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A Study of Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients Aged >/= 60 Years With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy

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ClinicalTrials.gov Identifier: NCT02670044
Recruitment Status : Recruiting
First Posted : February 1, 2016
Last Update Posted : February 19, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE January 28, 2016
First Posted Date  ICMJE February 1, 2016
Last Update Posted Date February 19, 2020
Actual Study Start Date  ICMJE March 9, 2016
Estimated Primary Completion Date May 27, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 28, 2016)
  • Phase Ib: Number of Participants with Dose Limiting Toxicities (DLTs) [ Time Frame: From Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 28 days ]
  • Phase Ib: Number of Participants with Adverse Events, Including Adverse Events of Special Interest and Serious Adverse Events [ Time Frame: Up to 2 years ]
  • Phase Ib: Number of Participants with Clinically Significant Changes in Safety Measurements, Including Vital Signs, Physical Exam Findings, Electrocardiograms (ECGs) and Clinical Laboratory [ Time Frame: Up to 2 years ]
  • Phase Ib: Mortality Rates, Including Thirty and Sixty Day [ Time Frame: Days 30 and 60 ]
  • Phase II: Percentage of Participants with Complete Remission (CR) [ Time Frame: Up to 2 years ]
  • Phase II: Percentage of Participants with Complete Remission with Incomplete Blood Count Recovery (CRi) [ Time Frame: Up to 2 years ]
  • Phase II: Percentage of Participants with Complete Remission with Incomplete Platelet Count Recovery (CRp) [ Time Frame: Up to 2 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2016)
  • Overall Response Rate (ORR) (CR + CRi + CRp + Partial Remission/Partial Response [PR]) [ Time Frame: Up to 2 years ]
  • Duration of Response (DOR) [ Time Frame: Up to 2 years ]
  • Time to Progression (TTP) [ Time Frame: Up to 2 years ]
  • Progression-Free Survival (PFS) [ Time Frame: Up to 2 years ]
  • Event-Free Survival (EFS) [ Time Frame: Up to 2 years ]
  • Leukemia-Free Survival (LFS) [ Time Frame: Up to 2 years ]
  • Overall Survival (OS) [ Time Frame: Up to 2 years ]
  • Pharmacokinetics of Venetoclax Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-t) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Venetoclax Maximum Observed Concentration (Cmax) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Cobimetinib Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-t) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Cobimetinib Maximum Observed Concentration (Cmax) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Cobimetinib Oral Apparent Clearance (CL/F) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Idasanutlin Oral Apparent Clearance (CL/F) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Idasanutlin Apparent Volume of Distribution (V/F) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Idasanutlin Maximum Observed Concentration (Cmax) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Idasanutlin Steady-State Concentration (Ctrough) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-t) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to 24 Hours (AUC24h) [ Time Frame: Up to 6 months ]
  • Pharmacokinetics of Idasanutlin Terminal Elimination Half-Life (t1/2) [ Time Frame: Up to 6 months ]
  • Number of Patients Reporting Symptoms in Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Questionnaire [ Time Frame: Up to 2 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients Aged >/= 60 Years With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy
Official Title  ICMJE A Phase IB/II Multi-Arm Study With Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients Aged >/= 60 Years With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy
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 >/= 60 years of age with relapsed or refractory acute myeloid leukemia (R/R) AML who are not eligible for cytotoxic therapy.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Leukemia, Myeloid, Acute
Intervention  ICMJE
  • Drug: Cobimetinib
    Cobimetinib will be administered orally daily on Days 1-21 of each 28-day treatment cycle.
  • Drug: Idasanutlin
    Idasanutlin will be administered orally daily or twice daily on Days 1-5 of each 28 day treatment cycle.
  • Drug: Venetoclax
    Venetoclax will be administered orally daily on Days 1-28 of each 28 day treatment cycle.
Study Arms  ICMJE
  • Experimental: 1) Phase Ib Dose-Escalation, Arm A (Venetoclax + Cobimetinib)
    Venetoclax in combination with cobimetinib
    Interventions:
    • Drug: Cobimetinib
    • Drug: Venetoclax
  • Experimental: 2) Phase Ib Dose-Escalation, Arm B (Venetoclax + Idasanutlin)
    Venetoclax in combination with idasanutlin
    Interventions:
    • Drug: Idasanutlin
    • Drug: Venetoclax
  • Experimental: 3) Phase II Expansion, Arm A (Venetoclax + Cobimetinib)
    Venetoclax in combination with cobimetinib
    Interventions:
    • Drug: Cobimetinib
    • Drug: Venetoclax
  • Experimental: 4) Phase II Expansion, Arm B (Venetoclax + Idasanutlin)
    Venetoclax in combination with idasanutlin
    Interventions:
    • Drug: Idasanutlin
    • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 28, 2016)
140
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 27, 2022
Estimated Primary Completion Date May 27, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age >/= 60 years
  • Histological confirmation of relapsed or refractory AML after prior anti-leukemic therapy by WHO Classification
  • Not eligible for cytotoxic therapies
  • Ineligible for allogeneic stem cell transplant
  • 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
  • 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 phase specific exclusion criteria:

Phase Ib 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

Phase Ib Dose-Escalation 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

  • Received hormonal therapy (apart from luteinizing hormone releasing hormone agonist/antagonist for prostate cancer and hormone replacement therapy) within 2 weeks prior to the first dose of study treatment
  • History of liver cirrhosis by radiologic, clinical or laboratory data, or biopsy despite normal liver function tests

Phase II Expansion Arm A and Arm B:

  • 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 or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/CSCR, RVO, or neovascular macular degeneration
  • LVEF below institutional LLN or below 50%, whichever is lower
  • Received hormonal therapy (apart from luteinizing hormone releasing hormone agonist/antagonist for prostate cancer and hormone replacement therapy) within 2 weeks prior to the first dose of study treatment
  • History of liver cirrhosis by radiologic, clinical or laboratory data, or biopsy despite normal liver function tests
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID Number: GH29914 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global.rochegenentechtrials@roche.com
Listed Location Countries  ICMJE Canada,   France,   Italy,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02670044
Other Study ID Numbers  ICMJE GH29914
2015-003386-28 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP