Botensilimab, Balstilimab and Regorafenib for the Treatment of Patients With Microsatellite Stable Metastatic Colorectal Cancer Who Have Progressed on Prior Chemotherapy

Prior immunotherapy with PD-1 or PD-L1 or CTLA-4 targeting agents

Patients with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses =\< 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease

Prior allogeneic organ transplantation

Surgical intervention within 4 weeks prior to study treatment, except for minor procedures such as port placement

Prior allergic reaction or hypersensitivity to any of the study drug components

Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years before starting treatment, i.e., with use of disease-modifying agents or immunosuppressive drugs

Uncontrolled hypertension, defined as systolic blood pressure (SBP) \> 150, diastolic blood pressure (DBP) \> 90

History of acute thrombotic venous events in the last 30 days before enrollment. If within 30 days, the patient should be on anticoagulants and without symptoms

Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 12 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class \>= III), or serious uncontrolled cardiac arrhythmia requiring medication

Obstructive bowel symptoms related to unresected primary or carcinomatosis

Any persistent toxicities (Common Terminology Criteria for Adverse Events \[CTCAE\] grade \>= 2) from prior cancer therapy, excluding endocrinopathies stable on medication, stable neuropathy that is grade 1 or less, and alopecia

Non-healing wounds

Symptomatic active bleeding

Active brain metastases or leptomeningeal metastases with the following exceptions:

* Treated brain metastases require a) surgical resection, or b) stereotactic radiosurgery. These patients must be off steroids \>= 10 days prior to randomization for the purpose of managing their brain metastases. Repeat brain imaging following surgical resection or stereotactic radiosurgery at least 4 weeks from treatment should document lack of progression

Concurrent non-colorectal second malignancy (present during screening) requiring treatment or history of a non-colorectal second primary metastatic malignancy within 2 years prior to the first dose of study treatment. Patients with history of prior early-stage basal/squamous cell skin cancer, low-risk prostate cancer eligible for active surveillance or noninvasive or in situ cancers who have undergone definitive treatment at any time are also eligible

Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids

Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study

History or current evidence of any condition, co-morbidity, therapy, any active infections, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator

Known previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to cycle 1 day 1 (C1D1)

Uncontrolled infection with human immunodeficiency virus (HIV). Patients on stable highly active antiretroviral therapy (HAART) with undetectable viral load and normal CD4 counts for at least 6 months prior to study entry are eligible. Serological testing for HIV at screening is not required

Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection. Patients who are receiving or who have received anti-HBV therapy and have undetectable HBV deoxyribonucleic acid (DNA) for at least 6 months prior to study entry are eligible. Serological testing for HBV at screening is not required

Known active hepatitis C virus (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Patients on or who have received antiretroviral therapy are eligible provided they are virus-free by PCR for at least 6 months prior to study entry. Serological testing for HCV at screening is not required

Dependence on total parenteral nutrition or intravenous hydration

Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures

Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

What this study is about