Clinical trial NCT02370498: A Study of Pembrolizumab (MK-3475) Versus Paclitaxel for Participants With Advanced Gastric/Gastroesophageal Junction Adenocarcinoma That Progressed After Therapy With Platinum and Fluoropyrimidine (MK-3475-061/KEYNOTE-061)
Official title: A Phase III, Randomized, Open-label Clinical Trial of Pembrolizumab (MK-3475) Versus Paclitaxel in Subjects With Advanced Gastric or Gastroesophageal Junction Adenocarcinoma Who Progressed After First-Line Therapy With Platinum and Fluoropyrimidine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gastric Adenocarcinoma
Gastroesophageal Junction Adenocarcinoma
Keywords: Gastric cancer
Gastroesophageal junction cancer
PD1
PD-1
PDL1
PD-L1
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-02-25
Enrollment: 592
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a study for participants with advanced gastric or gastroesophageal junction adenocarcinoma who have had tumor progression after first-line treatment with platinum and fluoropyrimidine doublet therapy. The primary study hypotheses are that pembrolizumab (MK-3475) prolongs progression free survival (PFS) and overall survival (OS) for participants with tumors that show positive programmed cell death ligand 1 (PD-L1) expression.

As of 20-March-2016, enrollment will be limited to PD-L1 positive participants.


Eligibility criteria: Inclusion Criteria:

* Histologically- or cytologically-confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma
* Confirmed metastatic or locally advanced, unresectable disease (by computed tomography \[CT\] scan or clinical evidence)
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Progression on or after prior first-line therapy containing any platinum/fluoropyrimidine doublet
* Willing to provide tumor tissue for PD-L1 biomarker analysis (new or archived specimens with agreement of Sponsor). As of 20 March 2016, participants must be PD-L1 positive to be enrolled.
* Human epidermal growth factor receptor 2 (HER-2/neu) status known and participants with HER2/neu positive tumors show documentation of disease progression on treatment containing trastuzumab
* Female participants of childbearing potential should 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 pembrolizumab or through 180 days after the last dose of paclitaxel.
* Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel.
* Adequate organ function

Exclusion Criteria:

* 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 medication
* Squamous cell or undifferentiated gastric cancer
* Active autoimmune disease that has required systemic treatment in past 2 years (replacement therapy is not considered a form of systemic treatment
* Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
* 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 not recovered from adverse events due to a previously administered agent or surgery
* Known additional malignancy that is progressing or requires active treatment (with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy)
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* History of (noninfectious) pneumonitis that required steroids or current pneumonitis
* Active infection requiring systemic therapy
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel.
* Prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or previously participated in Merck pembrolizumab (MK-3475) clinical trial
* Known history of human immunodeficiency virus (HIV)
* Known active Hepatitis B or Hepatitis C
* Live vaccine within 30 days of planned start of study therapy
* Known allergy or hypersensitivity to paclitaxel or any components used in the paclitaxel preparation or other contraindication for taxane therapy

Primary outcomes:
measure: Progression-free Survival (PFS) According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on Blinded Independent Central Review (BICR) in Programmed Death-Ligand 1 (PD-L1) Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: Overall Survival (OS) in PD-L1 Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
Secondary outcomes:
measure: PFS According to RECIST 1.1 Based on BICR in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: OS in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: PFS According to RECIST 1.1 Based on Investigator Assessment in PD-L1 Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: PFS According to RECIST 1.1 Based on Investigator Assessment in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: PFS According to Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) Based on BICR in PD-L1 Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: PFS According to irRECIST Based on BICR in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: Time to Tumor Progression (TTP) According to RECIST 1.1 Based on BICR in PD-L1 Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: TTP According to RECIST 1.1 Based on BICR in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: TTP According to RECIST 1.1 Based on Investigator Assessment in PD-L1 Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: TTP According to RECIST 1.1 Based on Investigator Assessment in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: Objective Response Rate (ORR) According to RECIST 1.1 Based on BICR in PD-L1 Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: ORR According to RECIST 1.1 Based on BICR in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: ORR According to RECIST 1.1 Based on Investigator Assessment in PD-L1 Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: ORR According to RECIST 1.1 Based on Investigator Assessment in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: Duration of Response (DOR) According to RECIST 1.1 Based on BICR in PD-L1 Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: DOR According to RECIST 1.1 Based on BICR in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: DOR According to RECIST 1.1 Based on Investigator Assessment in PD-L1 Positive Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: DOR According to RECIST 1.1 Based on Investigator Assessment in All Participants
timeFrame: Up to 30 months (through database cut-off date of 26 Oct 2017)
measure: Percentage of PD-L1 Positive Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to 71 months (through database cut-off date of 10 Jun 2021)
measure: Percentage of All Participants Who Experienced an AE
timeFrame: Up to 71 months (through database cut-off date of 10 Jun 2021)
measure: Percentage of PD-L1 Positive Participants That Discontinued Study Treatment Due to AE
timeFrame: Up to approximately 26.4 months
measure: Percentage of All Participants That Discontinued Study Treatment Due to AE
timeFrame: Up to approximately 26.4 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: Fuchs CS, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Van Cutsem E, Elme A, Thuss-Patience P, Chau I, Ohtsu A, Bhagia P, Wang A, Shih CS, Shitara K. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer. 2022 Jan;25(1):197-206. doi: 10.1007/s10120-021-01227-z. Epub 2021 Sep 1.
citation: Van Cutsem E, Amonkar M, Fuchs CS, Alsina M, Ozguroglu M, Bang YJ, Chung HC, Muro K, Goekkurt E, Benson AB 3rd, Sun W, Wainberg ZA, Norquist JM, Chen X, Shih CS, Shitara K. Health-related quality of life in advanced gastric/gastroesophageal junction cancer with second-line pembrolizumab in KEYNOTE-061. Gastric Cancer. 2021 Nov;24(6):1330-1340. doi: 10.1007/s10120-021-01200-w. Epub 2021 Aug 7.
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: Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133. doi: 10.1016/S0140-6736(18)31257-1. Epub 2018 Jun 4.