Regorafenib in Combination With Pembrolizumab or Pembrolizumab for MSI-H Colorectal Cancer

Inclusion Criteria:

1. Histologically confirmed mismatch repair deficient or microsatellite instability high advanced stage colorectal cancer
2. Measurable disease (per RECIST v1.1)
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
4. Age \> 18
5. The patient must be able to swallow oral medication.
6. Adequate organ function based on the following lab assessments:

   1. ANC must be ≥ 1500/mm3
   2. platelet count must be ≥ 100,000/mm3
   3. WBC count ≥ 2.5 × 109 /L
   4. Hemoglobin must be ≥ 9 g/dL
   5. Alkaline phosphatase ≤ 2.5× upper limit of normal (ULN) with the exception of patients with documented liver or bone metastases who should have ALP ≤ 5.0× ULN
   6. AST and ALT ≤ 2.5× ULN with the exception of patients with documented liver metastases who may have AST and/or ALT ≤ 5.0× ULN
   7. International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation
   8. Total bilirubin ≤ 1.5× ULN (≤ 3× ULN if Gilbert syndrome present)
   9. Serum albumin ≥ 2.8 g/dL or 28 g/L
   10. Creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula) or creatinine ≤ 1.5× ULN
7. No more than 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) excluding adjuvant treatment
8. Patients (male or female) of reproductive potential must agree to use an effective method of contraception (as discussed with treating physician) from the time consent is signed, during study therapy, and for at least 8 weeks after the last dose of study therapy.
9. Patients who received no more than 1 cycle of pembrolizumab monotherapy will be still eligible to be enrolled in lead in phase of the trial

Exclusion Criteria:

1. Prior anti-programmed death 1 (anti-PD-1) or anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) based therapy
2. 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
3. Active autoimmune disease
4. Pregnant or lactating females
5. Uncontrolled human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV); patients with undetectable viral load and CD4 count \> 200 will be eligible for enrollment
6. Active untreated brain metastasis
7. 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
8. Active infection or chronic infection requiring chronic suppressive antibiotics
9. No active cancer such as colon cancer other than adenocarcinoma (e.g., sarcoma, lymphoma, carcinoid) within 1 year
10. Patients with severe hepatic impairment (Child-Pugh C) are excluded as regorafenib has not been studied in this population and exposure might be increased in these patients
11. Major surgical procedure or significant traumatic injury within 28 days before start of study medication
12. Non-healing wound, non-healing ulcer, or non-healing bone fracture
13. Patients with evidence or history of any bleeding diathesis, irrespective of severity
14. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication:

    1. Major surgical procedure or significant traumatic injury within 28 days before start of study medication
    2. Non-healing wound, non-healing ulcer, or non-healing bone fracture
    3. Patients with evidence or history of any bleeding diathesis, irrespective of severity
    4. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication