Infinity

INFINITY is a Phase II, multicentre, single-arm, multi-cohort trial aimed at evaluating the activity and safety of the combination of tremelimumab and durvalumab as neoadjuvant (Cohort 1) and definitive (Cohort 2) treatment for gastric/gastroesophageal juction cancer patients. After central confirmation of MSI-high, dMMR and EBV-negative status, patients will be enrolled across 25 Italian Centres, and they will receive a pre-operative treatment with tremelimumab 300 mg single administration (day 1) and durvalumab 1500 mg Q4W for 3 cycles (day 1, 29 and 57). All patients will undergo a complete disease restaging with chest-abdomen-pelvis CT scan, 18-FDG PET/CT, EUS with biopsies and liquid biopsy. In Cohort 1 patients underwent standard gastrectomy with D2 lymphadenectomy between weeks 15 and 18 from enrolment (at least six weeks after the last treatment administration), followed by an active follow-up every 12 weeks for two years and then a standard follow-up every six months until the end of the fifth year from surgery. After the completion of enrolment in Cohort 1 and extensive evaluation of the final results of Cohort 1 by the Sponsor’s Steering Committee and an Independent Data Monitoring Committee made of foreign experts, and after the approval of the Ethics Committee and the Italian Medicines Agency, enrolment in Cohort 2 has started with specific amendments. In Cohort 2, patients with no evidence of complete clinical response (defined as absence of disease persistence at radiological imaging, liquid biopsy and EUS) will be treated as in Cohort 1. Patients with complete clinical response will undergo a non-operative management (NOM) and will start an active follow-up phase every 12 weeks for two years with chest-abdomen-pelvis CT with contrast, 18-FDG PET/TC, if clinically indicated by the Investigator, plus EUS with at least 4 bite-on-bite biopsies of the primary tumor site and FNA of clinically suspicious regional nodes and liquid biopsy, followed by standard follow-up every six months until the end of the fifth year. At any time during follow-up, in case of clinical suspicion or confirmation of residual gastric cancer, either at imaging, pathologically at tissue biopsies/cytological specimens or at ctDNA in liquid biopsy, the patients will undergo standard surgery according to the clinical practice at their Centre.

This study will pre-screen approximately 310 patients, in order to enrol a total number of 36 patients, 18 already enrolled and treated in Cohort 1 and additional 18 in Cohort 2, across 17 Italian Centres.
Inclusion criteria with specific amendments for Cohort 2:

1. Written informed consent and any locally required authorization.
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: cT ≥ 2, any cN, M0 or any cT, cN1-3, M0
   Amendment for Cohort 2: included only 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.
   Amendment for Cohort 2: 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.
9. Adequate bone marrow and organ function, as defined by laboratory tests.
10. 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:

1. Involvement in the planning and/or conduct of the study
2. Previous enrolment in the present study
3. Participation in another clinical study with an investigational product during last 12 months
4. Signs of distant metastases.
5. Prior medical treatments or irradiation for gastric cancer.
6. Major surgical procedure within 28 days prior to the first dose of IP.
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.
10. History of active primary immunodeficiency or active infection including tuberculosis, hepatitis B or C
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
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 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.

Primary objective:
To assess the activity of the immunotherapy combination of tremelimumab plus durvalumab as neoadjuvant or definitive treatment of resectable MSI-high gastric cancer.
Primary endpoint:
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 objectives:
To assess the impact of immunotherapy combination of tremelimumab plus durvalumab on patients’ quality of life in the neoadjuvant/potentially definitive treatment setting.
Endpoint: Cohort 1 and 2: Patient reported outcomes (completion of quality of life questionnaires, European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-STO-22 and EuroQol EQ-5D, during the pre-operative treatment phase).
To assess the efficacy of immunotherapy combination of tremelimumab plus durvalumab in terms of disease-free survival and overall survival in the neoadjuvant setting and in the NOM setting.

Endpoint:
Cohort 1 and 2: 3-year DFS, 5-year OS, Metastases-free survival
To assess the impact of immunotherapy combination of tremelimumab plus durvalumab on gastrectomy-free survival in the NOM setting.

Endpoint:
Only for Cohort 2: Gastrectomy-free survival, defined as time from the inclusion in the study to the occurrence of gastrectomy or death from any cause.
To assess the safety of immunotherapy combination of tremelimumab plus durvalumab in the neoadjuvant setting and in the NOM setting.

Endpoint:
Cohort 1 and 2:
Treatment safety (incidence of adverse events during the treatment and follow-up phases, assessed according to CTCAE v5.0);
Morbidity and mortality of gastrectomy following tremelimumab and durvalumab as pre-operative treatment strategy.

Exploratory objectives:
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.