Leukemia, Myeloid, Acute
Conditions
Brief summary
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.
Interventions
DRUGCobimetinib
Cobimetinib will be administered orally as per schedule in Arm description.
DRUGIdasanutlin
Idasanutlin will be administered orally as per schedule in Arm description.
DRUGVenetoclax
Venetoclax will be administered orally as per schedule in Arm description.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
| 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 |
| Pharmacokinetics of Venetoclax Maximum Observed Concentration (Cmax) | Up to 6 months |
| Complete Remission/complete response (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp) | Up to 2 years |
Countries
Canada, France, Italy, United States
Outcome results
None listed