Regorafenib in Combination with Pembrolizumab or Pembrolizumab Alone for the Treatment of Metastatic or Unresectable MSI-H Colorectal Cancer

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
• Participants age ≥ 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 within 28 days prior to registration
• Histologically confirmed colorectal adenocarcinoma per American Joint Committee on Cancer (AJCC) staging manual version (v) 9, metastatic or unresectable. Patients with other colorectal cancer histology such as adenosquamous carcinoma and adenocarcinoma with neuroendocrine differentiation in the presence of confirmed MSI-H/mismatch repair protein deficiency (MMR-D) may also be enrolled at sponsor-investigator discretion
• Deficient deoxyribonucleic acid (DNA) mismatch repair (dMMR) or microsatellite instability (MSI) high per validated test
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 28 days prior to registration
• Able to swallow oral medication
• Up to three cycles of prior fluoropyrimidine-based chemotherapy including folinic acid, fluorouracil, and oxaliplatin (FOLFOX); folinic acid, fluorouracil, and irinotecan (FOLFIRI); and, folinic acid, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) is allowed. NOTE: this is excluding adjuvant treatment. Patients who received 2 or 3 cycles of chemotherapy before registration in the study, should undergo new baseline (screening) scans after study registration before receiving study treatment
• Subjects who received no more than 1 cycle of pembrolizumab monotherapy are eligible to be enrolled in the lead in phase of the trial
• Up to three cycles of prior treatment with vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) directed therapies in combination with chemotherapy is allowed
• Platelets (Plt) ≥ 100,000 /mm^3 (obtained within 28 days prior to registration)
• Absolute neutrophil count (ANC) ≥ 1500 K/mm^3 (obtained within 28 days prior to registration)
• Hemoglobin (Hgb) ≥ 9 g/dL (obtained within 28 days prior to registration)
• Calculated creatinine clearance ≥ 50 mL/min OR creatinine ≤ 1.5 x upper limit of normal (ULN) (obtained within 28 days prior to registration) * Cockcroft-Gault formula will be used to calculate creatinine clearance
• Total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if Gilbert syndrome present) (obtained within 28 days prior to registration)
• Aspartate aminotransferase (AST) ≤ 2.5 x ULN with the exception of patients with documented liver metastases who may have AST and/or alanine aminotransferase (ALT) ≤ 5.0 x ULN (obtained within 28 days prior to registration)
• Alanine aminotransferase (ALT) ≤ 2.5 x ULN with the exception of patients with documented liver metastases who may have AST and/or ALT ≤ 5.0 x ULN (obtained within 28 days prior to registration)
• Alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN) with the exception of patients with documented liver or bone metastases who should have ALP ≤ 5.0 x ULN (obtained within 28 days prior to registration)
• Albumin ≥ 2.8 g/dL or 28 g/L (obtained within 28 days prior to registration)
• International normalized ratio (INR), activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation (obtained within 28 days prior to registration)
• Females of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to registration. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Females of childbearing potential who are sexually active with a male able to father a child must be willing to abstain from penile-vaginal intercourse or must use an effective method(s) of contraception. Males able to father a child who are sexually active with a female of childbearing potential must be willing to abstain from penile-vaginal intercourse or use an effective method(s) of contraception
• Known HIV-infected subjects on effective anti-retroviral therapy with undetectable viral load and a CD4 count > 200 within 6 months of registration are eligible for this trial. Testing is not required at screening unless mandated by local policy
• Subjects with known chronic hepatitis B virus (HBV) infection, must have an undetectable HBV viral load on suppressive therapy, if indicated. Subjects with a history of hepatitis C virus (HCV) infection must have been treated and cured. For subjects with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial. Testing is not required at screening unless mandated by local policy
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria

• Prior anti-programmed death 1 (anti-PD-1) or anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) based therapy. NOTE: Subjects who received no more than 1 cycle of pembrolizumab monotherapy may still be eligible to be enrolled in lead in phase of the trial
• More than 3 cycles of chemotherapy or progression of disease on first line therapy excluding adjuvant treatment and any systemic anticancer treatment within 2 weeks or 5 half-lives (whichever is shorter) prior to start of study treatment
• Uncontrolled hypertension (HTN: systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg on repeated measurements) and cardiovascular events within 12 months of start of treatment. Examples of cardiovascular events include, but are not limited to: congestive heart failure – New York Heart Association (NYHA) > class II, uncontrolled hypertension, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, recent cerebrovascular events (within 90 days), superior vena cava syndrome, active uncontrolled coagulopathy, bleeding disorders
• Severe hepatic impairment (Child-Pugh C)
• Major surgical procedure or significant traumatic injury within 28 days before start of study treatment
• Non-healing wound, non-healing ulcer, or non-healing bone fracture
• Evidence or history of any bleeding diathesis, irrespective of severity
• Any hemorrhage or bleeding event ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 3 within 4 weeks prior to the start of study treatment
• Active autoimmune disease requiring immune suppression except the following conditions: * Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone without an active complication are eligible for the study * Patients with well controlled type 1 diabetes mellitus who are actively on an insulin regimen are eligible for the study * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Disease is well controlled at baseline and requires only topical corticosteroids. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Active infection of grade 3 ≥ according to National Cancer Institute (NCI)-CTCAE version 5.0
• Interstitial lung disease with symptoms or signs of activity based on investigator assessment
• Pregnant or breastfeeding. NOTE: breast milk cannot be stored for future use while the mother is being treated on study
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) are not excluded
• Active untreated brain metastases
• Treatment with any investigational drug within 28 days prior to registration
• History of severe allergic anaphylactic reactions to study drug(s) or any of their excipients