Clinical trial NCT03374254: Safety and Efficacy of Pembrolizumab (MK-3475) Plus Binimetinib Alone or Pembrolizumab Plus Chemotherapy With or Without Binimetinib in Metastatic Colorectal Cancer (mCRC) Participants (MK-3475-651/KEYNOTE-651)
Official title: A Phase 1b Multi-cohort Study of the Combination of Pembrolizumab (MK-3475) Plus Binimetinib Alone or the Combination of Pembrolizumab Plus Chemotherapy With or Without Binimetinib in Participants With Metastatic Colorectal Cancer (KEYNOTE-651)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Metastatic Colorectal Cancer
Keywords: CRC, MSS, non-MSI-H, PD-1, anti-PD-1, anti PD-1, MEK, MEK inhibitor
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Array BioPharma
First posted: 2017-12-15
Enrollment: 116
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 purpose of this study is to determine safety and tolerability and to establish a preliminary recommended Phase 2 dose (RP2D) for the following combinations: pembrolizumab plus binimetinib (Cohort A), pembrolizumab plus mFOLFOX7 (oxaliplatin 85 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2) (Cohort B), pembrolizumab plus mFOLFOX7 and binimetinib (Cohort C), pembrolizumab plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\]400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) (Cohort D), and pembrolizumab plus FOLFIRI and binimetinib (Cohort E).


Eligibility criteria: Inclusion Criteria:

* At least 18 years of age
* Has a histologically-confirmed, unresectable or metastatic (Stage IV American Joint Committee on Cancer \[AJCC seventh edition\]) colorectal cancer (CRC)
* Has a locally determined non microsatellite instability high/ proficient mismatch repair (non-MSI-H/pMMR) tumor status
* Has at least 1 radiologically measurable lesion as defined by RECIST 1.1
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Has a life expectancy of at least 3 months
* Has the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption.
* Has adequate organ function
* Male participants must agree to use contraception during the treatment period and for ≥180 days, after the last dose of study treatment and refrain from donating sperm during this period. Male participants with pregnant partners must agree to use a condom
* Female participants eligible to participate if not pregnant, not breastfeeding, and is not a woman of childbearing potential (WOCBP) or is a WOCBP who agrees to follow contraceptive guidance during the treatment period and for ≥180 days after the last dose of study treatment

  * Participants for Cohort A:
* Has been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin

  * Participants for Cohorts B and C:
* Must not have received prior systemic chemotherapy for Stage IV CRC

  * Participants for Cohorts D and E:
* Must have been previously treated with 1 line of therapy including a fluoropyrimidine plus an oxaliplatin-based regimen

  * Participants for Cohorts A, C, and E:
* Have a 12-lead electrocardiogram (ECG) and echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed by the investigator or other qualified person to evaluate cardiac function prior to enrollment in the study

Exclusion Criteria:

* Is currently participating and receiving study therapy in a study of an investigational agent or has participated and received study therapy in a study of an investigational agent or has used an investigational device within 28 days of administration of MK-3475
* Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (prior to the first dose of study therapy, or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Gr 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier
* Has history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years
* Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has a known hypersensitivity, intolerability or contraindication to any component of study treatment, including premedication
* Has any active infection requiring systemic therapy
* Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
* Has received prior therapy with compounds targeting programmed death (PD)-1, PD-L1, PD-L2, or a mitogen-activated protein kinase (MAPK) pathway inhibitor
* Has an autoimmune disease that has required systemic treatment in the past 2 years with use of disease modifying agents, corticosteroids, or immunosuppressive drugs
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization
* Has known history of human immunodeficiency virus (HIV) infection
* Has a known history of Hepatitis B
* Has received live vaccine within 30 days of the planned start of study therapy
* Has undergone major surgery and has not recovered adequately from any toxicity and/or complications from the intervention prior to starting study therapy
* Has baseline peripheral neuropathy/paresthesia
* Has any medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol, or complete the study.
* Has symptomatic congestive heart failure (CHF)
* Has a history of acute or chronic pancreatitis
* Has existing uncontrolled arterial hypertension (systolic blood pressure \[SBP\] ≥150 mmHg or diastolic blood pressure \[DBP\] ≥100 mmHg) despite appropriate medical therapy
* Has a history of thromboembolic or cerebrovascular events within 6 months prior to registration
* Has neuromuscular disorders associated with an elevated creatine kinase
* A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment

  * Potential Participants for Cohorts A, C or E who are to Receive Binimetinib:
* Has a history of, or current, retinal vein occlusion (RVO) or current risk factors for RVO
* Has retinal degenerative disease

  * Potential Participants for Cohorts A, C, D or E:
* Has a known history of Gilbert's Syndrome

  * Potential Participants for Cohorts D or E:
* Has a previous treatment with irinotecan
* Has plans to use, or is using, any herbal medications/supplements or any medications or foods that are strong inhibitors or inducers of cytochrome P450 3A 4/5 ≤1 week prior to the start of study treatment

Primary outcomes:
measure: Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT)
timeFrame: Up to approximately first 28 days of treatment
Secondary outcomes:
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to Approximately 64 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center ( Site 0102)
state: California
city: Aurora
country: United States
facility: Anschutz Medical Campus, Anschutz Cancer Pavilion ( Site 0106)
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center ( Site 0108)
state: Connecticut
city: Tampa
country: United States
facility: Moffitt Cancer Center ( Site 0111)
state: Florida
city: Chicago
country: United States
facility: University of Chicago ( Site 0105)
state: Illinois
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey ( Site 0107)
state: New Jersey
city: Pittsburgh
country: United States
facility: UPMC Cancer Center/Hillman Cancer Center ( Site 0113)
state: Pennsylvania
city: Temple
country: United States
facility: Baylor Scott and White ( Site 0110)
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance ( Site 0104)
state: Washington
city: Tacoma
country: United States
facility: Northwest Medical Specialties, PLLC ( Site 0101)
state: Washington
city: Edmonton
country: Canada
facility: Cross Cancer Institute ( Site 0123)
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 0122)
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0124)
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital ( Site 0121)
state: Quebec
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Chen EX, Kavan P, Tehfe M, Kortmansky JS, Sawyer MB, Chiorean EG, Lieu CH, Polite B, Wong L, Fakih M, Spencer K, Chaves J, Li C, Leconte P, Adelberg D, Kim R. Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E. Clin Colorectal Cancer. 2024 Jun;23(2):183-193. doi: 10.1016/j.clcc.2024.03.002. Epub 2024 Apr 1.
citation: Kim R, Tehfe M, Kavan P, Chaves J, Kortmansky JS, Chen EX, Lieu CH, Wong L, Fakih M, Spencer K, Zhao Q, Predoiu R, Li C, Leconte P, Adelberg D, Chiorean EG. Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D. Clin Colorectal Cancer. 2024 Jun;23(2):118-127.e6. doi: 10.1016/j.clcc.2024.03.001. Epub 2024 Apr 1.