E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2 negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Gastric and gastric esophageal junction (GEJ) adenocarcinoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071114 |
E.1.2 | Term | Metastatic gastric adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058526 |
E.1.2 | Term | Oesophageal adenocarcinoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the overall survival (OS) of the participants following administration of pembrolizumab versus placebo when each is combined with chemotherapy
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E.2.2 | Secondary objectives of the trial |
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. To compare the objective response rate (ORR) per RECIST 1.1, as assessed by BICR, following administration of pembrolizumab versus placebo when each is combined with chemotherapy 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 PD-L1 CPS ≥10, PD-L1 CPS ≥1, and in all participants. To evaluate the safety and tolerability of pembrolizumab plus chemotherapy versus placebo plus chemotherapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, with known PD-L1 expression status. 2. Has HER2 negative cancer. HER2 negative is defined as: IHC (0, or 1+) or fluorescence in situ hybridization (FISH) negative (HER2:CEP17 ratio <2 with an average HER2 copy number <4.0 signals/cell). FISH can be replaced with locally available in situ hybridization (ISH) methods acceptable as per institutional guidelines (eg, DISH). 3. Is Male or Female. 4. Is at least 18 years of age at the time of signing the informed consent (or acceptable age according to local regulations, whichever is older). 5. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 95 days after the last dose of chemotherapy: •Refrain from donating sperm PLUS either: •Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR •Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [Appendix 5]) as detailed below: •Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant 6. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: •Is not a WOCBP OR •Is a WOCBP and using a contraceptive method 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 (abstinent on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least 180 days after the last dose of chemotherapy or 120 days after the last dose of pembrolizumab, whichever is last, and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. -A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours before the first dose of study intervention. 7. The participant (or legally acceptable representative if applicable) has provided documented informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research. 8. Has measurable disease per RECIST 1.1 as assessed by investigator assessment. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 9. Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. 10. Has provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis. 11. Has provided tumor tissue sample for MSI biomarker analysis. 12. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (within 3 days prior to the start of study intervention). 13. Has adequate organ function, as defined in the protocol. Specimens must be collected within 10 days prior to the start-of-study intervention. |
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E.4 | Principal exclusion criteria |
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, or anticipation of the need for major surgery during the course of study intervention. 3. Has pre-existing peripheral neuropathy >Grade 1. 4. Is a WOCBP who has a positive urine pregnancy test within24 hours for urine or within 72 hours for serum prior to randomization or treatment allocation. 5. Has had previous therapy for locally advanced, unresectable and/or metastatic gastric/GEJ cancer. Participants may have received prior neoadjuvant or adjuvant therapy as long as it was completed at least 6 months prior to randomization. 6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PDL2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). 7. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization. 8. Has received prior radiotherapy within 2 weeks prior to start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have 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 intervention. Administration of killed vaccines is allowed. 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 intervention. 11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention. 12. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. 13. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention. 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 (ie, with use of disease-modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 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 HCV RNA [qualitative] is detected) infection. 20. Has a known history of active tuberculosis. 21. 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. 22. Participants with hypokalemia (serum potassium less than the lower limit of normal). 23. Participants with hypomagnesemia (serum magnesium less than the lower limit of normal). 24. Participants with hypocalcemia (serum calcium less than the lower limit of normal). 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 greater. 27. Has had an allogenic tissue/solid organ transplant |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Overall survival (OS), defined as the time from randomization to death due to any cause - Progression-free Survival (PFS), defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall survival (OS) = time from randomization to death due to any cause; Progression-free survival (PFS) = time from randomization to the first documented disease progression per RECIST 1.1 by (blinded independent central review (BICR) or death due to any cause, whicherver occurs first |
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E.5.2 | Secondary end point(s) |
- Objective response (OR), defined as Complete response (CR) or partial response (PR) - Duration of Response (DOR), defined as the time from first response (CR or PR) to subsequent disease progression, or death from any cause, whichever occurs first
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Objective Response Rate (ORR) = proportion of participants who have an overall response – complete response (CR) or partial response (PR); - Duration of Response (DOR) =time from first response (CR or PR) to subsequent disease progression or death from any cause, whichever occurs first |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 103 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Chile |
Colombia |
Costa Rica |
Guatemala |
New Zealand |
Peru |
Switzerland |
Ukraine |
Hong Kong |
Taiwan |
Australia |
Brazil |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
South Africa |
United Kingdom |
United States |
Czechia |
Denmark |
France |
Germany |
Hungary |
Ireland |
Italy |
Poland |
Spain |
Türkiye |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The overall study ends when the last participant completes the last study-related telephone-call or visit, withdraws from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the investigator). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |