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Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy in Participants Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (MK-3475-859/KEYNOTE-859)

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ClinicalTrials.gov Identifier: NCT03675737
Recruitment Status : Recruiting
First Posted : September 18, 2018
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:

The purpose of this study is to evaluate the efficacy of pembrolizumab (MK-3745) in combination with chemotherapy (Cisplatin combined with 5-Fluorouracil [FP regimen] or oxaliplatin combined with capecitabine [CAPOX regimen]) versus placebo in combination with chemotherapy (FP or CAPOX regimens) in the treatment of human epidermal growth factor receptor 2 (HER2) negative advanced gastric or GEJ adenocarcinoma in adult participants.

The primary hypotheses of this study are that pembrolizumab plus chemotherapy is superior to placebo plus chemotherapy in terms of overall survival (OS), and progression-free survival (PFS).


Condition or disease Intervention/treatment Phase
Stomach Neoplasms Drug: Pembrolizumab Drug: Cisplatin Drug: 5-fluorouracil Drug: oxaliplatin Drug: capecitabine Drug: Placebo for Pembrolizumab Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 780 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-blind Clinical Study of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy as First-line Treatment in Participants With HER2 Negative, Previously Untreated, Unresectable or Metastatic Gastric Orgastroesophageal Junction Adenocarcinoma (KEYNOTE-859)
Actual Study Start Date : November 8, 2018
Estimated Primary Completion Date : February 2, 2024
Estimated Study Completion Date : February 2, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab + FP or CAPOX
Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 2 years) + physicians' choice of either cisplatin 80 mg/m^2 IV on Day 1 Q3W and 5-fluorouracil (5FU) 800 mg/m^2/day via continuous IV infusion on Days 1 to 5 Q3W OR oxaliplatin 130 mg/m^2 IV on Day 1 Q3W + capecitabine 1000 mg/m^2 orally twice a day (BID) on Days 1 to 14 Q3W. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).
Drug: Pembrolizumab
Administered as an IV infusion on Day 1 Q3W
Other Names:
  • KEYTRUDA®
  • MK-3475

Drug: Cisplatin
Administered as an IV infusion on Day 1 Q3W
Other Name: PLATINOL®

Drug: 5-fluorouracil
Administered as a continuous IV infusion on Days 1-5 Q3W
Other Names:
  • ADRUCIL®
  • 5FU

Drug: oxaliplatin
Administered as an IV infusion on Day 1 Q3W
Other Name: ELOXATIN®

Drug: capecitabine
Administered orally BID on Days 1 to 14 Q3W
Other Name: XELODA®

Active Comparator: Placebo + FP or CAPOX
Participants receive placebo for pembrolizumab IV on Day 1 Q3W for up to 35 cycles (approximately 2 years) + physicians' choice of either cisplatin 80 mg/m^2 IV on Day 1 Q3W and 5FU 800 mg/m^2/day via continuous IV infusion on Days 1 to 5 Q3W OR oxaliplatin 130 mg/m^2 IV on Day 1 Q3W + capecitabine 1000 mg/m^2 orally BID on Days 1 to 14 Q3W.
Drug: Cisplatin
Administered as an IV infusion on Day 1 Q3W
Other Name: PLATINOL®

Drug: 5-fluorouracil
Administered as a continuous IV infusion on Days 1-5 Q3W
Other Names:
  • ADRUCIL®
  • 5FU

Drug: oxaliplatin
Administered as an IV infusion on Day 1 Q3W
Other Name: ELOXATIN®

Drug: capecitabine
Administered orally BID on Days 1 to 14 Q3W
Other Name: XELODA®

Drug: Placebo for Pembrolizumab
Administered as an IV infusion on Day 1 Q3W




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Up to approximately 24 months ]
    OS is the time from randomization to death due to any cause.

  2. Progression-free Survival (PFS) [ Time Frame: Up to approximately 24 months ]
    PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR).


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: Up to approximately 24 months ]
    ORR was defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 as assessed by BICR.

  2. Duration of Response (DOR) [ Time Frame: Up to approximately 24 months ]
    DOR is determined by disease assessment and is defined as the time from first response (CR or PR) to disease progression, or death from any cause, whichever occurs first.

  3. Percentage of Participants Experiencing Adverse Events (AEs) [ Time Frame: From time of signing informed consent form (ICF) until the end of follow-up (up to approximately 27 months) ]
    Percentage of participants experiencing an AE defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study treatment

  4. Percentage of Participants Discontinuing Study Drug Due to AEs [ Time Frame: From time of signing ICF until the end of study treatment (up to approximately 24 months) ]
    Percentage of participants discontinuing study treatment due to an AE



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Has histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma with known programmed cell death ligand 1 (PD-L1) expression status
  • Has HER2 negative cancer
  • Male Participants must agree to use contraception during the treatment period and through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is greater, and must refrain from donating sperm during this period
  • Female Participants who are not pregnant, not breastfeeding, and at least one of the following conditions applies: not a woman of childbearing potential (WOCBP) OR agrees to use contraception during the treatment period and through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is greater
  • Has measurable disease per RECIST 1.1 as assessed by investigator assessment
  • Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
  • Has provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis
  • Has provided tumor tissue sample for microsatellite instability (MSI) biomarker analysis
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days prior to the start of study intervention
  • Has adequate organ function as demonstrated by laboratory testing within 10 days prior to the start of study treatment

Exclusion Criteria

  • Has squamous cell or undifferentiated gastric cancer
  • Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior to randomization, anticipation of the need for major surgery during the course of study intervention, or has not recovered adequately from the toxicity and/or complications from previous surgery
  • Has pre-existing peripheral neuropathy >Grade 1
  • Is a WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or treatment allocation
  • Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ cancer. Participants may have received prior neoadjuvant or adjuvant therapy as long as it was completed ≥6 months prior to randomization
  • Has received prior therapy with an anti-PD-1, anti-PD-L1 or anti- PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX- 40, CD137)
  • Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization or has not recovered from all AEs due to any previous therapies to ≤Grade 1 or baseline
  • Has received prior radiotherapy within 2 weeks prior to study start or has not recovered from all previous radiation-related toxicities, required corticosteroids, and have not had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease
  • Has received a live vaccine within 30 days prior to the first dose of study treatment
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
  • Has a known additional malignancy that is progressing or has required active treatment within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
  • Has known active CNS metastases and/or carcinomatous meningitis
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
  • Has an active autoimmune disease that has required systemic treatment in past 2 years
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  • Has an active infection requiring systemic therapy
  • Has a known history of human immunodeficiency virus (HIV) infection
  • Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as Hepatitis C virus [HCV] ribonucleic acid [RNA] detected qualitatively) infection
  • Has a known history of active tuberculosis
  • Has hypokalemia (serum potassium less than the lower limit of normal)
  • Has hypomagnesemia (serum magnesium less than the lower limit of normal)
  • Has hypocalcemia (serum calcium less than the lower limit of normal)
  • Has a history or current evidence of any condition (eg, known deficiency of the enzyme dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
  • Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
  • Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is greater
  • Has had an allogenic tissue/solid organ transplant
  • Has a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents (including, but not limited to, infusional 5-fluorouracil or oral capecitabine) and/or to any of their excipients
  • For participants taking Cisplatin: has Grade ≥2 audiometric hearing loss (25 decibels in two consecutive wave ranges)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03675737


Contacts
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

  Show 70 Study Locations
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03675737     History of Changes
Other Study ID Numbers: 3475-859
2018-001757-27 ( EudraCT Number )
MK-3475-859 ( Other Identifier: Merck Protocol Number )
KEYNOTE-859 ( Other Identifier: Merck )
First Posted: September 18, 2018    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:
programmed cell death 1 (PD-1, PD1)
programmed cell death ligand 1 (PD-L1, PDL1)
programmed cell death ligand 2 (PD-L2, PDL2)

Additional relevant MeSH terms:
Adenocarcinoma
Stomach Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Oxaliplatin
Pembrolizumab
Cisplatin
Capecitabine
Fluorouracil
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs