Phase II Study of Dostarlimab-Based Immunotherapy in Localized dMMR/MSI-H Esophagogastric Junction and Gastric Adenocarcinoma

Trial ID: 2023-506102-39-00
Protocol: DEWI G-123
Sponsor: Gercor

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Diseases & Conditions

Metastatic gastric cancer

Objectives

The primary objective of this study is to evaluate the **clinical complete response (cCR)** at 1 year in patients with localized deficient mismatch repair (dMMR) and/or microsatellite instability high (MSI-H) esophagogastric junction and gastric adenocarcinoma. This is defined as the rate of patients who, at 1 year from the start of therapy with dostarlimab, are alive, have not undergone surgery for tumor resection, are free of disease progression (locoregional or metastases), have all negative biopsies, and show endoscopy downstaging to stage 3 or 4 (endoscopic grade). This objective is clinically relevant as it aims to determine the efficacy of a watch-and-wait strategy using dostarlimab-based immunotherapy, potentially reducing the need for surgical intervention and its associated morbidities.

Secondary objectives include: - Assessing the number of patients who did not undergo surgery for tumor resection without distant metastases at 12 and 24 months. - Evaluating the number of patients who did not undergo surgery due to distant metastases at the same time points. - Assessing pathological response using the Tumor Regression Grade by Becker classification on surgical specimens. - Evaluating event-free survival (EFS), time to treatment failure (TTF), and overall survival (OS) for the entire population. - Assessing disease-free survival (DFS) in cases of surgery with and without adjuvant treatment with dostarlimab. - Evaluating the safety of dostarlimab using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. - Evaluating morbidity in case of surgery, defined as complications or death within 90 postoperative days according to the Clavien-Dindo classification. - Evaluating health-related quality of life (HRQoL) using the EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) and EORTC oesophago-gastric (EORTC QLQ-OG25) questionnaires. - Evaluating the efficacy of dostarlimab according to selected tumor biomarkers, including PD-1 and PD-L1 expression, CD3+, CD8+, and FOXP3 expression, and inflammatory signature upon RNAseq. - Evaluating whether the expression of PD-L1, PD-1, anti-CTL4, TIM-3, LAG-3, GAL9, IDO, and TIGIT could predict patient response. - Evaluating the presence of circulating tumor DNA (ctDNA) and its predictive and prognostic value at baseline, during treatment, and follow-up. - Evaluating blood proteome at baseline and during therapy. - Evaluating the predictive and prognostic significance of dMMR/MSI-H Lynch syndrome versus sporadic tumors.

Participants

The clinical trial involves participants diagnosed with **metastatic gastric cancer**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants over 75 years of age are eligible if specific conditions are met, such as a G8 questionnaire score above 14 and eligibility for surgery. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants were selected based on their ability to provide informed consent and meet specific health criteria, including adequate liver and renal function, and hematological status. They must not have received prior therapy for localized gastric or OGJ adenocarcinoma. Lifestyle considerations such as diet and physical activity are not detailed in the trial data. The trial includes a vulnerable population, and participants are required to comply with scheduled visits and study requirements. Key inclusion criteria include having an ECOG performance status of 0-1 and histologically proven non-metastatic gastric or OGJ adenocarcinoma. Participants must also be registered in a National Health Care System.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **dostarlimab** in patients with localized deficient mismatch repair (dMMR) and/or microsatellite instability high (MSI-H) esophagogastric junction and gastric adenocarcinoma. This is an open-label, phase II study with a primary objective to assess the clinical complete response (cCR) at one year. The trial employs a **randomized** and **controlled** design, ensuring robust data collection and analysis. The estimated duration of the trial is from October 2023 to December 2028, with a maximum treatment period of 52 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate liver and renal function, and histologically proven non-metastatic gastric or esophagogastric junction adenocarcinoma. Following the screening, participants will receive **dostarlimab** via intravenous infusion, with regular follow-up visits scheduled to monitor treatment response and safety. These visits will include radiological assessments, laboratory tests, and tumor biopsies. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected length of participant involvement is up to 52 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is the rate of patients achieving cCR at one year, while secondary endpoints include the number of patients avoiding surgery, pathological response, and overall survival metrics. The trial will also assess the safety profile of **dostarlimab** and its efficacy in relation to specific tumor biomarkers. Participants' involvement is crucial for the comprehensive evaluation of the investigational product's therapeutic potential in this patient population.

Treatment

The clinical trial involves the administration of **dostarlimab**, marketed under the name JEMPERLI, which is a **concentrate for solution for infusion**. This experimental medication is provided in a dosage of 500 mg per vial and is intended for **intravenous use**. The maximum daily dose is set at 1000 mg, with a total maximum dose of 10,000 mg over the course of the treatment. The treatment period is capped at 52 weeks. Dostarlimab is a protein-based therapeutic agent, specifically categorized under the ATC code L01FF07, and is produced by GlaxoSmithKline (Ireland) Limited. The medication is labeled for clinical trials and is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of dostarlimab to evaluate its efficacy in patients with localized deficient mismatch repair (dMMR) and/or microsatellite instability high (MSI-H) esophagogastric junction and gastric adenocarcinoma. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

Efficacy

The efficacy of the clinical trial will be assessed primarily by evaluating the rate of patients who achieve a **clinical complete response (cCR)** at 1 year from the start of treatment with dostarlimab. This primary endpoint is defined as the proportion of patients who are alive, have not undergone tumor resection surgery, are free of disease progression (locoregional or metastases), have all negative biopsies, and show endoscopy downstaging to stage 3 or 4 (endoscopic grade) at the 1-year mark.

Secondary endpoints include several parameters: the number of patients who did not undergo surgery for tumor resection without distant metastases at 12 and 24 months, the number of patients who did not undergo surgery with distant metastases at the same time points, and the pathological response assessed by the Tumor Regression Grade using the Becker classification on surgical specimens when surgery is performed. Additional secondary endpoints involve evaluating event-free survival (EFS), time to treatment failure (TTF), overall survival (OS), and disease-free survival (DFS) in cases of surgery with and without adjuvant treatment with dostarlimab. The safety of dostarlimab will be monitored using the NCI CTCAE v 5.0 criteria, and morbidity will be assessed according to the Clavien Dindo classification for complications or death occurring within 90 postoperative days.

Quality of life will be measured using the EORTC QLQ-C30 and EORTC QLQ-OG25 questionnaires in patients with or without surgery. The efficacy of dostarlimab will also be evaluated based on selected tumor biomarkers, including PD-1 and PD-L1 expression, CD3+, CD8+, and FOXP3, and inflammatory signature upon RNA sequencing. The association of various expressions such as PD-L1, PD-1, anti-CTL4, TIM-3, LAG-3, GAL9, IDO, and TIGIT with patient response will be explored. The prognostic value of circulating tumor DNA (ctDNA) presence at baseline and during follow-up, as well as the prognostic value of dMMR/MSI-H Lynch versus sporadic tumors, will also be assessed.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Is capable of giving signed and dated informed consent,
Has an ECOG PS of 0-1,
Is between ≥18 and ≤75 years old,The patient over 75 years of age is eligible only if all the following conditions are met: The patient’s G8 questionnaire score is above 14 AND The patient is eligible for surgery and has no contraindications to repeated UGI endoscopy with biopsies,
Has histologically proven non-metastatic gastric or OGJ adenocarcinoma cT2 to T4, Nx, M0 after computed tomography thorax-abdomen-pelvis (TAP-CT) and echo-endoscopy (EUS) according to the 7th Edition of the International Union Against Cancer;
Has no peritoneal carcinomatosis (optional coelioscopy; recommended in case of doubt/ suspicious on CT/ imaging),
Has not received prior therapy (chemotherapy, radiotherapy, or immunotherapy) for localized gastric or OGJ adenocarcinoma,
Tumor status confirmed to be dMMR/MSI-H
Has hematological status: absolute neutrophil count (ANC) ≥1.5 x 109/L; platelets ≥100 x 109/L; hemoglobin ≥9 g/dL,
Has adequate renal function: serum creatinine level ≤150 μM and clearance ≥50 ml/min (Modification of the Diet in Renal Disease [MDRD] or Cockcroft and Gault),
Has adequate liver function: ≤1.5 x upper limit of normal (ULN) of direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 x ULN (inclusion possible if known Gilbert syndrome), alkaline phosphatase <5 x ULN, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5 x ULN,
Has international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) ≤1.5 x ULN, except for the patient on anticoagulant therapy who must have PT-INR-aPTT within therapeutic range is deemed appropriate by the Investigator,
Has radiological tumor assessment at screening performed within 6 weeks before inclusion according to RECIST version 1.1 by chest, abdomen, and pelvis CT, showing the absence of metastatic or non-surgical disease,
A female participant is eligible to participate if she is not pregnant or breastfeeding,
Male participants are eligible to participate if they agree to the following during the study treatment and for 4 months after the last dose of dostarlimab:
Provides primary tumor tissue samples (processed as formalin-fixed, paraffin-embedded [FFPE] blocks or freshly frozen) acquired during UGI endoscopy together with images (mandatory),
Is willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study,
s registered in a National Health Care System (PUMa - Protection Universelle Maladie included).

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Exclusion Criteria

Has received prior concomitant unplanned antitumor therapy (e.g., chemotherapy, molecular targeted therapy, immunotherapy),
Has received treatment with any investigational medicinal product within 28 days prior to study entry,
Has a treatment anticoagulant or hemostasis disorder contraindicating - biopsies during endoscopy,
Has had major surgical procedure within 28 days (4 weeks) prior to the first dose of study treatment,
Has other serious and uncontrolled non-malignant disease (including active infection) or is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, non-infectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study,
Has other concomitant or previous malignancy other than the disease under study, except as noted below: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer from which the patients was in complete remission for ≥3 years,
Has metastases (M stage disease) whatever the location,
Is pregnant or breastfeeding,
Has human immunodeficiency virus (HIV),
Has active hepatitis B virus (HBV, defined as having a positive hepatitis B surface antigen [HBsAg] test) or hepatitis C virus (HCV) prior to inclusion,
Patient under a legal protection regime (guardianship, curatorship, judicial safeguard) or administrative decision or incapable of giving his/her consent,
Impossibility of submitting to the medical follow-up of the study for geographical, social, or psychiatric illness.
Has pyloric tumor,
Has any history of autoimmune disease including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis,
Has a history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest imaging,
Has received any live, attenuated vaccine within 14 days prior to the firs dose of study treatment or such administration is anticipated during the study,
Has received prior therapy with any immune-checkpoint inhibitors, including antibodies or drugs targeting CD137, CTLA-4, PD-1, or PD-L1 or other checkpoint pathways,
Has had prior allogeneic bone marrow transplantation or prior solid organ transplantation,
Has received treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to the first dose of adjuvant treatment or is required to receive systemic immunosuppressive medications during the study. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.