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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

NCT02670044

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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: 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

Clinical Trial IDs

  • ORG STUDY ID: GH29914
  • SECONDARY ID: 2015-003386-28
  • NCT ID: NCT02670044

Conditions

  • Leukemia, Myeloid, Acute

Interventions

DrugSynonymsArms
Cobimetinib1) Phase Ib Dose-Escalation, Arm A (Venetoclax + Cobimetinib)
Idasanutlin2) Phase Ib Dose-Escalation, Arm B (Venetoclax + Idasanutlin)
Venetoclax1) Phase Ib Dose-Escalation, Arm A (Venetoclax + Cobimetinib)

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.

Trial Arms

NameTypeDescriptionInterventions
1) Phase Ib Dose-Escalation, Arm A (Venetoclax + Cobimetinib)ExperimentalVenetoclax in combination with cobimetinib
  • Cobimetinib
  • Venetoclax
2) Phase Ib Dose-Escalation, Arm B (Venetoclax + Idasanutlin)ExperimentalVenetoclax in combination with idasanutlin
  • Idasanutlin
  • Venetoclax
3) Phase II Expansion, Arm A (Venetoclax + Cobimetinib)ExperimentalVenetoclax in combination with cobimetinib
  • Cobimetinib
  • Venetoclax
4) Phase II Expansion, Arm B (Venetoclax + Idasanutlin)ExperimentalVenetoclax in combination with idasanutlin
  • Idasanutlin
  • Venetoclax

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall Response Rate (ORR) (CR + CRi + CRp + Partial Remission/Partial Response [PR])
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Duration of Response (DOR)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Time to Progression (TTP)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Progression-Free Survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Event-Free Survival (EFS)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Leukemia-Free Survival (LFS)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Pharmacokinetics of Venetoclax Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-t)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Venetoclax Maximum Observed Concentration (Cmax)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Cobimetinib Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-t)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Cobimetinib Maximum Observed Concentration (Cmax)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Cobimetinib Oral Apparent Clearance (CL/F)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Idasanutlin Oral Apparent Clearance (CL/F)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Idasanutlin Apparent Volume of Distribution (V/F)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Idasanutlin Maximum Observed Concentration (Cmax)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Idasanutlin Steady-State Concentration (Ctrough)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-t)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to 24 Hours (AUC24h)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Pharmacokinetics of Idasanutlin Terminal Elimination Half-Life (t1/2)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

April 11, 2017