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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)

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ClinicalTrials.gov Identifier: NCT03374254
Recruitment Status : Recruiting
First Posted : December 15, 2017
Last Update Posted : July 20, 2018
Sponsor:
Collaborator:
Array BioPharma
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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).

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Biological: Pembrolizumab Drug: Binimetinib Drug: Oxaliplatin Drug: Leucovorin Drug: 5-Fluorouracil [5-FU] Drug: Irinotecan Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 16, 2018
Estimated Primary Completion Date : November 26, 2021
Estimated Study Completion Date : November 26, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab + Binimetinib (Cohort A)
During Part 1, participants in Cohort A will receive a standard dose (DL1) of pembrolizumab (200 mg) intravenous (IV) every 3 weeks (Q3W) plus binimetinib orally at a starting dose of 30 mg twice a day (BID). Based on dose-limiting toxicities (DLT) assessed during the initial 21 days of Cycle 1, the dose of binimetinib may be escalated to 45 mg orally BID (Dose Level 2 [DL2]). Once a preliminary RP2D for binimetinib is identified in Part 1 for Cohort A, participants will receive pembrolizumab 200 mg IV Q3W plus binimetinib orally at the preliminary RP2D during Part 2.
Biological: Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Other Name: MK-3475

Drug: Binimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
Other Name: MEK162, ARRY-162, ARRY-438162

Experimental: Pembrolizumab + mFOLFOX7 (Cohort B)
During Part 1, participants in Cohort B will receive a standard dose (DL1) of 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 every 2 weeks (Q2W). Based on DLTs assessed during the initial 28 days of Cycle 1, the dose of mFOLFOX7 may be de-escalated to oxaliplatin 70 mg/m^2; leucovorin (calcium folinate) 400 mg/m^2; 5-FU 2000 mg/m^2 over 46-48 hours] IV Q2W. Once a preliminary RP2D for mFOLFOX7 is identified in Part 1 for Cohort B, participants will receive pembrolizumab 200 mg IV Q3W plus mFOLFOX7 at the preliminary RP2D during Part 2.
Biological: Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Other Name: MK-3475

Drug: 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.

Drug: Leucovorin
400 mg/m^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
Other Name: calcium folinate

Drug: 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.

Experimental: Pembrolizumab + mFOLFOX7 + Binimetinib (Cohort C)
After an RP2D for mFOLFOX7 is identified in Part 1 for Cohort B, participants may enroll in Cohort C and receive pembrolizumab 200 mg IV Q3W plus mFOLFOX7 at the preliminary RP2D Q2W in combination with binimetinib orally at a starting dose of 30 mg BID during Part 1. Based on DLTs assessed during the initial 28 days of Cycle 1, the dose of binimetinib may be escalated to 45 mg orally BID (DL2). Once a preliminary RP2D for binimetinib is identified in Part 1 for this cohort, participants in Part 2 will receive pembrolizumab 200 mg IV Q3W plus mFOLFOX7 at the RP2D determined for Cohort B Q2W plus binimetinib orally at the RP2D determined for Cohort C in Part 1.
Biological: Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Other Name: MK-3475

Drug: Binimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
Other Name: MEK162, ARRY-162, ARRY-438162

Drug: 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.

Drug: Leucovorin
400 mg/m^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
Other Name: calcium folinate

Drug: 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.

Experimental: Pembrolizumab + FOLFIRI (Cohort D)
During Part 1, 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. Based on DLTs assessed during the initial 28 days of Cycle 1, the dose of FOLFIRI may be de-escalated to irinotecan 150 mg/m^2; leucovorin (calcium folinate) 400 mg/m^2; 5-FU 2000 mg/m^2 over 46-48 hours) IV Q2W. Once a preliminary RP2D for FOLFIRI is identified in Part 1 for Cohort D, participants will receive pembrolizumab 200 mg IV Q3W plus FOLFIRI at the preliminary RP2D during Part 2.
Biological: Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Other Name: MK-3475

Drug: Leucovorin
400 mg/m^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
Other Name: calcium folinate

Drug: 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.

Drug: 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.

Experimental: Pembrolizumab + FOLFIRI + Binimetinib (Cohort E)
After an RP2D for FOLFIRI is identified in Part 1 for Cohort D, participants may enroll in Cohort E and receive pembrolizumab 200 mg IV Q3W plus FOLFIRI at the preliminary RP2D Q2W in combination with binimetinib orally at a starting dose of 30 mg BID during Part 1. Based on DLTs assessed during the initial 28 days of Cycle 1, the dose of binimetinib may be escalated to 45 mg orally BID (DL2). Once a preliminary RP2D for binimetinib is identified in Part 1 for this cohort, participants in Part 2 will receive pembrolizumab 200 mg IV Q3W plus FOLFIRI at the RP2D determined for Cohort D Q2W plus binimetinib orally at the RP2D determined for Cohort E in Part 1.
Biological: Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
Other Name: MK-3475

Drug: Binimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
Other Name: MEK162, ARRY-162, ARRY-438162

Drug: Leucovorin
400 mg/m^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
Other Name: calcium folinate

Drug: 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.

Drug: 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.




Primary Outcome Measures :
  1. Percentage of participants with a dose limiting toxicity (DLT) [ Time Frame: Up to first 28 days of treatment ]
    Number of participants experiencing toxicities that are possibly, probably, or definitely related to study therapy; that meet pre-defined severity criteria; and result in a change in the given dose.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) [ Time Frame: Up to 2 years ]
    ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03374254


Contacts
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
United States, California
City of Hope National Medical Center ( Site 0102) Recruiting
Duarte, California, United States, 91010
Contact: Study Coordinator    626-471-9200      
United States, Colorado
Anschutz Medical Campus, Anschutz Cancer Pavilion ( Site 0106) Recruiting
Aurora, Colorado, United States, 80045
Contact: Study Coordinator    303-724-3532      
United States, Connecticut
Yale Cancer Center ( Site 0108) Recruiting
New Haven, Connecticut, United States, 06520
Contact: Study Coordinator    203-785-6661      
United States, Florida
Moffitt Cancer Center ( Site 0111) Recruiting
Tampa, Florida, United States, 33612
Contact: Study Coordinator    813-745-2742      
United States, Illinois
University of Chicago ( Site 0105) Recruiting
Chicago, Illinois, United States, 60637
Contact: Study Coordinator    773-702-7763      
United States, New Jersey
Rutgers Cancer Institute of New Jersey ( Site 0107) Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Study Coordinator    732-235-2465      
United States, Pennsylvania
UPMC Cancer Center/Hillman Cancer Center ( Site 0113) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Study Coordinator    412-623-2677      
United States, Texas
Baylor Scott and White ( Site 0110) Recruiting
Temple, Texas, United States, 76508
Contact: Study Coordinator    254-724-3796      
United States, Washington
Seattle Cancer Care Alliance ( Site 0104) Recruiting
Seattle, Washington, United States, 98109
Contact: Study Coordinator    206-288-6248      
Northwest Medical Specialties, PLLC ( Site 0101) Recruiting
Tacoma, Washington, United States, 98405
Contact: Study Coordinator    253-428-8738      
Canada, Alberta
Cross Cancer Institute ( Site 0123) Recruiting
Edmonton, Alberta, Canada, T6G 1Z2
Contact: Study Coordinator    7804328248      
Canada, Ontario
Princess Margaret Cancer Centre ( Site 0122) Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Study Coordinator    4169462263      
Canada, Quebec
Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0124) Recruiting
Montreal, Quebec, Canada, H2X 0C1
Contact: Study Coordinator    514890800025381      
Jewish General Hospital ( Site 0121) Recruiting
Montreal, Quebec, Canada, H3T 1E2
Contact: Study Coordinator    5143408222      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Array BioPharma
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03374254     History of Changes
Other Study ID Numbers: 3475-651
2017-000356-26 ( EudraCT Number )
MK-3475-651 ( Other Identifier: Merck Protocol Number )
First Posted: December 15, 2017    Key Record Dates
Last Update Posted: July 20, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:
CRC, MSS, non-MSI-H, PD-1, anti-PD-1, anti PD-1, MEK, MEK inhibitor

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Calcium, Dietary
Oxaliplatin
Pembrolizumab
Irinotecan
Fluorouracil
Levoleucovorin
Leucovorin
Bone Density Conservation Agents
Physiological Effects of Drugs
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors