Clinical trial NCT02335411: A Study of Pembrolizumab (MK-3475) in Participants With Recurrent or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (MK-3475-059/KEYNOTE-059)
Official title: A Phase II Clinical Trial of Pembrolizumab as Monotherapy and in Combination With Cisplatin+5-Fluorouracil in Subjects With Recurrent or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (KEYNOTE-059)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Gastric Adenocarcinoma
Gastroesophageal Junction Adenocarcinoma
Keywords: Gastric cancer
Gastroesophageal junction cancer
Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-01-09
Enrollment: 318
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a study of pembrolizumab (MK-3475) for advanced gastric or gastroesophageal junction adenocarcinoma; pembrolizumab will be given as monotherapy to participants who have had previous treatment or who are treatment-naïve; pembrolizumab will also be evaluated as combination therapy with cisplatin and 5-Fluorouracil (5-FU) or (Japan only) capecitabine in treatment-naïve participants. The primary study hypothesis is that pembrolizumab will provide a clinically meaningful Overall Response Rate (ORR).

Detailed description: This study will have 3 cohorts. In Cohort 1, participants who have received at least two prior therapies for their advanced disease will receive monotherapy with pembrolizumab. In Cohort 2, participants who have not received any previous therapy for their disease will receive pembrolizumab in combination with cisplatin and 5-FU or (Japan only) capecitabine. In Cohort 3, participants who have not received any previous therapy and who have programmed death ligand 1 (PD-L1)-positive tumors will receive pembrolizumab monotherapy.

Eligibility criteria: Inclusion Criteria - Cohort 1:

* Received and progressed on ≥2 prior chemotherapy regimens for their advanced disease; prior regimen must have included a cisplatin and a fluoropyridine
* Human epidermal growth factor receptor 2 (HER-2/neu) negative, or, if HER2/neu positive, must have previously received treatment with trastuzumab

Inclusion Criteria - Cohort 2 or 3:

* HER2/neu negative
* Has not received prior systemic anti-cancer therapy for their advanced carcinoma (systemic therapy received in the neoadjuvant and adjuvant setting does not count)

Inclusion Criteria - All Participants:

* Histologically- or cytologically-confirmed recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that is considered incurable by local therapies
* Willing to provide tissue for PD-L1 biomarker analysis from newly-obtained and/or archival tissue
* Measurable disease based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days prior to first dose of study drug
* Life expectancy of at least 3 months
* Female participants of childbearing potential should have a negative pregnancy test and be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study drug (180 days for participants receiving cisplatin + 5FU)
* Male participants should agree to use an adequate method of contraception starting with the first dose through 120 days after the last dose of study drug (180 days for participants receiving cisplatin + 5FU)
* Adequate organ function

Exclusion Criteria - All Participants:

* Currently participating and receiving study therapy or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study drug
* Active autoimmune disease that has required systemic treatment in past 2 years
* Immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
* Weight loss \>10% over 2 months prior to first dose of study drug
* Clinical evidence of ascites by physical exam
* Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from AEs due to agents administered more than 4 weeks earlier
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered from AEs due to a previously administered agent
* Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Known history of, or any evidence of active, non-infectious pneumonitis
* Active infection requiring systemic therapy
* 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 drug (180 days for participants receiving cisplatin + 5FU)
* Prior therapy with an anti-programmed death-1 (PD-1), anti-PD-L1, or anti-PD-L2 agent
* Human immunodeficiency virus (HIV)
* Hepatitis B or C
* Received live vaccine within 30 days of planned start of study drug

Primary outcomes:
measure: Number of Participants Experiencing Adverse Events (AEs)
timeFrame: Up to approximately 65 months
measure: Number of Participants Discontinuing Study Drug Due to AEs
timeFrame: Up to approximately 52 months
measure: Objective Response Rate (ORR) For All Participants in Cohorts 1 and 3
timeFrame: Up to approximately 75 months
measure: Objective Response Rate For PD-L1 Positive Participants in Cohorts 1 and 3
timeFrame: Up to approximately 75 months
Secondary outcomes:
measure: Objective Response Rate (ORR) For All Participants in Cohort 2
timeFrame: Up to approximately 75 months
measure: Objective Response Rate For PD-L1 Positive Participants in Cohort 2
timeFrame: Up to approximately 75 months
measure: Duration of Response (DOR) For All Participants
timeFrame: Up to approximately 75 months
measure: Duration of Response For PD-L1 Positive Participants
timeFrame: Up to approximately 75 months
measure: Progression-Free Survival (PFS) For All Participants
timeFrame: Up to approximately 75 months
measure: Progression-Free Survival For PD-L1 Positive Participants
timeFrame: Up to approximately 75 months
measure: Overall Survival (OS) For All Participants
timeFrame: Up to approximately 75 months
measure: Overall Survival For PD-L1 Positive Participants
timeFrame: Up to approximately 75 months
measure: Disease Control Rate (DCR) For All Participants
timeFrame: Up to approximately 75 months
measure: Disease Control Rate For PD-L1 Positive Participants
timeFrame: Up to approximately 75 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.
citation: Chao J, Fuchs CS, Shitara K, Tabernero J, Muro K, Van Cutsem E, Bang YJ, De Vita F, Landers G, Yen CJ, Chau I, Elme A, Lee J, Ozguroglu M, Catenacci D, Yoon HH, Chen E, Adelberg D, Shih CS, Shah S, Bhagia P, Wainberg ZA. Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials. JAMA Oncol. 2021 Jun 1;7(6):895-902. doi: 10.1001/jamaoncol.2021.0275.
citation: Bang YJ, Kang YK, Catenacci DV, Muro K, Fuchs CS, Geva R, Hara H, Golan T, Garrido M, Jalal SI, Borg C, Doi T, Yoon HH, Savage MJ, Wang J, Dalal RP, Shah S, Wainberg ZA, Chung HC. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study. Gastric Cancer. 2019 Jul;22(4):828-837. doi: 10.1007/s10120-018-00909-5. Epub 2019 Mar 25.
citation: Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018 May 10;4(5):e180013. doi: 10.1001/jamaoncol.2018.0013. Epub 2018 May 10.