Botensilimab, Balstilimab and Regorafenib or Botensilimab and Balstilimab for the Treatment of Advanced or Metastatic Microsatellite Stable Colorectal Cancer

COPRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of botensilimab, balstilimab and regorafenib (BBR) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients without metastatic liver lesions in the safety run-in. (Safety lead-in) II. Compare the overall response rate in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients without metastatic liver lesions receiving botensilimab, balstilimab and regorafenib (BBR) versus botensilimab and balstilimab (BB), by treatment arm. (Phase II) SECONDARY OBJECTIVES: I. Estimate the overall survival in MSS mCRC patients without metastatic liver lesions receiving BBR and BB, by treatment arm. II. Estimate the progression free survival in MSS mCRC patients without metastatic liver lesions receiving BBR and BB, by treatment arm. III. Estimate the duration of response (DOR) in MSS mCRC patients without metastatic liver lesions receiving BBR and BB that experience a response to therapy, by treatment arm. IV. Describe the safety of giving to BBR and BB to patients with MSS mCRC without metastatic liver lesions, by treatment arm. EXPLORATORY OBJECTIVE: I. Through the performance of baseline and on treatment biopsies and serial blood work (cytokines and flow cytometry), explore potential biomarkers of response to BBR and BB therapy given to MSS mCRC patients without metastatic liver lesions, by treatment arm. OUTLINE: Patients are randomized to 1 of 2 arms. ARM BBR: Patients receive botensilimab intravenously (IV) over 60 minutes on day 1 of each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and regorafenib orally (PO) once daily (QD) on days 1-7, 15-21, and 29-35 of each cycle or on days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study. ARM BB: Patients receive botensilimab IV over 60 minutes on day 1 of each cycle and balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study. After completion of study treatment, patients are followed up at 30 and 90 days and then every 2-3 months for 5 years.