Botensilimab and Balstilimab Optimization in Colorectal Cancer

3.1 Study Description

This is a single-arm, interventional, pilot clinical trial. Subjects with newly diagnosed, metastatic or unresectable, microsatellite stable colorectal cancer without liver, bone, or brain metastases will start study treatment with botensilimab and balstilimab alone. They will have restaging scans every 6 weeks. When the subject experiences progression on the study drug(s), they may choose to add mFOLFOX6 and either bevacizumab or panitumumab to the combination. The determinant of whether the subject crosses over will be radiographic progression (iCPD) per iRECIST. Subjects will continue on the new combination until radiographic or clinical progression, intolerable toxicity, or patient withdrawal.

No more than 20 subjects will be enrolled to ensure the trial obtains 15 evaluable subjects. All patients will be enrolled at the Duke Cancer Institute.

* Enrolled subjects are defined as subjects who give informed consent. * Screen failures are defined as subjects who give informed consent and do not meet eligibility criteria. * Accrued subjects are defined as subjects who give informed consent and meet eligibility criteria.

* Withdrawal: Subject accrued but later withdrawn from the study, either before or after receiving a study drug. * Evaluable: All subjects who are accrued and receive any infusion from Cycle 1 study treatment with botensilimab and balstilimab will be evaluable for safety. Subjects who are accrued, receive C1 study treatment, and complete the first cycle of safety assessments will be considered evaluable for the primary endpoints of disease control rate and safety. * Non-evaluable: Subjects who accrued but did not complete the first cycle of safety assessments due to reasons other than study treatment-attributed toxicity (e.g., disease progression or inter-current illness) are considered non-evaluable for safety and efficacy.

Study Treatment Botensilimab 75 mg IV Every 6 weeks for up to 4 doses Balstilimab 240 mg IV Every 2 weeks Oxaliplatin 85 mg/m2 IV Every 2 weeks Leucovorin 400 mg/m2 IV Every 2 weeks Fluorouracil 400 mg/m2 IV bolus Every 2 weeks Fluorouracil 2400 mg/m2 IV Every 2 weeks (over 46 hours) Bevacizumab 5 mg/kg IV Every 2 weeks Panitumumab 6 mg/kg IV Every 2 weeks

3.2 Crossover Criteria

Patients are treated with first line botensilimab and balstilimab with plans to add chemotherapy if they experience iCPD per iRECIST. Once the subject has iRECIST confirmed progression, they can add SOC therapy as described in section 3.1. Subject must meet the following criteria to qualify for treatment beyond progression on ICB therapy: