Abstract 2989: High-dose, intermittent sunitinib as an alternative treatment strategy
Authors: Rovithi Maria , Haas Richard R. de , Honeywell Richard J. , Voortman Johannes , Griffioen Arjan W. , Labots Mariette , Luik Anne Marije , Peters Godefridus J. , Broxterman Henk J. , Verheul Henk M.w. 
Published: May 2015

Abstract
Background: Increased exposure to sunitinib treatment is associated with improved outcome indicative of the importance of dose intensity in the efficacy/toxicity balance. The currently approved schedule (50 mg daily, 4 weeks on, 2 weeks off) precludes further dose intensification. We hypothesized that high doses of sunitinib would improve tumor response with limited toxicity, when applied intermittently.
Methods: In vitro proliferation was studied with MTT assays, one week after 3-9 hrs exposure of a panel of cancer cell lines (786-0, HT29, MDA-MB231, HCC827, A431) to high (5 and 20uM) concentrations of tyrosine kinase inhibitors (TKIs), namely sunitinib, sorafenib, erlotinib, pazopanib and axitinib. Apo-ONETM Homogenous Caspase 3/7 Assay (Promega) was applied to detect activation of apoptosis. The chick embryo chorioallantoic membrane (CAM) in vivo model was employed to further test the efficacy of the new scheduling, where sunitinib was topically administered on HT29 tumors growing on the CAM either daily at the commonly used dose of 40 mg/kg or once weekly at 200 mg/kg. Microvessel density (MVD) was determined by CD31 immunohistochemical staining. Plasma sunitinib concentrations were determined by LC-MS-MS from refractory patients with solid tumors participating in a phase I clinical trial (classical 3+3 design, EudraCT No: 2012-005756-41) in which high-dose, intermittent sunitinib treatment is being studied.
Results: Sunitinib was identified as one of the most potent inhibitors of cell growth from the panel of TKIs; 6 hrs exposure to 20 uM of sunitinib resulted in tumor cell death. This effect was tumor cell line-independent and mediated via activation of caspase 3/7 pathway. High dose treatment of CAM tumors resulted in significant decrease in tumor growth compared to the control (mean 0.17 mg vs. 0.23 mg respectively, p=0.04), irrespective of angiogenesis inhibition as denoted by lack of inhibitory effect on MVD. It also led to higher intratumoral sunitinib concentrations compared to the daily schedule (14.3 vs. 8 ng/mg tissue, respectively), while blood concentrations were identical between the two schedules, averaging at 170 ng/ml. Patients enrolled in the first cohort of the clinical trial received 200 mg sunitinib orally weekly. This schedule was well tolerated and no dose limiting toxicities occurred. Overall, sunitinib exhibited moderate interpatient variability. Maximum plasma concentrations on Day 1 averaged on 161 ng/ml (range 118-239.5 ng/ml) and were reached approximately 6 hours after administration. Plasma drug concentrations decreased to undetectable from one cycle to the other. We have proceeded to escalate the dose for the next cohort of patients.
Conclusion: Optimization of therapy with targeted agents remains an unmet challenge. Thus far, high-dose, intermittent sunitinib is well tolerated. These findings open new avenues that might contribute to improved treatment with sunitinib.
Citation Format: Maria Rovithi, Richard R. de Haas, Richard J. Honeywell, Johannes Voortman, Arjan W. Griffioen, Mariette Labots, Anne Marije Luik, Godefridus J. Peters, Henk J. Broxterman, Henk M.w. Verheul. High-dose, intermittent sunitinib as an alternative treatment strategy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2989. doi:10.1158/1538-7445.AM2014-2989