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

NCT02670044 | Completed Phase 1

• 2 other identifiers: GH299142015-003386-28
• Study Type: interventional
• Target: 88
• Locations: 4 countries
• Sites: 17

Brief Summary

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.

Conditions

Leukemia, Myeloid, Acute

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (19)

• 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

• Duration of Response (DOR)

  Up to 2 years

• Time to Progression (TTP)

  Up to 2 years

Study Arms (9)

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

EXPERIMENTAL

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; Drug: Venetoclax

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

EXPERIMENTAL

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; Drug: Venetoclax

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

EXPERIMENTAL

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; Drug: Venetoclax

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

EXPERIMENTAL

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; Drug: Venetoclax

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

EXPERIMENTAL

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: Idasanutlin; Drug: Venetoclax

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

EXPERIMENTAL

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: Idasanutlin; Drug: Venetoclax

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

EXPERIMENTAL

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: Idasanutlin; Drug: Venetoclax

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

EXPERIMENTAL

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: Idasanutlin; Drug: Venetoclax

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

EXPERIMENTAL

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: Idasanutlin; Drug: Venetoclax

Interventions

Cobimetinib DRUG

Cobimetinib will be administered orally as per schedule in Arm description.

Dose Escalation: Arm A (Venetoclax 400mg + Cobi 40mg); Dose Escalation: Arm A (Venetoclax 400mg + Cobi 60mg); Dose Escalation: Arm A (Venetoclax 600mg + Cobi 40mg); Dose Escalation: Arm A (Venetoclax 800mg + Cobi 40mg)

Idasanutlin DRUG

Idasanutlin will be administered orally as per schedule in Arm description.

Dose Escalation: Arm B (Venetoclax 400mg + Ida 200mg); Dose Escalation: Arm B (Venetoclax 400mg + Ida 400mg); Dose Escalation: Arm B (Venetoclax 600mg + Ida 150mg); Dose Escalation: Arm B (Venetoclax 600mg + Ida 200mg); Dose Optimisation: Arm B (Ven 600mg (Day 1 to 21) + Ida 150mg)

Venetoclax DRUG

Venetoclax will be administered orally as per schedule in Arm description.

Dose Escalation: Arm A (Venetoclax 400mg + Cobi 40mg); Dose Escalation: Arm A (Venetoclax 400mg + Cobi 60mg); Dose Escalation: Arm A (Venetoclax 600mg + Cobi 40mg); Dose Escalation: Arm A (Venetoclax 800mg + Cobi 40mg); Dose Escalation: Arm B (Venetoclax 400mg + Ida 200mg); Dose Escalation: Arm B (Venetoclax 400mg + Ida 400mg); Dose Escalation: Arm B (Venetoclax 600mg + Ida 150mg); Dose Escalation: Arm B (Venetoclax 600mg + Ida 200mg); Dose Optimisation: Arm B (Ven 600mg (Day 1 to 21) + Ida 150mg)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (17)

USC Norris Cancer Center

Los Angeles, California, 90033, United States

Location

UC Davis; Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

Univ of Calif, San Francisco

San Francisco, California, 94143, United States

Location

University of Colorado

Aurora, Colorado, 80045-2517, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 1Z1, Canada

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 1Z5, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Hopital Avicenne, Paris

Bobigny, 93009, France

Location

Institut Paoli Calmettes

Marseille, 13009, France

Location

CHU de Bordeaux

Pessac, 33600, France

Location

University of Bologna

Bologna, Emilia-Romagna, 40126, Italy

Location

Presidio san salvatore muraglia

Pesaro, Emilia-Romagna, 61122, Italy

Location

Universita di Roma

Roma, Emilia-Romagna, 100, Italy

Location

Related Publications (1)

• Daver NG, Dail M, Garcia JS, Jonas BA, Yee KWL, Kelly KR, Vey N, Assouline S, Roboz GJ, Paolini S, Pollyea DA, Tafuri A, Brandwein JM, Pigneux A, Powell BL, Fenaux P, Olin RL, Visani G, Martinelli G, Onishi M, Wang J, Huang W, Green C, Ott MG, Hong WJ, Konopleva MY, Andreeff M. Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial. Blood. 2023 Mar 16;141(11):1265-1276. doi: 10.1182/blood.2022016362.

  PMID: 36265087 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

cobimetinib; RG7388; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2016
• First Posted: February 1, 2016
• Study Start: March 9, 2016
• Primary Completion: December 10, 2020
• Study Completion: December 10, 2020
• Last Updated: January 3, 2022

Record last verified: 2021-12

Locations

FR (3); CA (3); US (8); IT (3)