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

This phase I/II trial tests how well botensilimab, balstilimab, and regorafenib works in treating patients with microsatellite stable colorectal cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and who have progressed on prior chemotherapy. Immunotherapy with monoclonal antibodies, such as botensilimab and balstilimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Regorafenib binds to and inhibits growth factor receptors, which may inhibit the growth of new blood vessels that tumors need to grow. Giving botensilimab, balstilimab, and regorafenib in combination may work better in treating patients with metastatic colorectal cancer than giving these drugs alone.

Inclusion Criteria:Documented informed consent of the participant and/or legally authorized representative.Assent, when appropriate, will be obtained per institutional guidelinesAge: >= 18 yearsEastern Cooperative Oncology Group (ECOG) =< 1Life expectancy >= 3 monthsAble to swallow and absorb oral tabletsHistological or cytological confirmed advanced, metastatic, or progressive proficient mismatch repair (pMMR)/MSS adenocarcinoma of colon or rectumMicrosatellite status should be performed per local standard of practice (e.g., immunohistochemistry [IHC] and/or polymerase chain reaction [PCR], or next-generation sequencing). Only participants with pMMR/MSS mCRC are eligiblePatients should have measurable metastatic disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelinesKnown extended RAS and BRAF status as per local standard of practice. TMB and PD-L1 status will be collected when available but not mandated for enrollmentPatients must have progressed following exposure to all of the following agents:Fluoropyrimidines (capecitabine or 5-FU)IrinotecanOxaliplatinAnti-EGFR therapy if RAS and BRAF wild type with left colon primaryPatients must have evidence of progression on or after the last treatment received and within 6 months prior to study enrollmentPatients who were intolerant to prior systemic chemotherapy regimens are eligible if there is documented evidence of clinically significant intolerance despite adequate supportive measuresAdjuvant/neoadjuvant chemotherapy can be considered as one line of chemotherapy for advanced/metastatic disease if the participant had disease recurrence within 6 months of completionFor patients with liver metastatic disease, patients must have no more than 5 hepatic metastases at the time of enrollmentPatients without liver metastatic disease should be either with no history of liver metastatic disease or with history of resected or ablated liver metastases without evidence of disease recurrence in the liver for at least 6 months before enrollmentTotal bilirubin =< 1.5 x upper limit of normal (ULN) (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)Aspartate aminotransferase (AST) =< 2.5 x ULN, unless presence of liver metastases for which =< 5 x ULN is allowed (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)Alanine aminotransferase (ALT) =< 2.5 x ULN, unless presence of liver metastases for which =< 5 x ULN is allowed (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)Serum creatinine =< 1.5 x ULN or creatinine clearance >= 40 mL/min (measured or calculated using the Cockcroft-Gault formula) (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)White blood cell (WBC) >= 2000/ul (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)Hemoglobin >= 9 g/dl (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)Absolute neutrophil count (ANC) >= 1500/ul (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)Platelets >= 75,000/mm^3 (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)Albumin >= 3.0 g/dl (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (to be performed within 7 days prior to day 1 of protocol therapy unless otherwise stated)Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from sexual activity for the course of the study through at least 120 days after the last dose of protocol therapyFemales of non-childbearing potential defined as:>= 50 years of age and has not had menses for greater than 1 yearAmenorrheic for >= 2 years without a hysterectomy and bilateral oophorectomy and a follicle stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluationStatus is post-hysterectomy, bilateral oophorectomy, or tubal ligationExclusion Criteria:Prior immunotherapy with PD-1 or PD-L1 or CTLA-4 targeting agentsPatients 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 diseasePrior allogeneic organ transplantationSurgical intervention within 4 weeks prior to study treatment, except for minor procedures such as port placementPrior allergic reaction or hypersensitivity to any of the study drug componentsActive 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 drugsUncontrolled hypertension, defined as systolic blood pressure (SBP) > 150, diastolic blood pressure (DBP) > 90History of acute thrombotic venous events in the last 30 days before enrollment. If within 30 days, the patient should be on anticoagulants and without symptomsClinically 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 medicationObstructive bowel symptoms related to unresected primary or carcinomatosisAny 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 alopeciaNon-healing woundsSymptomatic active bleedingActive 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 progressionConcurrent 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 eligibleAny evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoidsPsychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the studyHistory 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 investigatorKnown 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 requiredKnown 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 requiredKnown 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 requiredDependence on total parenteral nutrition or intravenous hydrationAny 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 proceduresProspective 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)