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)

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Binimetinib
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: 5-Fluorouracil [5-FU]
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Binimetinib (Cohort A)<br>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<br>* 200 mg Pembrolizumab solution for IV infusion Q3W<br>* Other names: MK-3475;Drug: Binimetinib<br>* tablet orally BID at 30 or 45 mg depending upon DLT profile<br>* Other names: MEK162, ARRY-162, ARRY-438162;|
| Experimental: Pembrolizumab + mFOLFOX7 (Cohort B)<br>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<br>* 200 mg Pembrolizumab solution for IV infusion Q3W<br>* Other names: MK-3475;Drug: Oxaliplatin<br>* 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.<br>Drug: Leucovorin<br>* 400 mg/m^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.<br>* Other names: calcium folinate;Drug: 5-Fluorouracil [5-FU]<br>* 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.<br>|
| Experimental: Pembrolizumab + mFOLFOX7 + Binimetinib (Cohort C)<br>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<br>* 200 mg Pembrolizumab solution for IV infusion Q3W<br>* Other names: MK-3475;Drug: Binimetinib<br>* tablet orally BID at 30 or 45 mg depending upon DLT profile<br>* Other names: MEK162, ARRY-162, ARRY-438162;Drug: Oxaliplatin<br>* 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.<br>Drug: Leucovorin<br>* 400 mg/m^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.<br>* Other names: calcium folinate;Drug: 5-Fluorouracil [5-FU]<br>* 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.<br>|
| Experimental: Pembrolizumab + FOLFIRI (Cohort D)<br>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<br>* 200 mg Pembrolizumab solution for IV infusion Q3W<br>* Other names: MK-3475;Drug: Leucovorin<br>* 400 mg/m^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.<br>* Other names: calcium folinate;Drug: 5-Fluorouracil [5-FU]<br>* 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.<br>Drug: Irinotecan<br>* 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.<br>|
| Experimental: Pembrolizumab + FOLFIRI + Binimetinib (Cohort E)<br>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<br>* 200 mg Pembrolizumab solution for IV infusion Q3W<br>* Other names: MK-3475;Drug: Binimetinib<br>* tablet orally BID at 30 or 45 mg depending upon DLT profile<br>* Other names: MEK162, ARRY-162, ARRY-438162;Drug: Leucovorin<br>* 400 mg/m^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.<br>* Other names: calcium folinate;Drug: 5-Fluorouracil [5-FU]<br>* 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.<br>Drug: Irinotecan<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRC, MSS, non-MSI-H, PD-1, anti-PD-1, anti PD-1, MEK, MEK inhibitor