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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)

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ClinicalTrials.gov Identifier: NCT04210115
Recruitment Status : Recruiting
First Posted : December 24, 2019
Last Update Posted : January 20, 2023
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Tracking Information
First Submitted Date  ICMJE December 20, 2019
First Posted Date  ICMJE December 24, 2019
Last Update Posted Date January 20, 2023
Actual Study Start Date  ICMJE February 28, 2020
Estimated Primary Completion Date February 11, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 13, 2022)
  • 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.
  • Overall Survival (OS) [ Time Frame: Up to ~72 months ]
    OS is defined as the time from randomization to death from any cause.
Original Primary Outcome Measures  ICMJE
 (submitted: December 20, 2019)
  • Overall Survival (OS) [ Time Frame: Up to ~72 months ]
    OS is defined as the time from randomization to death from any cause.
  • 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 recurrence of the treated esophageal cancer or death from any cause.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2019)
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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)
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
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Esophageal Squamous Cell Carcinoma (ESCC)
  • Gastroesophageal Junction Carcinoma (GEJC)
  • Esophageal Adenocarcinoma (EAC)
Intervention  ICMJE
  • Biological: pembrolizumab
    IV infusion
    Other Names:
    • MK-3475
    • KEYTRUDA®
  • 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®
Study Arms  ICMJE
  • 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.

    Interventions:
    • Biological: pembrolizumab
    • Drug: cisplatin
    • Drug: 5-FU
    • Radiation: radiotherapy
    • Drug: leucovorin
    • Drug: levoleucovorin
    • Drug: oxaliplatin
  • 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.

    Interventions:
    • Drug: placebo
    • Drug: cisplatin
    • Drug: 5-FU
    • Radiation: radiotherapy
    • Drug: leucovorin
    • Drug: levoleucovorin
    • Drug: oxaliplatin
Publications * Shah MA, Bennouna J, Doi T, Shen L, Kato K, Adenis A, Mamon HJ, Moehler M, Fu X, Cho BC, Bordia S, Bhagia P, Shih CS, Desai A, Enzinger P. KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma. Future Oncol. 2021 Apr;17(10):1143-1153. doi: 10.2217/fon-2020-0969. Epub 2021 Feb 3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 13, 2022)
700
Original Estimated Enrollment  ICMJE
 (submitted: December 20, 2019)
600
Estimated Study Completion Date  ICMJE February 11, 2027
Estimated Primary Completion Date February 11, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE Argentina,   Belgium,   Brazil,   Canada,   Chile,   China,   Denmark,   Estonia,   France,   Germany,   Guatemala,   Hong Kong,   Hungary,   Italy,   Japan,   Korea, Republic of,   Peru,   Philippines,   Portugal,   Romania,   Russian Federation,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04210115
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Current Responsible Party Merck Sharp & Dohme LLC
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Merck Sharp & Dohme LLC
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme LLC
PRS Account Merck Sharp & Dohme LLC
Verification Date January 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP