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
- Conditions
- Leukemia, Myeloid, Acute
- Interventions
- Registration Number
- NCT02670044
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 88
-
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
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Adequate liver and renal function
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dose Escalation: Arm A (Venetoclax 800mg + Cobi 40mg) Venetoclax 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. Dose Escalation: Arm A (Venetoclax 400mg + Cobi 40mg) Cobimetinib 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. Dose Escalation: Arm A (Venetoclax 400mg + Cobi 40mg) Venetoclax 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. Dose Escalation: Arm A (Venetoclax 600mg + Cobi 40mg) Cobimetinib 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. Dose Escalation: Arm A (Venetoclax 600mg + Cobi 40mg) Venetoclax 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. Dose Escalation: Arm A (Venetoclax 800mg + Cobi 40mg) Cobimetinib 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. Dose Escalation: Arm A (Venetoclax 400mg + Cobi 60mg) Cobimetinib 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. Dose Escalation: Arm A (Venetoclax 400mg + Cobi 60mg) Venetoclax 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. Dose Escalation: Arm B (Venetoclax 400mg + Ida 200mg) Venetoclax 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. Dose Escalation: Arm B (Venetoclax 600mg + Ida 200mg) Idasanutlin 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. Dose Escalation: Arm B (Venetoclax 600mg + Ida 150mg) Venetoclax 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. Dose Escalation: Arm B (Venetoclax 600mg + Ida 200mg) Venetoclax 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. Dose Escalation: Arm B (Venetoclax 400mg + Ida 400mg) Venetoclax 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. Dose Escalation: Arm B (Venetoclax 400mg + Ida 400mg) Idasanutlin 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. Dose Optimisation: Arm B (Ven 600mg (Day 1 to 21) + Ida 150mg) Venetoclax 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. Dose Escalation: Arm B (Venetoclax 400mg + Ida 200mg) Idasanutlin 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. Dose Escalation: Arm B (Venetoclax 600mg + Ida 150mg) Idasanutlin 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. Dose Optimisation: Arm B (Ven 600mg (Day 1 to 21) + Ida 150mg) Idasanutlin 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.
- Primary Outcome Measures
Name Time Method 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
Name Time Method Overall Survival (OS) 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 Progression-Free Survival (PFS) Up to 2 years Event-Free Survival (EFS) Up to 2 years Time to Progression (TTP) Up to 2 years Leukemia-Free Survival (LFS) Up to 2 years 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 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
Trial Locations
- Locations (17)
Weill Cornell Medical College
🇺🇸New York, New York, United States
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
Institut Paoli Calmettes
🇫🇷Marseille, France
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
University of Bologna
🇮🇹Bologna, Emilia-Romagna, Italy
USC Norris Cancer Center
🇺🇸Los Angeles, California, United States
UC Davis; Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Univ of Calif, San Francisco
🇺🇸San Francisco, California, United States
University of Colorado
🇺🇸Aurora, Colorado, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Princess Margaret Cancer Center
🇨🇦Toronto, Ontario, Canada
Hopital Avicenne, Paris
🇫🇷Bobigny, France
CHU de Bordeaux
🇫🇷Pessac, France
Presidio san salvatore muraglia
🇮🇹Pesaro, Emilia-Romagna, Italy
Universita di Roma
🇮🇹Roma, Emilia-Romagna, Italy
Wake Forest Baptist Medical Center
🇺🇸Winston-Salem, North Carolina, United States