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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

This study is currently recruiting participants.
See Contacts and Locations
Verified June 2017 by Hoffmann-La Roche
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT02670044
First received: January 28, 2016
Last updated: June 2, 2017
Last verified: June 2017
  Purpose
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.

Condition Intervention Phase
Leukemia, Myeloid, Acute Drug: Cobimetinib Drug: Idasanutlin Drug: Venetoclax Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 140
Actual Study Start Date: March 31, 2016
Estimated Study Completion Date: July 31, 2019
Estimated Primary Completion Date: September 30, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1) Phase Ib Dose-Escalation, Arm A (Venetoclax + Cobimetinib)
Venetoclax in combination with cobimetinib
Drug: Cobimetinib
Cobimetinib will be administered orally daily on Days 1-21 of each 28-day treatment cycle.
Drug: Venetoclax
Venetoclax will be administered orally daily on Days 1-28 of each 28 day treatment cycle.
Experimental: 2) Phase Ib Dose-Escalation, Arm B (Venetoclax + Idasanutlin)
Venetoclax in combination with idasanutlin
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.
Experimental: 3) Phase II Expansion, Arm A (Venetoclax + Cobimetinib)
Venetoclax in combination with cobimetinib
Drug: Cobimetinib
Cobimetinib will be administered orally daily on Days 1-21 of each 28-day treatment cycle.
Drug: Venetoclax
Venetoclax will be administered orally daily on Days 1-28 of each 28 day treatment cycle.
Experimental: 4) Phase II Expansion, Arm B (Venetoclax + Idasanutlin)
Venetoclax in combination with idasanutlin
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.

  Eligibility

Ages Eligible for Study:   60 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02670044

Contacts
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

Locations
United States, California
USC Norris Cancer Center Recruiting
Los Angeles, California, United States, 90033
UC Davis; Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Univ of Calif, San Francisco Recruiting
San Francisco, California, United States, 94143
Stanford Cancer Institute Withdrawn
Stanford, California, United States, 94305-5456
United States, Colorado
University of Colorado Recruiting
Aurora, Colorado, United States, 80045-2517
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Memorial Sloan-Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
Weill Cornell Medical College Recruiting
New York, New York, United States, 10065
United States, North Carolina
Wake Forest Baptist Medical Center Recruiting
Winston-Salem, North Carolina, United States, 27157
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Canada, Alberta
University of Alberta Hospital Recruiting
Edmonton, Alberta, Canada, T6G1Z1
Canada, Ontario
Princess Margaret Cancer Center Recruiting
Toronto, Ontario, Canada, M5G 1Z6
Canada, Quebec
Jewish General Hospital Recruiting
Montreal, Quebec, Canada, H3T 1E2
France
Hopital Avicenne, Paris Recruiting
Bobigny, France, 93009
Institut Paoli Calmettes Recruiting
Marseille, France, 13273
CHU de Bordeaux Recruiting
Pessac, France, 33600
Italy
University of Bologna Recruiting
Bologna, Emilia-Romagna, Italy, 40126
Presidio san salvatore muraglia Recruiting
Pesaro, Emilia-Romagna, Italy, 61122
Universita di Roma Recruiting
Roma, Emilia-Romagna, Italy, 100
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02670044     History of Changes
Other Study ID Numbers: GH29914
2015-003386-28 ( EudraCT Number )
Study First Received: January 28, 2016
Last Updated: June 2, 2017

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms

ClinicalTrials.gov processed this record on June 22, 2017