| 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 |
| Adenocarcinoma della giunzione gastrica o gastroesofageo localmente avanzato non resecabile o metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gastric Cancer |
| Cancro Gastrico |
|
| 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 |
|
| 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 overall survival of tislelizumab plus chemotherapy versus placebo plus chemotherapy in the programmed cell death protein ligand- 1 positive (PDL1+) and intent-to-treat analysis sets |
| • Confrontare la sopravvivenza complessiva di tislelizumab più chemioterapia rispetto a placebo più chemioterapia, nelle serie di analisi con positività al ligando 1 della proteina di morte cellulare programmata (PD-L1+) e intent-to-treat |
|
| E.2.2 | Secondary objectives of the trial |
• To compare progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1 as assessed by investigators of tislelizumab plus chemotherapy versus placebo plus chemotherapy in the programmed cell death protein ligand-1 positive and intent-to-treat analysis sets
• To evaluate overall response rate and duration of response per Resposne Evaluation Criteira in Solid Tumors 1.1 as assessed by Investigators
• 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-Dimensions5-Levels Health Questionnaire Score
• To evaluate the safety and tolerability profile of tislelizumab or placebo plus chemotherapy
• To evaluate disease control rate, clinical benefit rate, and time to response per Response Evaluation Criteria in Solid Tumors 1.1 as
assessed by investigators |
• To compare progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1 as assessed by investigators of tislelizumab plus chemotherapy versus placebo plus chemotherapy in the programmed cell death protein ligand-1 positive and intent-to-treat analysis sets
• To evaluate overall response rate and duration of response per Resposne Evaluation Criteira in Solid Tumors 1.1 as assessed by Investigators
• 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-Dimensions5-Levels Health Questionnaire Score
• To evaluate the safety and tolerability profile of tislelizumab or placebo plus chemotherapy
• To evaluate disease control rate, clinical benefit rate, and time to response per Response Evaluation Criteria in Solid Tumors 1.1 as
assessed by investigators |
|
| 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 or non-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. |
1. In grado di fornire il consenso informato scritto e in grado di comprendere e soddisfare i requisiti dello studio
2. Pazienti adulti (= 18 anni di età o età accettabile in base alla normativa locale, se precedente) al momento della firma volontaria del consenso informato.
3. Carcinoma GC o GEJ localmente avanzato non resecabile o metastatico e con adenocarcinoma confermato istologicamente
4. Almeno 1 lesione misurabile o non misurabile come definito per RECIST v1.1 come determinato dalla valutazione dello sperimentatore.
5. Nessuna precedente terapia sistemica per carcinoma gastrico / GEJ localmente avanzato non resecabile o metastatico. Nota: i pazienti possono aver ricevuto una precedente terapia neoadiuvante o adiuvante a condizione che siano stati completati e non presentino recidiva o progressione della malattia per almeno 6 mesi.
6. I pazienti devono essere in grado di fornire tessuti tumorali.
7. ECOG PS = 1 entro 7 giorni prima della randomizzazione
8. Funzione organo adeguata:
a. Conteggio assoluto dei neutrofili (ANC) = 1,5 x 109 / L, piastrine = 100 x 109 / L, emoglobina = 90 g / L. Nota: i pazienti non devono aver richiesto una trasfusione di sangue o un supporto per il fattore di crescita = 14 giorni prima della raccolta del campione
b. Creatinina sierica = 1,5 x limite superiore del normale (ULN) o tasso di filtrazione glomerulare stimato = 60 ml / min / 1,73 m2. (Appendice 8)
c. Aspartato transaminasi (AST) e alanina aminotransferasi (ALT) = 2,5 x ULN
d. Bilirubina totale sierica = 1,5 x ULN (la bilirubina totale deve essere <3 x ULN per i pazienti con sindrome di Gilberts)
e. Rapporto internazionale normalizzato (INR) o tempo di protrombina (PT) = 1,5 x ULN a meno che il paziente non stia ricevendo terapia anticoagulante e i valori PT rientrino nell'intervallo terapeutico previsto dell'anticoagulante
f. Tempo di tromboplastina parziale attivato (aPTT) = 1,5 x ULN
g. Albumina = 3,0 g / dl o 30 g / litro
9. Le donne in età fertile devono sottoporsi a un test di gravidanza con urina o siero negativo entro 7 giorni dalla randomizzazione e devono essere disposti a utilizzare un metodo di controllo delle nascite altamente efficace.
10. I maschi non sterili devono essere disposti a utilizzare un metodo di controllo delle nascite altamente efficace. |
|
| 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 at least once a week) and/or diuretics
within 7 days prior to randomization (The cytological confirmation of any
effusion is permitted).
6. Have clinically significant bleeding (CTCAE = Grade 2) from the gastrointestinal (GI) tract within month prior to randomization
7. Have a history of = Grade 2 (CTCAE) GI perforation and/or fistulae (including prior gastric fistula operation) within 6 months prior to randomization
8. Have a clinically significant bowel obstruction (CTCAE = Grade 2)
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 cardiovascular risk factors.
15. 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 |
1. Il paziente ha GC a cellule squamose o indifferenziate o di tipo istologico
2. malattia leptomeningea attiva o metastasi cerebrali incontrollate.
3. Malattie autoimmuni attive o anamnesi di malattie autoimmuni che possono recidivare.
4. Qualsiasi tumore maligno attivo = 2 anni prima della randomizzazione, con l'eccezione del cancro specifico sotto esame in questo studio e di qualsiasi tumore localmente ricorrente che sia stato trattato in modo curativo.
5. Uncontrollable pleural effusion, pericardial effusion, or ascitesrequiring frequent drainage at least once a week) and/or diuretics
within 7 days prior to randomization (The cytological confirmation of any effusion is permitted).
6. Have clinically significant bleeding (CTCAE = Grade 2) from the gastrointestinal (GI) tract within month prior to randomization
7. Have a history of = Grade 2 (CTCAE) GI perforation and/or fistulae (including prior gastric fistula operation) within 6 months prior to
randomization
8. Have a clinically significant bowel obstruction (CTCAE = Grade 2)
9. Diagnosi di adenocarcinoma gastrico o GEJ con HER2 positivo
10. Qualsiasi condizione che richiede un trattamento sistemico con corticosteroidi (> 10 mg al giorno di prednisone o equivalente) o altro farmaco immunosoppressivo = 14 giorni prima della randomizzazione
11. Con anamnesi di malattia polmonare interstiziale, polmonite non infettiva o malattie sistemiche incontrollate, tra cui diabete, ipertensione, fibrosi polmonare, malattie polmonari acute, ecc.
12. Con gravi infezioni croniche o attive che richiedono terapia antibatterica, antifungina o antivirale sistemica, compresa l'infezione da tubercolosi, ecc.
13. Una storia nota di infezione da HIV
14. Pazienti con fattori di rischio cardiovascolare.
15. Terapia precedente con un anti-PD-1, anti-PD-L1, anti-PD-L2 o qualsiasi altro anticorpo o farmaco specificamente mirato alla co-stimolazione delle cellule T o ai percorsi del checkpoint |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival – defined as the time from the date of randomization to the date of death due to any cause |
| • La sopravvivenza complessiva - definita come il tempo trascorso dalla data della randomizzazione alla data del decesso per qualsiasi causa |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| • Overall survival – defined as the time from the date of randomization to the date of death due to any cause |
| • La sopravvivenza complessiva - definita come il tempo trascorso dalla data della randomizzazione alla data del decesso per qualsiasi causa |
|
| E.5.2 | Secondary end point(s) |
• Progression-free survival as assessed by investigators
• Overall response rate as assessed by investigators
Duration of response (DOR) as assessed by investigators – 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 Score 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
• Disease control rate (ie, proportion of complete response + partial
response + stable disease), clinical benefit rate (ie, proportion of
complete response + partial response + durable stable disease), and
time to response (ie, time from randomization to the first determination of an objective response) per Response Evaluation Criteria in Solid Tumors 1.1 as assessed by investigators |
• La sopravvivenza libera da progressione, come valutata dagli sperimentatori
• Tasso di risposta complessiva, come valutato dagli sperimentatori
• Durata della risposta, come valutata dagli sperimentatori, -definita come il tempo trascorso dalla prima determinazione di una risposta obiettiva secondo i riteri di valutazione della risposta nei tumori solidi v1.1, fino alla prima documentazione di progressione o decesso, a seconda di quale evento si verifichi prima
• Variazione dal basale nei risultati del questionario per misurare la qualità della vita dell’Organizzazione europea per la ricerca e la cura dei tumori, modulo per il carcinoma gastrico QLQ-STO22, e la variazione dal basale nei risultati del questionario per misurare la qualità della vita principale a 30 item dell’Organizzazione europea per la ricerca e la cura dei tumori e del questionario europeo di valutazione della qualità della vita a 5 dimensioni e 5 livelli
• L’incidenza e la gravità degli eventi avversi secondo i Criteri comuni di terminologia per gli eventi avversi v5.0 del National Cancer Institute (NCI)
• Tasso di controllo della malattia (ossia, percentuale di risposta completa + risposta parziale + malattia stabile), tasso di beneficio clinico (ossia, percentuale di risposta completa + risposta parziale + malattia stabile durevole) e tempo alla risposta (ossia, tempo dalla randomizzazione alla prima determinazione di una risposta obiettiva) come valutato dagli sperimentatori secondo i Criteri di valutazione della risposta nei tumori solidi 1.1 |
|
| 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
• 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.
• Disease control rate, clinical benefit rate and time to response per Response Evaluation Criteria in Solid Tumors 1.1 |
• 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
• 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.
• Disease control rate, clinical benefit rate and time to response per Response Evaluation Criteria in Solid Tumors 1.1 |
|
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 | Information not present in EudraCT |
| 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 |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| Turkey |
| United States |
| Germany |
| Italy |
| Poland |
| Romania |
| Spain |
| United Kingdom |
|
| 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
|
| 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. |
| Lo studio continuerà fino a quando l'ultimo paziente è deceduto, si perde nel follow up o si ritira dallo studio, o fino a quando lo sponsor decide di interrompere lo studio. |
|
| 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 |
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