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

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).

Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum.
* Patients must have measurable disease per 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 hematologic, renal and hepatic function
* 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.
* Male patients willing to use adequate contraceptive measures. Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test performed within 72 hours prior to start of treatment.
* Willingness and ability to comply with the trial and follow-up procedures.
* Ability to understand the investigative nature of this trial and give written informed consent.

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.
* Women who are pregnant or lactating. All females of child-bearing potential must have negative serum or urine pregnancy tests within 72 hours prior to study treatment (see Appendix D)
* History of hypersensitivity to active or inactive excipients of any component of treatment (5 fluorouracil, bevacizumab, oxaliplatin, or axitinib), or known dipyrimidine dehydrogenase deficiency.
* Patients with proteinuria at screening as demonstrated by:

  * Urine dipstick for proteinuria \>=2+ (patients discovered to have \>=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection, and must demonstrate \<=1 g of protein/24 hours to be eligible)
* Patients with a serious non healing wound, active ulcer, or untreated bone fracture.
* 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.
* Patients requiring concomitant treatment with potent CYP3A4 or CYP1A2 inducers and CYP3A4 inhibitors.
* History of myocardial infarction or unstable angina \<=6 months prior to beginning treatment.
* Inadequately controlled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg while on antihypertensive medications). Initiation of antihypertensive agents is permitted provided adequate control is documented at least 1 week prior to Day 1 of study treatment.
* New York Heart Association Grade II or greater congestive heart failure.
* Serious cardiac arrhythmia requiring medication. Patients with chronic, rate-controlled atrial fibrillation are eligible.
* Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) \<=6 months prior to Day 1 of treatment.
* History of stroke or transient ischemic attack \<=6 months prior to beginning treatment.
* Any prior history of hypertensive crisis or hypertensive encephalopathy.
* History of abdominal fistula or gastrointestinal perforation \<=6 months prior to Day 1 of beginning treatment.
* Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
* Any known positive test for human immunodeficiency virus, hepatitis C virus or acute or chronic hepatitis B infection.
* Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
* Use of any non-approved or investigational agent \<=28 days prior to administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
* Past or current history of neoplasm other than the entry diagnosis with the exception of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a disease free survival \>=5 years.
* Infection requiring IV antibiotics.
* 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).
* Inability to swallow whole tablets.
* Patients with \> Grade 2 peripheral neuropathy.