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

Roche

Status and phase: Completed; Phase 1

Conditions: Leukemia, Myeloid, Acute

Treatments: Drug: Idasanutlin; Drug: Cobimetinib; Drug: Venetoclax

Study type: Interventional

Funder types: Industry

Identifiers

NCT02670044

GH29914

2015-003386-28 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 88 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

88 participants in 9 patient groups

Dose Escalation: Arm A (Venetoclax 400mg + Cobi 40mg)

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Drug: Venetoclax

Dose Escalation: Arm A (Venetoclax 600mg + Cobi 40mg)

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Drug: Venetoclax

Dose Escalation: Arm A (Venetoclax 800mg + Cobi 40mg)

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Drug: Venetoclax

Dose Escalation: Arm A (Venetoclax 400mg + Cobi 60mg)

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Drug: Venetoclax

Dose Escalation: Arm B (Venetoclax 400mg + Ida 200mg)

Experimental group

Description:

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.

Treatment:

Drug: Idasanutlin

Drug: Venetoclax

Dose Escalation: Arm B (Venetoclax 600mg + Ida 150mg)

Experimental group

Description:

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.

Treatment:

Drug: Idasanutlin

Drug: Venetoclax

Dose Escalation: Arm B (Venetoclax 600mg + Ida 200mg)

Experimental group

Description:

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.

Treatment:

Drug: Idasanutlin

Drug: Venetoclax

Dose Escalation: Arm B (Venetoclax 400mg + Ida 400mg)

Experimental group

Description:

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.

Treatment:

Drug: Idasanutlin

Drug: Venetoclax

Dose Optimisation: Arm B (Ven 600mg (Day 1 to 21) + Ida 150mg)

Experimental group

Description:

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.

Treatment:

Drug: Idasanutlin

Drug: Venetoclax