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

• Progression-Free Survival (PFS) based on Independent Radiological Review (IRR) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  The time from the date of randomization until the date of radiological disease progression assessed by the IRR or until death due to any cause, even in the absence of radiological progression.
• Overall survival (OS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  The time from the date of randomization until death from any cause.
• Objective Response Rate (ORR) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  The proportion of subjects with a confirmed complete response (CR ) or partial response (PR).
• Duration of Response (DoR) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  The time from the date of the first documented radiological response (CR or PR) to the date of first documented radiological progression.
• Time to Treatment Failure (TTF) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  The time from randomization to treatment discontinuation for any reason, including disease progression, toxicity, withdrawn consent, or death.
• Health Related Quality of life (HRQoL) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  Time to deterioration in HRQoL measured by Colorectal cancer (CRC) subscale of the Functional Assessment of cancer Therapy Colorectal (FACT-C) scale, change in score from baseline using the EQ-5D and Fact Colorectal Symptom Index (FCSI).
• Safety as assessed by physical examination, vital signs, laboratory assessments, 12-lead electrocardiogram (ECGs), and adverse events [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Assessment of relationship of biomarker that may be predictive of level of response between 2 study arms: Biomarker Lactate Dehydrogenase ( LDH) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Assessment of relationship of biomarker that may be predictive of level of response between 2 study arms: Vascular Endothelial Growth Factor (VEGF-C,VEGF-D, VEGF-A) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Assessment of relationship of biomarker that may be predictive of relationship between 2 study arms: CD68 [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Assessment of relationship of biomarker that may be predictive of level of response between 2 study arms: myeloid-derived gene signature (MGS) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Assessment of relationship of biomarker that may be predictive of level of response between 2 study arms: Serum soluble cytokines [ Time Frame: 3 years ] [ Designated as safety issue: No ]

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.

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.

• Drug: Tivozanib
  Oral and Intravenous
  Other Names:

  • AV951
  • ASP4130
• Drug: Bevacizumab
  Intravenous
  Other Name: Avastin
• Drug: mFOLFOX6
  Oxaliplatin, Leucovorin Calcium, Fluorouracil Bolus, Fluorouracil Infusion

• Experimental: Arm A: Tivozanib + mFOLFOX6
  Interventions:

  • Drug: Tivozanib
  • Drug: mFOLFOX6
• Active Comparator: Arm B: Bevacizumab + mFOLFOX6
  Interventions:

  • Drug: Bevacizumab
  • Drug: mFOLFOX6

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