E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001158 |
E.1.2 | Term | Adenocarcinoma gastric stage IV with metastases |
E.1.2 | System Organ Class | 100000004864 |
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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 progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1 of tislelizumab plus chemotherapy versus placebo plus chemotherapy in the intent-to-treat and programmed cell death protein ligand-1 (PD-L1) positive analysis sets • To compare overall survival of tislelizumab plus chemotherapy versus placebo plus chemotherapy in the intent-to-treat and programmed cell death protein ligand-1 positive analysis sets |
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E.2.2 | Secondary objectives of the trial |
• To evaluate overall response rate, and duration of response, per Response Evaluation Criteria in Solid Tumors 1.1. • To evaluate European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Gastric Cancer Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Score and European Quality of Life 5-Dimensions 5-Levels Health Questionnaire Score • To evaluate the safety and tolerability profile of tislelizumab or placebo plus chemotherapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Able to provide written informed consent and can understand and comply with the requirements of the study 2. Adult patients (≥18 years of age or acceptable age according to local regulations, whichever is older) at the time of voluntarily signing informed consent. 3. Locally advanced unresectable or metastatic GC or GEJ carcinoma and have histologically confirmed adenocarcinoma 4. At least 1 measurable lesion as defined per RECIST v1.1 as determined by investigator assessment. 5. No previous systemic therapy for locally advanced unresectable or metastatic gastric/GEJ cancer. Note: Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed and have no recurrence or disease progression for at least 6 months. 6. Patients must be able to provide tumor tissues. 7. ECOG PS ≤ 1 within 7 days prior to randomization 8. Adequate organ function: a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 90 g/L. Note: Patients must not have required a blood transfusion or growth factor support ≤ 14 days before sample collection b. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated Glomerular Filtration Rate ≥ 60 mL/min/1.73 m2. (Appendix 8) c. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN d. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilberts syndrome) e. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy and PT values are within the intended therapeutic range of the anticoagulant f. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN g. Albumin ≥ 3.0 g/dL or 30 g/liter 9. Females of childbearing potential must have a negative urine or serum pregnancy test within 7 days of randomization and must be willing to use a highly effective method of birth control. 10. Non-sterile males must be willing to use a highly effective method of birth control. Please refer to the study protocol for all inclusion criteria. |
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E.4 | Principal exclusion criteria |
1. Patient has squamous cell or undifferentiated or other histological type GC 2. Active leptomeningeal disease or uncontrolled brain metastasis. 3. Active autoimmune diseases or history of autoimmune diseases that may relapse. 4. Any active malignancy ≤ 2 years before randomization, with the exception of the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively. 5. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage within 7 days prior to randomization (The cytological confirmation of any effusion is permitted). 6. Have clinically significant bleeding from the gastrointestinal (GI) tract within 3 months prior to randomization 7. Have a history of GI perforation and/or fistulae within 6 months prior to randomization 8. Have a clinically significant bowel obstruction 9. Diagnosed with gastric or GEJ adenocarcinoma with positive HER2 10. Any condition that requires systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before randomization 11. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases, etc. 12. With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc. 13. A known history of HIV infection 14. Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers whose HBV DNA is ≥ 500 IU/mL or patients with positive hepatitis C virus (HCV) RNA should be excluded. Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL), and cured hepatitis C patients can be enrolled. 15. Patients with cardiovascular risk factors. 16. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Please refer to the study protocol for all exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Progression-free survival • Overall survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Progression-free survival– defined as the time from the date of randomization to the date of the first objectively documented tumor progression, assessed per Response Evaluation Criteria in Solid Tumors v1.1, or death, whichever occurs first. • Overall survival – defined as the time from the date of randomization to the date of death due to any cause |
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E.5.2 | Secondary end point(s) |
• Overall response rate. • Duration of response (DOR) – defined as the time from the first determination of an objective response per Response Evaluation Criteria in Solid Tumors v1.1, until the first documentation of progression or death, whichever occurs first • Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Gastric Cancer Module QLQ-STO22 Score and change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and European Quality of Life 5-Dimensions 5-Levels Health Questionnaire Score • The incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Overall response rate: Defined as the proportion of patients whose best overall response is complete response or partial response per Response Evaluation Criteria in Solid Tumors v1.1 • Duration of response – defined as the time from the first determination of an objective response per Response Evaluation Criteria in Solid Tumors v1.1, until the first documentation of progression or death, 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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
China |
Germany |
Italy |
Japan |
Korea, Republic of |
Poland |
Romania |
Russian Federation |
Spain |
Taiwan |
Turkey |
United Kingdom |
United States |
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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 study will continue until the last patient has died, becomes lost to follow up, or withdraws from study, or until sponsor decides to terminate the study. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 43 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 43 |
E.8.9.2 | In all countries concerned by the trial days | 0 |