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

Study Overview
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Brief Summary
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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 Event-free Survival (EFS) and Overall Survival (OS) in: participants whose tumors express Programmed Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 participants whose tumors express PD-L1 CPS ≥1 all participants The primary study hypotheses are that dCRT+ pembrolizumab is better than dCRT + placebo with respect to: EFS in participants whose tumors express PD-L1 CPS ≥10 EFS in participants whose tumors express PD-L1 CPS ≥1 EFS in all participants OS in participants whose tumors express PD-L1 CPS ≥10 OS in participants whose tumors express PD-L1 CPS ≥1 OS in all participants

Detailed Description
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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).

Official Title
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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)

Conditions
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Esophageal Squamous Cell Carcinoma (ESCC), Gastroesophageal Junction Carcinoma (GEJC), Esophageal Adenocarcinoma (EAC)

Intervention / Treatment
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* Biological: pembrolizumab
* Drug: placebo
* Drug: cisplatin
* Drug: 5-FU
* Radiation: radiotherapy
* Drug: leucovorin
* Drug: levoleucovorin
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically or cytologically confirmed diagnosis of CTX N+ M0 or cT2-T4a NX M0 ESCC, GEJC, EAC, or histologically or cytologically confirmed diagnosis of cTX N+ M1 cervical or upper thoracic esophageal carcinoma with supraclavicular lymph node metastases only 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) and refrain from donating sperm during the study treatment period and through 90 days after the last dose of chemotherapy. 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 or has radiographic evidence of >90 degree encasement or invasion of a major blood vessel, or of intratumoral cavitation. 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; participants with gastric or esophageal fistulae are excluded 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 symptomatic 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 coinhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137) Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention; administration of killed vaccines is allowed 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy<br>Participants 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. | Biological: pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: cisplatin<br>* IV infusion<br>* Other names: PLATINOL®;Drug: 5-FU<br>* IV infusion<br>* Other names: ADRUCIL®;Radiation: radiotherapy<br>* external radiation<br>Drug: leucovorin<br>* IV infusion<br>* Other names: folinic acid;Drug: levoleucovorin<br>* IV infusion<br>* Other names: levofolinic acid;Drug: oxaliplatin<br>* IV infusion<br>* Other names: ELOXATIN®;|
| Placebo Comparator: Placebo+FP or FOLFOX Therapy+Radiotherapy<br>Participants 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. | Drug: placebo<br>* IV infusion<br>* Other names: Normal saline solution;Drug: cisplatin<br>* IV infusion<br>* Other names: PLATINOL®;Drug: 5-FU<br>* IV infusion<br>* Other names: ADRUCIL®;Radiation: radiotherapy<br>* external radiation<br>Drug: leucovorin<br>* IV infusion<br>* Other names: folinic acid;Drug: levoleucovorin<br>* IV infusion<br>* Other names: levofolinic acid;Drug: oxaliplatin<br>* IV infusion<br>* Other names: ELOXATIN®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | EFS is defined as the time from randomization to an event defined as local, regional, or distant radiological recurrence as assessed by the investigator; clinical recurrence as assessed by the investigator with histopathologic confirmation (in the absence of radiological disease recurrence by investigator assessment); or death from any cause, whichever occurs first. | Up to  60 months | 
| Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. | Up to  72 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with an adverse event (AE) | 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. | Up to  15 months | 
| Number of participants discontinuing study treatment due to an adverse event (AE) | 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. | Up to  12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Programmed Death-Ligand 2 (PDL2, PD-L2)