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

Inclusion Criteria

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

• Age ≥18 years of age (no upper age limit)
• Histological or cytological documentation of adenocarcinoma of the colon or rectum
• Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies required
• Metastatic disease not amenable to surgical resection with curative intent
• 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

• Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix C)
• Life expectancy of at least 3 months
• 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 150 mmHg or diastolic pressure >90 mmHg despite optimal medical management)
• Patients with pheochromocytoma
• Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of FOLFIRI
• Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0)
• Known history of human immunodeficiency virus (HIV) infection
• Known history of chronic hepatitis B or C
• Patients with seizure disorder requiring medication
• 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)
• History of organ allograft
• Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 4 within 4 weeks of start of FOLFIRI
• Non-healing wound, ulcer, or bone fracture
• Renal failure requiring hemo- or peritoneal dialysis
• Dehydration according to NCI-CTC v 4.0 Grade >1
• Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
• Known hypersensitivity to any of the study drugs, study drug cla