This randomized (2:1), multi-center, placebo-controlled, phase II efficacy study is designed to compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients with mCRC previously treated with a FOLFOX regimen.

This randomized (2:1 ratio), multi-center, placebo-controlled, phase II efficacy study is designed to compare progression-free survival (PFS) between regorafenib + FOLFIRI (5-fluorouracil + leucovorin + irinotecan [ARM A] versus placebo + FOLFIRI [ARM B]) in patients with metastatic colorectal carcinoma (mCRC) previously treated with a FOLFOX (5-fluorouracil + leucovorin + oxaliplatin) regimen. Secondary objectives include objective response (OR) rates, disease control (DC) rates, and overall survival (OS). A pharmacokinetic (PK) evaluation of irinotecan will be conducted in a subset of patients at selected sites. This trial also incorporates a number of exploratory analyses designed to evaluate potential correlations between blood and tissue biomarkers and clinical benefit.

Inclusion Criteria

Subject must meet all of the inclusion criteria to participate in this study:

1. Age ≥18 years of age (no upper age limit)

2. Histological or cytological documentation of adenocarcinoma of the colon or rectum

3. Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies required

4. Metastatic disease not amenable to surgical resection with curative intent

5. Progression during or within 6 months following administration of a standard regimen[2] for treatment of metastatic disease that included oxaliplatin with any of the following agents with or without bevacizumab:

   • 5-fluorouracil (F-FU) with or without leucovorin or levoleucovorin
   • Capecitabine

   Note: In patients receiving FOLFOX, oxaliplatin is sometimes discontinued due to toxicity or as part of maintenance therapy strategy. If such patients progress while on 5-FU alone, they are eligible for this trial. As an example, a patient who is begun on FOLFOX or CapeOx (capecitabine with oxaliplatin, with or without bevacizumab), whose oxaliplatin is held for neurotoxicity and who is switched to capecitabine monotherapy or capecitabine with bevacizumab, would be considered to have had one prior therapy.

   OR

   Patients who develop metastatic disease within 9 months of adjuvant FOLFOX for stage II or III colon cancer

6. Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1.

7. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix C)

8. Life expectancy of at least 3 months

9. Adequate bone marrow, renal, and hepatic function, as evidenced by the following:

   • absolute neutrophil count (ANC) ≥1,500/mm3
   • platelets ≥100,000/mm3
   • hemoglobin ≥9.0 g/dL
   • serum creatinine ≤1.5 x upper limit of normal (ULN)
   • Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 (see Appendix A)
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer
   • Bilirubin ≤1.5 X ULN
   • Alkaline phosphatase ≤3 x ULN (≤5 x ULN with liver involvement of their cancer)
   • Amylase and lipase ≤1.5 x ULN
   • Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urine analysis.If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours
   • International normalized ratio (INR)/Partial thromboplastin time (PTT) ≤1.5 x ULN

   Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.

10. Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care.

11. The subject is capable of understanding and complying with parameters as outlined in the protocol

12. Signed, Institutional Review Board (IRB)-approved written informed consent

Exclusion Criteria

Any subject meeting any of the following exclusion criteria at baseline will be ineligible for study participation:

1. Prior treatment with regorafenib

2. More than 1 prior chemotherapy regimen for mCRC (see section 3.1.5) Previous adjuvant FOLFOX based chemotherapy is allowed. Prior FOLFIRI or single agent irinotecan is prohibited.

3. Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator

4. Pregnant or breastfeeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of FOLFIRI treatment, and a negative result must be documented before start of treatment.

5. History of Gilbert's syndrome

6. Known Dihydropyrimidine dehydrogenase (DPD) deficiency

7. Pernicious anemia or other anemias due to vitamin B12 deficiency (due to potential masking of deficiency with leucovorin)

8. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of Day 1 of treatment with FOLFIRI

9. Radiotherapy within 4 weeks prior to first dose of FOLFIRI

10. Active cardiac disease including any of the following:

    • Congestive heart failure (New York Heart Association (NYHA)) ≥Class 2 (see Appendix D)
    • Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of Day 1 of FOLFIRI
    • Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
    • Uncontrolled hypertension. (Systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management)

11. Patients with pheochromocytoma

12. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of FOLFIRI

13. Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0)

14. Known history of human immunodeficiency virus (HIV) infection

15. Known history of chronic hepatitis B or C

16. Patients with seizure disorder requiring medication

17. Symptomatic metastatic brain or meningeal tumors unless the patient is >6 months from definitive therapy, has a negative imaging study within 4 weeks of FOLFIRI initiation, and is clinically stable with respect to the tumor at the time of study entry. Also, the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies)

18. History of organ allograft

19. Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 4 within 4 weeks of start of FOLFIRI

20. Non-healing wound, ulcer, or bone fracture

21. Renal failure requiring hemo- or peritoneal dialysis

22. Dehydration according to NCI-CTC v 4.0 Grade >1

23. Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results

24. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation

25. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent

26. Inability to swallow oral medications

27. Any malabsorption condition

28. Unresolved toxicity higher than CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin-induced neurotoxicity (which must be ≤Grade 2)

29. Patients unable or unwilling to discontinue (and substitute if necessary) use of prohibited drugs for at least 30 days prior to Day 1 of FOLFIRI initiation (see Appendix B for list of prohibited drugs)

30. Unwilling to provide consent for genetic studies of tumor, whole blood, or plasma specimens