Platform Study of Immunotherapy Combinations in Colorectal Cancer Liver Metastases

This is a single-center, 3-arm, randomized, open-label, phase II, screening study to assess the initial immunological changes in the tumor microenvironment in response to treatment with combination immunotherapy (Botensilimab/ Balstilimab), with or without radiation and/or additional TGFβ-CD73 trap, in patients with colorectal cancer liver metastases.

Participants who meet eligibility criteria will be randomized to receive one of 3 investigational treatment: botensilimab + balstilimab (Arm 1); botensilimab + balstilimab + AGEN1423 (Arm 2); or botensilimab + balstilimab + radiation (Arm 3). The study arms are not directly or formally compared with each other. It is established that the tumor infiltrating lymphocytes have been predictive of patient survival following resection of colorectal cancer liver metastases. Immunotherapy combinations with an increase in the ratio of CD8+ T cells: Tregs will be considered for further investigation.

All participants will have a total of four treatment visits to receive immunotherapy infusions. Two visits will occur prior to surgery, each approximately 3 weeks apart. Surgery will be scheduled between day 28-42. After surgery, you will return for two more treatment visits. After the last dose of immunotherapy, participants will come to the clinic approximately 3 weeks and 3 months later for follow-up visits. Participants will be followed remotely for up to two years.

Inclusion criteria

• Diagnosis of metastatic colorectal adenocarcinoma with liver metastases
• Participant must be planning to undergo a surgical resection of their liver metastases.
• Tumor is non-MSI-H/dMMR
• Presence of measurable disease
• Participants must be willing to consent to additional molecular analyses of tumor samples removed during surgery for research purposes
• Women of childbearing potential (WOCBP), or anyone with a uterus, must not be pregnant or breastfeeding. All participants of childbearing potential must agree to use highly effective contraception during this study
• Participants may not receive chemotherapy, growth factor support, transfusions, or albumin administration within 14 days of start of study treatment.

Exclusion criteria

• Not eligible for surgery
• Any medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
• Previous allogeneic tissue/organ transplant
• Previously received PD-1, PD-L1, or CTLA-4 therapy including experimental immunologic agents
• Participants must not have any contraindications to immune checkpoint inhibitors
• Participants must not have active autoimmune disease that has required systemic treatment within 2 years prior to registration. Some exceptions are allowed