subscales is indicative of better functioning.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- P4503A --- --- P4503A ---

Primary Outcomes

Description: PFS was assessed as time to disease progression or death whichever occurred first by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeter (mm) and the appearance of new lesions.

Measure: Progression-Free Survival (PFS) by Investigator Assessment

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: PFS was assessed percentage of participants with disease progression or death whichever occurred first by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeter (mm) and the appearance of new lesions.

Measure: Percentage of Participants With PFS Event by Investigator Assessment

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Secondary Outcomes

Description: PFS was assessed as time to disease progression or death whichever occurred first by IRC assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions.

Measure: PFS Independent Review Committee (IRC)-Assessed

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: PFS was assessed as percentage of participants with disease progression or death whichever occurred first by IRC assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions.

Measure: Percentage of Participants With PFS Event by IRC

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: CNS progression was assessed as percentage of participants with an event defined as time from randomization until first radiographic evidence of CNS progression by IRC. The risk for a CNS progression without a prior non-CNS progression with alectinib compared with crizotinib.

Measure: Percentage of Participants With Central Nervous System (CNS) Progression as Determined by IRC Using RECIST V1.1 Criteria

Time: Randomization to CNS PD as first occurrence of disease progression (assessed every 8 weeks up to 33 months)

Description: CNS progression was assessed as percentage of participants with event defined as time from randomization until first radiographic evidence of CNS progression by IRC. The risk for a CNS progression without a prior non-CNS progression with alectinib compared with crizotinib.

Measure: Percentage of Participants With Central Nervous System (CNS) Progression as Determined by IRC Using Revised Assessment in Neuro Oncology (RANO) Criteria

Time: Randomization to the first occurrence of disease progression in the CNS (assessed every 8 weeks up to 33 months)

Description: ORR was defined as the percentage of participants who attained CR or PR. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Percentage of Participants With Objective Response Rate (ORR) of Complete Response (CR) or Partial Response (PR) as Determined by The Investigators According to RECIST V1.1 Criteria

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. DOR was evaluated for participants who had a best overall response (BOR) of CR or PR.

Measure: Duration of Response (DOR) According to RECIST V1.1 Criteria as Assessed by the Investigators

Time: First occurrence of objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: Overall survival (OS) was defined as the time from randomization to death from any cause.

Measure: Overall Survival (OS)

Time: From randomization until death (up to 43 months)

Description: Overall survival (OS) was defined as the time from randomization to death from any cause.

Measure: Percentage of Participants With OS Event

Time: From randomization until death (up to 43 months)

Description: CNS ORR was defined as the percentage of participants who attained CR or PR and had measurable/non-measurable CNS lesions at baseline. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Percentage of Participants With CNS ORR of CR or PR IRC-assessed According to RECIST v1.1 Criteria

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: CNS DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. DOR was evaluated for participants who had a best overall response (BOR) of CR or PR.

Measure: CNS DOR IRC-assessed According to RECIST v1.1 Criteria

Time: First occurrence of CNS objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Measure: Percentage of Participants With Adverse Events

Time: Baseline up to 28 months in the crizotinib arm and up to 30 months in the alectinib arm

Measure: Area Under The Concentration-Time Curve (AUC) of Alectinib

Time: Pre-dose (within 2 hours before alectinib) (baseline), 1, 2, 4, 6, and 8 hours post-dose at Visit 0 (first dosing day) and Week 4; Pre-dose (within 2 hours) at Week 8, then every 8 weeks until disease progression or death/withdrawal (up to 33 months)

Measure: Maximum Concentration (Cmax) of Alectinib

Time: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)

Measure: Time to Reach Cmax (Tmax) of Alectinib

Time: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)

Measure: AUC of Alectinib Metabolite

Time: Pre-dose (within 2 hours before alectinib) (baseline), 1, 2, 4, 6, and 8 hours post-dose at Visit 0 (first dosing day) and Week 4; Pre-dose (within 2 hours) at Week 8, then every 8 weeks until disease progression or death/withdrawal (up to 33 months)

Measure: Cmax of Alectinib Metabolite

Time: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)

Measure: Tmax of Alectinib Metabolite

Time: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)

Description: The EORTC QLQ-30 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in global health status or function is defined as a >or=10-point decrease from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point decrease from baseline followed by death within 5 weeks from the last assessment.

Measure: Time to Deterioration by European Organization for The Research And Treatment of Cancer (EORTC) Quality Of Life Questionnaire Core 30 (C30)

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-30 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in global health status or function is defined as a >or=10-point decrease from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point decrease from baseline followed by death within 5 weeks from the last assessment.

Measure: Percentage of Participants With Deterioration by EORTC Quality Of Life Questionnaire Core 30 (C30)

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in lung cancer symptoms is defined as a >or=10-point increase from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point increase above baseline followed by death within 5 weeks from the last assessment.

Measure: Time to Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in lung cancer symptoms is defined as a >or=10-point increase from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point increase above baseline followed by death within 5 weeks from the last assessment.

Measure: Percentage of Participants With Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: Health-Related Quality of Life (HRQoL) by EORTC Quality of Life Questionnaire C30 Score

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Coughing

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Dyspnoea

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Chest

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Arm and Shoulder

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

4 A Phase 1 Study of the Safety and Pharmacokinetics of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4

The purpose of this study is to evaluate the safety and pharmacokinetics of enfortumab vedotin as well as assess the immunogenicity and antitumor activity in subjects with metastatic urothelial cancer and other malignant solid tumors that express Nectin-4.

NCT02091999 Metastatic Urothelial Cancer and Other Malignant Solid Tumors Drug: enfortumab vedotin
MeSH:Neoplasms
HPO:Neoplasm

- Any P-glycoprotein (P-gp) inducers/inhibitors or strong cytochrome P4503A (CYP3A) inhibitors within 14 days prior to the first dose of study drug - Thromboembolic events and/or bleeding disorders ≤ 14 days (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE)) prior to the first dose of study drug - Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of enfortumab vedotin. --- P4503A ---

Primary Outcomes

Measure: Incidence of adverse events

Time: up to 36 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Concentration at the end of infusion (CEOI)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Maximum observed concentration (Cmax)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Trough concentration (Ctrough)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Time to maximum concentration (Tmax)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Partial area under the serum concentration-time curve after first dose and as appropriate (AUC0-7)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Terminal or apparent terminal half-life (t1/2)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Systemic clearance (CL)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Volume of distribution at steady state (Vss)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Secondary Outcomes

Measure: Incidence of Anti-Drug Antibody (ADA)

Time: up to 24 months

Description: Incidence of tumor response defined as either a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) that is confirmed ≥ 28 days later

Measure: Tumor response

Time: up to 24 months

Description: Defined as the percentage of subjects who experience a best response of either CR or PR in that cohort. CR and PR must be confirmed ≥ 28 days later.

Measure: Objective response rate

Time: up to 24 months

Description: Defined as the percentage of subjects who experience a best response of CR, PR or stable disease (SD)

Measure: Disease control rate

Time: up to 24 months

Description: Time from the date of first infusion to the earliest date of documented disease progression per radiological evidence or death from any cause

Measure: Progression Free Survival (PFS)

Time: 36 months

Description: Time from the date of first infusion until the date of death from any cause.

Measure: Overall Survival

Time: 36 months

Description: Time from the date of the first response complete response (CRC) or partial response (PR) to the earliest date of disease progression or death from any cause. DOR is only defined for subjects who have best overall response of CR or PR

Measure: Duration of Response

Time: 36 months

5 A Multiarm, Open-label, Phase 1b Study of MLN2480 (an Oral A-, B-, and CRAF Inhibitor) in Combination With MLN0128 (an Oral mTORC 1/2 Inhibitor), or Alisertib (an Oral Aurora A Kinase Inhibitor), or Paclitaxel, or Cetuximab, or Irinotecan, in Adult Patients With Advanced Nonhematologic Malignancies

The primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with advanced nonhematologic malignancies.

NCT02327169 Advanced Nonhematologic Malignancies Drug: MLN2480 Drug: MLN0128 Drug: Alisertib Drug: Paclitaxel Drug: Cetuximab Drug: Irinotecan
MeSH:Neoplasms
HPO:Neoplasm

Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan): 1. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the first dose of irinotecan. --- P4503A ---

Primary Outcomes

Description: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.

Measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)

Description: DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia <7 days duration; Grade 3 or 4 neutropenia with fever >38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.

Measure: Number of Participants With Dose-Limiting Toxicities (DLTs)

Time: From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)

Measure: Maximum Tolerated Dose (MTD) for MLN2480

Time: Day 1, Cycle 1 up to 28 days

Measure: Recommended Phase 2 Dose (RP2D) of MLN2480

Time: Day 1, Cycle 1 up to 28 days

Secondary Outcomes

Measure: Cmax : Maximum Observed Plasma Concentration for MLN2480

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Cmax: Maximum Observed Plasma Concentration for MLN0128

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Cmax: Maximum Observed Plasma Concentration for Alisertib

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Cmax: Maximum Observed Plasma Concentration for Paclitaxel

Time: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel

Time: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel

Time: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Terminal Elimination Half-life (T1/2) for Paclitaxel

Time: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Description: ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.

Measure: Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)

Time: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)

Description: Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first.

Measure: Duration of Response

Time: From first documented response until disease progression (Up to 13 months)

Description: Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response.

Measure: Time to Response

Time: From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)

Description: PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Progression Free Survival (PFS)

Time: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)

6 A Phase II Study of Ibrutinib Plus Rituximab With Hyper-CVAD Consolidation in Newly Diagnosed Young Patients With Mantle Cell Lymphoma: A Window Period for Bioimmunotherapy Before Chemotherapy

This phase II trial studies how well ibrutinib, rituximab, and consolidation chemotherapy consisting of cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine work in treating young patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving ibrutinib together with rituximab and consolidation chemotherapy may be a better treatment for mantle cell lymphoma.

NCT02427620 Blastoid Variant Mantle Cell Lymphoma CD20 Positive Mantle Cell Lymphoma Pleomorphic Variant Mantle Cell Lymphoma Drug: Cyclophosphamide Drug: Cytarabine Drug: Dexamethasone Drug: Doxorubicin Drug: Doxorubicin Hydrochloride Drug: Ibrutinib Other: Laboratory Biomarker Analysis Drug: Methotrexate Biological: Rituximab Drug: Vincristine Drug: Vincristine Sulfate
MeSH:Lymphoma Lymphoma, Mantle-Cell
HPO:Lymphoma

Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.. Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Blastoid Variant Mantle Cell Lymphoma CD20 Positive Mantle Cell Lymphoma Pleomorphic Variant Mantle Cell Lymphoma Lymphoma Lymphoma, Mantle-Cell PRIMARY OBJECTIVES: I. To evaluate the response rate of ibrutinib plus rituximab in young newly diagnosed mantle cell lymphoma (MCL) including young high-risk patients. --- P4503A ---

Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.. Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Blastoid Variant Mantle Cell Lymphoma CD20 Positive Mantle Cell Lymphoma Pleomorphic Variant Mantle Cell Lymphoma Lymphoma Lymphoma, Mantle-Cell PRIMARY OBJECTIVES: I. To evaluate the response rate of ibrutinib plus rituximab in young newly diagnosed mantle cell lymphoma (MCL) including young high-risk patients. --- P4503A --- --- P4503A ---

Primary Outcomes

Description: Will be monitored using the Bayesian stopping boundaries calculated based on beta-binomial distribution. Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate.

Measure: Overall response rate (complete response + partial response)

Time: At 8 weeks

Secondary Outcomes

Description: Will be monitored using the Bayesian stopping boundaries calculated based on beta-binomial distribution. Logistic regression will be utilized to assess the effect of patient prognostic factors on the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.

Measure: Incidence of adverse events

Time: At 4 weeks

Description: Will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.

Measure: Overall survival

Time: Up to 6 years

Description: Will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.

Measure: Progression free survival

Time: Up to 6 years

7 Randomized, Multicenter, Phase III, Open-Label Study of Alectinib Versus Crizotinib in Asian Patients With Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer

This randomized, multicenter, Phase III, open-label study will evaluate the efficacy and safety of alectinib versus crizotinib and to evaluate the pharmacokinetics of alectinib in asian participants with treatment-naive ALK-positive advanced NSCLC. Participants will be randomized 2:1 into one of the two treatment groups to receive either alectinib (600 milligrams [mg] twice daily [BID]) or crizotinib (250 mg BID) orally, respectively.

NCT02838420 Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer Drug: Alectinib Drug: Crizotinib
MeSH:Lymphoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Lymphoma Neoplasm of the lung Non-small cell lung carcinoma

Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception Exclusion Criteria: - A malignancy within the previous 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact in progression-free survival (PFS) or overall survival (OS) for the current NSCLC) - Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection - Liver disease characterized by: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than (>) 3× the upper limit of normal (ULN; >=5×ULN for participants with concurrent liver metastases) confirmed on two consecutive measurements; or - Impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices; or - Acute viral or active autoimmune, alcoholic, or other types of hepatitis - National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 Grade 3 or higher toxicities because of any previous therapy (e.g., radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Baseline QTc >470 ms or symptomatic bradycardia - Administration of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the receiving the first dose of study treatment and during treatment with alectinib or crizotinib - Administration of agents with potential QT interval prolonging effects within 14 days prior to receiving the first dose of study drug - History of hypersensitivity to any of the additives in the alectinib or crizotinib drug formulation - Pregnant or lactating - Known human immunodeficiency virus (HIV-positivity or acquired immunodeficiency syndrome (AIDS)-related illness - Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol requirements or follow-up procedures; those conditions should be discussed with the participant before study entry Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test. --- P4503A ---

Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception Exclusion Criteria: - A malignancy within the previous 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact in progression-free survival (PFS) or overall survival (OS) for the current NSCLC) - Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection - Liver disease characterized by: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than (>) 3× the upper limit of normal (ULN; >=5×ULN for participants with concurrent liver metastases) confirmed on two consecutive measurements; or - Impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices; or - Acute viral or active autoimmune, alcoholic, or other types of hepatitis - National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 Grade 3 or higher toxicities because of any previous therapy (e.g., radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Baseline QTc >470 ms or symptomatic bradycardia - Administration of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the receiving the first dose of study treatment and during treatment with alectinib or crizotinib - Administration of agents with potential QT interval prolonging effects within 14 days prior to receiving the first dose of study drug - History of hypersensitivity to any of the additives in the alectinib or crizotinib drug formulation - Pregnant or lactating - Known human immunodeficiency virus (HIV-positivity or acquired immunodeficiency syndrome (AIDS)-related illness - Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol requirements or follow-up procedures; those conditions should be discussed with the participant before study entry Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer Lymphoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- P4503A ---

Primary Outcomes

Description: PFS was defined as the time (in months) from randomization to the first documentation of disease progression, as determined by the investigators, or to death from any cause, whichever occurred first.

Measure: Progression-Free Survival (PFS) as Determined by Investigator Using Response Evaluation Criteria in Solid Tumor (RECIST) v1.1

Time: From the date of randomization to the date of the first documented disease progression or death, whichever occurred first (up to overall period of approximately 40 months)

Secondary Outcomes

Description: PFS was defined as the time (in months) from randomization to the first documentation of disease progression, as determined by an independent review committee, or to death from any cause, whichever occurred first.

Measure: PFS as Determined by Independent Review Committee (IRC) Using RECIST v1.1

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Percentage of Participants With Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by Investigator Using RECIST v1.1

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Time to Progression of Disease in the CNS as Determined by IRC Using RECIST v1.1

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Time to Progression of Disease in the CNS as Determined by IRC Using Response Assessment in Neuro-Oncology (RANO)

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Duration of Response (DOR) Assessed by Investigator Using RECIST v1.1

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Overall Survival Time

Time: Baseline, until death (up to overall period of approximately 40 months)

Description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Measure: Percentage of Participants With Non-serious Adverse Events and Serious Adverse Events

Time: Up to overall period of approximately 40 months

Measure: Time to Deterioration Assessed Using EORTC Quality of Life Questionnaire-Core (QLQ-C30) Score

Time: Baseline, Week 4, thereafter every 4 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Time to Deterioration Assessed Using EORTC Quality of Life Questionnaire-Lung Cancer Module (QLQ-LC13) Score

Time: Baseline, Week 4, thereafter every 4 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Description: AUC was collected for both alectinib and its major metabolite, M4, and was based on their concentrations in plasma over time.

Measure: Area Under the Plasma Concentration-time Curve (AUC) of Alectinib and Its Metabolite

Time: Baseline and Week 4 predose (within 2 hours before administration of study drug)

Description: Cmax was collected for both alectinib and its major metabolite, M4, and was based on their concentrations in plasma over time.

Measure: Maximum Plasma Concentration Observed (Cmax) of Alectinib and Its Metabolite

Time: Baseline and Week 4 predose (within 2 hours before administration of study drug)

Description: Tmax was collected for both alectinib and its major metabolite, M4, and was based on their concentrations in plasma over time.

Measure: Time to Cmax (Tmax) of Alectinib and Its Metabolite

Time: Baseline and Week 4 predose (within 2 hours before administration of study drug)

8 A Clinical Trial to Evaluate the Safety and Efficacy of Fycompa in Subjects With Amyotrophic Lateral Sclerosis (ALS)

This is a pilot trial to test perampanel (Fycompa; Eisai, Inc.) in ALS patients. The investigators will focus on safety and preliminary signs of efficacy. Perampanel is approved by the FDA for treatment of seizures in patients with epilepsy. In this study, perampanel will be used off-label for adults with ALS at an oral medication dose on the low end of the recommended dose range for epilepsy. This study will consist of two treatments arms: perampanel and matching placebo randomized at a 1:1 ratio. Subjects will receive medication for 9 months.

NCT03020797 Amyotrophic Lateral Sclerosis Drug: Perampanel Drug: Placebo Oral Tablet
MeSH:Motor Neuron Disease Amyotrophic Lateral Sclerosis Sclerosis
HPO:Abnormal anterior horn cell morphology Amyotrophic lateral sclerosis

Inclusion Criteria: 1. diagnosis of ALS 2. first clinical weakness within past 3 years 3. slow vital capacity >= 60% of predicted within 1 month of treatment 4. may be on stable dose of riluzole for at least 30 days, or otherwise agree to not initiate riluzole for duration of the trial 5. may be on stable dose of edaravone for at least 30 days, otherwise agree to not initiate edaravone for duration of the trial 6. can travel to Stony Brook to receive medical care 7. must have a monitor who can be contacted at regular intervals to report on subject's clinical/psychiatric status Exclusion Criteria: 1. use of tracheostomy or mechanical ventilation within last 3 months 2. hepatic insufficiency or abnormal liver function 3. renal insufficiency 4. clinically significant psychiatric disorder 5. active malignancy 6. history of HIV, clinically significant chronic hepatitis, or other active infection 7. history of stomach or intestinal surgery or condition that could interfere with absorption, distribution, metabolism or secretion of study drug 8. history of alcohol or substance abuse within 3 months prior to entry (subjects will be instructed to refrain from alcohol during the study) 9. use of strong cytochrome P4503A inhibitors or inducers, anticonvulsants or other drugs known to interact strongly with perampanel. --- P4503A ---

10. pregnancy or lactation 11. clinically significant medical condition (other than ALS) that would pose a risk to the subject if they were to participate 12. know hypersensitivity to perampanel 13. currently participating, or has participated in a study with an investigation or marketed compound within 3 months of entry Inclusion Criteria: 1. diagnosis of ALS 2. first clinical weakness within past 3 years 3. slow vital capacity >= 60% of predicted within 1 month of treatment 4. may be on stable dose of riluzole for at least 30 days, or otherwise agree to not initiate riluzole for duration of the trial 5. may be on stable dose of edaravone for at least 30 days, otherwise agree to not initiate edaravone for duration of the trial 6. can travel to Stony Brook to receive medical care 7. must have a monitor who can be contacted at regular intervals to report on subject's clinical/psychiatric status Exclusion Criteria: 1. use of tracheostomy or mechanical ventilation within last 3 months 2. hepatic insufficiency or abnormal liver function 3. renal insufficiency 4. clinically significant psychiatric disorder 5. active malignancy 6. history of HIV, clinically significant chronic hepatitis, or other active infection 7. history of stomach or intestinal surgery or condition that could interfere with absorption, distribution, metabolism or secretion of study drug 8. history of alcohol or substance abuse within 3 months prior to entry (subjects will be instructed to refrain from alcohol during the study) 9. use of strong cytochrome P4503A inhibitors or inducers, anticonvulsants or other drugs known to interact strongly with perampanel. --- P4503A ---

Primary Outcomes

Measure: Incidence of treatment-emergent adverse events

Time: 9 months

Secondary Outcomes

Measure: Efficacy as measured by change in ALSFRS-R score (ALS functional rating scale-revised);

Time: 9 months

9 A Phase II Study of Ibrutinib Plus Rituximab and Lenalidomide in Elderly Patients With Newly Diagnosed MCL

This phase II trial studies how well ibrutinib plus rituximab and lenalidomide work in treating elderly participants with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ibrutinib plus rituximab and lenalidomide may work better in treating elderly participants with newly diagnosed mantle cell lymphoma.

NCT03232307 CCND1 Positive CD20-Positive Neoplastic Cells Present Mantle Cell Lymphoma Drug: Dexamethasone Drug: Ibrutinib Drug: Lenalidomide Biological: Rituximab
MeSH:Lymphoma Lymphoma, Mantle-Cell
HPO:Lymphoma

- Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors. --- P4503A ---

Primary Outcomes

Description: The overall response (complete response + partial response) at four months and toxicity at one month (during course 1) will be monitored simultaneously using the Bayesian approach of Thall, Simon, Estey as extended by Thall and Sung. Independence was assumed between or and toxicity, where toxicity is defined as dose-limiting toxicity (DLT) within cycle 1.

Measure: Overall response rate (ORR) per International Workshop Standardization Response Criteria for non-Hodgkin's lymphoma

Time: At 4 months (each cycle is 28 days)

Secondary Outcomes

Description: Toxicity data by type and severity will be summarized by frequency tables. For the efficacy endpoints, intend-to-treat analysis will be performed. For the toxicity endpoint, per-treated analysis will be performed to include any patient who received the treatment regardless of the eligibility nor the duration or dose of the treatment received.

Measure: Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03

Time: At 1 month (cycle 1 is 28 days)

Description: Summary statistics will be provided for continuous variables. Frequency tables will be used to summarize categorical variables. The distribution of time-to-event endpoints including overall survival and progression free survival will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-event outcomes.

Measure: Overall survival (OS)

Time: Up to 4 years

Description: Summary statistics will be provided for continuous variables. Frequency tables will be used to summarize categorical variables. The distribution of time-to-event endpoints including overall survival and progression free survival will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-event outcomes.

Measure: Progression-free survival

Time: Up to 4 years

10 A Phase 1b Study of TAK-659 in Combination With Venetoclax for Adult Patients With Previously Treated Non-Hodgkin Lymphoma

The purpose of this study is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of TAK-659 and venetoclax when administered in combination in participants with non-Hodgkin lymphoma (NHL) relapsed and/or refractory after at least 1 prior line of therapy and to evaluate safety and tolerability of TAK-659 and venetoclax when administered in combination.

NCT03357627 Lymphoma, Non-Hodgkin Lymphoma, Large B-cell, Diffuse Lymphoma, Follicular Drug: TAK-659 Drug: Venetoclax
MeSH:Lymphoma Lymphoma, Non-Hodgkin Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular
HPO:Lymphoma Non-Hodgkin lymphoma

Use or consumption of: - Medications or supplements that are known to be strong or moderate Cytochrome P4503A (CYP3A) inhibitors or strong or moderate CYP3A inducers and/or P-glycoprotein (P-gp) inhibitors or inducers within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) before the first dose of study drugs. --- P4503A ---

Primary Outcomes

Description: Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), Version 5.0 DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications and that occur within the first cycle.

Measure: Number of Participants with a Dose Limiting Toxicity (DLT)

Time: Baseline up to 5 weeks

Description: AE Grades will be evaluated as per NCI CTCAE, version 5.0.

Measure: Percentage of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs), Grade 3 or Higher Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation

Time: Baseline up to 13 months

Secondary Outcomes

Measure: Cmax: Maximum Observed Plasma Concentration for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length is equal to [=] 35 days)

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: AUCτ: Area Under the Plasma Concentration-time Curve from Time 0 to Time Over the Dosing Interval for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: Oral Clearance (CL/F) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: Peak-trough Ratio (PTR) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: Accumulation Ratio (Rac) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: Trough Concentration (C trough) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Description: ORR is calculated as percentage of participants with complete response (CR) + percentage of participants with partial response (PR) as assessed by International Working Group (IWG) criteria for malignant lymphoma.

Measure: Overall Response Rate (ORR)

Time: Up to 12 months

Measure: Duration of Overall Response

Time: Up to 12 months

Description: CR rate is calculated as percentage of participants with CR as assessed by IWG criteria for malignant lymphoma.

Measure: CR Rate

Time: Up to 12 months

Measure: Duration of CR

Time: Up to 12 months

Description: TTP will be measured as the time in months from the first dose of study treatment to the date of the first documented disease progression as assessed using IWG criteria.

Measure: Time to Progression (TTP)

Time: Up to 13 months

Description: PFS is defined as the time from date of first study drug administration to the day of first documented disease progression or death due to any cause, whichever occurs first.

Measure: Progression-free Survival (PFS)

Time: Up to 18 months

11 Liposomal iRInotecan, Carboplatin or oXaliplatin in the First Line Treatment of Esophagogastric Cancer: a Randomized Phase 2 Study

This is a multi-center, open label, randomized phase II trial for patients with previously untreated metastatic or locally advanced esophagogastric cancer, using a pick the winner design to identify the best combination therapy in terms of progression free survival and neurotoxicity.

NCT03764553 Esophageal Cancer Drug: Liposomal Irinotecan Drug: Carboplatin Drug: Capecitabine Drug: Oxaliplatin Drug: 5-fluorouracil Drug: Leucovorin

- Current use or any use in last two weeks of strong cytochrome P4503A (CYP3A-enzyme), CYP2C8, and/or strong UDP glucuronosyltransferase (UGT1A) inhibitors/inhibitors - Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness to use a reliable method of birth control, during therapy and for 3 months following the last dose of study treatment. --- P4503A ---

Primary Outcomes

Description: To compare the progression free survival

Measure: Progression free survival

Time: 42 months

Description: Number of participants with treatment-related Neurotoxicity according to CTCAE v4.0

Measure: Number of participants with treatment-related Neurotoxicity

Time: 42 months

Secondary Outcomes

Description: To determine the overall survival of F-Nal-IRI, capecitabine/Carboplatin (CapCar) and capecitabine/oxaliplatin (CapOx)

Measure: Overall survival

Time: 54 months

Description: To determine the response rate of F-Nal-IRI, CapCar and CapOx

Measure: response rate

Time: 42 months

Description: To determine the adverse events of F-Nal-IRI, CapCar and CapOx according to NCI common toxicity criteria (CTC) version 4

Measure: adverse events

Time: 42 months

Description: Overall Quality of life ranging from 0-100 with 100 being best Quality of Life

Measure: Quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ C30))

Time: 42 months

Description: The percentage of patients proceeding to subsequent lines of treatment after progression and describe the types of treatment.

Measure: percentage subsequent treatment lines

Time: 42 months

Description: Reasons for forgoing subsequent treatment after progression on first-line treatment

Measure: the reasons for forgoing subsequent treatment

Time: 42 months

Other Outcomes

Description: Percentage of stroma and tumor immune infiltrate in metastatic tumor tissue as predictor of response to treatment and survival.

Measure: Tumor micro environment

Time: 54 months

Description: Concentration of ADAM12 in blood

Measure: Stromal markers in blood

Time: 54 months

Description: Growth velocity of tumor organoids after treatment measured in days

Measure: Growth velocity of patient derived tumor organoids

Time: 54 months

Description: Concentration circulating tumour DNA (ctDNA) as a marker of response to treatment

Measure: ctDNA

Time: 54 months

Description: Composition of the fecal microbiome as a potential biomarker for response to treatment and toxicity

Measure: Fecal microbiome

Time: 54 months

Description: The cost effectiveness in terms of QUALYs associated with treatment of F-Nal-IRI, CapCar and CapOx

Measure: Costs associated with treatment of F-Nal-IRI, CapCar and CapOx

Time: 54 months

Description: Expression of ADAM12 in metastatic tumor tissue

Measure: Stromal Markers in tumor

Time: 54 months

12 A Phase 2, Open-label Study of Zanubrutinib (BGB-3111) in Patients With Relapsed or Refractory Marginal Zone Lymphoma

This is a single arm study to evaluate the efficacy, safety and tolerability of zanubrutinib (BGB-3111) in participants with relapsed/refractory marginal zone lymphoma (R/R MZL).

NCT03846427 Marginal Zone Lymphoma Drug: Zanubrutinib
MeSH:Lymphoma Lymphoma, B-Cell, Marginal Zone
HPO:Lymphoma

Requires ongoing treatment with a strong Cytochrome P4503A (CYP3A) inhibitor or inducer 14. --- P4503A ---

Primary Outcomes

Measure: Overall response rate (ORR) determined by independent central review

Time: Up to 3 years

Secondary Outcomes

Measure: ORR by investigator assessment

Time: Up to 3 years

Measure: Progression-free survival (PFS)

Time: Up to 3 years

Measure: Overall survival (OS)

Time: Up to 3 years

Measure: Duration of response (DOR)

Time: Up to 3 years

Measure: Time to response (TTR)

Time: Up to 3 years

Measure: Participant-reported outcomes (PROs) as measured by the EuroQo EQ-5D-5L questionnaire

Time: Up to 3 years

Measure: PROs as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)

Time: Up to 3 years

Measure: Occurrence and severity of treatment-emergent adverse events (safety and tolerability)

Time: Up to 3 years


HPO Nodes


HP:0002664: Neoplasm
Genes 1489
WHCR ATP7A PHOX2B KRT17 IL2RG HMGA2 PORCN KRAS TET2 IDH2 FLT3 ERCC4 AR BRCA1 BRCA2 GATA1 TCF4 TCTN3 GPR101 SMAD7 KRT6B PIK3CA KCNJ10 MAP2K2 REST TTC37 MC2R TRPS1 SIX6 ALX4 PIK3CA BRAF TP53 STK11 TSR2 EXT2 EDN1 RNF43 TRNL1 ATM SDHC EXT1 BCL10 BAP1 NF1 OCRL TP53 CHD7 TINF2 ERCC6 NF1 MAFA PMS2 ASXL1 PHOX2B CTNNB1 CR2 RET TCTN3 C11ORF95 PTPN3 PIEZO2 ABCB11 SETBP1 PDCD10 LRP5 LMOD1 MALT1 ASXL1 LZTR1 TINF2 RAD51C RECQL4 MAP2K1 FOXO1 PTCH2 RPS20 FLI1 BMPR1A SMARCAD1 BMPR1A MAP3K8 DNASE1L3 SUFU TP53 FOXP1 PTCH1 PDGFRB ND1 PIK3CA ZSWIM6 SETD2 INS NRAS HBB MEN1 AIP CLCNKB RPS10 HFE COX2 TSC2 DHH CTRC MEN1 EYA1 BRCA1 GINS1 MSH3 GLI2 TRNS1 HABP2 SSX1 SUFU PRKN CD81 TNFSF12 MYH11 KIT VEGFC WWOX H19 SDHD FGF3 TNFRSF1B RMRP XRCC2 HRAS MTM1 EPHB2 PLCD1 NBN CDKN1B TUBB RECQL4 EDNRB VHL ACAN MSH6 CDKN2B DCC TJP2 HRAS CDKN2A VHL REST NKX2-1 ANTXR1 RPL35 DNM2 FGFR3 SNAI2 NLRP1 ACTG2 GNB1 EWSR1 CBFB NSD1 FLCN ERBB2 MLH1 H19 EIF2AK4 RPL10 TMEM107 TRNK RAD54L RAD51C INPP5E NFKB1 CDKN1A KDM6B F13B SLC26A2 TRNS1 RPL26 CYLD H19 PTEN PTPN11 DCLRE1C MPL FLCN NEK1 MITF MSH3 NUTM1 IL7 STAT3 TRNS2 TG ERCC3 MNX1 NRAS MLH3 TSC1 GLI3 CDK4 SDHC NF1 BRCA2 CIB1 ATRX BRCA2 ADAMTS3 ZFPM2 COL2A1 TET2 ZIC2 SLCO2A1 BLM GJA1 MAP3K1 PIK3CA SDHA RTEL1 CDK4 KCNH1 SH2B3 APC ESCO2 FANCC TERT USP9X APC RAD54B NF2 SDHB RPS14 PPP2R1B RPS19 RPL35A MSH2 WRAP53 RASA1 LMNA ACVRL1 POLH SDHB DIS3L2 PIGA GNPTAB CXCR4 MSH2 SLC25A13 BMP2 NNT PSENEN FOXI1 APC IL1RN MITF ACD PTEN MPL RUNX1 ERCC3 ERCC4 DLEC1 CHEK2 BRCA2 JAK2 SBDS BRCA1 SDHD SEMA3D MSH6 HFE TREM2 APC CCDC22 MINPP1 DISP1 FAM20C MAP2K1 ALK BRCA1 STIM1 SLC25A13 RFWD3 HRAS GLI1 TET2 DVL3 COL7A1 HMBS TFAP2A ICOS CALR PTEN UROD DKC1 FDPS LIG4 TXNRD2 SRSF2 ND5 SDHD CHEK2 NRAS BCL6 GPC3 XPC MEN1 ERCC2 AXIN2 MYC RAD51 GBA KIF1B SDHB EXT2 EXT2 NTHL1 SRY RPGRIP1L MPL MTOR CASP8 RB1CC1 IGF2 FANCC ERCC4 WRN PGM3 VHL ING1 PLAG1 WT1 MYLK KLLN PIK3CA G6PC RPS7 MCM4 ANTXR1 POLH BRCA2 DLL1 OGG1 WRN F13A1 SBDS EFL1 TAF15 GLI3 GPC3 KRAS CDKN2B MAPK1 DIS3L2 GPR101 NRTN DKC1 KLLN NSUN2 MAP3K1 ERBB2 PHKG2 SRGAP1 CYLD NBN ALK MAX WT1 ACTB PALB2 TBX18 FIBP CASP10 DVL1 TYR MSH2 RECQL4 PIGL EDN3 WT1 ATP7B RPL27 RET USP8 FGFR2 PDGFRL H19 CCND1 ATM AXIN2 COL7A1 AKT1 TERT MUTYH HOXD13 DICER1 THPO GDF5 CEL SDHB EXT2 SRP72 TERT TRNF TP53 LIN28B APC NPM1 FGFR3 PTEN SMPD1 SLC22A18 SDHC PRDM16 KIT STK11 RPL11 LETM1 CALR SDHC RB1 PIK3CA PLCB4 COL4A5 CASP8 SKI H19 COL1A1 CC2D2A CASP10 GCGR GLI3 PIK3CA RPS29 RSPO1 PTEN MYSM1 BAP1 SRY UBE2T BRCA1 USP8 COL7A1 RNASEH2B KIF1B MN1 RELA SMAD4 VHL SH3KBP1 BCR CD79B SRP54 SRP54 SSX2 CHRNG RPL18 NF1 WWOX RERE LZTS1 WT1 MSH3 TYROBP ASCL1 IKBKG ABCC6 FAH KIT GDNF FANCE TERT BIN1 FANCL KIF11 SDHB WDPCP SLC6A17 TP53 HNF1A KEAP1 POLE HSPA9 SMO PTCH2 PTCH1 PMS1 ELMO2 BCL2 NSD2 EXT1 SRD5A3 STAT6 MVD TERC SF3B1 MNX1 FGFR1 CYSLTR2 POU2AF1 SMARCB1 NOD2 GJB2 SDHC FLT4 KRT9 CDH1 IRF1 SEC23B MYCN MGMT RPL10 RPL5 KIF7 TCF3 KRAS MUTYH TMEM127 KRAS IGH CTSC GNAS CD28 WWOX HNF1A BUB1B MC1R WNT10A CBL WT1 BRAF ADAR GAS1 GTF2E2 SMARCB1 RPS17 PARN TMEM127 BRIP1 SHH SRC GNAI3 STAR GDNF SLC22A18 FOXH1 SNAI2 GPC4 TNFRSF13C KARS1 TBC1D24 BMPR1A TET2 CD27 CASP8 DHCR7 KDSR HNF1A SH3GL1 PNP USB1 TSC2 TRIP13 TMEM67 EDN3 PMS1 PTPN11 GNA11 CREB1 ADA RAG2 PRSS1 KCNQ1 GPR101 PRF1 MTAP FANCA MSH6 TRNQ BRCA2 KRT1 RNASEL POU6F2 ACD SCN9A APC NSD2 INTU BRAF POU6F2 BRCA2 RB1 GTF2H5 PIK3CA FANCM TARS1 BRAF CASR RET VHL GPR143 TRNP GCM2 TMEM231 CPLANE1 RPS15A SOX9 GFI1B EPCAM MEN1 TERT KRAS SDHAF2 NF1 TRIP13 GATA2 SLC26A4 APC MPLKIP SAMD9L IL6 GNAS IGH AKT1 FANCD2 ESR1 SDHA APC MYF6 RASGRP1 SMAD4 MLLT10 LIG4 CPLANE1 BRCA2 MC1R MRE11 DLST SUFU LMO1 SDHB ABCA5 RMRP SDHC NUP214 AKT1 SMARCD2 DLC1 C1S TRNW THPO CHEK2 KIT SLC37A4 BCHE KCNJ11 ARID1B APC2 SAMD9 TMC6 SLX4 TNFRSF13B FGFR1 TRNH RAD21 KCNN3 DKC1 VANGL1 AXIN2 TCOF1 RPS19 SLC26A2 GPR35 CR2 TFAP2A KRAS FGFR3 PRKCD JAK2 EGFR AIP CTNNB1 KCNJ10 FANCI LYST TET2 SLC25A11 TP53 TCTN3 MUTYH ANTXR2 SEMA3C MMP1 AKT1 PDX1 JAK2 TCIRG1 PTCH1 MUC5B EXT1 DNMT3A BMPR1A SERPINA1 FAN1 CDC73 PTCH2 PIK3CA H19 FERMT1 GPC3 RET RET APC PALLD LPP BRD4 GNAS BMPR1B MAPRE2 DICER1 CTC1 TAL1 DICER1 STK11 HRAS GATA1 BCL10 KCNE3 XRCC4 HNF4A BDNF KLF11 SF3B1 MLH3 GNAQ TRPV3 IGLL1 PAX7 CRKL GDNF GATA2 ARL6IP6 ENG PTCH1 NEK9 TSC1 RNF139 ERCC3 PDGFRA IL2RG CTHRC1 WT1 BAP1 ATP7A SRP54 ABCC8 ESCO2 GPC4 OFD1 TNFSF15 APPL1 RNF6 CTSA TNFRSF1B TP53 PHOX2B DCLRE1C DDB2 BCL10 BCR KRT14 ALX3 EVC2 CD70 SMARCB1 AHCY SDHAF2 RAD51D SPINK1 SDHD ATM GABRD WT1 FASLG CTBP1 NOTCH1 NF2 DPM1 ERCC6 STS PHOX2B BUB1 FLT4 L2HGDH LAMC2 NTHL1 STAG3 ENG SDHD CTNNB1 DAXX NRAS MST1 MSTO1 SLC26A4 RAF1 STS FGFR3 EXOC6B VAMP7 NELFA HRAS ANTXR2 LEMD3 TNFSF12 GPC4 MLH1 SMAD4 RAD50 SUFU TRIP13 REST GNAS CBL RHBDF2 ASXL1 SMAD4 TCF4 ERCC6 WT1 BRAF APC TRIM28 TERT DNAJC21 RPL15 PAX3 SETBP1 CDH1 GNAS SMARCB1 AKT1 ASCL1 KRAS NAB2 ERCC5 RECQL4 KRAS DNMT3A EDN3 POLD1 FAM149B1 CDKN1C KRAS TP53 SMARCE1 PTEN PALB2 SEMA4A TEK NBN NHP2 GPC3 ETV6 FGF8 COL11A2 SMAD4 RNASEH2A NRAS MC1R TDGF1 FGFRL1 FGFR1 CTNNB1 IGH DNAJC21 CCND1 RET DIS3L2 DHCR24 CARD14 BRCA2 SQSTM1 NFKB2 TRNQ NDP SFTPA2 PAX4 COL7A1 TP53 RSPRY1 IFNG HMMR PALB2 FAT4 MBTPS2 MDM2 KRAS GNAS C2CD3 POT1 ABL1 WNT5A FANCE ABL1 ICOS SDHD RAD21 NSD1 SOS1 IL12A LIG4 PIK3CA TBXT RAD51 EWSR1 FZD2 FLNA BRCA2 NRAS TWIST1 TET2 TSC1 INHBA CAT CTNNB1 PIGL IRF1 PTCH2 TRNH MLH1 GFI1 CDC73 RET FANCD2 EVC NF2 TNPO3 SOX2 DYNC2H1 HRAS NEK1 CCND1 KRT10 AKT1 KIT PALB2 VHL CYLD IL1B GJC2 MLH1 SDHC FGFR2 CYP2A6 FOXE1 ARMC5 ERCC2 SLC25A11 LAMA3 FLCN BRCA1 BIRC3 MVK TOP2A PDGFB TCF4 RFWD3 ATP6V1B2 GDNF GATA4 CTNNB1 CDKN1B C2CD3 BRCA2 FUZ STK11 AKT1 FGFR2 SHOX TGFBR1 BTK LEMD3 FIBP SF3B1 SUFU PRLR NR5A1 FN1 ERBB2 CD19 RNR1 PTPN11 KIT RAD51 WAS PTEN TGFBR2 RPS24 CYLD RNF113A MYO1H ALX3 JAK2 BLM CTNNB1 CDKN2A PARN SH2B3 POLD1 CHEK2 COX1 KRT1 EXT1 BRAF PRCC MSH2 GATA2 REST NRAS RB1 TINF2 BMPR1A NR4A3 AGGF1 SIX3 RAG1 ND4 COL2A1 CDKN2A SDHD TREX1 WNT10A SEC23B XPA MET TP53 CDKN1B RPS27 PCNA HMBS RPS26 KIT FGFR2 TRIM37 HPGD ERCC5 PAX6 SLX4 PICALM PSAP FCN3 BMPR1A USF3 XPC DNAJC21 KRT16 BUB3 H19-ICR GPC6 STAC3 RPS28 FANCA RNF43 AP2S1 PDGFB DYNC2LI1 CYP11B1 ABCA5 PTCH1 TERF2IP KRAS DYNC2LI1 CDH1 CDC73 TERC SPRED1 PDGFB TRNF MTMR14 MAD2L2 FOXI1 ERCC2 GJB4 KAT6B MSH6 FASLG KRAS SEC23A RUNX1 CD19 WASHC5 KIT HLA-DRB1 WRAP53 FLT3 CEP57 KDR TREX1 TMEM216 PDGFRA ERCC3 KIT NOTCH3 WIPF1 TERC CTLA4 NQO2 CDKN2A RSPO1 STK4 PTPN11 GJB2 KRAS MET SPINK1 PDGFRB RHOH BUB1 ND6 CDKN2C TFE3 EP300 CHIC2 HNF1B NUMA1 BRCA1 SRY FLCN MLH3 SCN10A GNPTAB KRAS NODAL TGFBR2 PPM1D DOCK8 EPAS1 PHOX2B OCA2 KCNQ1OT1 CYP2D6 ITK DICER1 PRKCD ASPSCR1 SUFU IDH1 RUNX1 ATRX FOXC2 MFN2 SAMD9L SCN4A KIF1B DHH POLE VHL POLR1D KCNAB2 BRAF SLC12A3 CARMIL2 ENPP1 NRAS LRRC8A KIT SH2B3 MST1R CEBPA NRAS MRAP TP53 ND5 FH LAMB3 CALR SLC37A4 PERP KLHDC8B FH SFTPC TGIF1 CHEK2 SLC17A9 SLC22A18 TERT CDH23 MDH2 KRT17 PTEN FGFR3 RB1 YY1 ELANE EP300 SPRTN GJB3 XPA IDH2 MAGT1 ATR GNA14 OFD1 IL7R GREM1 ESCO2 HRAS PRKAR1A MMP1 TP53 KRT17 COL14A1 RHBDF2 MPL OFD1 RYR1 IFIH1 SCN11A IDH1 JAK2 WT1 TP53 ARSA LIG4 CCBE1 FANCG KCNH1 ELANE COL18A1 HACE1 NUP214 MYC CD79A AR CDH1 BRIP1 WT1 BCR BUB1B ERCC3 KRIT1 NBN IGF2 FANCF PDGFRA BLNK PCGF2 MSH6 MEN1 FAS BRIP1 PTH1R SIX1 RNF6 BRAF DHCR7 BMPER BUB1B TP53 RET CTLA4 HABP2 ARHGAP26 DLST GCK ERCC2 RAD54L POLE HSPG2 GNA11 ADA SMAD4 BCL10 RB1 STAT1 TAF1 RPS14 BCR IL12RB1 IRF5 TMC8 TNFRSF13B CYP26C1 CALR POT1 MINPP1 POLR1C CD28 ATP7A HNF1B ERCC2 ACVR1 RPL31 VANGL1 TP63 ERCC4 SLC45A2 OFD1 LMX1B PIK3CA ASCC1 TET2 IGF2R BARD1 TUBB IGF2 BTK MSTO1 CIB1 PHB CDKN2A TNFRSF10B KIAA0753 TBX2 FOXE1 EPCAM TNFRSF13C SLC26A2 ATRX MGAT2 SKIV2L CXCR4 PIK3R1 RTEL1 TSC1 HAX1 SDHB PRKAR1A DDB2 GFI1 CDH23 XRCC3 PMVK TP53 PIK3CA GJB2 NF2 KLF6 AR ZSWIM6 SDHB CDC73 PIK3CA CCND1 GJB6 ATM SOS1 NOTCH3 DDX41 TSC2 FLT4 FGFR3 RASA1 GDF2 F5 PMS2 PTEN HBB TSC2 CASP10 ADA2 AIP WT1 LETM1 PNP COMP TRIM28 TP53 PALB2 RAD51C CCL2 CDC73 SH2D1A COX3 ZAP70 PIK3CA CYP11B2 PDGFRB PTPN11 PHOX2B FH KIT HNF4A RNASEH2C MYD88 PDE6D JAG1 TYR SEC23A FH NPM1 PHKA2 DICER1 PIK3CA HFE GNAQ DMRT3 MS4A1 MYH8 VANGL2 SHOX PUF60 GATA2 BAP1 B3GALT6 TRNS2 HRAS HDAC4 FANCG SAMHD1 GATA2 LIG4 AXIN1 TNFRSF4 OPCML PRKN FGFR2 ECM1 TGFBR2 LMNA WDPCP KCNQ1OT1 BLK GCM2 ALX1 NRAS KIT AAGAB FAH MAX RARA NEUROD1 TGFBR2 MYD88 PHF21A IDH1 MLH1 FANCB CPLX1 SMARCA4 EXTL3 AIP TERT BCL10 XIAP IGF2 SASH1 PIK3R1 PTEN NAGS TMC6 NBEAL2 NOP10 JAK2 SDHB MSH2 ECE1 BARD1 APC PMS2 CCM2 JAK2 MMEL1 RET SDHA SDHD IGHM CACNA1S FAS NR0B1 POT1 SPIB TAL2 NF2 CDON WT1 TET2 PTPRJ CD96 TRNL1 DOCK8 DCC MPL GNAQ CREBBP CDKN2A TRNK MSR1 KRT5 PRKAR1A ERBB3