Clinical Trials /

Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Previously-Treated Locally Advanced Unresectable or Metastatic Colorectal Cancer (MK-3475-164/KEYNOTE-164)

NCT02460198

Description:

In this study, participants with previously-treated locally-advanced unresectable or metastatic mismatched repair (MMR) deficient or microsatellite instability-high (MSI-H) colorectal carcinoma (CRC) will be treated with pembrolizumab (MK-3475, KEYTRUDA®) monotherapy. There will be two cohorts in this study: Cohort A and Cohort B. For Cohort A, participants are required to have been previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan. Enrollment into Cohort A has been completed. For Cohort B, participants are required to have been previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti-vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. The primary hypothesis is that Objective Response Rate (ORR) based on Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST 1.1) assessed by central imaging vendor in participants with locally advanced unresectable or metastatic MMR deficient or MSI high CRC is greater than 15%.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Previously-Treated Locally Advanced Unresectable or Metastatic Colorectal Cancer (MK-3475-164/KEYNOTE-164)
  • Official Title: A Phase II Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects With Previously Treated Locally Advanced Unresectable or Metastatic (Stage IV) Mismatched Repair Deficient or Microsatellite Instability-High Colorectal Carcinoma (KEYNOTE-164)

Clinical Trial IDs

  • ORG STUDY ID: 3475-164
  • SECONDARY ID: 2015-001852-32
  • SECONDARY ID: 153046
  • SECONDARY ID: MK-3475-164
  • SECONDARY ID: KEYNOTE-164
  • NCT ID: NCT02460198

Conditions

  • Colorectal Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Cohort A - Pembrolizumab 200 mg

Purpose

In this study, participants with previously-treated locally-advanced unresectable or metastatic mismatched repair (MMR) deficient or microsatellite instability-high (MSI-H) colorectal carcinoma (CRC) will be treated with pembrolizumab (MK-3475, KEYTRUDA®) monotherapy. There will be two cohorts in this study: Cohort A and Cohort B. For Cohort A, participants are required to have been previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan. Enrollment into Cohort A has been completed. For Cohort B, participants are required to have been previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti-vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. The primary hypothesis is that Objective Response Rate (ORR) based on Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST 1.1) assessed by central imaging vendor in participants with locally advanced unresectable or metastatic MMR deficient or MSI high CRC is greater than 15%.

Detailed Description

      With protocol amendment 08 (13-Nov-2019), once study participants have achieved the study
      objective or the study has ended, participants will be discontinued from this study and may
      be enrolled in a pembrolizumab extension study (NCT03486873) to continue protocol-defined
      assessments and treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A - Pembrolizumab 200 mgExperimentalParticipants were previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan. Cohort A participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week cycle (Q3W) for up to approximately 52 cycles (up to approximately 4 years).
  • Pembrolizumab
Cohort B - Pembrolizumab 200 mgExperimentalParticipants were previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. Cohort B participants receive pembrolizumab 200 mg IV on Day 1 Q3W for up to approximately 52 cycles (up to approximately 4 years).
  • Pembrolizumab

Eligibility Criteria

        Inclusion criteria:

          -  Histologically-proven locally advanced unresectable or metastatic colorectal carcinoma

          -  Locally confirmed MMR deficient or MSI-H status

          -  Has been previously treated with standard therapies, which must include, for Cohort A,
             fluoropyrimidine, oxaliplatin, and irinotecan, and for Cohort B, at least one line of
             systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine
             + irinotecan +/- anti-VEGF/EGFR monoclonal antibody (mAb).

          -  Eastern Cooperative Oncology Group performance status of 0 or 1

          -  Life expectancy of greater than 3 months

          -  Provides an archival or newly obtained (≤60 days prior to first dose of study
             treatment) tumor tissue sample (Cohort B)

          -  At least one measurable lesion

          -  Female participants of childbearing potential should be willing to use acceptable
             methods of contraception or be surgically sterile, or abstain from heterosexual
             activity for the course of the study through 120 days after the last dose of study
             treatment

          -  Male participants should agree to use an adequate method of contraception starting
             with the first dose of study treatment through 120 days after the last dose of study
             treatment

          -  Adequate organ function

        Exclusion criteria:

          -  Currently participating in another study and receiving trial treatment, participated
             in a study of an investigational agent and received trial treatment within 4 weeks of
             the first dose of treatment in this study, or used an investigational device within 4
             weeks of the first dose of treatment in this study

          -  Active autoimmune disease that has required systemic treatment in past 2 years

          -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
             form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment

          -  Known active central nervous system metastases and/or carcinomatous meningitis

          -  Prior monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or
             radiation therapy within 2 weeks prior to study Day 1 or not recovered (i.e., ≤ Grade
             1 or at baseline) from adverse events (AEs) due to a previously administered agent

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

          -  Received a live vaccine within 30 days of planned start of study treatment

          -  Known history of human immunodeficiency virus (HIV)

          -  Known active Hepatitis B or C

          -  Has known history of, or any evidence of interstitial lung disease or active,
             noninfectious pneumonitis

          -  Active infection requiring systemic therapy

          -  Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the study

          -  Pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of study treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor
Time Frame:Up to approximately 4 years
Safety Issue:
Description:Objective response rate was defined as the percentage of the participants in the analysis population who had a complete response (CR) or partial response (PR). Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responses were based upon blinded central imaging vendor per RECIST 1.1. The point estimate and 95% confidence interval for the ORR, were provided using an exact binomial distribution (Clopper and Pearson method). Participants without response data were counted as nonresponders. The data cutoff date was 09-SEP-2019.

Secondary Outcome Measures

Measure:Disease Control Rate (DCR) Per RECIST 1.1 Assessed by Central Imaging Vendor.
Time Frame:Up to approximately 4 years
Safety Issue:
Description:Disease Control Rate was defined as the percentage of participants who achieved confirmed CR or PR or had demonstrated stable disease (SD) for at least 24 weeks prior to any evidence of progression. Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive Disease: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. or the appearance of new lesion(s). Participants in the analysis population with missing DCR were considered as disease not under control. The data cutoff date was 09-SEP-2019.
Measure:Progression-Free Survival (PFS) Per RECIST 1.1 Assessed by Central Imaging Vendor.
Time Frame:Up to approximately 4 years
Safety Issue:
Description:PFS is defined as the time from first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Progressive Disease: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions was also considered progression). PFS was summarized by Kaplan-Meier (KM) methods. The data cutoff date was 09-SEP-2019.
Measure:Overall Survival (OS)
Time Frame:Up to approximately 4 years
Safety Issue:
Description:OS is defined as the time from first day of study treatment to death due to any cause. Participants without documented death at the time of analysis are censored at the date of the last follow-up. OS was summarized by Kaplan-Meier (KM) methods. The data cutoff date was 09-SEP-2019.
Measure:Number of Participants Who Experienced an Adverse Event (AE).
Time Frame:Up to approximately 4 years
Safety Issue:
Description:An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study.
Measure:Number of Participants Who Discontinued Study Treatment Due to an AE.
Time Frame:Up to approximately 4 years
Safety Issue:
Description:An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study.
Measure:Duration of Response (DOR) Per RECIST 1.1 as Assessed by the Central Imaging Vendor
Time Frame:Up to approximately 4 years
Safety Issue:
Description:For participants who demonstrated a CR or PR, duration of response was defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurred first. Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responses were based upon blinded central imaging vendor per RECIST 1.1. Duration of Response was based on IRC review using RECIST 1.1 and was summarized by Kaplan-Meier (KM) methods for censored data. Nonresponders were excluded from the analysis of DOR.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)
  • MSI-H
  • MSI

Last Updated

March 22, 2021