Clinical Trials /

Study of Pembrolizumab (MK-3475) Versus Placebo in Participants With Esophageal Carcinoma Who Are Receiving Chemotherapy and Radiation Therapy (MK-3475-975/KEYNOTE-975)

NCT04210115

Description:

The purpose of this study is to assess the efficacy and safety of treatment with definitive chemoradiotherapy (dCRT) + pembrolizumab (MK-3475) compared to treatment with dCRT + placebo with respect to Overall Survival (OS) and Event-free survival (EFS) in: - participants with esophageal squamous cell carcinoma (ESCC), - participants whose tumors express Programmed Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10, and - all participants. The primary study hypotheses are that dCRT+ pembrolizumab is better than dCRT + placebo with respect to: - OS in participants with ESCC, - OS in participants whose tumors express PD-L1 CPS ≥10, - OS in all participants, - EFS in participants with ESCC, - EFS in participants whose tumors express PD-L1 CPS ≥10, and - EFS in all participants.

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

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study of Pembrolizumab (MK-3475) Versus Placebo in Participants With Esophageal Carcinoma Who Are Receiving Chemotherapy and Radiation Therapy (MK-3475-975/KEYNOTE-975)
  • Official Title: A Randomized, Double-blind, Placebo-controlled Phase 3 Trial of Pembrolizumab (MK-3475) Versus Placebo in Participants With Esophageal Carcinoma Receiving Concurrent Definitive Chemoradiotherapy (KEYNOTE 975)

Clinical Trial IDs

  • ORG STUDY ID: 3475-975
  • SECONDARY ID: 2019-002006-51
  • SECONDARY ID: MK-3475-975
  • SECONDARY ID: KEYNOTE-975
  • SECONDARY ID: PHRR200210-002490
  • NCT ID: NCT04210115

Conditions

  • Esophageal Squamous Cell Carcinoma (ESCC)
  • Siewert Type I Adenocarcinoma of the Esophagogastric Junction (EGJ)
  • Esophageal Adenocarcinoma (EAC)

Interventions

DrugSynonymsArms
pembrolizumabMK-3475, KEYTRUDA®Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
placeboNormal saline solutionPlacebo+FP or FOLFOX Therapy+Radiotherapy
cisplatinPLATINOL®Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
5-FUADRUCIL®Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy
leucovorincalcium folinate, folinic acidPembrolizumab+FP or FOLFOX Therapy+Radiotherapy
levoleucovorinFUSILEV®, calcium levofolinate, levofolinic acidPembrolizumab+FP or FOLFOX Therapy+Radiotherapy
oxaliplatinELOXATIN®Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy

Purpose

The purpose of this study is to assess the efficacy and safety of treatment with definitive chemoradiotherapy (dCRT) + pembrolizumab (MK-3475) compared to treatment with dCRT + placebo with respect to Overall Survival (OS) and Event-free survival (EFS) in: - participants with esophageal squamous cell carcinoma (ESCC), - participants whose tumors express Programmed Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10, and - all participants. The primary study hypotheses are that dCRT+ pembrolizumab is better than dCRT + placebo with respect to: - OS in participants with ESCC, - OS in participants whose tumors express PD-L1 CPS ≥10, - OS in all participants, - EFS in participants with ESCC, - EFS in participants whose tumors express PD-L1 CPS ≥10, and - EFS in all participants.

Detailed Description

      Participants receive pembrolizumab or placebo PLUS one of two chemotherapy regimens PLUS
      radiation therapy for up to approximately one year. The chemotherapy regimens are either:

        -  FP (5-fluorouracil [5-FU] + cisplatin) or

        -  FOLFOX (5-FU + oxaliplatin + leucovorin or levoleucovorin).
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab+FP or FOLFOX Therapy+RadiotherapyExperimentalParticipants receive pembrolizumab 200 mg on Day 1 of each 3-week cycle for 8 cycles followed by pembrolizumab 400 mg on Day 1 of each 6-week cycle for 5 cycles PLUS either: FP therapy: cisplatin 75 mg/m^2 on Day 1 of Weeks 1, 5, 8 and 11 PLUS 5-fluorouracil (5-FU)] 1000 mg/m^2 per day on Days 1-4 of Weeks 1, 5, 8 and 11 OR 800 mg/m^2/day on each of Days 1-5 at Weeks 1, 5, 8, and 11 PLUS radiotherapy (either 50 Gray [Gy] in 25 fractions OR 60 Gy in 30 fractions) on Days 1-5 of each 3-week cycle OR FOLFOX therapy: oxaliplatin 85 mg/m^2 AND either leucovorin 400 mg/m^2 OR levoleucovorin 200 mg/m^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 PLUS either 5-FU 400 mg/m^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 OR 5-FU 800 mg/m^2 per day on Days 1 and 2 of Weeks 1, 3, 5, 7, 9 and 11 PLUS radiotherapy (50 Gy in 25 fractions) on Days 1-5 of each 3-week cycle. All treatments except radiotherapy are given by intravenous (IV) infusion. Total treatment duration is approximately 1 year.
  • pembrolizumab
  • cisplatin
  • 5-FU
  • leucovorin
  • levoleucovorin
  • oxaliplatin
Placebo+FP or FOLFOX Therapy+RadiotherapyPlacebo ComparatorParticipants receive placebo on Day 1 of each 3-week cycle for 8 cycles followed by placebo on Day 1 of each 6-week cycle for 5 cycles PLUS either: FP therapy: cisplatin 75 mg/m^2 on Day 1 of Weeks 1, 5, 8 and 11 PLUS 5-FU 1000 mg/m^2 per day on Days 1-4 of Weeks 1, 5, 8 and 11 OR 800 mg/m^2/day on each of Days 1-5 at Weeks 1, 5, 8, and 11 PLUS radiotherapy (either 50 Gy in 25 fractions OR 60 Gy in 30 fractions) on Days 1-5 of each 3-week cycle OR FOLFOX therapy: oxaliplatin 85 mg/m^2 AND either leucovorin 400 mg/m^2 OR levoleucovorin 200 mg/m^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 PLUS either 5-FU 400 mg/m^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 OR 5-FU 800 mg/m^2 per day on Days 1 and 2 of Weeks 1, 3, 5, 7, 9 and 11 PLUS radiotherapy (50 Gy in 25 fractions) on Days 1-5 of each 3-week cycle. All treatments except radiotherapy are given by IV infusion. Total treatment duration is approximately 1 year.
  • placebo
  • cisplatin
  • 5-FU
  • leucovorin
  • levoleucovorin
  • oxaliplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Has Siewert Type I adenocarcinoma of the EGJ, or EAC

          -  Is deemed suitable for dCRT

          -  Is ineligible for curative surgery based on the documented opinion of a qualified
             medical/surgical/radiation oncologist

          -  Is not expected to require tumor resection during the course of the study

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

          -  Has adequate organ function

          -  Male participants must use adequate contraception (a male condom plus partner use of
             an additional contraceptive method) unless confirmed to be azoospermic (vasectomized
             or secondary to medical cause) during the study 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

          -  Female participants who are a Woman of Childbearing Potential (WOCBP) must use
             contraception that is highly effective (with a failure rate of <1% per year), with low
             user dependency, or be abstinent from heterosexual intercourse as their preferred and
             usual lifestyle, during the study treatment period through 180 days after the last
             dose of chemotherapy or 120 days after the last dose of pembrolizumab, whichever is
             greater, and agree not to donate eggs to others or freeze/store for her own use for
             the purpose of reproduction during this period

          -  Female participants must not be pregnant or breastfeeding

        Exclusion Criteria:

          -  Has direct invasion of tumor into adjacent organs such as the aorta or trachea

          -  Has had major surgery other than for insertion of a feeding tube, open biopsy, or
             significant traumatic injury within 28 days prior to randomization, or anticipates the
             need for major surgery during study treatment

          -  Has had weight loss of >20% in the previous 3 months

          -  Has had prior chemotherapy or radiotherapy for esophageal cancer

          -  Has had a myocardial infarction within the past 6 months

          -  Has severe congestive heart failure

          -  Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1),
             anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand
             2 (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 a live vaccine within 30 days prior to the first dose of study treatment

          -  Has received any prior systemic anticancer therapy for esophageal cancer including
             investigational agents

          -  Has not recovered from all adverse events (AEs) due to previous non-anticancer
             therapies to ≤Grade 1 or Baseline

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             or any other form of immunosuppressive therapy within 7 days prior the first dose of
             study treatment

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
             cervical cancer in situ) that have undergone potentially curative therapy are not
             excluded from the study. Participants with localized prostate cancer that has
             undergone potentially curative treatment can be enrolled in the study.

          -  Has severe hypersensitivity (≥Grade 3) to pembrolizumab, any of the study chemotherapy
             agents, or their 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 or known active Hepatitis C virus infection

          -  Has a known history of active tuberculosis (TB; Bacillus tuberculosis)

          -  Is 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 (180 days for participants receiving cisplatin
             who are breastfeeding)

          -  Has had an allogenic tissue/solid organ transplant
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to ~72 months
Safety Issue:
Description:OS is defined as the time from randomization to death from any cause.

Secondary Outcome Measures

Measure:Number of participants with an adverse event (AE)
Time Frame:Up to ~15 months
Safety Issue:
Description:An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Measure:Number of participants discontinuing study treatment due to an adverse event (AE)
Time Frame:Up to ~12 months
Safety Issue:
Description:An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)
  • Programmed Death-Ligand 2 (PDL2, PD-L2)

Last Updated

April 17, 2020