A Study Combining mFOLFOX6 With Tivozanib or Bevacizumab in Patients With Metastatic Colorectal Cancer as First Line Therapy

A 2:1 randomization between tivozanib in combination with mFOLFOX6 to bevacizumab in
combination with mFOLFOX6. Subjects will be stratified by origin of cancer, Lactate
Dehydrogenase (LDH) status, and number of metastatic sites.

Inclusion Criteria:

- Documented diagnosis of metastatic colorectal cancer

- One measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

- No prior systemic chemotherapy for advanced colorectal cancer; no fluorouracil
containing adjuvant therapy in previous 6 months

- Eastern Cooperative Oncology Group (ECOG) status of 0 or 1

Exclusion Criteria:

- Any prior Vascular Endothelial Growth Factor (VEGF)-directed therapy or any other
agent or investigational agent targeting the VEGF pathway

- Primary Central Nervous System (CNS) malignancies or CNS metastases

- Hematologic abnormalities:

- Hemoglobin < 9.0 g/dL,

- ANC < 2000 per mm3,

- Platelet count < 100,000 per mm3,

- Prothrombin (PT) or Partial Thromboplastin Time (PTT) > 1.5 X Upper Limit of
Normal (ULN)

- Serum chemistry abnormalities:

- Total bilirubin > 1.5 X ULN,

- Aspartate aminotransferase (AST) or Alanine Aminotransferase (ALT) > 2.5 X
ULN,

- Alkaline phosphatase > 2.5 X ULN,

- Serum albumin < 2.0 g/dL,

- Creatinine > 1.5 X ULN,

- Proteinuria > 2+ by urine dipstick

- Significant cardiovascular disease

- Significant thromboembolic or vascular disorders within 6 months prior to
administration of first dose of study drug

- Non-healing wound, bone fracture, or skin ulcer

- Inadequate recovery from any prior surgical procedure or major surgical procedure
within 8 weeks prior to administration, or anticipation of major surgical procedure
during the course of the study

- History of significant gastrointestinal (GI) toxicity, diarrhea, or stomatitis within
the last 6 weeks

- An active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or
other gastrointestinal condition with increased risk of perforation

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 4 weeks prior to administration of first dose of study drug

- Serious/active infection or infection requiring antibiotics

- Significant bleeding disorders within 6 months prior to administration of first dose
of study drug

- Active second primary malignancy, other than non-melanoma skin cancers,
non-metastatic prostate cancer, in situ cervical cancer and ductal or lobular
carcinoma in situ of the breast. Subject is not considered to have a currently active
malignancy if they have completed anti-cancer therapy and have been disease free for
> 5 years

- History of allergic reactions, or intolerance, attributed to compounds of similar
chemical or biologic composition to 5-fluorouracil, history of Grade 3
hypersensitivity to oxaliplatin, history of allergic reaction to folic acid

- Female subject is pregnant or lactating

- Known history of genetic or acquired immune suppression disease including Human
Immunodeficiency Virus (HIV); subjects on immune suppressive therapy for organ
transplant

- Inability to swallow pills, malabsorption syndrome or gastrointestinal disease, major
resection of the stomach or small bowel, or gastric bypass

- Uncontrolled neuro-psychiatric disorder or altered mental status

- Peripheral neuropathy ≥ Grade 2

- Participating in another interventional protocol