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
Leukemia, Myeloid, Acute
About this trial
This is an interventional treatment trial for Leukemia, Myeloid, Acute
Eligibility Criteria
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.
Sites / Locations
- USC Norris Cancer Center
- UC Davis; Comprehensive Cancer Center
- Univ of Calif, San Francisco
- University of Colorado
- Dana Farber Cancer Institute
- Weill Cornell Medical College
- Wake Forest Baptist Medical Center
- MD Anderson Cancer Center
- University of Alberta Hospital
- Princess Margaret Cancer Center
- Jewish General Hospital
- Hopital Avicenne, Paris
- Institut Paoli Calmettes
- CHU de Bordeaux
- University of Bologna
- Presidio san salvatore muraglia
- Universita di Roma
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Dose Escalation: Arm A (Venetoclax 400mg + Cobi 40mg)
Dose Escalation: Arm A (Venetoclax 600mg + Cobi 40mg)
Dose Escalation: Arm A (Venetoclax 800mg + Cobi 40mg)
Dose Escalation: Arm A (Venetoclax 400mg + Cobi 60mg)
Dose Escalation: Arm B (Venetoclax 400mg + Ida 200mg)
Dose Escalation: Arm B (Venetoclax 600mg + Ida 150mg)
Dose Escalation: Arm B (Venetoclax 600mg + Ida 200mg)
Dose Escalation: Arm B (Venetoclax 400mg + Ida 400mg)
Dose Optimisation: Arm B (Ven 600mg (Day 1 to 21) + Ida 150mg)
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.
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.
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.
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.
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.
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.
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.
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.
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.