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)
NCT ID: NCT03374254
Last Updated: 2024-11-21
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1
116 participants
INTERVENTIONAL
2018-02-16
2023-07-18
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Cohort A Part 1: Pembrolizumab +Binimetinib 30 mg
Participants 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.
Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Binimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
Cohort A Part 1: Pembrolizumab +Binimetinib 45 mg
Participants 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.
Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Binimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
Cohort B Part 1: Pembrolizumab + mFOLFOX7
Participants 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.
Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Oxaliplatin
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.
Leucovorin
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
5-Fluorouracil [5-FU]
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.
Cohort B Part 2: Pembrolizumab + mFOLFOX
During 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.
Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Oxaliplatin
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.
Leucovorin
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
5-Fluorouracil [5-FU]
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.
Cohort C Part 1: Pembrolizumab + mFOLFOX7 + Binimetinib 30 mg
Participants 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.
Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Binimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
Oxaliplatin
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.
Leucovorin
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
5-Fluorouracil [5-FU]
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.
Cohort D Part 1: Pembrolizumab + FOLFIRI
Participants 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.
Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Leucovorin
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
5-Fluorouracil [5-FU]
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.
Irinotecan
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.
Cohort D Part 2: Pembrolizumab + FOLFIRI
During 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.
Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Leucovorin
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
5-Fluorouracil [5-FU]
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.
Irinotecan
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.
Cohort E Part 1: Pembrolizumab + FOLFIRI + Binimetinib 30 mg
Participants 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.
Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Binimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
Leucovorin
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
5-Fluorouracil [5-FU]
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.
Irinotecan
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.
Cohort E Part 1: Pembrolizumab + FOLFIRI + Binimetinib 45 mg
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. 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.
Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Binimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
Leucovorin
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
5-Fluorouracil [5-FU]
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.
Irinotecan
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.
Interventions
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Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Binimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
Oxaliplatin
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.
Leucovorin
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
5-Fluorouracil [5-FU]
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.
Irinotecan
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
ALL
No
Sponsors
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Array BioPharma
INDUSTRY
Merck Sharp & Dohme LLC
INDUSTRY
Responsible Party
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Principal Investigators
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Medical Director
Role: STUDY_DIRECTOR
Merck Sharp & Dohme LLC
Locations
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City of Hope National Medical Center ( Site 0102)
Duarte, California, United States
Anschutz Medical Campus, Anschutz Cancer Pavilion ( Site 0106)
Aurora, Colorado, United States
Yale Cancer Center ( Site 0108)
New Haven, Connecticut, United States
Moffitt Cancer Center ( Site 0111)
Tampa, Florida, United States
University of Chicago ( Site 0105)
Chicago, Illinois, United States
Rutgers Cancer Institute of New Jersey ( Site 0107)
New Brunswick, New Jersey, United States
UPMC Cancer Center/Hillman Cancer Center ( Site 0113)
Pittsburgh, Pennsylvania, United States
Baylor Scott and White ( Site 0110)
Temple, Texas, United States
Seattle Cancer Care Alliance ( Site 0104)
Seattle, Washington, United States
Northwest Medical Specialties, PLLC ( Site 0101)
Tacoma, Washington, United States
Cross Cancer Institute ( Site 0123)
Edmonton, Alberta, Canada
Princess Margaret Cancer Centre ( Site 0122)
Toronto, Ontario, Canada
Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0124)
Montreal, Quebec, Canada
Jewish General Hospital ( Site 0121)
Montreal, Quebec, Canada
Countries
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References
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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.
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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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Merck Clinical Trials Information
Other Identifiers
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MK-3475-651
Identifier Type: OTHER
Identifier Source: secondary_id
KEYNOTE-651
Identifier Type: OTHER
Identifier Source: secondary_id
3475-651
Identifier Type: -
Identifier Source: org_study_id
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