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

A Phase 2, Open Label, Multicenter, Randomized Trial Comparing Tivozanib in Combination With mFOLFOX6 to Bevacizumab in Combination With mFOLFOX6, In Stage IV Metastatic Colorectal Cancer (mCRC) Subjects

The objective of this study is to compare the progression free survival (PFS), overall survival (OS), objective response rate (ORR), time to treatment failure (TTF), duration of response (DoR), quality of life, safety and tolerability of tivozanib in combination with mFOLFOX6 and bevacizumab in combination with mFOLFOX6.

Imaging scans (computed tomography [CT]/magnetic resonance imaging [MRI]) to assess disease progression were to be completed within 28 days prior to first study drug administration, approximately every 8 weeks for the first 18 months and then approximately every 12 weeks until the patient showed progressive disease (PD) per the investigator, withdrew consent, was lost to follow-up or died. Per the original protocol, all patients were to be contacted by the study site every 12 weeks for survival following the end-of-treatment visit until death or for no more than 3 years after the end-of-treatment visit.

The interim futility analysis was conducted in December 2013, based on a pre-specified analysis cutoff date of 13 September 2013. The study was brought to a close as specified in the protocol due to the results of the interim futility analysis and only those participants who were deriving benefit (per the treating physician) from their current treatment remained on study until one of the discontinuation criteria was met.

Given the early closure of the study, no updated or additional efficacy analyses were performed after the interim analysis. A biomarker analysis was conducted in January 2014, based on the data from the cutoff date of 13 September 2013. The safety analysis was updated with a new cutoff date of 28 February 2014.

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,
  • Absolute neutrophil count (ANC) < 2000 per mm^3,
  • Platelet count < 100,000 per mm^3,
  • 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