Regorafenib, Ipilimumab and Nivolumab for the Treatment of Chemotherapy Resistant Microsatellite Stable Metastatic Colorectal Cancer

Exclusion Criteria

• •Participants with microsatellite instability high (MSI-H) colorectal cancer
• •Prior therapy with regorafenib, anti-PD-1, PD-L1, or CTLA-4 inhibitors
• •Systemic anti-cancer treatment within 14 days or less than 5 half-lives (whichever is shorter) of the first dose of study treatment
• •Has unresolved clinically significant toxicity of greater than or equal to National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) (NCI-CTCAE, v5.0) grade 2 attributed to any prior therapies (excluding anemia, lymphopenia, alopecia, skin pigmentation, and platinum-induced neurotoxicity)
• •Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication)
• •Congestive heart failure \>= New York Heart Association (NYHA) class 2
• •Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), myocardial infarction less than 6 months before start of study drug
• •Uncontrolled cardiac arrhythmias
• •Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 mmHg despite optimal medical management
• •Persistent proteinuria of NCI-CTCAE grade 3. Urine dipstick result of 3+ or abnormal, based on type of urine test strip used, is allowed if protein excretion (estimated by urine protein/creatinine ratio on a random urine sample) is \< 3.5 g/24 hr
• •Major surgical procedure or significant traumatic injury within 28 days before start of study medication. Note: If participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• •Non-healing wound, non-healing ulcer, or non-healing bone fracture
• •Participants with evidence or history of any bleeding diathesis, irrespective of severity
• •Any hemorrhage or bleeding event \>= NCI-CTCAE grade 3 within 28 days prior to the start of study medication
• •Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or \>= NCI-CTCAE grade 2 diarrhea of any etiology
• •Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus (T1DM), hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• •Participants with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start 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
• •History of (non-infectious) pneumonitis that required steroids or current pneumonitis
• •History of interstitial lung disease
• •Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission prior to study entry and no additional therapy is required or anticipated to be required during the study period
• •Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy
• •Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed treatment (such as radiotherapy or surgery). Participants with stable CNS disease or previously treated lesions are eligible for study entry. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of 10 mg daily prednisone (or equivalent)
• •Ongoing infection \> grade 2 NCI-CTCAE requiring systemic therapy
• •Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies)
• •Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating presence of virus, e.g. hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleic acid \[RNA\] negative)
• •Pregnancy or breast feeding
• •Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up (FU) schedule
• •Previous treatment with live vaccine within 30 days of planned start of study drugs (seasonal flu vaccines that do not contain a live virus are permitted)
• •Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation