AzTrials
AzTrials

Metastatic Colorectal CancerPhase 1NCT03374254

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)

A Phase 1 study testing Pembrolizumab, Binimetinib and Oxaliplatin in people with Metastatic Colorectal Cancer, run by Merck Sharp & Dohme LLC at 14 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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]… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Colorectal Cancer
What is being tested?
Pembrolizumab, Binimetinib and Oxaliplatin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
116 participants
Where
14 sitesin 2 countries
Study dates
16 Feb 2018to 18 Jul 2023
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 18Show fewer
  • 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

Who cannot join

  • 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
Show all 30Show fewer
  • 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

Trial locations and contacts

14 sites in 2 countries.

14 sites in 2 countries

United States10 sites

  • Anschutz Medical Campus, Anschutz Cancer Pavilion ( Site 0106)

    Aurora, Colorado, 80045

  • University of Chicago ( Site 0105)

    Chicago, Illinois, 60637

  • City of Hope National Medical Center ( Site 0102)

    Duarte, California, 91010

  • Rutgers Cancer Institute of New Jersey ( Site 0107)

    New Brunswick, New Jersey, 08903-2681

  • Yale Cancer Center ( Site 0108)

    New Haven, Connecticut, 06520

  • UPMC Cancer Center/Hillman Cancer Center ( Site 0113)

    Pittsburgh, Pennsylvania, 15232

  • Seattle Cancer Care Alliance ( Site 0104)

    Seattle, Washington, 98109

  • Northwest Medical Specialties, PLLC ( Site 0101)

    Tacoma, Washington, 98405

  • Moffitt Cancer Center ( Site 0111)

    Tampa, Florida, 33612

  • Baylor Scott and White ( Site 0110)

    Temple, Texas, 76508

Other trials in United States

Canada4 sites

  • Cross Cancer Institute ( Site 0123)

    Edmonton, Alberta, T6G 1Z2

  • Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0124)

    Montreal, Quebec, H2X 3E4

  • Jewish General Hospital ( Site 0121)

    Montreal, Quebec, H3T 1E2

  • Princess Margaret Cancer Centre ( Site 0122)

    Toronto, Ontario, M5G 2M9

Other trials in Canada

About this study

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)

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).

Being tested
Pembrolizumab, Binimetinib, Oxaliplatin, Leucovorin, 5-Fluorouracil [5-FU]
Keywords
CRC, MSS, non-MSI-H, PD-1, anti-PD-1, anti PD-1, MEK, MEK inhibitor
Medical subject headings
Colorectal Neoplasms, Spinocerebellar Degenerations, Parkinson Disease 4, Autosomal Dominant Lewy Body

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PembrolizumabBiological

    Also called MK-3475

    200 mg Pembrolizumab solution for IV infusion Q3W

  • BinimetinibDrug

    Also called MEK162, ARRY-162, ARRY-438162

    tablet orally BID at 30 or 45 mg depending upon DLT profile

  • OxaliplatinDrug

    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.

  • LeucovorinDrug

    Also called calcium folinate

    400 mg/m^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.

  • 5-Fluorouracil [5-FU]Drug

    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.

  • IrinotecanDrug

    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.

Study groups in NCT03374254
Study groupRoleWhat they receive
Cohort A Part 1: Pembrolizumab +Binimetinib 30 mgExperimentalParticipants 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.
Receives: Biological: Pembrolizumab; Drug: Binimetinib
Cohort A Part 1: Pembrolizumab +Binimetinib 45 mgExperimentalParticipants 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.
Receives: Biological: Pembrolizumab; Drug: Binimetinib
Cohort B Part 1: Pembrolizumab + mFOLFOX7ExperimentalParticipants 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.
Receives: Biological: Pembrolizumab; Drug: Oxaliplatin; Drug: Leucovorin; Drug: 5-Fluorouracil [5-FU]
Cohort B Part 2: Pembrolizumab + mFOLFOXExperimentalDuring 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.
Receives: Biological: Pembrolizumab; Drug: Oxaliplatin; Drug: Leucovorin; Drug: 5-Fluorouracil [5-FU]
Cohort C Part 1: Pembrolizumab + mFOLFOX7 + Binimetinib 30 mgExperimentalParticipants 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.
Receives: Biological: Pembrolizumab; Drug: Binimetinib; Drug: Oxaliplatin; Drug: Leucovorin; Drug: 5-Fluorouracil [5-FU]
Cohort D Part 1: Pembrolizumab + FOLFIRIExperimentalParticipants 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.
Receives: Biological: Pembrolizumab; Drug: Leucovorin; Drug: 5-Fluorouracil [5-FU]; Drug: Irinotecan
Cohort D Part 2: Pembrolizumab + FOLFIRIExperimentalDuring 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.
Receives: Biological: Pembrolizumab; Drug: Leucovorin; Drug: 5-Fluorouracil [5-FU]; Drug: Irinotecan
Cohort E Part 1: Pembrolizumab + FOLFIRI + Binimetinib 30 mgExperimentalParticipants 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.
Receives: Biological: Pembrolizumab; Drug: Binimetinib; Drug: Leucovorin; Drug: 5-Fluorouracil [5-FU]; Drug: Irinotecan
Cohort E Part 1: Pembrolizumab + FOLFIRI + Binimetinib 45 mgExperimentalDuring 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.
Receives: Biological: Pembrolizumab; Drug: Binimetinib; Drug: Leucovorin; Drug: 5-Fluorouracil [5-FU]; Drug: Irinotecan

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT)

    The occurrence of any of the following toxicities during Part 1 of the study (the first 21 days for Cohort A, first 28 days for Cohorts B,C, D, \& E), if possibly, probably or definitely related to study treatment, was considered a DLT:

    Grade (Gr) 4 non hematologic toxicity, Gr 4 hematologic toxicity lasting >7 days, Gr 3 thrombocytopenia, Any non-hematologic AE ≥Gr 3 in severity, Any Gr 3 or Gr 4 non-hematologic laboratory value, Febrile neutropenia Gr 3 or Gr 4, Any prolonged delay in initiating study therapy due to a treatment-related AE that started during the DLT period, Any treatment-related toxicity that causes the participant to discontinue treatment during the DLT period, Missing >25% of binimetinib doses as a result of drug-related AE(s), Gr 5 toxicity, Cardiac disorders and vascular disorders, Eye disorders (Retinopathy or retinal detachment Gr ≥ 3).

    Measured: Up to approximately first 28 days of treatment

Secondary outcomes (1)

  1. Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)

    ORR was determined in all participants and was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). The percentage of participants who experienced CR or PR is presented. Per Protocol, analysis was per cohort.

    Measured: Up to Approximately 64 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Dec 2017
  2. Study start16 Feb 2018
  3. Primary completion8 Sep 2021
  4. Study completion18 Jul 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
116 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03374254
Sponsor's protocol ID
3475-651
Other IDs
MK-3475-651, KEYNOTE-651
Status last verified
Nov 2024
First submitted
12 Dec 2017
Last updated
21 Nov 2024
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Publications

  • 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.

    PubMed 38653648

  • 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.

    PubMed 38762348

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Pembrolizumab, Binimetinib and Oxaliplatin in people with Metastatic Colorectal Cancer, run by Merck Sharp & Dohme LLC at 14 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT) (time frame: Up to approximately first 28 days of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03374254, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Nov 2024.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in