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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

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT02670044
Collaborator
(none)
88
Enrollment
17
Locations
9
Arms
57.1
Actual Duration (Months)
5.2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
88 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Mar 9, 2016
Actual Primary Completion Date :
Dec 10, 2020
Actual Study Completion Date :
Dec 10, 2020

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

  1. Number of Participants with Dose Limiting Toxicities (DLTs) [From Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 28 days]

  2. 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

  1. 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]

  2. Complete Remission/complete response (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp) [Up to 2 years]

  3. CR + Complete Remission with Partial Hematologic Recovery (CRh) Rate [Up to 2 years]

  4. Duration of Response (DOR) [Up to 2 years]

  5. Time to Progression (TTP) [Up to 2 years]

  6. Progression-Free Survival (PFS) [Up to 2 years]

  7. Event-Free Survival (EFS) [Up to 2 years]

  8. Leukemia-Free Survival (LFS) [Up to 2 years]

  9. Overall Survival (OS) [Up to 2 years]

  10. Pharmacokinetics of Venetoclax Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr) [Up to 6 months]

  11. Pharmacokinetics of Venetoclax Maximum Observed Concentration (Cmax) [Up to 6 months]

  12. Pharmacokinetics of Cobimetinib Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr) [Up to 6 months]

  13. Pharmacokinetics of Cobimetinib Maximum Observed Concentration (Cmax) [Up to 6 months]

  14. Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr) [Up to 6 months]

  15. Pharmacokinetics of Idasanutlin Maximum Observed Concentration (Cmax) [Up to 6 months]

  16. Number of Participants Reporting Symptoms in Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Questionnaire [Up to 2 years]

  17. Rate of Transfusion Independence [Up to 2 years]

  18. 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]

  19. Minimal Residual Disease (MRD) In The Bone Marrow To Evaluate The Depth Of Response [Up to 2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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:

  1. 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.

Contacts and Locations

Locations

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

Sponsors and Collaborators

  • Hoffmann-La Roche

Investigators

  • Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT02670044
Other Study ID Numbers:
  • GH29914
  • 2015-003386-28
First Posted:
Feb 1, 2016
Last Update Posted:
Jan 3, 2022
Last Verified:
Dec 1, 2021
Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Venetoclax

Study Results

No Results Posted as of Jan 3, 2022