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Trial record 1 of 1 for:    NCT04210115
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Study of Pembrolizumab (MK-3475) Versus Placebo in Participants With Esophageal Carcinoma Who Are Receiving Chemotherapy and Radiation Therapy (MK-3475-975/KEYNOTE-975)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04210115
Recruitment Status : Recruiting
First Posted : December 24, 2019
Last Update Posted : May 30, 2023
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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Brief Summary:

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

Condition or disease Intervention/treatment Phase
Esophageal Squamous Cell Carcinoma (ESCC) Gastroesophageal Junction Carcinoma (GEJC) Esophageal Adenocarcinoma (EAC) Biological: pembrolizumab Drug: placebo Drug: cisplatin Drug: 5-FU Radiation: radiotherapy Drug: leucovorin Drug: levoleucovorin Drug: oxaliplatin Phase 3

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).
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 700 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 28, 2020
Estimated Primary Completion Date : February 11, 2027
Estimated Study Completion Date : February 11, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy

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
IV infusion
Other Names:
  • MK-3475
  • KEYTRUDA®

Drug: cisplatin
IV infusion
Other Name: PLATINOL®

Drug: 5-FU
IV infusion
Other Name: ADRUCIL®

Radiation: radiotherapy
external radiation

Drug: leucovorin
IV infusion
Other Names:
  • calcium folinate
  • folinic acid

Drug: levoleucovorin
IV infusion
Other Names:
  • FUSILEV®
  • calcium levofolinate
  • levofolinic acid

Drug: oxaliplatin
IV infusion
Other Name: ELOXATIN®
Placebo Comparator: Placebo+FP or FOLFOX Therapy+Radiotherapy

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
IV infusion
Other Name: Normal saline solution

Drug: cisplatin
IV infusion
Other Name: PLATINOL®

Drug: 5-FU
IV infusion
Other Name: ADRUCIL®

Radiation: radiotherapy
external radiation

Drug: leucovorin
IV infusion
Other Names:
  • calcium folinate
  • folinic acid

Drug: levoleucovorin
IV infusion
Other Names:
  • FUSILEV®
  • calcium levofolinate
  • levofolinic acid

Drug: oxaliplatin
IV infusion
Other Name: ELOXATIN®


Outcome Measures
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Primary Outcome Measures :
  1. Event-free Survival (EFS) [ Time Frame: Up to ~60 months ]
    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.

  2. Overall Survival (OS) [ Time Frame: Up to ~72 months ]
    OS is defined as the time from randomization to death from any cause.


Secondary Outcome Measures :
  1. Number of participants with an adverse event (AE) [ Time Frame: Up to ~15 months ]
    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.

  2. Number of participants discontinuing study treatment due to an adverse event (AE) [ Time Frame: Up to ~12 months ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 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
Contacts and Locations
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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): NCT04210115


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

Locations
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Sponsors and Collaborators
Merck Sharp & Dohme LLC
Investigators
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Study Director: Medical Director Merck Sharp & Dohme LLC
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT04210115    
Other Study ID Numbers: 3475-975
MK-3475-975 ( Other Identifier: Merck )
KEYNOTE-975 ( Other Identifier: Merck )
PHRR200210-002490 ( Registry Identifier: PHRR )
205261 ( Registry Identifier: Japic-CTI )
2019-002006-51 ( EudraCT Number )
First Posted: December 24, 2019    Key Record Dates
Last Update Posted: May 30, 2023
Last Verified: May 2023
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme LLC:
Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Programmed Death-Ligand 2 (PDL2, PD-L2)
Additional relevant MeSH terms:
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Carcinoma
Esophageal Squamous Cell Carcinoma
Esophageal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Squamous Cell
Neoplasms, Squamous Cell
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
 Calcium, Dietary
Leucovorin
Pembrolizumab
Oxaliplatin
Calcium
Levoleucovorin
Antineoplastic Agents
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Bone Density Conservation Agents
Antidotes
Protective Agents