A Study of Pembrolizumab (MK-3475) Versus Placebo in Participants With Esophageal Carcinoma Receiving Concurrent Definitive Chemoradiotherapy (KEYNOTE 975)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

24 Jan 2020 → ongoing

Decision date (initial)

2023-03-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-501531-16-00

EudraCT number

2019-002006-51

WHO UTN

U1111-1281-0822

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacogenomic, Safety, Efficacy, Pharmacogenetic

1. To compare dCRT + pembrolizumab to dCRT + placebo with respect to EFS per investigator by radiological assessment or histopathologic confirmation in participants whose tumors express PD-L1 CPS ≥10, in PD-L1 CPS ≥1, and in all participants.
2. To compare dCRT + pembrolizumab to dCRT + placebo with respect to OS in participants whose tumors express PD-L1 CPS ≥10, in PD-L1 CPS ≥1, and in all participants.

Secondary objectives 1

1. To evaluate the safety and tolerability profile of dCRT + pembrolizumab.

Conditions and MedDRA coding

esophageal carcinoma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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
2. Is deemed suitable for dCRT
3. Is ineligible for curative surgery based on the documented opinion of a qualified medical/surgical/radiation oncologist
4. Is not expected to require tumor resection during the course of the study
5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 3 days of the first dose of study treatment.
6. Has adequate organ function
7. 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.
8. 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
9. Female participants must not be pregnant or breastfeeding

Exclusion criteria 21

1. 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.
2. 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
3. Has had weight loss of >20% in the previous 3 months
4. Has had prior chemotherapy or radiotherapy for esophageal cancer
5. Has had a myocardial infarction within the past 6 months
6. Has symptomatic congestive heart failure
7. 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)
8. 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
9. Has received any prior systemic anticancer therapy for esophageal cancer including investigational agents
10. Has not recovered from all adverse events (AEs) due to previous non-anticancer therapies to ≤Grade 1 or Baseline
11. 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
12. 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.
13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, any of the study chemotherapy agents, or their excipients
14. Has an active autoimmune disease that has required systemic treatment in past 2 years
15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
16. Has an active infection requiring systemic therapy
17. Has a known history of human immunodeficiency virus (HIV) infection
18. Has a known history of Hepatitis B or known active Hepatitis C virus infection
19. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
20. 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)
21. Has had an allogenic tissue/solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Overall Survival (OS)
2. Event-free Survival (EFS)

Secondary endpoints 2

1. Number of participants with an adverse event (AE)
2. Number of participants discontinuing study treatment due to an adverse event (AE)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Sonal Bordia

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Sonal Bordia

Third parties 8

Locations

10 EU/EEA countries · 47 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 106 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

24 submissions — initial application plus substantial / non-substantial modifications