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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

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ClinicalTrials.gov Identifier: NCT02670044
Recruitment Status : Active, not recruiting
First Posted : February 1, 2016
Last Update Posted : September 29, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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
Leukemia, Myeloid, Acute Drug: Cobimetinib Drug: Idasanutlin Drug: Venetoclax Phase 1

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Study Type : Interventional  (Clinical Trial)
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 : March 9, 2016
Estimated Primary Completion Date : February 26, 2021
Estimated Study Completion Date : March 26, 2022


Arm Intervention/treatment
Experimental: Dose-Escalation, Arm A (Venetoclax + Cobimetinib)
Participants will receive Venetoclax daily on Days 1-28 of each 28 day treatment cycle and Cobimetinib 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 + Idasanutlin)
Participants will receive Venetoclax on Days 1-28 of each 28 day treatment cycle and Idasanutlin 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: Dosing Schedule Optimization, Arm B (Venetoclax+Idasanutlin)
Participants will receive Venetoclax on Days 1-21 or Days 1-14 of each 28-day treatment cycle and Idasanutlin 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.




Primary Outcome Measures :
  1. 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 ]
  2. Phase Ib: Number of Participants with Adverse Events, Including Adverse Events of Special Interest and Serious Adverse Events [ Time Frame: Up to 2 years ]
  3. 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 ]
  4. Phase Ib: Mortality Rates, Including Thirty and Sixty Day [ Time Frame: Days 30 and 60 ]

Secondary Outcome Measures :
  1. Overall Response Rate (ORR) (CR + CRi + CRp + Partial Remission/Partial Response [PR]) [ Time Frame: Up to 2 years ]
  2. Duration of Response (DOR) [ Time Frame: Up to 2 years ]
  3. Time to Progression (TTP) [ Time Frame: Up to 2 years ]
  4. Progression-Free Survival (PFS) [ Time Frame: Up to 2 years ]
  5. Event-Free Survival (EFS) [ Time Frame: Up to 2 years ]
  6. Leukemia-Free Survival (LFS) [ Time Frame: Up to 2 years ]
  7. Overall Survival (OS) [ Time Frame: Up to 2 years ]
  8. Pharmacokinetics of Venetoclax Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-t) [ Time Frame: Up to 6 months ]
  9. Pharmacokinetics of Venetoclax Maximum Observed Concentration (Cmax) [ Time Frame: Up to 6 months ]
  10. Pharmacokinetics of Cobimetinib Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-t) [ Time Frame: Up to 6 months ]
  11. Pharmacokinetics of Cobimetinib Maximum Observed Concentration (Cmax) [ Time Frame: Up to 6 months ]
  12. Pharmacokinetics of Idasanutlin Maximum Observed Concentration (Cmax) [ Time Frame: Up to 6 months ]
  13. Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-t) [ Time Frame: Up to 6 months ]
  14. 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 ]
  15. Complete remission (CR) + Complete Remission with Incomplete Blood Count Recovery (CRi) + Complete Remission with Incomplete Platelet Count Recovery (CRp) [ Time Frame: Up to 2 years ]
  16. CR + Complete Remission with Partial Hematologic Recovery (CRh) Rate [ Time Frame: Up to 2 years ]
  17. Rate of Transfusion Independence [ Time Frame: 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 [ Time Frame: Up to 2 years ]
  19. Minimal Residual Disease (MRD) In The Bone Marrow To Evaluate The Depth Of Response [ Time Frame: Up to 2 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02670044


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02670044    
Other Study ID Numbers: GH29914
2015-003386-28 ( EudraCT Number )
First Posted: February 1, 2016    Key Record Dates
Last Update Posted: September 29, 2020
Last Verified: September 2020
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Venetoclax
Antineoplastic Agents