A Study of Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy

Study Overview
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Brief Summary
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The primary objective for this study is to assess the safety and tolerability as well as preliminary efficacy of venetoclax in combination with cobimetinib, and venetoclax in combination with idasanutlin in patients with relapsed or refractory acute myeloid leukemia (R/R) AML who are not eligible for cytotoxic therapy.

Official Title
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A Phase IB Multi-Arm Study With Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: Cobimetinib
* Drug: Idasanutlin
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmation of relapsed or refractory AML after prior anti-leukemic therapy by WHO classification Ineligible for cytotoxic therapy defined by the following: a. Age (>/=) 75 years or b. age 18- 74 years with at least one of the following comorbidities: i. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3 ii. Cardiac history of congestive heart failure requiring treatment or ejection fraction (</=) 50% or chronic stable angina iii. Diffusing capacity of the lungs for carbon monoxide (</=) 65% or forced expiratory volume in the first second of expiration (</=) 65% iv. Creatinine clearance (>/=) 30 mL/min to< 45 mL/min v. any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Medical Monitor before screening and study enrollment. Life expectancy of at least 12 weeks Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Adequate liver and renal function Exclusion Criteria: Patients with acute promyelocytic leukemia (French-American-British [FAB] class M3 AML) Known active central nervous system (CNS) involvement with AML at study entry ECOG Performance Status (>/=) 3 in patients who are (>/=) 75 years old or ECOG Performance Status of 4, regardless of age Prior exposure to Bcl-2 inhibitors, murine double minute 2 (MDM2) antagonists or prior exposure to experimental treatment targeting Raf, mitogen-activated protein kinase (MEK), or the mitogen-activated protein kinase (MAPK) RAS/RAF/MEK/ERK MAPK pathway Positive for hepatitis C virus (HCV), hepatitis B surface antigen (HBsAg) and known history of HIV, malignancy, active infection and cardiovascular diseases (CVs) Received strong cytochrome (CYP) 3A inhibitors, moderate CYP3A inhibitors, strong CYP3A inducers and moderate CYP3A inducers within 7 days prior to initiation of study treatment History of symptomatic Clostridium difficile infection within 1 month prior to dosing Additional arm specific exclusion criteria: Dose Escalation Arm A (Venetoclax and Cobimetinib): History or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower Arm B (Venetoclax and Idasanutlin): Received the following within 7 days prior to the initiation of study treatment: Strong CYP2C8 inhibitors or CYP2C8 substrates, OATP1B1/3 substrates Received the following within 14 days prior to the initiation of study treatment: Strong CYP2C8 inducers History of liver cirrhosis by radiologic, clinical or laboratory data, or biopsy despite normal liver function tests Received treatment with oral or parenteral anticoagulants/anti-platelet agents within 7 days prior to initiation of study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation: Arm A (Venetoclax 400mg + Cobi 40mg)<br>Participants received Venetoclax 400mg daily on Days 1-28 of each 28 day treatment cycle and Cobimetinib 40mg daily on Days 1-21 of each 28-day treatment cycle. | Drug: Cobimetinib<br>* Cobimetinib will be administered orally as per schedule in Arm description.<br>Drug: Venetoclax<br>* Venetoclax will be administered orally as per schedule in Arm description.<br>|
| Experimental: Dose Escalation: Arm A (Venetoclax 600mg + Cobi 40mg)<br>Participants received Venetoclax 600mg daily on Days 1-28 of each 28 day treatment cycle and Cobimetinib 40mg daily on Days 1-21 of each 28-day treatment cycle. | Drug: Cobimetinib<br>* Cobimetinib will be administered orally as per schedule in Arm description.<br>Drug: Venetoclax<br>* Venetoclax will be administered orally as per schedule in Arm description.<br>|
| Experimental: Dose Escalation: Arm A (Venetoclax 800mg + Cobi 40mg)<br>Participants received Venetoclax 800mg daily on Days 1-28 of each 28 day treatment cycle and Cobimetinib 40mg daily on Days 1-21 of each 28-day treatment cycle. | Drug: Cobimetinib<br>* Cobimetinib will be administered orally as per schedule in Arm description.<br>Drug: Venetoclax<br>* Venetoclax will be administered orally as per schedule in Arm description.<br>|
| Experimental: Dose Escalation: Arm A (Venetoclax 400mg + Cobi 60mg)<br>Participants received Venetoclax 400mg daily on Days 1-28 of each 28 day treatment cycle and Cobimetinib 60mg daily on Days 1-21 of each 28-day treatment cycle. | Drug: Cobimetinib<br>* Cobimetinib will be administered orally as per schedule in Arm description.<br>Drug: Venetoclax<br>* Venetoclax will be administered orally as per schedule in Arm description.<br>|
| Experimental: Dose Escalation: Arm B (Venetoclax 400mg + Ida 200mg)<br>Participants received Venetoclax 400mg daily on Days 1-28 of each 28 day treatment cycle and Idasanutlin 200mg daily or twice daily on Days 1-5 of each 28 day treatment cycle. | Drug: Idasanutlin<br>* Idasanutlin will be administered orally as per schedule in Arm description.<br>Drug: Venetoclax<br>* Venetoclax will be administered orally as per schedule in Arm description.<br>|
| Experimental: Dose Escalation: Arm B (Venetoclax 600mg + Ida 150mg)<br>Participants received Venetoclax 600mg daily on Days 1-28 of each 28 day treatment cycle and Idasanutlin 150mg daily or twice daily on Days 1-5 of each 28 day treatment cycle. | Drug: Idasanutlin<br>* Idasanutlin will be administered orally as per schedule in Arm description.<br>Drug: Venetoclax<br>* Venetoclax will be administered orally as per schedule in Arm description.<br>|
| Experimental: Dose Escalation: Arm B (Venetoclax 600mg + Ida 200mg)<br>Participants received Venetoclax 600mg daily on Days 1-28 of each 28 day treatment cycle and Idasanutlin 200mg daily or twice daily on Days 1-5 of each 28 day treatment cycle. | Drug: Idasanutlin<br>* Idasanutlin will be administered orally as per schedule in Arm description.<br>Drug: Venetoclax<br>* Venetoclax will be administered orally as per schedule in Arm description.<br>|
| Experimental: Dose Escalation: Arm B (Venetoclax 400mg + Ida 400mg)<br>Participants received Venetoclax 400mg daily on Days 1-28 of each 28 day treatment cycle and Idasanutlin 400mg daily or twice daily on Days 1-5 of each 28 day treatment cycle. | Drug: Idasanutlin<br>* Idasanutlin will be administered orally as per schedule in Arm description.<br>Drug: Venetoclax<br>* Venetoclax will be administered orally as per schedule in Arm description.<br>|
| Experimental: Dose Optimisation: Arm B (Ven 600mg (Day 1 to 21) + Ida 150mg)<br>Participants received Venetoclax 600mg daily on Days 1-21 of each 28 day treatment cycle and Idasanutlin 150mg daily on Days 1-5 of each 28 day treatment cycle. | Drug: Idasanutlin<br>* Idasanutlin will be administered orally as per schedule in Arm description.<br>Drug: Venetoclax<br>* Venetoclax will be administered orally as per schedule in Arm description.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose Limiting Toxicities (DLTs) |  | From Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 28 days | 
| Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) |  | Baseline up until 30 days after the last dose of study drug (up to a maximum of 4 years, 9 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) (Complete Remission (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp) + Partial Remission/Partial Response [PR]) |  | Up to 2 years | 
| Complete Remission/complete response (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp) |  | Up to 2 years | 
| CR + Complete Remission with Partial Hematologic Recovery (CRh) Rate |  | Up to 2 years | 
| Duration of Response (DOR) |  | Up to 2 years | 
| Time to Progression (TTP) |  | Up to 2 years | 
| Progression-Free Survival (PFS) |  | Up to 2 years | 
| Event-Free Survival (EFS) |  | Up to 2 years | 
| Leukemia-Free Survival (LFS) |  | Up to 2 years | 
| Overall Survival (OS) |  | Up to 2 years | 
| Pharmacokinetics of Venetoclax Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr) |  | Up to 6 months | 
| Pharmacokinetics of Venetoclax Maximum Observed Concentration (Cmax) |  | Up to 6 months | 
| Pharmacokinetics of Cobimetinib Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr) |  | Up to 6 months | 
| Pharmacokinetics of Cobimetinib Maximum Observed Concentration (Cmax) |  | Up to 6 months | 
| Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr) |  | Up to 6 months | 
| Pharmacokinetics of Idasanutlin Maximum Observed Concentration (Cmax) |  | Up to 6 months | 
| Number of Participants Reporting Symptoms in Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Questionnaire |  | Up to 2 years | 
| Rate of Transfusion Independence |  | Up to 2 years | 
| Duration Of Transfusion Independence, Defined As The Number Of Consecutive Days Of Transfusion Independence, Measured From 1 Day After Last Transfusion To Disease Progression Or Subsequent Transfusion |  | Up to 2 years | 
| Minimal Residual Disease (MRD) In The Bone Marrow To Evaluate The Depth Of Response |  | Up to 2 years |