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
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
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.
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.