Phase II Study of Tremelimumab and Durvalumab in Resectable MSI-High Gastric and Gastroesophageal Junction Cancer

Trial ID: 2024-518842-26-00
Protocol: INFINITY
Sponsor: Fondazione GONO G.I.

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Diseases & Conditions

Adenocarcinoma gastric

Objectives

The primary objective of this study is to assess the activity of the **immunotherapy** combination of tremelimumab plus durvalumab as neoadjuvant (cohort 1) or definitive (cohort 2) treatment for resectable microsatellite instability (MSI)-high gastric cancer. This is clinically relevant as it aims to determine the potential of this combination therapy to improve treatment outcomes in patients with this specific type of gastric cancer, which is characterized by its genetic instability and potential responsiveness to immunotherapy.

Secondary objectives include:

Assessing the impact of the immunotherapy combination on patients' quality of life in the definitive treatment setting.
Evaluating the efficacy in terms of disease-free survival and overall survival in the non-operative management (NOM) setting.
Assessing the impact on gastrectomy-free survival in the NOM setting.
Evaluating the safety of the combination in the NOM setting.
Conducting exploratory translational analyses to identify subgroups of patients who may derive the highest chance of definitive cure from the therapy.

Participants

The clinical trial involves participants diagnosed with **gastric cancer** or cancer at the gastroesophageal junction, specifically those with microsatellite instability-high status and no EBV infection. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have a body weight greater than 30 kg and a life expectancy of at least 12 weeks. The trial does not provide the total number of participants, as this information was not disclosed by the sponsor. The selection criteria emphasize the absence of distant metastases, confirmed by imaging techniques, and adequate bone marrow and organ function as determined by specific laboratory tests. The trial population includes individuals who are considered vulnerable, and participants are required to be accessible for treatment and follow-up at the participating center. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of a combination of **tremelimumab** and **durvalumab** as a treatment for patients with resectable gastric or gastroesophageal junction cancer characterized by microsatellite instability. This is a multicenter, single-arm, multi-cohort, Phase II study. The trial employs a non-randomized, open-label design, focusing on two cohorts: one receiving the combination as neoadjuvant therapy and the other as definitive treatment. The trial is expected to run from April 2021 to January 2026, with the primary objective of assessing the pathological complete response and 2-year complete response rate in the respective cohorts.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and cancer diagnosis. The screening process will include assessments to ensure the absence of distant metastases and confirmation of **MSI-high** status. Following the screening, participants will receive the investigational drugs intravenously, with **durvalumab** administered at a maximum daily dose of 1500 mg and **tremelimumab** at 300 mg. The treatment period is set for a maximum of 12 months.

Follow-up visits will be scheduled to monitor the participants' response to treatment and to assess any adverse effects. These visits will include radiological examinations and biopsies to evaluate the presence of residual disease. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, which may be necessitated by factors such as disease progression, unacceptable toxicity, or withdrawal of consent.

The expected length of participant involvement is up to 12 months, with additional follow-up for survival outcomes. Conditions that may lead to early termination from the study include the development of distant metastases, significant adverse reactions, or voluntary withdrawal by the participant. The trial aims to provide valuable insights into the potential of **tremelimumab** and **durvalumab** as a therapeutic strategy for this specific cancer population.

Treatment

The clinical trial involves the administration of **durvalumab**, an experimental medication used in the study. Durvalumab is a monoclonal antibody classified under the ATC code L01XC28. It is administered in an **intravenous** form, with a pharmaceutical form code of PHF00230MIG. The maximum daily dose of durvalumab is 1500 mg, with a total maximum dose of 13500 mg over a treatment period of up to 12 months. The administration schedule is designed to ensure optimal therapeutic efficacy while monitoring participant compliance closely.

Another experimental medication used in the trial is **tremelimumab**, also a monoclonal antibody, classified under the ATC code L01FX20. Tremelimumab is administered intravenously, similar to durvalumab, with the same pharmaceutical form code of PHF00230MIG. The maximum daily dose for tremelimumab is 300 mg, with a total maximum dose of 300 mg over a treatment period of up to 12 months. The dosing schedule is structured to align with the study's objectives, ensuring consistent administration and monitoring of participant adherence to the treatment regimen.

Both durvalumab and tremelimumab are utilized in combination as part of the study's investigational treatment strategy. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on evaluating the efficacy of the combination of these two immunotherapeutic agents in the management of microsatellite instability-high gastric cancer. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol and to assess the safety and efficacy of the treatment regimen.

Efficacy

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the **pathological complete response** (ypT0N0) and negative circulating tumor DNA (ctDNA) status after neoadjuvant immunotherapy in the intention-to-treat population for Cohort 1. For Cohort 2, the primary endpoint is the 2-year complete response rate, defined as the absence of macroscopic or microscopic residual disease at radiological examinations, tissue, and liquid biopsy, in the absence of salvage gastrectomy.

Secondary endpoints will evaluate long-term outcomes, including 3-year disease-free survival, 5-year overall survival, metastases-free survival, and gastrectomy-free survival for Cohort 2. These endpoints are defined as the time from enrollment in the study to the occurrence of specific events such as disease relapse, death, or the need for gastrectomy. The efficacy parameters will be measured and collected at specified timepoints throughout the trial, with analysis conducted to determine the effectiveness of the immunotherapy combination of tremelimumab and durvalumab in treating resectable microsatellite instability-high gastric cancer.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.
Age ≥ 18 years old.
ECOG Performance Status 0-1.
Body weight >30 kg.
Diagnosis of resectable gastric or gastroesophageal junction (Siewert II-III) cancer, categorized according to TNM classification 8th edition:  cT2-3, any cN, M0
Absence of distant metastases as defined by negativity of computed tomography (CT) and 18-fluorodeoxyglucose positron-emission tomography (18-FDG PET).
Life expectancy of at least 12 weeks
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.
Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating Centre.

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Exclusion Criteria

Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
Previous enrolment in the present study
Participation in another clinical study with an investigational product during the last 12 months
Signs of distant metastases.
Prior medical treatments or irradiation for gastric cancer.
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.
Previous treatments with immune checkpoint inhibitors targeting CTLA4, including tremelimumab, PD-1 or PD-L1, including durvalumab.
History of allergy or severe hypersensitivity reaction to monoclonal antibodies.
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
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
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)
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).
History of allogenic organ transplantation
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
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.
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.