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

Lab values

•  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.

•  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