A Study of Venetoclax in combination with Cobimetinib and Venetoclax in combination with Idasanutlin in Patients aged >=60 years with Relapsed or Refractory Acute Myeloid Leukemia who are not eligible for Cytotoxic Therapy

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 140

Inclusion Criteria

- Age >= 60 years
- Histological confirmation of relapsed or refractory AML after prior anti-leukemic therapy by WHO Classification
- Not eligible for cytotoxic therapies
- Ineligible for allogeneic stem cell transplant
- Life expectancy of at least 12 weeks
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2
- Adequate liver and renal function
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 120

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
- 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 phase specific exclusion criteria:
Phase Ib 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
Phase Ib Dose-Escalation 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
- Received hormonal therapy (apart from luteinizing hormone releasing hormone agonist/antagonist for prostate cancer and hormone replacement therapy) within 2 weeks prior to the first dose of study treatment
- History of liver cirrhosis by radiologic, clinical or laboratory data, or biopsy despite normal liver function tests
Phase II Expansion Arm A and Arm B:
- 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 or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/CSCR, RVO, or neovascular macular degeneration
- LVEF below institutional LLN or below 50%, whichever is lower
- Received hormonal therapy (apart from luteinizing hormone releasing hormone agonist/antagonist for prostate cancer and hormone replacement therapy) within 2 weeks prior to the first dose of study treatment
- History of liver cirrhosis by radiologic, clinical or laboratory data, or biopsy despite normal liver function tests

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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