Study on the combination of two immunotherapeutic agents as pre-surgical therapy or definitive treatment in patients with resectable gastric or gastroesophageal junction cancer with microsatellite instability.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO G.I.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Jan 2025 → ongoing

Decision date (initial)

2025-01-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-518842-26-00

EudraCT number

2020-003440-92

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To assess the activity of the immunotherapy combination of tremelimumab plus durvalumab as neoadjuvant (cohort 1) or definitive (cohort 2) treatment of resectable microsatellite instability (MSI)-high gastric cancer.

Secondary objectives 5

1. To assess the impact of immunotherapy combination of tremelimumab plus durvalumab on patients’ quality of life in the definitive treatment setting.
2. To assess the efficacy of immunotherapy combination of tremelimumab plus durvalumab in terms of disease-free survival and overall survival in the NOM setting.
3. To assess the impact of immunotherapy combination of tremelimumab plus durvalumab on gastrectomy-free survival in the NOM setting.
4. To assess the safety of immunotherapy combination of tremelimumab plus durvalumab in \in the NOM setting
5. To conduct exploratory translational analyses aimed at identifying which subgroup of patients may derive the highest chance of definitive cure from immunotherapy combination of tremelimumab plus durvalumab.

Conditions and MedDRA coding

Cancer in the stomach or in the junction between the stomach and the oesophagus, without metastases in other organs and surgically resectable, with microsatellite instability and no EBV infection.

Study design 2 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Written informed consent and any locally required authorization (such as the European Union [EU] Data Privacy Directive) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
2. Age ≥ 18 years old.
3. ECOG Performance Status 0-1.
4. Body weight >30 kg.
5. Diagnosis of resectable gastric or gastroesophageal junction (Siewert II-III) cancer, categorized according to TNM classification 8th edition:  cT2-3, any cN, M0
6. Absence of distant metastases as defined by negativity of computed tomography (CT) and 18-fluorodeoxyglucose positron-emission tomography (18-FDG PET).
7. Life expectancy of at least 12 weeks
8. MSI-high status confirmed by IHC and multiplex PCR, and EBV-negative status by ISH, as determined centrally at the Co-ordinating Centre. Lack of heterogeneity of dMMR status as showed by lack of tumor cells showing concomitant expression of all 4 protein markers. A minimum of five biopsy specimens, and optimally six to eight, should be obtained to account for intratumoral heterogeneity and to provide sufficient tumor specimens for diagnosis and biomarker testing, and this is also recommended by the NCCN Guidelines. As well, if there is concern about the adequacy of the specimen, it is recommended that additional available primary or metastatic GEA tumor tissue be tested.Adequate bone marrow and organ function, as defined by laboratory tests: a. Neutrophil count ≥ 1.5 x 103/μL b. Platelet count ≥ 100 x 106/μL c. Haemoglobin ≥ 9 g/dL d. Total bilirubin lower than 1.5 time the upper-normal limits (ULN) of the Institutional normal values e. AST (SGOT) and/or ALT (SGPT) < 2.5 x ULN f. Creatinine clearance (calculated according to Cockroft and Gault) > 40 mL/min or serum creatinine < 1.5 x ULN.
9. Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating Centre.

Exclusion criteria 16

1. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
2. Previous enrolment in the present study
3. Participation in another clinical study with an investigational product during the last 12 months
4. Signs of distant metastases.
5. Prior medical treatments or irradiation for gastric cancer.
6. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
7. Previous treatments with immune checkpoint inhibitors targeting CTLA4, including tremelimumab, PD-1 or PD-L1, including durvalumab.
8. History of allergy or severe hypersensitivity reaction to monoclonal antibodies.
9. History of autoimmune diseases or history of organ transplantation that require immunosuppressive therapy. The following are exceptions to this criterion:  Patients with vitiligo or alopecia  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement  Any chronic skin condition that does not require systemic therapy  Patients with celiac disease controlled by diet alone
10. History of active primary immunodeficiency Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
11. Any condition requiring systemic treatment with corticosteroids at doses equal or superior to 10 mg daily of prednisone or equivalents, or other immunosuppressive drugs within 14 days from the inclusion in the study. The following medications are exceptions to this criterion:  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection)  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent  Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
12. Administration of live vaccines within 4 weeks from the inclusion in the study. Note: Patients, if enrolled, should not receive live vaccine while receiving study drug(s) and up to 30 days after the last dose of study drug(s).
13. History of allogenic organ transplantation
14. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
15. Women in pregnancy or lactation condition. Women with child-bearing potential or sexually-active men not willing to use adequate contraception during the whole study period.
16. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Cohort 1: Pathological complete response (ypT0N0) and negative ctDNA status after neoadjuvant immunotherapy in the intention-to-treat population. Cohort 2: 2-year complete response rate, defined as the absence of macroscopic or microscopic residual disease (locally, regionally and distantly) at radiological examinations, tissue and liquid biopsy, in absence of salvage gastrectomy.

Secondary endpoints 4

1. 3-year disease-free survival, defined as time from the enrollment in the study to the occurrence of disease relapse (local and/or distant), second GC/GEJC primary, or death from any cause.
2. 5-year overall survival, defined as time from the enrollment in the study to the occurrence of death.
3. Metastases-free survival, defined as time from the enrollment in the study to the first evidence of metastases or death from any cause.
4. Gastrectomy-free survival (for Cohort 2 only), defined as time from the enrollment in the study to the occurrence of gastrectomy or death from any cause.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO G.I.

Sponsor organisation

Fondazione GONO G.I.

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Third parties 5

Locations

1 EU/EEA country · 7 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 10 files

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

Application history

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