Botensilimab and Balstilimab with Combination Chemotherapy for the Treatment of Patients with Metastatic Microsatellite Stable Colorectal Cancer

Inclusion Criteria

• Participants of any gender who are at least 18 years of age on the day of signing informed consent
• Histologically confirmed metastatic and/or unresectable colorectal cancer without liver metastasis or known or suspected bone or brain metastases * Up to 3 patients with peritoneal carcinomatosis will be included. Other than those three, subjects must only have lung, lymph node, and locoregional sites of disease (primary tumor or serosal implant without carcinomatosis)
• Microsatellite stable disease, as documented in the participant’s medical record at the time of consent by the absence of MSI-H or dMMR result in a Food and Drug Administration (FDA)-approved assay or an in vitro diagnostic (IVD) offered as a laboratory-developed test (LDT) that includes microsatellite stability biomarker
• Subject must be willing to provide fresh biopsy of tumor lesion *Note: Those who do not have a tumor lesion that is safe and amenable to biopsy may still be enrolled
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• No prior systemic therapy for colon cancer * Subjects who received systemic therapy in the neoadjuvant or adjuvant setting completed at least 6 months prior to enrollment may be eligible with approval from the lead principal investigator (PI)
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• People of child-bearing potential must not be pregnant or breast feeding and meet at least one of the following conditions: * Not a person of childbearing potential (POCBP) * A POCBP must agree to use a reliable method of contraception during the treatment period and for at least 180 days after the last dose of study treatment
• All participants must practice effective contraceptive methods during the treatment period, unless documentation of infertility exists
• Expected to survive > 3 months per investigator assessment
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
• Absolute neutrophil count (ANC) >= 1500/uL (must have been collected within 7 days prior to the start of study treatment)
• Platelets >= 100,000/uL (must have been collected within 7 days prior to the start of study treatment)
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (must have been collected within 7 days prior to the start of study treatment) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within the last 2 weeks
• Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can be used in place of creatinine clearance [CrCl]) >= 45 mL/min (must have been collected within 7 days prior to the start of study treatment) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (must have been collected within 7 days prior to the start of study treatment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (must have been collected within 7 days prior to the start of study treatment)
• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (must have been collected within 7 days prior to the start of study treatment)
• Activated partial thromboplastin time (aPTT) =<1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (must have been collected within 7 days prior to the start of study treatment)

Exclusion Criteria

• Prior therapy with an immune checkpoint inhibitor
• A POCBP who is pregnant or breastfeeding or has a positive pregnancy test within 72 hours prior to receiving study treatment
• Not willing to use an effective method of birth control
• Known liver, bone, or central nervous system (CNS) metastases and/or carcinomatous meningitis
• Diagnosis of other carcinomas within the last 2 years, except cured non-melanoma skin cancer, treated thyroid cancer, curatively treated in-situ cervical cancer, or localized prostate cancer treated curatively with no evidence of biochemical or imaging recurrence
• Documented history of clinically significant autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo, type 1 diabetes mellitus, psoriasis not requiring systemic treatment, well-controlled hypothyroidism, or conditions not expected to recur in the absence of and external trigger are permitted to enroll
• Any history of chronic or autoimmune pancreatitis
• Known history of or any evidence of active, non-infectious pneumonitis
• Current use of medications specified by the protocol as prohibited for administration in combination with study drug * Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to the start of study drug are not eligible * Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease * Corticosteroids administered as pre-medication for IV contrast allergy are also allowed
• Received a live vaccine within 30 days prior to the start of study drug * Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu-Mist) are live-attenuated vaccines, and are not allowed within 28 days of study treatment * Coronavirus disease (COVID)-19 vaccines will be allowed. However, COVID vaccines are not allowed within 7 days of starting study drug treatment
• Recent or current active infectious disease requiring systemic antivirals, antibiotics or antifungals, or treatment within 2 weeks prior to the start of study drug
• Concurrent severe and/or uncontrolled medical conditions, which may compromise participation in the study, including impaired heart function or clinically significant heart disease
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the start of study drug (56 days for hepatectomy, open thoracotomy, major neurosurgery) or anticipation of need for major surgical procedure during the course of the study
• Serious, non-healing wound, ulcer, or bone fracture
• Patients with a history of organ or allogenic hematopoietic stem cell transplantation
• Partial or complete bowel obstruction within the last 3 months, signs/ symptoms of bowel obstruction, or known radiologic evidence of impeding obstruction
• Refractory ascites defined as requiring 2 or more therapeutic paracenteses within the last 4 weeks or >= 4 times within the last 90 days or >= 1 time within the last 2 weeks prior to study entry or requiring diuretics within 2 weeks of study entry
• Positive tuberculosis (TB) test at screening
• Tumor location or size that may result in life-threatening complications. For example, lesions that may put patient at risk for intestinal perforation or obstruction
• Known or suspected allergy or hypersensitivity to any investigational or standard of care therapy agents, or any of the inactive ingredients in any of the components of the study drug regimen
• Peripheral neuropathy from prior neoadjuvant or adjuvant oxaliplatin must have resolved to grade (G)2 or lower