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Study of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy in Participants With Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (MK-3475-585/KEYNOTE-585)

NCT03221426

Description:

The purpose of this study is to evaluate the efficacy of pembrolizumab (MK-3745) in the neoadjuvant (prior to surgery) or adjuvant (after surgery) treatment of previously untreated adults with gastric and gastroesophageal junction (GEJ) adenocarcinoma. The primary study hypotheses are that: - Neoadjuvant and adjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab is superior to neoadjuvant and adjuvant placebo plus chemotherapy, followed by adjuvant placebo in terms of Event-free Survival (EFS) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), and - Neoadjuvant pembrolizumab plus chemotherapy is superior to neoadjuvant placebo plus chemotherapy in terms of rate of Pathological Complete Response (pathCR) at the time of surgery.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy in Participants With Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (MK-3475-585/KEYNOTE-585)
  • Official Title: A Phase III, Randomized, Double-Blind, Clinical Trial of Pembrolizumab (MK-3475) Plus Chemotherapy (XP or FP) Versus Placebo Plus Chemotherapy (XP or FP) as Neoadjuvant/Adjuvant Treatment for Subjects With Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma (KEYNOTE-585)

Clinical Trial IDs

  • ORG STUDY ID: 3475-585
  • SECONDARY ID: 2016-004408-76
  • SECONDARY ID: MK-3475-585
  • SECONDARY ID: 173786
  • SECONDARY ID: KEYNOTE-585
  • SECONDARY ID: PHRR200226-002534
  • NCT ID: NCT03221426

Conditions

  • Gastric Cancer
  • Gastroesophageal Junction Cancer

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Pembrolizumab+Chemotherapy
PlaceboNormal saline solutionPlacebo+Chemotherapy
CisplatinPLATINOL®Pembrolizumab+Chemotherapy
CapecitabineXELODA®Pembrolizumab+Chemotherapy
5-fluorouracilADRUCIL®, 5FUPembrolizumab+Chemotherapy
DocetaxelTAXOTERE®Pembrolizumab+FLOT Cohort
OxaliplatinELOXATIN®Pembrolizumab+FLOT Cohort
LeucovorinWELLCOVORIN®Pembrolizumab+FLOT Cohort

Purpose

The purpose of this study is to evaluate the efficacy of pembrolizumab (MK-3745) in the neoadjuvant (prior to surgery) or adjuvant (after surgery) treatment of previously untreated adults with gastric and gastroesophageal junction (GEJ) adenocarcinoma. The primary study hypotheses are that: - Neoadjuvant and adjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab is superior to neoadjuvant and adjuvant placebo plus chemotherapy, followed by adjuvant placebo in terms of Event-free Survival (EFS) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), and - Neoadjuvant pembrolizumab plus chemotherapy is superior to neoadjuvant placebo plus chemotherapy in terms of rate of Pathological Complete Response (pathCR) at the time of surgery.

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab+ChemotherapyExperimentalNeoadjuvant: Prior to surgery, participants receive 3 cycles of pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) PLUS cisplatin 80 mg/m^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m^2 via oral tablets twice each day (BID) on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m^2 via IV infusion on Day 1 Q3W and 5-fluorouracil (5FU) via continuous IV infusion on Days 1 to 5 of each 3-week cycle. Adjuvant: 4 to 10 weeks post-surgery, participants receive pembrolizumab 200 mg via IV infusion on Day 1 Q3W PLUS cisplatin 80 mg/m^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m^2 via oral tablets BID on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m^2 via IV infusion on Day 1 Q3W and 5FU via continuous IV infusion on Days 1 to 5 of each 3-week cycle for up to 14 cycles.
  • Pembrolizumab
  • Cisplatin
  • Capecitabine
  • 5-fluorouracil
Placebo+ChemotherapyPlacebo ComparatorNeoadjuvant: Prior to surgery, participants receive 3 cycles of placebo (normal saline solution) via IV infusion on Day 1 Q3W PLUS cisplatin 80 mg/m^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m^2 via oral tablets BID on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m^2 via IV infusion on Day 1 Q3W and 5FU via continuous IV infusion on Days 1 to 5 of each 3-week cycle. Adjuvant: 4 to 10 weeks post-surgery, participants receive placebo via IV infusion on Day 1 Q3W PLUS cisplatin 80 mg/m^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m^2 via oral tablets BID on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m^2 via IV infusion on Day 1 Q3W and 5FU via continuous IV infusion on Days 1 to 5 of each 3-week cycle for up to 14 cycles.
  • Placebo
  • Cisplatin
  • Capecitabine
  • 5-fluorouracil
Pembrolizumab+FLOT CohortExperimentalFLOT=docetaxel+oxaliplatin+5FU+leucovorin (calcium folinate). Neoadjuvant: Prior to surgery, participants receive 3 cycles of pembrolizumab 200 mg via IV infusion on Day 1 Q3W PLUS docetaxel 50 mg/m^2 via IV infusion, oxaliplatin 85 mg/m^2 via IV infusion, 5FU 2600 mg/m^2 via IV infusion, and leucovorin (calcium folinate) 200 mg/m^2 via IV infusion Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3) for 4 administrations. Adjuvant: 4 to 10 weeks postsurgery, participants receive pembrolizumab 200 mg via IV infusion Day 1 Q3W for up to 11 cycles PLUS docetaxel 50 mg/m^2, oxaliplatin 85 mg/m^2, 5FU 2600 mg/m^2, and leucovorin 200 mg/m^2 Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3) for 4 administrations.
  • Pembrolizumab
  • 5-fluorouracil
  • Docetaxel
  • Oxaliplatin
  • Leucovorin
Placebo+FLOT CohortPlacebo ComparatorNeoadjuvant: Prior to surgery, participants receive 3 cycles of placebo (normal saline solution) via IV infusion on Day 1 Q3W PLUS docetaxel 50 mg/m^2 via IV infusion, oxaliplatin 85 mg/m^2 via IV infusion, 5FU 2600 mg/m^2 via IV infusion, and leucovorin 200 mg/m^2 via IV infusion Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3) for 4 administrations. Adjuvant: 4 to 10 weeks postsurgery, participants receive placebo via IV infusion on Day 1 Q3W PLUS docetaxel 50 mg/m^2 via IV infusion, oxaliplatin 85 mg/m^2 via IV infusion, 5FU 2600 mg/m^2 via IV infusion, and leucovorin 200 mg/m^2 via IV infusion Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3) for 4 administrations.
  • Placebo
  • 5-fluorouracil
  • Docetaxel
  • Oxaliplatin
  • Leucovorin

Eligibility Criteria

        Inclusion Criteria:

          -  Has previously untreated localized gastric or GEJ adenocarcinoma as defined by T3 or
             greater primary lesion or the presence of any positive nodes - N+ (clinical nodes)
             without evidence of metastatic disease.

          -  Plans to proceed to surgery following pre-operative chemotherapy based on standard
             staging studies per local practice.

          -  Is willing to provide tissue from a tumor lesion at baseline and at time of surgery.

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1
             within 3 days prior to the first dose of study treatment.

          -  Has adequate organ function.

          -  Male participants of childbearing potential must agree to use an adequate method of
             contraception for the course of the study through 180 days after the last dose of
             chemotherapy.

          -  Female participants of childbearing potential must be willing to use an adequate
             method of contraception for the course of the study through 180 days after the last
             dose of chemotherapy or through 120 days after the last dose of pembrolizumab,
             whichever is greater.

          -  Has life expectancy of greater than 6 months.

        Exclusion Criteria:

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Is currently participating in or has participated in a trial of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment.

          -  Has received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1),
             anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent
             directed to another stimulatory or co-inhibitory T-cell receptor (i.e., cytotoxic
             T-lymphocyte-associated protein 4 [CTLA-4], tumor necrosis factor receptor superfamily
             member 4 [OX-40], necrosis factor receptor superfamily member 9 [CD137]) or has
             previously participated in a Merck pembrolizumab (MK-3475) clinical trial.

          -  Has received prior systemic anti-cancer therapy including investigational agents for
             the current malignancy.

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 14 days prior the first dose of study treatment.

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 5 years. Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ that have undergone
             potentially curative therapy are not excluded.

          -  Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active substance
             and/or any of its excipients, or to any of the study chemotherapy agents and/or to any
             of their excipients.

          -  Has an active autoimmune disease that has required systemic treatment in past 2 years.

          -  Has a known history of human immunodeficiency virus (HIV) infection.

          -  Has a known history of Hepatitis B or known active Hepatitis C virus infection.

          -  Has a known history of active tuberculosis (TB).

          -  Female participants who are pregnant or breastfeeding or expecting to conceive
             children within the projected duration of the study, starting with the screening visit
             through180 days after the last dose of chemotherapy or through 120 days after the last
             dose of pembrolizumab, whichever is greater.

          -  Male participants who are expecting to father children within the projected duration
             of the study, starting with the screening visit through 180 days after the last dose
             of chemotherapy.

          -  Has had an allogenic tissue/solid organ transplant.

          -  Has received a live vaccine within 30 days prior to the first dose of study treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free Survival (EFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+Chemotherapy and Placebo+Chemotherapy Treatment Arms
Time Frame:Up to approximately 2 years
Safety Issue:
Description:EFS is based on RECIST 1.1 as assessed by the investigator and is defined as the time from randomization to the first of the following events: radiographic disease progression per RECIST 1.1; local or distant recurrence as assessed by computer tomography (CT) scan or biopsy if indicated (for participants who are disease free after surgery); clinical progression as evidenced by peritoneal carcinomatosis confirmed by preoperative laparoscopy or laparotomy (for participants who are confirmed to be free of peritoneal involvement by laparoscopy at screening); or death due to any cause. A second primary malignancy, or radiographic progressive disease (PD) during the neoadjuvant phase that does not preclude successful surgery (i.e., disease free after surgery), are not considered EFS events.

Secondary Outcome Measures

Measure:Percentage of Participants Who Experience One or More Adverse Events (AEs) - Pembrolizumab+Chemotherapy and Placebo+Chemotherapy Treatment Arms Separately and in Combination with the Pembrolizumab+FLOT and Placebo+FLOT Cohorts
Time Frame:Up to approximately 27 months
Safety Issue:
Description:An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants who experience at least one AE will be presented.
Measure:Percentage of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) - Pembrolizumab+Chemotherapy and Placebo+Chemotherapy Treatment Arms Separately and in Combination with the Pembrolizumab+FLOT and Placebo+FLOT Cohorts
Time Frame:Up to approximately 2 years
Safety Issue:
Description:An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants who discontinue study treatment due to an AE will be presented.
Measure:Overall Survival (OS) - Pembrolizumab+Chemotherapy and Placebo+Chemotherapy Treatment Arms
Time Frame:Up to approximately 2 years
Safety Issue:
Description:OS is defined as the time from randomization to death due to any cause.
Measure:Disease-free Survival (DFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+Chemotherapy and Placebo+Chemotherapy Treatment Arms
Time Frame:Up to approximately 2 years
Safety Issue:
Description:DFS is defined as the time from post-surgery baseline scan until the first occurrence of local/distant recurrence or death from any cause and is based on RECIST 1.1 as assessed by the investigator.
Measure:Overall Survival (OS) - Pembrolizumab+Chemotherapy and Placebo+Chemotherapy Treatment Arms and Pembrolizumab+FLOT and Placebo+FLOT Cohorts
Time Frame:Up to approximately 2 years
Safety Issue:
Description:OS is defined as the time from randomization to death due to any cause.
Measure:Event-free Survival (EFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+Chemotherapy and Placebo+Chemotherapy Treatment Arms and Pembrolizumab+FLOT and Placebo+FLOT Cohorts
Time Frame:Up to approximately 2 years
Safety Issue:
Description:EFS is based on RECIST 1.1 as assessed by the investigator and is defined as the time from randomization to the first of the following events: radiographic disease progression per RECIST 1.1; local or distant recurrence as assessed by CT scan or biopsy if indicated (for participants who are disease free after surgery); clinical progression as evidenced by peritoneal carcinomatosis confirmed by preoperative laparoscopy or laparotomy (for participants who are confirmed to be free of peritoneal involvement by laparoscopy at screening); or death due to any cause. A second primary malignancy, or radiographic progressive disease (PD) during the neoadjuvant phase that does not preclude successful surgery (i.e., disease free after surgery), are not considered EFS events.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)

Last Updated

February 17, 2021