Clinical Trials /

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)

NCT03374254

Description:

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).

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • 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 IDs

  • ORG STUDY ID: 3475-651
  • SECONDARY ID: 2017-000356-26
  • SECONDARY ID: MK-3475-651
  • NCT ID: NCT03374254

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
PembrolizumabMK-3475Pembrolizumab + Binimetinib (Cohort A)
BinimetinibMEK162, ARRY-162, ARRY-438162Pembrolizumab + Binimetinib (Cohort A)
OxaliplatinPembrolizumab + mFOLFOX7 (Cohort B)
Leucovorincalcium folinatePembrolizumab + mFOLFOX7 (Cohort B)
5-Fluorouracil [5-FU]Pembrolizumab + mFOLFOX7 (Cohort B)
IrinotecanPembrolizumab + FOLFIRI (Cohort D)

Purpose

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 Arms

NameTypeDescriptionInterventions
Pembrolizumab + Binimetinib (Cohort A)ExperimentalDuring 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.
  • Binimetinib
Pembrolizumab + mFOLFOX7 (Cohort B)ExperimentalDuring 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.
  • Oxaliplatin
  • Leucovorin
  • 5-Fluorouracil [5-FU]
Pembrolizumab + mFOLFOX7 + Binimetinib (Cohort C)ExperimentalAfter 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.
  • Binimetinib
  • Oxaliplatin
  • Leucovorin
  • 5-Fluorouracil [5-FU]
Pembrolizumab + FOLFIRI (Cohort D)ExperimentalDuring 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.
  • Leucovorin
  • 5-Fluorouracil [5-FU]
  • Irinotecan
Pembrolizumab + FOLFIRI + Binimetinib (Cohort E)ExperimentalAfter 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.
  • Binimetinib
  • Leucovorin
  • 5-Fluorouracil [5-FU]
  • Irinotecan

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of participants with a dose limiting toxicity (DLT)
Time Frame:Up to first 28 days of treatment
Safety Issue:
Description: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

Measure:Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
Time Frame:Up to 2 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • CRC, MSS, non-MSI-H, PD-1, anti-PD-1, anti PD-1, MEK, MEK inhibitor

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