Evaluation of Retifanlimab, Capecitabine, and Oxaliplatin in First-Line Treatment of dMMR Metastatic Esophagogastric Cancer: A Proof-of-Principle Study

Trial ID: 2023-509380-24-00
Sponsor: Amsterdam UMC Stichting

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Diseases & Conditions

Gastrooesophageal cancer Gastrointestinal cancer metastatic

Objectives

The primary objective of this study is to evaluate changes in **Interferon gamma (IFN-γ)** expression signature and the infiltration of cytotoxic T cells within the tumor immune microenvironment in patients with deficient mismatch repair (dMMR) esophagogastric cancer. These assessments will be conducted at baseline, following two courses of Capecitabine and Oxaliplatin (CapOx), and after 8 weeks of maintenance therapy with the **PD-1** inhibitor, Retifanlimab. This objective is clinically relevant as it aims to understand the immunological changes associated with the treatment regimen, which could inform future therapeutic strategies for dMMR esophagogastric cancer.

Participants

The clinical trial involves participants diagnosed with **metastatic upper gastrointestinal cancer**, specifically cancer of the esophagus and stomach. The study population includes both male and female adult patients over the age of 18, with no specific upper age limit provided. Participants are required to have a histologically confirmed diagnosis of metastatic or irresectable HER2 negative adenocarcinoma of the stomach or esophagus. The trial does not include a vulnerable population. Participants must have measurable or evaluable disease as assessed by RECIST 1.1 and an ECOG performance status of 0-2, indicating a range from fully active to capable of all self-care but unable to carry out any work activities. Adequate hepatic, renal, and hematological function is also required. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants have not been pre-treated with chemotherapy or radiotherapy for irresectable or metastatic disease, although palliative radiotherapy is permissible under certain conditions. The trial aims to assess changes in the tumor immune microenvironment, focusing on Interferon gamma expression and cytotoxic T cell infiltration.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **retifanlimab**, a **solution for infusion**, in combination with capecitabine and oxaliplatin for the first-line treatment of patients with metastatic upper gastrointestinal cancer, specifically cancer of the esophagus and stomach. This is a Phase II, randomized, double-blind, controlled trial. The primary objective is to assess changes in Interferon gamma (IFN-γ) expression signature and the infiltration of cytotoxic T cells in the tumor immune microenvironment at baseline, after two courses of CapOx, and after 8 weeks of PD-1 inhibition maintenance using retifanlimab in patients with deficient mismatch repair (dMMR).

The trial is expected to last until November 2026, with recruitment having started in November 2021. Participants will be involved in the study for a maximum treatment period of 24 months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have a histologically confirmed diagnosis of metastatic or irresectable HER2-negative adenocarcinoma of the stomach or esophagus, with measurable disease as assessed by RECIST 1.1, and adequate hepatic, renal, and hematological function. Participants must also provide written informed consent according to ICH/GCP and national/local regulations.

Participants may be withdrawn from the study early if they experience unacceptable adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The primary endpoint is the expression of IFN-γ and the number of infiltrating cytotoxic T-cells. Secondary endpoints include overall survival, progression-free survival, response rate according to RECIST 1.1 or iRECIST, adverse events according to NCI CTCAE version 5.0, quality of life, and the percentage of patients proceeding to subsequent lines of treatment after progression. The trial is not classified as low intervention and is conducted under the sponsorship of Incyte Corporation.

Treatment

The clinical trial involves the administration of **Retifanlimab (INCMGA00012)**, a **solution for infusion** developed by Incyte Corporation. Retifanlimab is an experimental medication classified as a **protein** of other origin. The pharmaceutical form of Retifanlimab is a solution intended for **intravenous administration**. The dosage regimen specifies a maximum daily dose of 500 mg, with the same amount being the maximum total dose per administration. The treatment period for Retifanlimab is set to a maximum of 24 weeks. This medication is not formulated for pediatric use and is not classified as an orphan drug.

In addition to Retifanlimab, the study includes the administration of **Capecitabine** and **Oxaliplatin** as part of the standard-of-care therapy for the first-line treatment of **dMMR esophagogastric cancer**. Capecitabine is an oral chemotherapeutic agent, while Oxaliplatin is administered intravenously. These agents are used in combination to form the CapOx regimen, which is a standard treatment protocol for this type of cancer. The study aims to assess changes in the tumor immune microenvironment, specifically focusing on the expression of Interferon gamma (IFN-γ) and the infiltration of cytotoxic T cells, at baseline, after two courses of CapOx, and after 8 weeks of PD-1 inhibition maintenance using Retifanlimab.

Efficacy

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints include changes in **Interferon gamma (IFN-γ)** expression and the number of infiltrating cytotoxic T-cells within the tumor immune microenvironment. These parameters will be evaluated at baseline, after two courses of Capecitabine and Oxaliplatin (CapOx), and following 8 weeks of PD-1 inhibition maintenance using retifanlimab in patients with deficient mismatch repair (dMMR) esophagogastric cancer.

Secondary endpoints encompass a range of clinical outcomes, including overall survival, progression-free survival, and response rate as determined by RECIST 1.1 or iRECIST criteria. Additionally, adverse events will be monitored according to the NCI CTCAE version 5.0. Quality of life assessments will be conducted, and the percentage of patients proceeding to subsequent lines of treatment after progression will be recorded, along with the types of subsequent treatments and reasons for forgoing further treatment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

 Patients must provide written informed consent according to ICH/GCP, and national/local regulations prior to any screening procedures.  dMMR identified by IHC of mismatch repair proteins MLH1, PMS2, MSH2 en MSH6  Primary tumor or metastasis accessible for repeat fresh histological biopsies  Male or female adult patients (> 18 years).  Patients with histologically confirmed diagnosis of metastatic or irresectable HER2 negative adenocarcinoma of the stomach or oesophagus, patients with HER2 positive disease are eligible when treatment with trastuzumab is contraindicated.  Patients with metastatic or irresectable adenocarcinoma of the stomach or oesophageal junction (Siewert II or III) not pre-treated with chemotherapy or radiotherapy for irresectable or metastatic disease. Palliative radiotherapy on the primary tumor or a metastatic lesion is allowed if other untreated lesions for RECIST evaluation are present. Chemoradiation with carboplatin area under the curve (AUC) 2 and paclitaxel 50 mg/m2 for irresectable disease is allowed if subsequent disease progression is proven on radiological imaging.  Measurable/evaluable disease as assessed by RECIST 1.1  ECOG (WHO) performance status 0-2  Adequate hepatic, renal and hematological function

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Exclusion Criteria

 Severe renal impairment (CLcr ≤ 30 ml/min)  Any clinically significant disorder impacting the risk-benefit balance negatively per physician’s judgment.  Presence of additional malignancy that is progressing or has required active treatment in the last 5 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are not excluded.  Active autoimmune disease that has required systemic treatment in past 2 years, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention.  Any clinically significant gastrointestinal disorder, including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 2.  Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) in last 6 months.  NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure. Or known abnormal ECG with clinically significant abnormal findings.  Active infection or an unexplained fever >38.5°C (excluding tumor fever), which in the physician’s opinion might compromise the patient’s health.  Current use or any use in last two weeks of strong CYP3A-enzyme, CYP2C8, and/or strong UGT1A inhibitors/inducers.  Known hypersensitivity or contraindications to any of the components of capecitabine or oxaliplatin.  History of severe and unexpected reactions to fluoropyrimidine therapy.  Known complete dihydropyrimidine dehydrogenase (DPD) deficiency.  Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness to use a reliable method of birth control, during therapy and for 3 months following the last dose of cytotoxic agents.  Treatment within 4 weeks with DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine.  Pre-existing motor or sensory neurotoxicity greater than WHO grade 1.  History of organ transplant, including allogeneic stem cell transplantation.  Receiving probiotics as of the first dose of study treatment.