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

A Phase II 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).

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.