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 with relapsed or refractory acute myeloid leukemia
(R/R) AML who are not eligible for cytotoxic therapy.
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
Interventions
Drug | Synonyms | Arms |
---|
Cobimetinib | | 1) Phase Ib Dose-Escalation, Arm A (Venetoclax + Cobimetinib) |
Idasanutlin | | 2) Phase Ib Dose-Escalation, Arm B (Venetoclax + Idasanutlin) |
Venetoclax | | 1) 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
Name | Type | Description | Interventions |
---|
1) Phase Ib Dose-Escalation, Arm A (Venetoclax + Cobimetinib) | Experimental | Venetoclax in combination with cobimetinib | |
2) Phase Ib Dose-Escalation, Arm B (Venetoclax + Idasanutlin) | Experimental | Venetoclax in combination with idasanutlin | |
3) Phase II Expansion, Arm A (Venetoclax + Cobimetinib) | Experimental | Venetoclax in combination with cobimetinib | |
4) Phase II Expansion, Arm B (Venetoclax + Idasanutlin) | Experimental | Venetoclax in combination with idasanutlin | |
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