Clinical trial NCT02460198: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Carcinoma
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
MSI-H
MSI
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-06-02
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor
timeFrame: Up to approximately 48 months
Secondary outcomes:
measure: Disease Control Rate (DCR) Per RECIST 1.1 Assessed by Central Imaging Vendor.
timeFrame: Up to approximately 66 months
measure: Progression-Free Survival (PFS) Per RECIST 1.1 Assessed by Central Imaging Vendor.
timeFrame: Up to approximately 66 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 66 months
measure: Number of Participants Who Experienced an Adverse Event (AE).
timeFrame: Up to approximately 66 months
measure: Number of Participants Who Discontinued Study Treatment Due to an AE.
timeFrame: Up to approximately 36 months
measure: Duration of Response (DOR) Per RECIST 1.1 as Assessed by the Central Imaging Vendor
timeFrame: Up to approximately 66 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
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.
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.
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.