Anti-PD-1, Capecitabine, and Oxaliplatin for the first-line treatment of dMMR esophagogastric cancer(AuspiCiOus-dMMR): a proof-of-principle study

Phase 1

Recruiting

Conditions: Metastatic upper gastrointestinal cancer, cancer of esophagus and stomach
Therapeutic area: Diseases [C] - Neoplasms [C04]

Registration Number: CTIS2023-509380-24-00

Lead Sponsor: Amsterdam UMC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: All

Target Recruitment: 25

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

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.