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)

Metastatic Colorectal Cancer Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03374254
• Other study ID #: 3475-651
• Secondary ID: MK-3475-6512017-
• Status: Completed
• Phase: Phase 1
• Start date: February 16, 2018
• Est. completion date: July 18, 2023

Study information

• Verified date: September 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 114
• Est. completion date: July 18, 2023
• Est. primary completion date: September 8, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Biological:
• Pembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W

Drug:
• 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.

Locations

Country	Name	City	State
Canada	Cross Cancer Institute ( Site 0123)	Edmonton	Alberta
Canada	Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0124)	Montreal	Quebec
Canada	Jewish General Hospital ( Site 0121)	Montreal	Quebec
Canada	Princess Margaret Cancer Centre ( Site 0122)	Toronto	Ontario
United States	Anschutz Medical Campus, Anschutz Cancer Pavilion ( Site 0106)	Aurora	Colorado
United States	University of Chicago ( Site 0105)	Chicago	Illinois
United States	City of Hope National Medical Center ( Site 0102)	Duarte	California
United States	Rutgers Cancer Institute of New Jersey ( Site 0107)	New Brunswick	New Jersey
United States	Yale Cancer Center ( Site 0108)	New Haven	Connecticut
United States	UPMC Cancer Center/Hillman Cancer Center ( Site 0113)	Pittsburgh	Pennsylvania
United States	Seattle Cancer Care Alliance ( Site 0104)	Seattle	Washington
United States	Northwest Medical Specialties, PLLC ( Site 0101)	Tacoma	Washington
United States	Moffitt Cancer Center ( Site 0111)	Tampa	Florida
United States	Baylor Scott and White ( Site 0110)	Temple	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC	Array BioPharma

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of participants with a dose limiting toxicity (DLT)	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.	Up to first 28 days of treatment
Secondary	Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)	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.	Up to 2 years

External Links

•   Merck Clinical Trials Information