Clinical trial NCT02670044: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia, Myeloid, Acute
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-02-01
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Number of Participants with Dose Limiting Toxicities (DLTs)
timeFrame: From Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 28 days
measure: Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)
timeFrame: Baseline up until 30 days after the last dose of study drug (up to a maximum of 4 years, 9 months)
Secondary outcomes:
measure: Overall Response Rate (ORR) (Complete Remission (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp) + Partial Remission/Partial Response [PR])
timeFrame: Up to 2 years
measure: Complete Remission/complete response (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp)
timeFrame: Up to 2 years
measure: CR + Complete Remission with Partial Hematologic Recovery (CRh) Rate
timeFrame: Up to 2 years
measure: Duration of Response (DOR)
timeFrame: Up to 2 years
measure: Time to Progression (TTP)
timeFrame: Up to 2 years
measure: Progression-Free Survival (PFS)
timeFrame: Up to 2 years
measure: Event-Free Survival (EFS)
timeFrame: Up to 2 years
measure: Leukemia-Free Survival (LFS)
timeFrame: Up to 2 years
measure: Overall Survival (OS)
timeFrame: Up to 2 years
measure: Pharmacokinetics of Venetoclax Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr)
timeFrame: Up to 6 months
measure: Pharmacokinetics of Venetoclax Maximum Observed Concentration (Cmax)
timeFrame: Up to 6 months
measure: Pharmacokinetics of Cobimetinib Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr)
timeFrame: Up to 6 months
measure: Pharmacokinetics of Cobimetinib Maximum Observed Concentration (Cmax)
timeFrame: Up to 6 months
measure: Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr)
timeFrame: Up to 6 months
measure: Pharmacokinetics of Idasanutlin Maximum Observed Concentration (Cmax)
timeFrame: Up to 6 months
measure: Number of Participants Reporting Symptoms in Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Questionnaire
timeFrame: Up to 2 years
measure: Rate of Transfusion Independence
timeFrame: Up to 2 years
measure: 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
timeFrame: Up to 2 years
measure: Minimal Residual Disease (MRD) In The Bone Marrow To Evaluate The Depth Of Response
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC Norris Cancer Center
state: California
city: Sacramento
country: United States
facility: UC Davis; Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: Univ of Calif, San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Bobigny
country: France
facility: Hopital Avicenne, Paris
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Pessac
country: France
facility: CHU de Bordeaux
city: Bologna
country: Italy
facility: University of Bologna
state: Emilia-Romagna
city: Pesaro
country: Italy
facility: Presidio san salvatore muraglia
state: Emilia-Romagna
city: Roma
country: Italy
facility: Universita di Roma
state: Emilia-Romagna
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: