SNPMiner Trials by Shray Alag


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Report for Mutation P4503A

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 13 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 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 An International, Phase 2, Open-Label, Randomized Study of BGB-3111 Combined With Obinutuzumab Compared With Obinutuzumab Monotherapy in Relapsed/ Refractory Follicular Lymphoma

The purpose of the study is to evaluate the efficacy, safety and tolerability and of BGB-3111plus obinutuzumab versus obinutuzumab alone in participants with relapsed/refractory non-Hodgkin follicular lymphoma.

NCT03332017 Relapsed/Refractory Follicular Non-Hodgkin Lymphoma Drug: BGB-3111 Drug: obinutuzumab
MeSH: Lymphoma Lymphoma, Follicular Lymphoma, Non-Hodgkin
HPO: Lymphoma Non-Hodgkin lymphoma

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

Primary Outcomes

Measure: Objective response rate (ORR)

Time: up to 3 years

Secondary Outcomes

Measure: Progression free survival (PFS)

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

Description: Safety and Tolerability

Measure: Incidence, timing, severity of treatment-emergent adverse events (TEAEs)

Time: up to 3 years

11 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

12 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

13 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 Margina 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


Lymphoma
Genes 133
ATM KRAS CD19 IGH DDX41 BCL10 BIRC3 FOXP1 MS4A1 TP63 RAG1 LIG4 NFKB2 MSH6 TERC RECQL4 NTHL1 WIPF1 CTC1 LYST NOP10 RASGRP1 TNFRSF1B XRCC4 PRKCD NHP2 MAGT1 TNFRSF13B IGH RMRP RUNX1 CTLA4 DCLRE1C FAS ICOS RNF43 NSUN2 XIAP IL7R CASP10 BCL6 CDKN2A ATM IL2RG RTEL1 PARN NBN KIT TNFRSF13C TCF4 ICOS TNFSF12 CHEK2 USB1 CD19 CR2 NRAS MSH2 WAS BCL10 CASP10 MYD88 COL14A1 PRKCD TNFRSF13B MYC MDM2 SH2D1A CCND1 BCL10 CFTR CD27 PGM3 TCF4 CHD7 IGH LIG4 BLM BCL2 TET2 HLA-DRB1 PRSS1 NPM1 KIF11 ITK WRAP53 RAD54B TINF2 FAS DKC1 APC CD81 LIG4 BLM CD28 DKC1 AAGAB RAG2 TNFRSF1B MLH1 TNFRSF13C DNASE1L3 NFKB1 PMS2 ASXL1 IL2RG PRF1 PTEN MALT1 RAD54L CTLA4 CD28 PNP SRSF2 TNFSF12 STAT3 POLE ADA CR2 ADA FASLG PIK3R1 TP53 CTRC ZAP70 MYD88 RB1 RMRP SPINK1 TERT KLHDC8B NBN RHOH
Non-Hodgkin lymphoma
Genes 32
ATM FAS CASP10 CTLA4 FAS BCL10 CD28 BIRC3 FOXP1 TNFRSF1B MYC CCND1 ASXL1 ATM MALT1 CTLA4 CD28 SRSF2 KIT POLE IGH ADA TET2 FASLG PIK3R1 NTHL1 RASGRP1 TNFRSF1B PRKCD NBN RHOH IGH
Non-small cell lung carcinoma
Genes 3
TP53 TP53 BAP1
Neoplasm of the lung
Genes 61
REST GPC3 WT1 HPGD BRAF PIK3CA TP53 TRIM28 RB1 TRIP13 SLCO2A1 AKT1 CASP8 KRAS TSC1 POU6F2 EWSR1 PRKN LMNA NAB2 TERT TSC2 SLC22A18 BRCA2 PPP2R1B STAT6 STK11 MUC5B ERBB2 TSC2 MBTPS2 BAP1 TSC2 DICER1 PDGFRB PERP EGFR TSC1 DIS3L2 NOTCH3 KEAP1 DICER1 DICER1 WT1 TSC1 C11ORF95 IRF1 CYP2A6 WRN RELA WT1 PTEN SFTPC SFTPA2 ERCC6 TRPV3 TP53 H19 TRIM28 FASLG MAP3K8
Neoplasm
Genes 1473
GPC3 LETM1 LZTS1 REST MPL ARID1B RPL18 MGMT GLI3 BIRC3 ZSWIM6 TRNS2 ETV6 HNF1B KIT BRCA1 SUFU PLAG1 SOX9 TP63 CTSC RASA1 ATRX TRIM37 SUFU BTK CYP11B1 NOTCH3 EPCAM PORCN PIGL AR TET2 FH TGIF1 HMBS ATRX TREX1 SMAD4 KRT17 FGFR1 WDPCP SF3B1 GPR101 KIT GLI1 SLC25A11 XRCC4 SDHD PRKCD RNF43 SDHB BAP1 EGFR PIGA NF1 ASCL1 MPL RET C2CD3 GDNF NR5A1 DICER1 TNFRSF4 CASP10 TERC FGF8 PSAP CIB1 SLC22A18 PTCH2 ENPP1 CDKN2C SLC25A11 GPR101 KIT AXIN2 TREX1 DYNC2LI1 ERCC4 RPS14 COMP TINF2 FOXE1 DHCR24 RPS7 TYROBP HOXD13 ERBB2 BLK EYA1 ZFPM2 ERCC6 NLRP1 STAC3 ERCC5 NUTM1 MEN1 WT1 BCL10 GNPTAB KRAS TP53 KDR PUF60 TRNF FCN3 SDHC KCNH1 MSTO1 EP300 BUB1B GNA11 KCNE3 DOCK8 SEMA3C ACD GLI2 SMPD1 SUFU NF1 PTCH2 ACAN DCC WT1 CTSA KIF11 BCR SRGAP1 KIT PTEN LEMD3 MLLT10 SCN4A BRCA2 BMPR1A NOTCH3 SEC23A CDKN1C BARD1 SPIB RSPO1 MC2R CALR ATP6V1B2 NBN RAD54L MST1 SUFU MYCN TMEM127 SRD5A3 IGF2 CD28 RUNX1 OGG1 HAX1 SDHC CTNNB1 MST1R SDHA IGF2 KCNJ10 IL12RB1 MEN1 RAD51 TFE3 ND5 MMEL1 MVK APC FLI1 RNF6 NF1 BRCA2 SUFU GPC6 NR4A3 TTC37 KIT NRTN BLNK IGH SPRED1 TXNRD2 IGF2R FOXP1 BUB1B SOS1 LRP5 GJB2 DNMT3A PMS2 PRKN RET MSH6 ACVRL1 MPLKIP ERCC2 AIP GNAS TAL1 NNT RECQL4 PMS1 DLL1 EIF2AK4 STAT6 MNX1 SDHB KRAS MEN1 MN1 SH2B3 EFL1 VHL KLLN RMRP RUNX1 SIX3 GDNF FANCD2 EXT1 CDH23 BRD4 DLEC1 NODAL CARMIL2 SDHB MSH2 HMBS SMAD4 SRP72 NRAS DOCK8 SPRTN BRCA1 MAP2K1 KRT14 LETM1 TERT MAP2K2 HRAS WHCR WT1 IDH1 TMEM107 SCN10A GJB3 SDHD KRAS GATA1 RPS20 GJB2 SLX4 USP8 PRKAR1A CR2 JAK2 HFE MPL POT1 BRCA2 GNAI3 SDHB ALK OCA2 TP53 GPC4 ACTG2 CTNNB1 HSPG2 AR FGFR1 STK4 MET TMC8 MRAP MSH6 CCBE1 EWSR1 LMO1 EDN3 LEMD3 PGM3 FGFR3 CASP8 RB1CC1 SCN9A FANCL TG SDHD COX3 IGF2 COL11A2 AGGF1 GPR101 PRKN PLCB4 SDHD NF1 GTF2E2 MAP2K1 ESCO2 CDC73 WRAP53 TET2 PDGFRB RNASEH2A RAD21 HNF1A TGFBR2 POLD1 COX2 TNFRSF10B MINPP1 DNAJC21 FAS EXT1 SLC26A2 APC SDHAF2 TINF2 LIG4 POLR1D WWOX TMC6 RPS19 ERCC2 SASH1 MC1R MVD SEC23B CYP2A6 GPC3 KIT HRAS RAD54L SDHA GDNF NKX2-1 GFI1 ALX3 STAT3 MYH11 DYNC2LI1 FGFR2 TCOF1 PTEN MAFA PIK3R1 SLC25A13 HRAS VHL COL7A1 GNAS FGFR2 PIK3CA GPC4 DICER1 ERCC3 PIK3CA RAD51C RB1 RMRP MLH3 ATM COL7A1 LIG4 NF1 VAMP7 RPL35A RB1 SETD2 BCL10 LPP NRAS KRAS ABCA5 ERCC2 PDE6D KCNQ1OT1 MS4A1 SLC22A18 APC LIG4 JAK2 FANCD2 GAS1 STAG3 NRAS PALLD SLC22A18 RFWD3 PPP2R1B APC PTPN11 PTEN WIPF1 PIK3CA NOP10 IL7 UROD TNFRSF1B TP53 REST SLC37A4 NHP2 CXCR4 KIT CYSLTR2 FZD2 ALX4 BMPR1A SRY TRNQ SDHD PIGL CCM2 FIBP FANCI GJB4 SPINK1 RPL10 NSD2 MAP3K1 RET CDK4 HSPA9 TET2 GFI1B MAD2L2 DCC AP2S1 SMAD7 BRCA2 TRNK ERCC3 BRCA1 ELANE SFTPC PTH1R COL1A1 FUZ OFD1 RET FLT4 PRKAR1A SBDS RPL26 SMARCE1 SMARCAD1 MSH2 BCR GPR35 INTU FANCA STAT1 ANTXR2 FGFRL1 TUBB BRAF SLX4 CASP10 TERT RAD21 MTOR TRIP13 MYD88 DPM1 RSPO1 PTPN11 CTNNB1 AIP PTEN VANGL1 CYP2D6 RPS10 GCK KRT16 DNAJC21 BCL2 AKT1 KRAS KLF6 NOTCH1 FLNA MAX NF2 PALB2 TP53 PSENEN RNF6 TSC1 HNF1B TP53 RFWD3 SDHD PERP TP53 DIS3L2 B3GALT6 STS PDGFB SMARCB1 BRAF BRIP1 CBFB BUB1 BLM INHBA CALR NBN MLH3 TAF1 MLF1 PIK3CA MSH2 CTLA4 ND6 PALB2 WT1 PTCH1 POLE ADA MC1R FLT4 ATP7A MLH3 SMO TRNF NRAS LMNA DLST TRNL1 MTAP TP53 ZAP70 SDHB CHEK2 PALB2 FLT4 CDK4 NBN MSR1 CC2D2A TNPO3 ECE1 RPS15A NAGS TMEM67 HNF1A PIK3CA ATP7A AKT1 NRAS SDHAF2 CXCR4 TSC2 NF2 EPHB2 WDPCP OFD1 BUB1 FLT3 APC SMARCA4 CDKN2A RPS29 MCM4 PDGFRA ESCO2 CTC1 ESR1 SDHB MSH6 APC HABP2 GNAQ KIF1B SH3GL1 CD70 MPL IGH ZIC2 GCM2 VEGFC HRAS CTNNB1 KCNH1 LRRC8A BRAF FAS ICOS NSD1 RNF43 AKT1 BIN1 DLC1 SH2B3 RARA WNT10A CARD14 SDHC EXOC6B ESCO2 POLR1C G6PC MSH6 KRT1 PDX1 TNFRSF13C ERCC3 EVC SNAI2 CD79A BRCA1 RNASEH2B CCND1 TP53 RPS19 H19 H19 BRCA2 TFAP2A ARMC5 FASLG FGFR3 APC F5 EDN1 MAP3K8 AIP APC AKT1 TERC CCND1 CEL MYC TP53 GPC4 ERCC5 HNF1A POLE DAXX NUP214 TRIP13 AKT1 TET2 CDC73 ND1 MUTYH PIK3R1 TERT CEBPA EXT2 OCRL DIS3L2 ADAR TGFBR2 BRCA2 MRE11 SOS1 HNF4A FAH TMEM127 WT1 AXIN2 TCF4 EDN3 PTPN3 KRAS SEMA4A PIK3CA XPA MFN2 TINF2 PIK3CA APPL1 RUNX1 GNPTAB FGFR3 NRAS PDCD10 RAG2 PTEN CTNNB1 SOX2 BMPR1A HBB TERT USP9X NFKB1 FANCC PRF1 WRN SRY SRSF2 PMS2 RHBDF2 PHOX2B RPS17 PAX3 RECQL4 KIF1B SQSTM1 RB1 EXT1 XPC CYLD TOP2A MYD88 CDKN1B TET2 GJB2 PTEN UBE2T RTEL1 PTCH1 KLHDC8B GATA1 POLH JAK2 RHOH FLCN DCLRE1C MTMR14 GTF2H5 PTEN SBDS TBC1D24 PAX7 AR TP53 ASPSCR1 MTM1 RECQL4 ERCC2 TGFBR2 ERCC4 JAK2 SF3B1 CDKN2B XPC GATA4 KIT POU2AF1 BRCA2 GREM1 CDON NTHL1 DICER1 GINS1 ATM RAD51D SHOX EXT1 RASGRP1 WT1 GATA2 NF2 ERCC4 TUBB MBTPS2 DHCR7 MYLK KCNN3 TCTN3 TMEM216 TMEM231 KRT1 CTNNB1 MPL PDGFRB FANCG RPGRIP1L KEAP1 DICER1 WT1 BAP1 FOXI1 ERCC4 CDKN2A FGFR3 KDSR CBL HRAS BMPR1A DISP1 RELA MAP3K1 PARN BCR ENG COL7A1 LMOD1 KRAS PAX6 SNAI2 GLI3 FANCF FOXO1 RPL15 TBX18 TRPV3 PIK3CA NRAS CDH1 GNAS SMARCB1 KLF11 ADA2 EDN3 POU6F2 CDH1 GNAS IL1B SMAD4 H19-ICR SDHB STK11 NF2 TRIM28 SEC23A SLCO2A1 BRCA2 BRAF DNMT3A MDM2 BMP2 BRCA2 DHH NRAS POU6F2 CTBP1 PTCH2 FLCN CALR BAP1 LIG4 HRAS REST BRAF SAMD9 NDP TYR KRT17 MUC5B PRSS1 MEN1 NPM1 ITK MSH2 CYLD TAL2 SRP54 IFIH1 HMMR TCTN3 ND5 JAK2 FAM20C RET NEK9 DMRT3 KRAS MINPP1 SH3KBP1 THPO FAH KRT5 JAK2 PHKG2 TSC1 TNFRSF13C MEN1 FH RPL31 FANCG PIK3CA IL2RG DNAJC21 VANGL2 MYO1H ALX1 CDKN2A AIP H19 NRAS TWIST1 PTEN TRNK TRPS1 RPS26 MAPRE2 RPS27 TCF3 KRT17 ERCC6 DHH MMP1 FGFR1 SEMA3D PTCH1 ABL1 CDKN2A SKI APC WWOX ZSWIM6 NF2 WNT10A KRAS GPC3 REST GJB6 HRAS VHL CTNNB1 TGFBR1 IL6 TDGF1 RPL11 IL1RN BRCA1 MGAT2 POT1 ASCC1 XPA TBX2 FLCN HFE NTHL1 SMARCB1 DVL3 TRNH IDH1 FANCA LAMB3 CD79B RAD51C PRDM16 PHOX2B GNAQ CCL2 PDGFRA CREB1 SRP54 PIEZO2 TRNL1 GBA GNAS WNT5A PIK3CA STS FANCB KRAS MAGT1 RAD51 IDH1 TNFRSF13B TREM2 GABRD BCL10 SKIV2L POLD1 KRIT1 KRAS ARSA SMAD4 RAD51 TP53 DIS3L2 KIAA0753 PRLR CD96 LZTR1 WRN GATA2 EDNRB MUTYH ATM CHIC2 TP53 CYLD PAX4 SLC26A4 RTEL1 VHL NEK1 TRNS1 GCM2 TYR ATP7B CTHRC1 BRAF ASXL1 OFD1 MLH1 CDKN1A PHOX2B XRCC2 CD19 RB1 FOXC2 TRIM28 EWSR1 TERT GNA11 F13B CDKN2A KARS1 BCL10 TP53 WT1 CDKN2A FDPS KIT COX1 COL14A1 VHL WT1 TERT SMAD4 STAR NUMA1 RPL5 PDGFB PCGF2 CFTR KCNQ1OT1 KIT GJA1 GNAQ CD27 FANCC IDH2 EVC2 BRCA2 TCF4 KRAS PIK3CA CDC73 ACVR1 BRIP1 TRNW PRCC GCGR CDKN1B STK11 SCN11A TGFBR2 AXIN2 ERBB2 RPL35 APC TSC2 IL12A SSX2 TET2 KIF1B DICER1 TRNP BTK CCDC22 PDGFRA ALX3 ADAMTS3 CD81 RET DKC1 GLI3 FGF3 SMAD4 STK11 ERCC6 WT1 ELANE C11ORF95 SAMD9L SLC45A2 NQO2 PTPN11 ATR PDGFRL TNFSF12 BRCA2 ADA BUB1B FASLG GDF5 KRAS CPLANE1 CREBBP CDC73 CLCNKB GATA2 CTRC SDHA ACTB APC BMPER SPINK1 APC2 MC1R FOXI1 DYNC2H1 KIT PPM1D SDHC NSD1 SDHC DDX41 ANTXR1 CASP8 F13A1 SUFU INS NUP214 ANTXR2 KIF7 NFKB2 ABCC8 TARS1 ERCC3 TCIRG1 ND4 ERCC2 GNAS TERT WASHC5 SLC49A4 RERE CALR MSH3 PHOX2B SLC25A13 BMPR1B CYLD SIX6 ASCL1 IDH2 FAN1 CHRNG CBL NEUROD1 MSH3 THPO VANGL1 CDKN2B TAF15 PTCH2 HMGA2 MSH6 CHEK2 FN1 GATA2 IRF1 KRAS BMPR1A NPM1 ERCC3 CDH1 ALK DNM2 ERBB3 PTPN11 DLST MUTYH PARN GFI1 NBN FGFR3 CHEK2 EP300 RNF113A TNFSF15 TEK TERF2IP ICOS COL18A1 TNFSF12 BRAF CHEK2 IFNG TMC6 USB1 KDM6B GJC2 SLC26A2 MDH2 TP53 ENG MLH1 KRT6B MNX1 PDGFB TRNH POLE CASP10 HPGD TET2 RB1 PHOX2B JAG1 GNB1 ACD TNFRSF13B MYC BRAF TSC1 SAMD9L BCL10 H19 POT1 USP8 IGF2 OFD1 CYP11B2 KCNQ1 CDH1 LMX1B TET2 ANTXR1 JAK2 SMARCB1 ELMO2 PTCH1 SIX1 L2HGDH WRAP53 BUB3 AXIN1 RET KCNJ11 ABL1 FANCE RAD54B FANCM TSC2 MAX IGHM TSC1 HACE1 CASR RNF139 MITF RAF1 WT1 TCTN3 POLH LIG4 TP53 KRT10 AAGAB SRY RAD50 TNFRSF1B TRNQ DNASE1L3 FAM149B1 KRT9 VHL FLCN TBXT SLC37A4 DKC1 PNP DDB2 SETBP1 ECM1 MSH2 CR2 COL2A1 COL7A1 MLH1 FH SFTPA2 PIK3CA FOXH1 MET HNF4A H19 KAT6B GPR143 PHB PMS1 ATP7A FAT4 TJP2 TFAP2A GDF2 AHCY TSC2 CD19 TRNS1 BDNF TRIP13 AKT1 FGFR2 RAG1 BRCA1 SDHC MLH1 XRCC3 NSD2 LMNA SDHC TERC EXT2 PIK3CA MSH3 SDHD SRC CHEK2 C1S ABCA5 HBB RYR1 FGFR2 CDC73 KIT FANCE RET LYST KCNJ10 BCHE HDAC4 INPP5E CRKL PHOX2B BAP1 CPLX1 PDGFRB ARL6IP6 RNASEL SETBP1 CTLA4 PALB2 DCLRE1C NSUN2 XIAP TRNS2 BMPR1A IL7R BCL6 COL4A5 PIK3CA NOD2 PRKAR1A NELFA IL2RG MYH8 RHBDF2 IGLL1 PIK3CA SERPINA1 FOXE1 ARHGAP26 TCF4 MITF ABCB11 ERBB2 GNA14 SLC26A2 NSD1 SH2B3 STK11 PTCH1 GDNF RPL27 DHCR7 WAS CIB1 SHH CACNA1S LIN28B SF3B1 ATM PRKCD RPS24 LAMA3 ATRX CASP8 AKT1 OPCML HFE SH2D1A ING1 CCND1 SLC12A3 HABP2 H19 LAMC2 RAD51C NAB2 NRAS MAPK1 CPLANE1 CYP26C1 CDKN1B CHD7 IGH MYF6 BLM ASXL1 FH NEK1 HLA-DRB1 SLC26A4 RPS14 SHOX RNASEH2C SMARCD2 GATA2 CDH23 WT1 EPCAM NR0B1 KLLN DVL1 SEC23B GPC3 SLC17A9 BRCA1 SRP54 DKC1 RECQL4 CD28 PTPN11 HRAS NBEAL2 BARD1 MLH1 DDB2 PMS2 IRF1 ABCC6 EXT2 ASXL1 TSR2 PTEN MALT1 PTEN BCR PALB2 BRIP1 SSX1 PHKA2 FGFR2 SDHB FERMT1 KCNAB2 FLT3 PMVK MSTO1 CEP57 MMP1 PICALM IRF5 TP53 PTPRJ RNR1 WWOX PLCD1 RPS28 FGFR3 COL2A1 IKBKG TERT RASA1 SAMHD1 PHF21A
Leukemia
Genes 190
ATM KRAS KIT RPS15A NF1 MPL RPL35A RPL11 RPL18 DDX41 SBDS LPP ETV6 BUB1B F13A1 DNMT3A JAK2 NUP214 FANCD2 MSH6 FANCA PIGL NRAS TCIRG1 BUB1 TET2 FLT3 TAL1 ATRX TREX1 PDGFRA SRP54 RPS29 PTPN11 CALR FANCE WIPF1 SF3B1 GATA2 GLI1 STS SH3GL1 XRCC4 MPL SH2B3 EFL1 PIGA TREM2 CBL MPL RUNX1 MPL PIGL THPO FANCG NSD1 BRD4 NSUN2 SH2B3 RARA GATA2 NPM1 CBL CHIC2 ERBB3 GFI1 TERT KIT BCR ARHGAP26 DYNC2LI1 EVC SCN10A GATA1 ELANE RNASEH2B RPS14 SH2B3 JAK2 RPL15 SBDS NRAS RPL26 RPL27 ADA2 RPS7 TYROBP F13B MSH2 BCR WAS TERC TP53 TRIP13 MYD88 NUTM1 RPS24 GNB1 TP53 DNMT3A TERT NUMA1 NUP214 RPL5 SAMD9L TET2 CFTR POT1 FANCC RPS10 EP300 EVC2 BUB1B CEBPA BRCA2 DNAJC21 CALR SCN9A LIG4 ADAR BLM TET2 JAK2 SMPD1 RNASEH2C SCN11A GATA2 BUB3 PRSS1 KIF11 BCR RPL35 TAL2 SRP54 IFIH1 ABL1 PDGFRB KRAS RNASEH2A TET2 MLLT10 SRP54 DNAJC21 DKC1 RUNX1 APC LIG4 CBFB BLM THPO CALR NBN JAK2 MLH1 RPS19 ELANE SAMD9L RPL31 PMS2 ASXL1 TSR2 MLF1 PIK3CA DNAJC21 RUNX1 GFI1 SRSF2 SETBP1 HAX1 RPS26 RPS17 FLT3 RPS27 PIK3R1 KRAS CEP57 PICALM CREBBP GATA2 CTRC MYD88 TET2 RPS28 ABL1 RB1 SPINK1 GATA1 NBN JAK2 SAMHD1
Abnormal anterior horn cell morphology
Genes 18
ASAH1 TFG CPLANE1 CEP126 DCTN1 IGHMBP2 PRPH SMN1 SMN2 VRK1 SMN1 ATXN3 UBA1 SOD1 SMN1 NEFH SETX GLE1
Polyneuropathy
Genes 59
GCLC NAGS SLC12A6 ERCC6 AIFM1 C12ORF65 PSAP CYP7B1 COX3 PEX11B ATP6 ARL6IP1 COQ7 OPA1 PIK3R5 SH3TC2 LDB3 PEX12 ALAD ABHD12 FAM126A EDNRB NGLY1 ND2 ABCD1 CYTB PEX7 RPIA GSN TBC1D24 GRM1 SNAP29 TTR ND5 PDK3 ND4 GSN DGUOK PMM2 ND4L DHH ND1 TTR SEPTIN9 FUCA1 DARS2 PRPS1 SETX SLC25A19 PDYN ATP7B ERCC8 DHH DMXL2 MYOT MYD88 ARL6IP1 CD59 ND6
Amyotrophic lateral sclerosis
Genes 77
MATR3 TREM2 VCP FUS PRPH ANXA11 ALS2 C9ORF72 HNRNPA1 PRPH PFN1 FUS UBQLN2 SQSTM1 ATXN2 MATR3 TBK1 CHMP2B SIGMAR1 PON1 OPTN MAPT MATR3 ANG VCP DAO ERBB4 SQSTM1 SPG11 NEFH EPHA4 CCNF ANG TARDBP DCTN1 PON2 SOD1 ANXA11 UBQLN2 GLT8D1 FIG4 OPTN DCTN1 TARDBP CHMP2B VAPB SIGMAR1 HNRNPA1 CFAP410 PFN1 PSEN1 HNRNPA1 SOD1 SPG11 C9ORF72 ALS2 TRPM7 ERBB4 CHCHD10 KIF5A VAPB PON3 FIG4 GLE1 NEK1 CHCHD10 PPARGC1A TUBA4A VCP UNC13A TBK1 VCP HNRNPA2B1 TAF15 FUS NEFH SETX
Lymphoid leukemia