Back to resultsStudy of Pembrolizumab (MK-3475) as Monotherapy in Participants With Previously-Treated Locally Advanced Unresectable or Metastatic Colorectal Cancer (MK-3475-164/KEYNOTE-164)
Primary Purpose
Colorectal Carcinoma
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Pembrolizumab
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Carcinoma focused on measuring Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), MSI-H, MSI
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Cohort A - Pembrolizumab 200 mg
Cohort B - Pembrolizumab 200 mg
Arm Description
Participants 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 3 years).
Participants 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 3 years).
Outcomes
Primary Outcome Measures
Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor
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-SEPT-2019.
Secondary Outcome Measures
Disease Control Rate (DCR) Per RECIST 1.1 Assessed by Central Imaging Vendor.
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 19-Feb-2021.
Progression-Free Survival (PFS) Per RECIST 1.1 Assessed by Central Imaging Vendor.
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 19-FEB-2021.
Overall Survival (OS)
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 19-FEB-2021.
Number of Participants Who Experienced an Adverse Event (AE).
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.
Number of Participants Who Discontinued Study Treatment Due to an AE.
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.
Duration of Response (DOR) Per RECIST 1.1 as Assessed by the Central Imaging Vendor
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 Independent radiologist review (IRC) using RECIST 1.1 and was summarized by Kaplan-Meier (KM) methods for censored data. Nonresponders were excluded from the analysis of DOR.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02460198
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)
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
August 25, 2015 (Actual)
Primary Completion Date
September 9, 2019 (Actual)
Study Completion Date
February 19, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Carcinoma
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), MSI-H, MSI
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
124 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort A - Pembrolizumab 200 mg
Arm Type
Experimental
Arm Description
Participants 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 3 years).
Arm Title
Cohort B - Pembrolizumab 200 mg
Arm Type
Experimental
Arm Description
Participants 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 3 years).
Intervention Type
Biological
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
MK-3475, KEYTRUDA®
Intervention Description
IV infusion
Primary Outcome Measure Information:
Title
Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor
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-SEPT-2019.
Time Frame
Up to approximately 48 months
Secondary Outcome Measure Information:
Title
Disease Control Rate (DCR) Per RECIST 1.1 Assessed by Central Imaging Vendor.
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 19-Feb-2021.
Time Frame
Up to approximately 66 months
Title
Progression-Free Survival (PFS) Per RECIST 1.1 Assessed by Central Imaging Vendor.
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 19-FEB-2021.
Time Frame
Up to approximately 66 months
Title
Overall Survival (OS)
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 19-FEB-2021.
Time Frame
Up to approximately 66 months
Title
Number of Participants Who Experienced an Adverse Event (AE).
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.
Time Frame
Up to approximately 66 months
Title
Number of Participants Who Discontinued Study Treatment Due to an AE.
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.
Time Frame
Up to approximately 36 months
Title
Duration of Response (DOR) Per RECIST 1.1 as Assessed by the Central Imaging Vendor
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 Independent radiologist review (IRC) using RECIST 1.1 and was summarized by Kaplan-Meier (KM) methods for censored data. Nonresponders were excluded from the analysis of DOR.
Time Frame
Up to approximately 66 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Citations:
PubMed Identifier
31725351
Citation
Le DT, Kim TW, Van Cutsem E, Geva R, Jager D, Hara H, Burge M, O'Neil B, Kavan P, Yoshino T, Guimbaud R, Taniguchi H, Elez E, Al-Batran SE, Boland PM, Crocenzi T, Atreya CE, Cui Y, Dai T, Marinello P, Diaz LA Jr, Andre T. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J Clin Oncol. 2020 Jan 1;38(1):11-19. doi: 10.1200/JCO.19.02107. Epub 2019 Nov 14.
Results Reference
result
PubMed Identifier
37141828
Citation
Le DT, Diaz LA Jr, Kim TW, Van Cutsem E, Geva R, Jager D, Hara H, Burge M, O'Neil BH, Kavan P, Yoshino T, Guimbaud R, Taniguchi H, Elez E, Al-Batran SE, Boland PM, Cui Y, Leconte P, Marinello P, Andre T. Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164. Eur J Cancer. 2023 Jun;186:185-195. doi: 10.1016/j.ejca.2023.02.016. Epub 2023 Feb 24.
Results Reference
result
PubMed Identifier
31395089
Citation
van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.
Results Reference
derived
Links:
URL
https://merckclinicaltrials.com/
Description
Merck Clinical Trials Information
Learn more about this trial
Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Previously-Treated Locally Advanced Unresectable or Metastatic Colorectal Cancer (MK-3475-164/KEYNOTE-164)
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