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)
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)
3 other identifiers
interventional
116
2 countries
14
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).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Feb 2018
Longer than P75 for phase_1
14 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
December 12, 2017
CompletedFirst Posted
Study publicly available on registry
December 15, 2017
CompletedStudy Start
First participant enrolled
February 16, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 8, 2021
CompletedStudy Completion
Last participant's last visit for all outcomes
July 18, 2023
CompletedResults Posted
Study results publicly available
October 15, 2024
CompletedNovember 21, 2024
November 1, 2024
3.6 years
December 12, 2017
July 11, 2024
November 5, 2024
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT)
The occurrence of any of the following toxicities during Part 1 of the study (the first 21 days for Cohort A, first 28 days for Cohorts B,C, D, \& E), if possibly, probably or definitely related to study treatment, was considered a DLT: Grade (Gr) 4 non hematologic toxicity, Gr 4 hematologic toxicity lasting \>7 days, Gr 3 thrombocytopenia, Any non-hematologic AE ≥Gr 3 in severity, Any Gr 3 or Gr 4 non-hematologic laboratory value, Febrile neutropenia Gr 3 or Gr 4, Any prolonged delay in initiating study therapy due to a treatment-related AE that started during the DLT period, Any treatment-related toxicity that causes the participant to discontinue treatment during the DLT period, Missing \>25% of binimetinib doses as a result of drug-related AE(s), Gr 5 toxicity, Cardiac disorders and vascular disorders, Eye disorders (Retinopathy or retinal detachment Gr ≥ 3).
Up to approximately first 28 days of treatment
Secondary Outcomes (1)
Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
Up to Approximately 64 months
Study Arms (9)
Cohort A Part 1: Pembrolizumab +Binimetinib 30 mg
EXPERIMENTALParticipants in Cohort A will receive pembrolizumab (200 mg) intravenous (IV) every 3 weeks (Q3W) plus binimetinib orally at of 30 mg twice a day (BID) until disease progression or discontinuation.
Cohort A Part 1: Pembrolizumab +Binimetinib 45 mg
EXPERIMENTALParticipants in Cohort A will receive pembrolizumab (200 mg) IV Q3W plus binimetinib orally at 45 mg BID (Dose Level 2 \[DL2\]) until disease progression or discontinuation.
Cohort B Part 1: Pembrolizumab + mFOLFOX7
EXPERIMENTALParticipants in Cohort B will receive pembrolizumab (200 mg) IV Q3W plus mFOLFOX7 (oxaliplatin 85 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2 over 46-48 hours) IV Q2W until disease progression or discontinuation.
Cohort B Part 2: Pembrolizumab + mFOLFOX
EXPERIMENTALDuring Part 2, participants in Cohort B will receive pembrolizumab (200 mg) IV Q3W plus mFOLFOX7 (oxaliplatin 85mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2 over 46-48 hours) IV Q2W until disease progression or discontinuation.
Cohort C Part 1: Pembrolizumab + mFOLFOX7 + Binimetinib 30 mg
EXPERIMENTALParticipants in Cohort C will receive pembrolizumab 200 mg IV Q3W plus mFOLFOX7 (oxaliplatin 85mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2 over 46-48 hours) IV Q2W in combination with binimetinib orally at a starting dose of 30 mg BID until disease progression or discontinuation.
Cohort D Part 1: Pembrolizumab + FOLFIRI
EXPERIMENTALParticipants in Cohort D will receive a standard dose (DL1) of pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) IV Q2W until disease progression or discontinuation.
Cohort D Part 2: Pembrolizumab + FOLFIRI
EXPERIMENTALDuring Part 2, participants in Cohort D will receive pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) until disease progression or discontinuation.
Cohort E Part 1: Pembrolizumab + FOLFIRI + Binimetinib 30 mg
EXPERIMENTALParticipants in Cohort E will receive pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) Q2W in combination with binimetinib orally at a starting dose of 30 mg BID until disease progression or discontinuation.
Cohort E Part 1: Pembrolizumab + FOLFIRI + Binimetinib 45 mg
EXPERIMENTALDuring Part 2, participants in Cohort E received pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) Q2W plus binimetinib orally at the starting dose of 45 mg BID until disease progression or discontinuation. Cohort A During Part 2, participants in Cohort E received pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) Q2W plus binimetinib orally at the starting dose of 45 mg BID until disease progression or discontinuation.
Interventions
200 mg Pembrolizumab solution for IV infusion Q3W
tablet orally BID at 30 or 45 mg depending upon DLT profile
85 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 cocktail. Dose may be de-escalated to 70 mg/m\^2 if the standard dose of mFOLFOX7 is deemed too toxic per mTPI, based upon occurrence of DLTs.
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
2400 mg/m\^2 over 46-48 hours as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation. Dose may be de-escalated to 2000 mg/m\^2 if the standard dose of mFOLFOX7 or FOLFIRI is deemed too toxic per mTPI, based upon occurrence of DLTs.
180 mg/m\^2 as IV infusion. Administered Q2W as part of FOLFIRI cocktail. Dose may be de-escalated to 150 mg/m\^2 if the standard dose of FOLFIRI is deemed too toxic per mTPI, based upon occurrence of DLTs.
Eligibility Criteria
You may qualify if:
- 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:
- +3 more criteria
You may not qualify if:
- 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
- +15 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Merck Sharp & Dohme LLClead
- Array BioPharmacollaborator
Study Sites (14)
City of Hope National Medical Center ( Site 0102)
Duarte, California, 91010, United States
Anschutz Medical Campus, Anschutz Cancer Pavilion ( Site 0106)
Aurora, Colorado, 80045, United States
Yale Cancer Center ( Site 0108)
New Haven, Connecticut, 06520, United States
Moffitt Cancer Center ( Site 0111)
Tampa, Florida, 33612, United States
University of Chicago ( Site 0105)
Chicago, Illinois, 60637, United States
Rutgers Cancer Institute of New Jersey ( Site 0107)
New Brunswick, New Jersey, 08903-2681, United States
UPMC Cancer Center/Hillman Cancer Center ( Site 0113)
Pittsburgh, Pennsylvania, 15232, United States
Baylor Scott and White ( Site 0110)
Temple, Texas, 76508, United States
Seattle Cancer Care Alliance ( Site 0104)
Seattle, Washington, 98109, United States
Northwest Medical Specialties, PLLC ( Site 0101)
Tacoma, Washington, 98405, United States
Cross Cancer Institute ( Site 0123)
Edmonton, Alberta, T6G 1Z2, Canada
Princess Margaret Cancer Centre ( Site 0122)
Toronto, Ontario, M5G 2M9, Canada
Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0124)
Montreal, Quebec, H2X 3E4, Canada
Jewish General Hospital ( Site 0121)
Montreal, Quebec, H3T 1E2, Canada
Related Publications (2)
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.
PMID: 38653648RESULTKim 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.
PMID: 38762348RESULT
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Senior Vice President, Global Clinical Development
- Organization
- Merck Sharp & Dohme LLC
Study Officials
- STUDY DIRECTOR
Medical Director
Merck Sharp & Dohme LLC
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
December 12, 2017
First Posted
December 15, 2017
Study Start
February 16, 2018
Primary Completion
September 8, 2021
Study Completion
July 18, 2023
Last Updated
November 21, 2024
Results First Posted
October 15, 2024
Record last verified: 2024-11
Data Sharing
- IPD Sharing
- Will share
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf