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

Inclusion Criteria:

• A signed informed consent must be obtained prior to conducting any study-specificprocedures

• Histological or cytological confirmed advanced, metastatic, or progressive mismatchrepair protein proficient (pMMR)/microsatellite stable (MSS) adenocarcinoma of colonor 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 metastaticcolorectal cancer (mCRC) are eligible

• Known extended RAS and BRAF status as per local standard of practice

• Participant must have progressed following exposure of all the following agents orbelow:

• Prior exposure to the following:

• Fluoropyrimidines (capecitabine or fluorouracil [5-FU])

• Irinotecan

• Oxaliplatin

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

• Patient must have evidence of progression on or after the last treatmentregimen received and 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

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

• Total bilirubin =< 1.5 x the upper limit of normal (ULN) (performed within 7 daysbefore treatment initiation)

• Alanine transaminase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN if noliver metastases; ALT or AST =< 5 x ULN allowed for patients with liver involvement (performed within 7 days before treatment initiation)

• Platelet count >= 100,000 /mm^3 (performed within 7 days before treatmentinitiation)

• Hemoglobin (Hb) >= 9 g/dL (performed within 7 days before treatment initiation)

• White blood cells (WBC) >= 2000/uL (performed within 7 days before treatmentinitiation)

• Absolute neutrophil count (ANC) >= 1500/mm^3 (performed within 7 days beforetreatment initiation)

• Serum creatinine =< 1.5 x ULN or creatinine clearance >= 40 mL/min (measured orcalculated using the Cockcroft-Gault formula) (performed within 7 days beforetreatment initiation)

• Measurable disease as determined by RECISTv1.1

• Provision of recent tumor tissue (as defined below) is mandatory for allparticipants at screening (Formalin-fixed paraffin-embedded block or minimum of 20slides)

• Tumor tissue obtained within 180 days of enrollment and after the last dose ofmost recent anti-cancer therapy

• Or a new biopsy Exceptions for patients with no recent baseline tumor tissuesor biopsies may be considered after documented discussion and approval with theprincipal investigator (PI) of the study

• Anticipated life expectancy greater than 3 months

• Be able to swallow and absorb oral tablets

• Women of childbearing potential (WOCBP) must agree to follow instructions formethod(s) of contraception for the duration of study intervention and 120 days afterlast dose of regorafenib and 5 months after the last dose of nivolumab. Males whoare sexually active with WOCBP must agree to follow instructions for method(s) ofcontraception for the duration of study intervention and 120 days after last dose ofregorafenib and 7 months after the last dose of nivolumab. In addition, maleparticipants must be willing to refrain from sperm donation during this time.Contraceptive use by men or women should be consistent with local regulationsregarding the methods of contraception for those participating in clinical studies

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 (whicheveris shorter) of the first dose of study treatment

• Has unresolved clinically significant toxicity of greater than or equal to NationalCancer 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 embolismwithin 3 months before the start of study medication (except for adequately treatedcatheter-related venous thrombosis occurring more than one month before the start ofstudy medication)

• Congestive heart failure >= New York Heart Association (NYHA) class 2

• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3months), 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+ orabnormal, 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/24hr

• Major surgical procedure or significant traumatic injury within 28 days before startof study medication. Note: If participants received major surgery, they must haverecovered adequately from the toxicity and/or complications from the interventionprior to starting therapy

• Non-healing wound, non-healing ulcer, or non-healing bone fracture

• Participants with evidence or history of any bleeding diathesis, irrespective ofseverity

• Any hemorrhage or bleeding event >= NCI-CTCAE grade 3 within 28 days prior to thestart 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. Participantswith type I diabetes mellitus (T1DM), hypothyroidism only requiring hormonereplacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiringsystemic treatment, or conditions not expected to recur in the absence of anexternal trigger are permitted to enroll

• Participants with a condition requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressivemedications within 14 days of start of study treatment. Inhaled or topical steroids,and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, arepermitted in the absence of active autoimmune disease

• History of (non-infectious) pneumonitis that required steroids or currentpneumonitis

• History of interstitial lung disease

• Subjects with previous malignancies (except non-melanoma skin cancers, and thefollowing in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, orbreast) are excluded unless a complete remission prior to study entry and noadditional therapy is required or anticipated to be required during the study period

• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (indosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy

• Presence of symptomatic central nervous system (CNS) metastases, or CNS metastasesthat require local CNS-directed treatment (such as radiotherapy or surgery).Participants with stable CNS disease or previously treated lesions are eligible forstudy entry. In addition, subjects must be either off corticosteroids, or on astable 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, Australiaantigen) positive, or hepatitis C antibody (anti-HCV) positive (except ifHCV-ribonucleic acid [RNA] negative)

• Pregnancy or breast feeding

• Psychological, familial, or sociological condition potentially hampering compliancewith 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 excipientsin the formulation