Pembrolizumab/placebo plus chemotherapy as first-line therapy in participants with HER2 negative advanced gastric or GEJ adenocarcinoma

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] - Neoplasms [C04]

Trial duration

5 Dec 2018 → 4 Mar 2025

Decision date (initial)

2024-05-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2023-508890-10-00

EudraCT number

2018-001757-27

WHO UTN

U1111-1299-1405

ClinicalTrials.gov

NCT03675737

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic, Pharmacodynamic, Pharmacogenetic, Pharmacogenomic, Therapy

1. To compare the overall survival (OS) of the participants following administration of pembrolizumab versus placebo when each is combined with chemotherapy

Secondary objectives 4

1. To compare the progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), as assessed by blinded independent central review (BICR), following administration of pembrolizumab versus placebo when each is combined with chemotherapy
2. To compare the overall response rate (ORR) per RECIST 1.1, as assessed by BICR, following administration of pembrolizumab versus placebo when each is combined with chemotherapy
3. To describe the duration of response (DOR) per RECIST 1.1, as assessed by BICR, following administration of pembrolizumab versus placebo when each is combined with chemotherapy in participants with Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10, PD-L1 CPS ≥1, and in all participants
4. To evaluate the safety and tolerability of pembrolizumab plus chemotherapy versus placebo plus chemotherapy

Conditions and MedDRA coding

Gastric and gastric esophageal junction (GEJ) adenocarcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Has histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with known PD-L1 expression status
2. Has human epidermal growth factor receptor 2 (HER2) negative cancer
3. Male participants must agree to use contraception during the treatment period and through 95 days after the last dose of chemotherapy, refrain from donating sperm, and be abstinent from heterosexual intercourse, as their preferred and usual lifestyle, and agree to remain abstinent or must agree to use contraception per study protocol unless confirmed to be azoospermic during this period
4. Female participants who are not pregnant, not breastfeeding, and at least one of the following conditions applies: not a woman of childbearing potential (WOCBP) OR is a WOCBP who agrees to use contraception or be abstinent from heterosexual intercourse, as their preferred and usual lifestyle, during the treatment period and through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is last, and agrees not to donate eggs to others or freeze/store for her own use for the purpose of reproduction during this period
5. Has measurable disease per RECIST 1.1 as assessed by investigator assessment
6. Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
7. Has provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis
8. Has provided tumor tissue sample for microsatellite instability (MSI) biomarker analysis
9. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days prior to the start of study intervention
10. Has adequate organ function as demonstrated by laboratory testing within 10 days prior to the start of study treatment

Exclusion criteria 29

1. Has squamous cell or undifferentiated gastric cancer
2. Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior to randomization, anticipation of the need for major surgery during the course of study intervention, or has not recovered adequately from the toxicity and/or complications from previous surgery
3. Has preexisting peripheral neuropathy >Grade 1
4. Is a WOCBP who has a positive urine pregnancy test within 24 hours for urine or within 72 hours for serum prior to randomization or treatment allocation
5. Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ cancer. Participants may have received prior neoadjuvant and/or adjuvant therapy as long as it was completed ≥6 months prior to randomization
6. Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1 or anti-programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX- 40, CD137)
7. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization or has not recovered from all adverse events (AEs) due to any previous therapies to ≤Grade 1 or baseline
8. Has received prior radiotherapy within 2 weeks prior to study start or has not recovered from all previous radiation-related toxicities, required corticosteroids, and have not had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease
9. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study treatment
10. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
12. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
13. Has known active CNS metastases and/or carcinomatous meningitis
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
15. Has an active autoimmune disease that has required systemic treatment in past 2 years
16. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
17. Has an active infection requiring systemic therapy
18. Has a known history of human immunodeficiency virus (HIV) infection
19. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as Hepatitis C virus [HCV] ribonucleic acid [RNA] detected qualitatively) infection
20. Has a known history of active tuberculosis
21. Has hypokalemia (serum potassium less than the lower limit of normal)
22. Has hypomagnesemia (serum magnesium less than the lower limit of normal)
23. Has hypocalcemia (serum calcium less than the lower limit of normal)
24. Has a history or current evidence of any condition (eg, known deficiency of the enzyme dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
25. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
26. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is last
27. Has had an allogenic tissue/solid organ transplant
28. Has a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents (including, but not limited to, infusional 5-fluorouracil or oral capecitabine) and/or to any of their excipients
29. For participants taking cisplatin: has Grade ≥2 audiometric hearing loss

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. OS in All Participants
2. OS In Participants With PD-L1 CPS ≥1
3. OS In Participants With PD-L1 CPS ≥10

Secondary endpoints 11

1. PFS Per RECIST 1.1 Assessed by BICR in All Participants
2. PFS Per RECIST 1.1 Assessed by BICR In Participants With PD-L1 CPS ≥1
3. PFS Per RECIST 1.1 Assessed by BICR In Participants With PD-L1 CPS ≥10
4. ORR Per RECIST 1.1 Assessed by BICR in All Participants
5. ORR Per RECIST 1.1 Assessed by BICR in Participants With PD-L1 CPS ≥1
6. ORR Per RECIST 1.1 Assessed by BICR in Participants With PD-L1 CPS ≥10
7. DOR Per RECIST 1.1 Assessed by BICR in All Participants
8. DOR Per RECIST 1.1 Assessed by BICR In Participants With PD-L1 CPS ≥1
9. DOR Per RECIST 1.1 Assessed by BICR In Participants With PD-L1 CPS ≥10
10. Number of Participants Who Experienced an Adverse Event (AE)
11. Number of Participants Who Discontinued Study Treatment Due To an AE

Investigational products

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

Test 1

Placebo 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue, P. O. Box 2000 P. O. Box 2000

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 7

Locations

8 EU/EEA countries · 24 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 86 files

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

Application history

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