A Trial of Single Agent Axitinib as Maintenance Therapy for Patients With First Line Metastatic Colorectal Cancer (mCRC)

• Objective Response Rate (ORR) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Determine the Response Rate of patients with first-line mCRC treated with maintenance axitinib after initial treatment with FOLFOX plus bevacizumab.
• Toxicities [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
  Abnormal Thyroid Function - Serum or plasma thyroid function tests; Gastrointestinal Disorders - Supportive care for these events may include pre-medication with anti-emetics; Hematological and Urinary Disorders - Urine dipstick test; Hypertension - Measurements of BP
• Time To Progression (TTP) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Determine Time To Progression of patients with first-line mCRC treated with maintenance axitinib after initial treatment with FOLFOX plus bevacizumab.
• Overall Survival (OS) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Determine Overall Survival (OS) of patients with first-line mCRC treated with maintenance axitinib after initial treatment with FOLFOX plus bevacizumab.

• Objective Response Rate (ORR) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Determine the Response Rate of patients with first-line mCRC treated with maintenance axitinib after initial treatment with FOLFOX plus bevacizumab.
• Toxicities [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
  Abnormal Thyroid Function - Serum or plasma thyroid function tests; Gastrointestinal Disorders - Supportive care for these events may include pre-medication with anti-emetics; Hematological and Urinary Disorders - Urine dipstick test; Hypertension - Measurements of BP
• Time To Progression (TTP) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Determine Time To Progression of patients with first-line mCRC treated with maintenance axitinib after initial treatment with FOLFOX plus bevacizumab.
• Overall Survival (OS) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Determine Overal Survival (OS) of patients with first-line mCRC treated with maintenance axitinib after intial treatment with FOLFOX plus bevacizumab.

This is a non-randomized, open-label, Phase II trial investigating axitinib as a single-agent maintenance therapy following standard first-line FOLFOX/bevacizumab therapy for patients with mCRC.

All patients will receive FOLFOX/bevacizumab for four 28-day cycles (a total of 16 weeks). After 4 cycles, maintenance axitinib will be started. With approval of the Medical Monitor,patients who are having significant benefit from FOLFOX/bevacizumab may continue chemotherapy to a maximum of six 28-day cycles. During trial treatment, all patients will be assessed for response every 8 weeks (2 cycles).

• Drug: Axitinib
  5-mg tablets PO BID
• Drug: Bevacizumab
  5 mg/kg Days 1 and 15; IV
• Drug: 5-FU
  400 mg/m2 Days 1 and 15; IV
  Other Name: Fluorouracil
• Drug: 5-FU
  2400 mg/m2 over 46-48 hours Days 1 and 15; Continuous Intravenous
  Other Name: Fluorouracil
• Drug: Leucovorin
  400 mg/m2 Days 1 and 15; IV
• Drug: Oxaliplatin
  85 mg/m2 Days 1 and 15; IV

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum.
• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
• No previous systemic therapy for metastatic colorectal cancer. Previous radiosensitizing chemotherapy is allowed, , if completed at least 4 weeks prior to Cycle 1 Day 1 of study treatment, and previous neoadjuvant and/or adjuvant chemotherapy is allowed, if completed at least 6 months prior to diagnosis of metastatic disease.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1
• Life expectancy ≥12 weeks.

• Adequate liver function defined as:

  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x the institutional upper limit of normal (ULN) or ≤5.0 x the institutional ULN in patients with liver metastases.
  • Total bilirubin within normal limits (WNL) (or ≤1.5 x the institutional ULN in patients with liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin within normal limits in patients with well documented Gilbert Syndrome).

• Adequate renal function defined as:

  • Serum creatinine ≤1.5 mg/dL OR calculated 24-hour creatinine clearance ≥60 mL/min.

• Patients who are on coumadin should have an INR value within the therapeutic range (i.e., 2 to 3 x ULN). Patients who are on stable, chronic doses of coumadin are eligible.

Exclusion Criteria:

• History or known presence of central nervous system (CNS) metastases.
• Patients who have had a major surgical procedure (not including mediastinoscopy or significant traumatic injury ≤4 weeks prior to beginning treatment.
• Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
• Patients with history of hematemesis or hemoptysis (defined as having bright red blood of ½ teaspoon or more per episode) ≤1 month prior to study enrollment.
• Serious cardiac arrhythmia requiring medication. Patients with chronic, rate-controlled atrial fibrillation are eligible. History of stroke or transient ischemic attack ≤6 months prior to beginning treatment.
• Any prior history of hypertensive crisis or hypertensive encephalopathy.
• Any known positive test for human immunodeficiency virus, hepatitis C virus or acute or chronic hepatitis B infection.
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g. active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or significant small bowel resection).