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Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02563002
Recruitment Status : Active, not recruiting
First Posted : September 29, 2015
Results First Posted : March 16, 2022
Last Update Posted : March 16, 2022
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Tracking Information
First Submitted Date  ICMJE September 28, 2015
First Posted Date  ICMJE September 29, 2015
Results First Submitted Date  ICMJE January 6, 2022
Results First Posted Date  ICMJE March 16, 2022
Last Update Posted Date March 16, 2022
Actual Study Start Date  ICMJE November 30, 2015
Actual Primary Completion Date February 19, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 23, 2022)
  • Progression-Free Survival (PFS) Per RECIST1.1 As Assessed by Central Imaging Vendor [ Time Frame: Up to approximately 59 months ]
    PFS was defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Hazards ratio (HR) and associated 95% confidence intervals (CIs) from a Cox proportional hazard model with Efron's method of tie handling and with a single treatment covariate was presented for the first course study treatment per protocol.
  • Overall Survival (OS) [ Time Frame: Up to approximately 59 months ]
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of analysis were censored at the date of last known contact. HR and associated 95% CIs from a Cox proportional hazard model with Efron's method of tie handling and with a single treatment covariate was presented for the first course study treatment per protocol.
Original Primary Outcome Measures  ICMJE
 (submitted: September 28, 2015)
Progression-free Survival (PFS) [ Time Frame: Up to 57 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 23, 2022)
  • Overall Response Rate (ORR) Per RECIST1.1 as Assessed by Central Imaging Vendor [ Time Frame: Up to approximately 59 months ]
    ORR was defined as the percentage of the participants who experienced a 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) and was assessed using RECIST 1.1 as assessed by the central imaging vendor. The percentage of participants who experienced a CR or PR was presented for the first course of study treatment per protocol.
  • Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 59 months ]
    An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE was presented for the first course study treatment per protocol.
  • Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 59 months ]
    An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE was presented for the first course study treatment per protocol.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 28, 2015)
  • Overall Response Rate (ORR) [ Time Frame: Up to 57 months ]
  • Overall Survival (OS) [ Time Frame: Up to 57 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177)
Official Title  ICMJE A Phase III Study of Pembrolizumab (MK-3475) vs. Chemotherapy in Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (KEYNOTE-177)
Brief Summary In this study, participants with stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) colorectal carcinoma (CRC) will be randomly assigned to receive either pembrolizumab or the Investigator's choice of 1 of 6 standard of care (SOC) chemotherapy regimens for the treatment of advanced colorectal carcinoma. The primary study hypothesis is that pembrolizumab will prolong progression-free survival (PFS) or overall survival (OS) compared to current SOC chemotherapy.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Colorectal Carcinoma
Intervention  ICMJE
  • Drug: mFOLFOX6
    Regimen consists of oxaliplatin 85 mg/m^2 IV on Day 1, leucovorin 400 mg/m^2 or levoleucovorin 200 mg/m^2 IV on Day 1, 5-fluorouracil (5-FU) 400 mg/m^2 IV bolus on Day 1 and then 1200 mg/m^2/day IV over 2 days for total dose of 2400 mg/m^2 in each 2-week cycle
  • Drug: FOLFIRI
    Regimen consists of irinotecan 180 mg/m^2 IV on Day 1, leucovorin 400 mg/m^2 or levoleucovorin 200 mg/m^2 IV on Day 1, 5-FU 400 mg/m^2 IV bolus on Day 1 and then 1200 mg/m^2/day IV over 2 days for total dose of 2400 mg/m^2 in each 2-week cycle
  • Biological: pembrolizumab
    MK-3475 SCH 900475 KEYTRUDA®
    Other Name: IV infusion
  • Biological: bevacizumab
    Other Name: IV infusion
  • Biological: cetuximab
    Other Name: IV infusion
Study Arms  ICMJE
  • Experimental: Pembrolizumab
    Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 treatments (approximately 2 years). Participants that have stopped the initial course of pembrolizumab and have stable disease but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 year additional).
    Intervention: Biological: pembrolizumab
  • Active Comparator: Standard of Care (SOC)
    Participants receive 1 of 6 possible standard chemotherapy regimens: mFOLFOX6, or mFOLFOX6+bevacizumab 5 mg/kg IV on Day 1 of each 2-week cycle, or mFOLFOX6+cetuximab 400 mg/m^2 IV over 2 hours then 250 mg/m^2 over 1 hour weekly in each 2-week cycle, or FOLFIRI, or FOLFIRI+bevacizumab 5 mg/kg IV on Day 1 of each 2-week cycle, or FOLFIRI+cetuximab 400 mg/m^2 IV over 2 hours then 250 mg/m^2 over 1 hour weekly in each 2-week cycle. Participants with documented disease progression following chemotherapy can crossover to receive pembrolizumab for up to 35 cycles (approximately 2 years). Participants that have stopped pembrolizumab and have stable disease but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 year additional).
    Interventions:
    • Drug: mFOLFOX6
    • Drug: FOLFIRI
    • Biological: pembrolizumab
    • Biological: bevacizumab
    • Biological: cetuximab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 11, 2021)
307
Original Estimated Enrollment  ICMJE
 (submitted: September 28, 2015)
270
Estimated Study Completion Date  ICMJE February 20, 2023
Actual Primary Completion Date February 19, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Locally confirmed dMMR or MSI-H stage IV colorectal carcinoma
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 10 days prior to study start
  • Life expectancy of at least 3 months
  • Measurable disease
  • Female participants of childbearing potential must be willing to use adequate contraception for the course of the study starting with the first dose of study medication through 180 days after the last dose of standard of care (SOC) therapy or 120 days after the last pembrolizumab dose
  • Male participants must agree to use adequate contraception for the course of the study starting with the first dose of study medication through 180 days after the last dose of SOC therapy or 120 days after the last pembrolizumab dose
  • Adequate organ function

Exclusion Criteria:

  • Has received prior systemic therapy for Stage IV colorectal cancer. May have received prior adjuvant chemotherapy for colorectal cancer as long as it was completed at least 6 months prior to randomization on this study
  • Currently participating and receiving treatment in another study, or participated in a study of an investigational agent and received treatment, or used an investigational device within 4 weeks of randomization
  • Active autoimmune disease that has required systemic treatment in past 2 years
  • Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization on this study
  • Radiation therapy within 4 weeks prior to randomization on this study and not recovered to baseline from adverse events due to radiation therapy
  • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization on this study
  • Has received prior therapy with an immune checkpoint inhibitor (e.g., anti-programmed cell death [PD]-1, anti-PD ligand 1 [L1], anti-PD-L2 agent, or anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] agent, etc.)
  • Another malignancy that is progressing or requires active treatment with the exception of non-melanomatous skin cancer that has undergone potentially curative therapy and in situ cervical carcinoma
  • Received a live vaccine within 30 days of planned start of study medication
  • Known history of Human Immunodeficiency Virus (HIV), Hepatitis B or C
  • Known history of, or any evidence of interstitial lung disease or active, non-infectious pneumonitis
  • Known history of active tuberculosis (Bacillus tuberculosis [TB])
  • Active infection requiring systemic therapy
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
  • Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of SOC or 120 days after the last dose of pembrolizumab
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Australia,   Belgium,   Brazil,   Canada,   Denmark,   Finland,   France,   Germany,   Ireland,   Israel,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Norway,   Singapore,   South Africa,   Spain,   Sweden,   Switzerland,   Taiwan,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT02563002
Other Study ID Numbers  ICMJE 3475-177
2015-002024-89 ( EudraCT Number )
163238 ( Registry Identifier: JAPIC-CTI )
MK-3475-177 ( Other Identifier: Merck )
KEYNOTE-177 ( Other Identifier: Merck )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Current Responsible Party Merck Sharp & Dohme LLC
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Merck Sharp & Dohme LLC
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme LLC
PRS Account Merck Sharp & Dohme LLC
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP