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Only for patients with MSS metastatic colorectal adenocarcinoma with liver metastases who are planning to undergo a surgical resection of their liver metastases.
No prior immunotherapy allowed.

Participants will be randomly assigned to one of these arms

• Botensilimab and balstilimab
• Botensilimab, balstilimab, and AGEN1423
• Botensilimab, balstilimab, and radiation

Botensilimab is a next-generation, Fc-enhanced, CTLA-4 inhibitor, and balstilimab is a PD-1 inhibitor. AGEN1423 is an anti-CD73-TGFβ-trap bifunctional antibody. Agents will be administered before and after surgery.

The combination of Botensilimab and balstilimab has results from expanded phase 1a/1b study, NCT03860272: “The administration of these two immunotherapies resulted in objective response rate (ORR) at 23%, disease control rate at 76%, progression-free survival (PFS) 4.1 months, and the median overall survival has not been reached. (“Response” is a tumor reduction of greater than 30%, with stable disease at +/- 30%). The estimated 12-month overall survival at 63% is better than the current standard of care.

Patients had received a median of four prior lines of therapy, and 59% had RAS mutations. Prior immunotherapy was allowed in this trial.

Most patients (91%) reported immune-related adverse events (irAEs). The most common were diarrhea/colitis (43%) and fatigue (34%). The most common grade 3 irAEs were diarrhea/colitis (20%), fatigue (4%), and pyrexia (raised body temperature) (4%)” See Helpful Links.

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Inclusion Criteria

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

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