Regorafenib+FOLFIRI Versus Placebo+FOLFIRI as 2nd Line Tx in Metastatic Colorectal Cancer

Exclusion Criteria

• •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