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 Phase IB Multi-Arm Study With 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.

Study Overview

• Status: Completed
• Conditions: Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: Cobimetinib; Drug: Venetoclax; Drug: Idasanutlin

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z1
      • University of Alberta Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z5
      • Princess Margaret Cancer Center
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• France
  • Bobigny, France, 93009
    • Hopital Avicenne, Paris
  • Marseille, France, 13009
    • Institut Paoli Calmettes
  • Pessac, France, 33600
    • CHU de Bordeaux
• Italy
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40126
      • University of Bologna
    • Pesaro, Emilia-Romagna, Italy, 61122
      • Presidio san salvatore muraglia
    • Roma, Emilia-Romagna, Italy, 100
      • Universita Di Roma
• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC Norris Cancer Center
    • Sacramento, California, United States, 95817
      • UC Davis; Comprehensive Cancer Center
    • San Francisco, California, United States, 94143
      • Univ of Calif, San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045-2517
      • University of Colorado
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Dose Escalation: Arm A (Venetoclax 400mg + Cobi 40mg); 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.	Drug: Cobimetinib; Cobimetinib will be administered orally as per schedule in Arm description.; Drug: Venetoclax; Venetoclax will be administered orally as per schedule in Arm description.
EXPERIMENTAL: Dose Escalation: Arm A (Venetoclax 600mg + Cobi 40mg); 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.	Drug: Cobimetinib; Cobimetinib will be administered orally as per schedule in Arm description.; Drug: Venetoclax; Venetoclax will be administered orally as per schedule in Arm description.
EXPERIMENTAL: Dose Escalation: Arm A (Venetoclax 800mg + Cobi 40mg); 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.	Drug: Cobimetinib; Cobimetinib will be administered orally as per schedule in Arm description.; Drug: Venetoclax; Venetoclax will be administered orally as per schedule in Arm description.
EXPERIMENTAL: Dose Escalation: Arm A (Venetoclax 400mg + Cobi 60mg); 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.	Drug: Cobimetinib; Cobimetinib will be administered orally as per schedule in Arm description.; Drug: Venetoclax; Venetoclax will be administered orally as per schedule in Arm description.
EXPERIMENTAL: Dose Escalation: Arm B (Venetoclax 400mg + Ida 200mg); 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.	Drug: Venetoclax; Venetoclax will be administered orally as per schedule in Arm description.; Drug: Idasanutlin; Idasanutlin will be administered orally as per schedule in Arm description.
EXPERIMENTAL: Dose Escalation: Arm B (Venetoclax 600mg + Ida 150mg); 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.	Drug: Venetoclax; Venetoclax will be administered orally as per schedule in Arm description.; Drug: Idasanutlin; Idasanutlin will be administered orally as per schedule in Arm description.
EXPERIMENTAL: Dose Escalation: Arm B (Venetoclax 600mg + Ida 200mg); 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.	Drug: Venetoclax; Venetoclax will be administered orally as per schedule in Arm description.; Drug: Idasanutlin; Idasanutlin will be administered orally as per schedule in Arm description.
EXPERIMENTAL: Dose Escalation: Arm B (Venetoclax 400mg + Ida 400mg); 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.	Drug: Venetoclax; Venetoclax will be administered orally as per schedule in Arm description.; Drug: Idasanutlin; Idasanutlin will be administered orally as per schedule in Arm description.
EXPERIMENTAL: Dose Optimisation: Arm B (Ven 600mg (Day 1 to 21) + Ida 150mg); 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.	Drug: Venetoclax; Venetoclax will be administered orally as per schedule in Arm description.; Drug: Idasanutlin; Idasanutlin will be administered orally as per schedule in Arm description.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
Overall Survival (OS)	Up to 2 years
Duration of Response (DOR)	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
CR + Complete Remission with Partial Hematologic Recovery (CRh) Rate	Up to 2 years
Time to Progression (TTP)	Up to 2 years
Progression-Free Survival (PFS)	Up to 2 years
Event-Free Survival (EFS)	Up to 2 years
Leukemia-Free Survival (LFS)	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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 9, 2016
• Primary Completion (ACTUAL): December 10, 2020
• Study Completion (ACTUAL): December 10, 2020

Study Registration Dates

• First Submitted: January 28, 2016
• First Submitted That Met QC Criteria: January 28, 2016
• First Posted (ESTIMATE): February 1, 2016

Study Record Updates

• Last Update Posted (ACTUAL): January 3, 2022
• Last Update Submitted That Met QC Criteria: December 13, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: GH29914; 2015-003386-28 (EUDRACT_NUMBER)