M7824 in Patients With Metastatic Colorectal Cancer or With Advanced Solid Tumors With Microsatellite Instability

Inclusion Criteria

• Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum that is metastatic or unresectable (cohorts A,B); histologically or cytologically confirmed carcinoma not originating in the colon or rectum (cohort C); or histologically or cytologically confirmed adenocarcinoma of the colon or the rectum following resection of the primary tumor and metastatic disease, following completion of standard-of-care perioperative therapy at the discretion of the treating provider (cohort D).
• Confirmation of: a) Cohort A: microsatellite instability in colorectal cancer (CRC); b) Cohort B: CMS4 CRC classification on pretreatment primary tumor; c) Cohort C: microsatellite instability in non-CRC solid tumor; d. Cohort D: microsatellite stability.
• Ability to provide written informed consent.
• Documented progression to prior therapies (Cohorts A, B, and C): a) Cohort A: Disease progression following prior immune checkpoint blockade therapy; b) Cohort B: Progression or intolerance to at least 2 prior lines of standard therapy for unresectable or metastatic CRC; c) Cohort C: Disease progression following prior immune checkpoint blockade therapy.
• Available primary tumor tissue for CMS4 biomarker assessment.
• Life expectancy >= 12 weeks as judged by the treating physician.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1(Cohorts A, B, and C). For cohort B, measureable lesions must be identified apart from the irradiated tumor lesion. Patients in cohort D must have no evidence of radiographically evident disease at the time of study entry.
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (in absence of blood transfusion).
• Lymphocyte count >= 0.5 x 10^9/L (in absence of blood transfusion).
• Platelet count >= 100 x 10^9/L (in absence of blood transfusion).
• Hemoglobin (Hgb) >= 9 g/dL (in absence of blood transfusion).
• Total bilirubin level = 30 mL/min according to the Cockcroft-Gault formula or be measure for creatinine clearance from 24-hour urine collection.
• Highly effective contraception for both male and female subjects if the risk of conception exists. Highly effective contraception must be used 30 days prior to first trial administration, for the duration of trial treatment, and at least for 4 months after stopping trial treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately.
• Ability to tolerate receipt of radiotherapy to a metastasis not adjacent to a normal dose-limiting structure, at the discretion of the treating radiation oncologist (cohort B).
• Presence of detectable ctDNA following completion of R0 resection with or without perioperative therapy, with confirmation of somatic mutations in the resected tumor (cohort D only).
• Completion of all standard-of-care adjuvant therapy (cohort D).

Exclusion Criteria

• Concurrent treatment with non-permitted drugs and other interventions.
• Anticancer treatment within 14 days before the start of trial treatment (e.g., cytoreductive therapy, radiotherapy [with the exception of palliative radiotherapy delivered in a normal organ-sparing technique], immune therapy, or cytokine therapy).
• Major surgery as determined by the investigator within 28 days before the start of trial treatment (prior diagnostic biopsy is permitted).
• Systemic therapy with immunosuppressive agents within 7 days before the start of treatment; or use of any investigational drug within 28 days before the start of trial treatment.
• Cohort A and C only: Intolerance or serious adverse immune related adverse events (irAEs) that were symptomatic or required or continues to require ongoing immunosuppression to previous immune checkpoint therapy.
• Cohort B and D: prior exposure to any immune checkpoint blockade agent o