First-line Esophageal Carcinoma Study With Chemo vs. Chemo Plus Pembrolizumab (MK-3475-590/KEYNOTE-590)
Condition: Esophageal Neoplasms
MeSH terms: Esophageal Neoplasms
Intervention: Pembrolizumab; Placebo; Cisplatin; 5-FU
Intervention description: 200 mg administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.; Placebo to pembrolizumab (saline) administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.; 80 mg/m^2 administered IV Q3W on Day 1 of each 3-week cycle. Duration of cisplatin treatment will be capped at 6 doses.; 800 mg/m^2/day (4000 mg/m^2 total per cycle) administered as continuous IV infusion on Days 1 to 5 (120 hours) of each 3-week cycle, or per local standard for 5-FU administration, up to 35 administrations.
Intervention MeSH terms: Pembrolizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 749.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Programmed Cell Death-1 (PD1, PD-1),; Programmed Cell Death Receptor Ligand 1 (PDL1, PD-L1); Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)

Summary:

      The purpose of this trial is to evaluate efficacy and safety of pembrolizumab plus standard
      of care (SOC) chemotherapy with cisplatin and 5-fluorouracil (5-FU) versus placebo plus SOC
      chemotherapy with cisplatin and 5-FU as first-line treatment in participants with locally
      advanced or metastatic esophageal carcinoma.

      The overall primary efficacy hypotheses are as follows:

        1. In participants with esophageal squamous cell carcinoma (ESCC), participants whose
           tumors are programmed cell death-ligand 1 (PD-L1)-positive (defined as combined positive
           score [CPS] ≥10), ESCC participants whose tumors are PD-L1 positive (CPS ≥10), and in
           all participants, overall survival (OS) is superior with pembrolizumab plus SOC
           chemotherapy compared with placebo plus SOC chemotherapy.

        2. In participants with ESCC, participants whose tumors are PD-L1 positive (CPS ≥10), and
           in all participants, progression-free survival (PFS) according to Response Evaluation
           Criteria in Solid Tumors (RECIST) 1.1 as assessed by investigator is superior with
           pembrolizumab plus SOC chemotherapy compared with placebo plus SOC chemotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has histologically- or cytologically-confirmed diagnosis of locally advanced
             unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus
             or advanced/metastatic Siewert type 1 adenocarcinoma of the esophagogastric junction
             (EGJ)

          -  Has measurable disease per RECIST 1.1 as determined by the local site
             investigator/radiology assessment

          -  Eastern Cooperative Group (ECOG) performance status of 0 to 1

          -  Can provide either a newly obtained or archival tissue sample for PD-L1 by
             immunohistochemistry analysis

          -  Female participants of childbearing potential must have a negative urine or serum
             pregnancy test within 72 hours prior to randomization and be willing to use an
             adequate method of contraception (e.g. abstinence, intrauterine device, diaphragm with
             spermicide, etc.) for the course of the study through 120 days after the last dose of
             study treatment and up to 180 days after last dose of cisplatin

          -  Male participants of childbearing potential must agree to use an adequate method of
             contraception (e.g. abstinence, vasectomy, male condom, etc.) starting with the first
             dose of study treatment through 120 days after the last dose of study treatment and up
             to 180 days after last dose of cisplatin, and refrain from donating sperm during this
             period

          -  Has adequate organ function

        Exclusion Criteria:

          -  Has locally advanced esophageal carcinoma that is resectable or potentially curable
             with radiation therapy (as determined by local investigator)

          -  Has had previous therapy for advanced/metastatic adenocarcinoma or squamous cell
             cancer of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the
             EGJ

          -  Has had major surgery, open biopsy, or significant traumatic injury within 28 days
             prior to randomization, or anticipation of the need for major surgery during the
             course of study treatment

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include early-stage cancers (carcinoma in situ or Stage 1) treated with
             curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, in situ cervical cancer, in situ breast cancer that has undergone potentially
             curative therapy, and in situ or intramucosal pharyngeal cancer

          -  Has known active central nervous system metastases and/or carcinomatous meningitis.

          -  Has an active autoimmune disease that has required systemic treatment in past 2 years

          -  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 7 days prior to the first dose of study treatment, or
             has a history of organ transplant, including allogeneic stem cell transplant

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis, or has an active infection requiring systemic therapy

          -  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 medication and up to 180 days after last dose of
             cisplatin

          -  Has received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1),
             anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory
             T-cell receptor or has previously participated in a pembrolizumab (MK-3475) clinical
             trial

          -  Has severe hypersensitivity (≥ Grade 3) to any study treatment (pembrolizumab,
             cisplatin, or 5-FU) and/or any of its excipients

          -  Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis) or human
             immunodeficiency virus (HIV) infection

          -  Has known history of or is positive for hepatitis B or hepatitis C

          -  Has received a live vaccine within 30 days prior to the first dose of study treatment

          -  Has had radiotherapy within 14 days of randomization. Participants who received
             radiotherapy >14 days prior to randomization must have completely recovered from any
             radiotherapy-related AEs/toxicities