Annals of Oncology Advance Access published online on November 25, 2009
Annals of Oncology, doi:10.1093/annonc/mdp489
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A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors
1 Section of Gastrointestinal Oncology, Nevada Cancer Institute, Las Vegas, NV
2 Department of Internal Medicine, Eastern Carolina Internal Medicine, Pollocksville, NC
3 Drug Development and Gastrointestinal Cancer Research, Sarah Cannon Research Institute, Nashville, TN
4 Indiana Oncology Hematology Consultants, St Francis Cancer Care Center, Indianapolis, IN
5 Oncology Development, Pfizer, San Diego, CA
6 Bay Area Cancer Research Group, Department of Medical Oncology and Hematology, Concord, CA, USA
* Correspondence to: Dr S. Sharma, Section of Gastrointestinal Oncology, Nevada Cancer Institute, 1 Breakthrough Way, Las Vegas, NV 89135, USA. Tel: +1-702-822-5433; Fax: +1-702-944-6076; E-mail: sunil.sharma{at}hci.utah.edu
Background: Axitinib and bevacizumab are targeted therapies against the vascular endothelial growth factor pathway.
Methods: Patients with previously treated solid tumors received axitinib (starting dose 5 mg twice daily) combined with FOLFOX plus bevacizumab (1, 2, or 5 mg/kg, cohorts 1–3, respectively), FOLFOX (cohort 4), or FOLFIRI (cohort 5). Safety and pharmacokinetics were assessed.
Results: Thirty patients were enrolled (n = 16, 8, and 6 for cohorts 1–3, 4, and 5, respectively). Plasma concentrations and pharmacokinetic (PK) parameters were similar when drugs were administered alone and in various combinations. Most treatment-emergent adverse events (AEs) were mild to moderate and clinically manageable (most common: nausea, fatigue, diarrhea, anorexia, hypertension). Two of the four patients receiving axitinib with FOLFOX plus 5 mg/kg bevacizumab experienced dose-limiting toxicity (DLT) of inability to resume treatment for 14 days following treatment interruption (associated AE: hypertension); the maximum tolerated dose of bevacizumab in this combination was 2 mg/kg. No DLTs occurred with axitinib plus FOLFIRI or FOLFOX. Ten patients had RECIST-confirmed partial tumor responses (objective response rate: 33.3%).
Conclusion: Axitinib is well tolerated in combination with FOLFOX, FOLFIRI, or FOLFOX plus 2 mg/kg bevacizumab. PK interactions appear to be absent.
axitinib, bevacizumab, colorectal cancer, FOLFIRI, FOLFOX
Received for publication June 18, 2009. Revision received August 25, 2009. Accepted for publication August 27, 2009.