Clinical trial NCT03271047: Study of Binimetinib + Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer With RAS Mutation
Official title: An Open-label Phase 1b/2 Study of Binimetinib Administered in Combination With Nivolumab or Nivolumab Plus Ipilimumab in Patients With Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer With RAS Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: MSS
RAS-mutant Colorectal Cancer
Keywords: cancer
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2017-09-01
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In phase 1 it is sequential and then in phase 2 it is parallel.
Primary purpose: TREATMENT

Brief summary: This is a multicenter, open-label, Phase 1B/2 study to evaluate the safety and assess the preliminary anti-tumor activity of binimetinib administered in combination with nivolumab or nivolumab + ipilimumab in adult patients with advanced metastatic colorectal cancer (mCRC) with microsatellite stable (MSS) disease and presence of a RAS mutation that have received at least one prior line of therapy and no more than 2 prior lines of therapy. The study contains a Phase 1b period to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and schedule of binimetinib followed by a randomized Phase 2 period to assess the efficacy of the combinations.


Eligibility criteria: Key Inclusion Criteria

* Measurable, histologically/cytologically confirmed metastatic colorectal cancer (mCRC).
* Able to provide a sufficient amount of representative tumor specimen for central laboratory testing of RAS mutation status and microsatellite stable (MSS).

  * If a fresh tissue sample is provided, a blood sample is required.
* Metastatic colorectal cancer (mCRC) categorized as microsatellite stable (MSS) by polymerase chain reaction (PCR) per local assay at any time prior to Screening or by the central laboratory.
* RAS mutation per local assay at any time prior to Screening or by the central laboratory.
* Have received at least 1 prior line of therapy and meets at least one of the following criteria:

  * were unable to tolerate the prior first-line regimen
  * experienced disease progression during or after prior first-line regimen for metastatic disease
  * progressed during or within 3 months of completing adjuvant chemotherapy. Note: Generally, treatments that are separated by an event of progression are considered different regimens.
* Have received no more than 2 prior lines of therapy (maintenance therapy given in the metastatic setting will not be considered a separate regimen). Generally, treatments that are separated by an event of progression are considered different regimens.
* Adequate bone marrow, cardiac, kidney and liver function
* Able to take oral medications
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
* Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of child-bearing potential
* Non-sterile male patients who are sexually active with female partners of childbearing potential must agree to follow instructions for acceptable or highly effective method(s) of contraception for the duration of study treatment and for 7 months after the last dose of study treatment with nivolumab

Key Exclusion Criteria

* Prior treatment with any MEK inhibitor, an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
* Any untreated central nervous system (CNS) lesion.
* Patients with an active, known or suspected autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
* Known history of retinal vein occlusion (RVO).
* Known history of Gilbert's syndrome.
* Pregnant or breastfeeding females.
* Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) within 2 weeks prior to first day of study treatment:
* History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli.
* Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
* Concurrent neuromuscular disorder that is associated with the potential of elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
* History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
* Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.
* Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or detectable virus.

Primary outcomes:
measure: Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLT)
timeFrame: Cycle 1: Day 1 up to Day 28
measure: Phase 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
timeFrame: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 2: maximum up to 26 months approximately)
Secondary outcomes:
measure: Phase 1b: Objective Response Rate (ORR) Per RECIST v1.1
timeFrame: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately)
measure: Duration of Response (DOR) as Per RECIST v1.1
timeFrame: From date of first documented CR/PR to date of first documented PD, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately, Phase 2: maximum up to 26 months approximately)
measure: Percentage of Participants With Complete Response as Per RECIST v1.1
timeFrame: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately and Phase 2: maximum up to 26 months approximately)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAE) Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (Phase 1b: maximum up to 9 months approximately and Phase 2: maximum up to 26 months approximately)
measure: Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03: Hematology and Coagulation
timeFrame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
measure: Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Hematology and Coagulation
timeFrame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
measure: Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on CTCAE v4.03: Chemistry
timeFrame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
measure: Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Chemistry and Thyroid Function
timeFrame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
measure: Number of Participants With Abnormal Hepatic Laboratory Values
timeFrame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
measure: Concentration Versus Time Summary of Plasma Concentration of Binimetinib
timeFrame: 1.5 hours post dose of binimetinib on Day 1, 15 of Cycle 1; pre dose of binimetinib on Day 15 of Cycle 1, 2, 3, 4, 5
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Hematology/Oncology
state: California
city: Santa Monica
country: United States
facility: UCLA Hematology/Oncology - Santa Monica
state: California
city: Newark
country: United States
facility: Christiana Care Health Services, Helen F. Graham Cancer Center Pharmacy, Suite 3200
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health Services, Helen F. Graham Cancer Center
state: Delaware
city: Newark
country: United States
facility: Christiana Care Oncology Hematology, Helen F Graham Cancer Center, Suite 2400
state: Delaware
city: Newark
country: United States
facility: Medical Oncology Hematology Consultants, PA, Helen F. Graham Cancer Center
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health Services, Christiana Hospital
state: Delaware
city: Washington
country: United States
facility: Georgetown University Medical Center Department of Pharmacy, Research
state: District of Columbia
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Port Saint Lucie
country: United States
facility: Hematology Oncology Associates of the Treasure Coast
state: Florida
city: Indianapolis
country: United States
facility: Indiana CTSI Clinical Research Center (ICRC)
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Health Hospital
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Health Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Investigational Drug Services IUHSCC
state: Indiana
city: Indianapolis
country: United States
facility: Sidney &Lois Eskenazi Hospital
state: Indiana
city: Indianapolis
country: United States
facility: Spring Mill Medical Center
state: Indiana
city: Creve Coeur
country: United States
facility: Siteman Cancer Center - West County
state: Missouri
city: Florissant
country: United States
facility: Siteman Cancer Center - North County
state: Missouri
city: Saint Louis
country: United States
facility: Center for Outpatient Health (Dermatology Clinic)
state: Missouri
city: Saint Louis
country: United States
facility: Center for Outpatient Health (Ophthalmology Clinic)
state: Missouri
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center - South County
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center - Barnes St. Peters
state: Missouri
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Investigational Drug Service of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Chattanooga
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Chattanooga
country: United States
facility: SCRI Tennessee Oncology Chattanooga
state: Tennessee
city: Cleveland
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology NASH - SCRI - PPDS
state: Tennessee
city: Nashville
country: United States
facility: The Sarah Cannon Research Institute.
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Leuven
country: Belgium
facility: UZ Leuven - Dermatology
city: Leuven
country: Belgium
facility: UZ Leuven - Ophthalmology
city: Leuven
country: Belgium
facility: UZ Leuven
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute Antoni Van Leeuwenhoek
state: Noord-holland
city: Amsterdam
country: Netherlands
facility: OLVG locatie Oost
state: Noord-holland
city: Amsterdam
country: Netherlands
facility: Amsterdam Medical Center (AMC)
state: Noord-holland
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón - PPDS
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: MAdrid
country: Spain
facility: Clinica Rementeria
city: Madrid
country: Spain
facility: Hospital Universitario 12 Octubre
city: Madrid
country: Spain
facility: Hospital HM Universitario Sanchinarro, CIOCC
city: London
country: United Kingdom
facility: Royal Marsden Hospital - London
state: London, CITY OF
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: Oxfordshire
city: Surrey
country: United Kingdom
facility: Royal Marsden Hospital NHS Foundation Trust
state: Sutton
city: London
country: United Kingdom
facility: Royal Marsden Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Marsden Hospital -Fulham Road
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: