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

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative.

• Assent, when appropriate, will be obtained per institutional guidelines

• Age: >= 18 years

• Eastern Cooperative Oncology Group (ECOG) =< 1

• Life expectancy >= 3 months

• Able to swallow and absorb oral tablets

• Histological or cytological confirmed advanced, metastatic, or progressiveproficient mismatch repair (pMMR)/MSS adenocarcinoma of colon or rectum

• Microsatellite status should be performed per local standard of practice (e.g.,immunohistochemistry [IHC] and/or polymerase chain reaction [PCR], ornext-generation sequencing). Only participants with pMMR/MSS mCRC are eligible

• Patients should have measurable metastatic disease as per Response EvaluationCriteria in Solid Tumors (RECIST) 1.1 guidelines

• Known extended RAS and BRAF status as per local standard of practice. TMB and PD-L1status will be collected when available but not mandated for enrollment

• Patients must have progressed following exposure to all of the following agents:

• Fluoropyrimidines (capecitabine or 5-FU)

• Irinotecan

• Oxaliplatin

• Anti-EGFR therapy if RAS and BRAF wild type with left colon primary

• Patients must have evidence of progression on or after the last treatment receivedand within 6 months prior to study enrollment

• Patients who were intolerant to prior systemic chemotherapy regimens areeligible if there is documented evidence of clinically significant intolerancedespite adequate supportive measures

• Adjuvant/neoadjuvant chemotherapy can be considered as one line of chemotherapyfor advanced/metastatic disease if the participant had disease recurrencewithin 6 months of completion

• For patients with liver metastatic disease, patients must have no more than 5hepatic metastases at the time of enrollment

• Patients without liver metastatic disease should be either with no history of livermetastatic disease or with history of resected or ablated liver metastases withoutevidence of disease recurrence in the liver for at least 6 months before enrollment

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (to be performed within 7 daysprior to day 1 of protocol therapy unless otherwise stated)

• Aspartate aminotransferase (AST) =< 2.5 x ULN, unless presence of liver metastasesfor which =< 5 x ULN is allowed (to be performed within 7 days prior to day 1 ofprotocol therapy unless otherwise stated)

• Alanine aminotransferase (ALT) =< 2.5 x ULN, unless presence of liver metastases forwhich =< 5 x ULN is allowed (to be performed within 7 days prior to day 1 ofprotocol therapy unless otherwise stated)

• Serum creatinine =< 1.5 x ULN or creatinine clearance >= 40 mL/min (measured orcalculated using the Cockcroft-Gault formula) (to be performed within 7 days priorto day 1 of protocol therapy unless otherwise stated)

• White blood cell (WBC) >= 2000/ul (to be performed within 7 days prior to day 1 ofprotocol therapy unless otherwise stated)

• Hemoglobin >= 9 g/dl (to be performed within 7 days prior to day 1 of protocoltherapy unless otherwise stated)

• Absolute neutrophil count (ANC) >= 1500/ul (to be performed within 7 days prior today 1 of protocol therapy unless otherwise stated)

• Platelets >= 75,000/mm^3 (to be performed within 7 days prior to day 1 of protocoltherapy unless otherwise stated)

• Albumin >= 3.0 g/dl (to be performed within 7 days prior to day 1 of protocoltherapy unless otherwise stated)

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required (to be performed within 7 days prior to day 1 of protocoltherapy unless otherwise stated)

• Agreement by females and males of childbearing potential to use an effective methodof birth control or abstain from sexual activity for the course of the study throughat least 120 days after the last dose of protocol therapy

• Females of non-childbearing potential defined as:

• >= 50 years of age and has not had menses for greater than 1 year

• Amenorrheic for >= 2 years without a hysterectomy and bilateraloophorectomy and a follicle stimulating hormone value in thepostmenopausal range upon pre-study (screening) evaluation

• Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation

Exclusion Criteria:

• 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 immunosuppressivemedication within 30 days of the first dose of study treatment. Inhaled or topicalsteroids, and adrenal replacement steroid doses =< 10 mg daily prednisoneequivalent, are permitted in the absence of active autoimmune disease

• Prior allogeneic organ transplantation

• Surgical intervention within 4 weeks prior to study treatment, except for minorprocedures 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 systemictreatment within 2 years before starting treatment, i.e., with use ofdisease-modifying agents or immunosuppressive drugs

• Uncontrolled hypertension, defined as systolic blood pressure (SBP) > 150, diastolicblood pressure (DBP) > 90

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

• Clinically significant (i.e., active) cardiovascular disease: cerebral vascularaccident/stroke or myocardial infarction within 12 months of enrollment, unstableangina, congestive heart failure (New York Heart Association class >= III), orserious 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 onmedication, 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) stereotacticradiosurgery. These patients must be off steroids >= 10 days prior torandomization for the purpose of managing their brain metastases. Repeat brainimaging following surgical resection or stereotactic radiosurgery at least 4weeks from treatment should document lack of progression

• Concurrent non-colorectal second malignancy (present during screening) requiringtreatment 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 priorearly-stage basal/squamous cell skin cancer, low-risk prostate cancer eligible foractive surveillance or noninvasive or in situ cancers who have undergone definitivetreatment at any time are also eligible

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

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

• History or current evidence of any condition, co-morbidity, therapy, any activeinfections, 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 isnot in the best interest of the patient to participate, in the opinion of thetreating investigator

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

• Uncontrolled infection with human immunodeficiency virus (HIV). Patients on stablehighly active antiretroviral therapy (HAART) with undetectable viral load and normalCD4 counts for at least 6 months prior to study entry are eligible. Serologicaltesting for HIV at screening is not required

• Known to be positive for hepatitis B virus (HBV) surface antigen, or any otherpositive test for HBV indicating acute or chronic infection. Patients who arereceiving or who have received anti-HBV therapy and have undetectable HBVdeoxyribonucleic 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 andconfirmed by polymerase chain reaction (PCR). Patients on or who have receivedantiretroviral 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 notrequired

• Dependence on total parenteral nutrition or intravenous hydration

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

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