Background: Optimization of the clinical use of multi-targeting tyrosine kinase inhibitors (TKIs), as sunitinib, is needed to fully exploit their potential antitumor activity. Sunitinib was developed to inhibit angiogenesis-related kinases, but at conventional daily dosing it also directly inhibits tumor cell growth. The inhibitory activity of sunitinib is dependent on its discriminative affinity for specific kinases, its intracellular concentrations reached at the tumor level and the presence and activity of kinases in tumor cells. Administration of sunitinib in a higher dose, similar to convential chemotherapy, might further utilize this direct antitumor effect and the strong broad kinase inhibitory potency of sunitinib. In a recent phase I trial of high dose intermittent sunitinib the maximum tolerated dose of 700 mg once every two weeks (Q2W) resulted in high peak plasma concentrations (Cmax) of >500 µg/l, without drug accumulation. 63% of 69 heavily pretreated patients with advanced cancer had clinical benefit, with similar toxicity compared to standard daily dosing. Pharmacokinetic (PK) evaluation showed significant interpatient variability of this alternative regimen. In the current study, we evaluated the effect of food on the interpatient variation in bioavailability and studied whether food would further increase Cmax. Methods: 700 mg sunitinib Q2W was administered to patients with refractory solid tumors. Patients were randomized to either start sunitinib after a 10-hour fasted regimen or within 30 minutes after a high fat meal followed by the alternative at the second cycle. PK and safety assessments were obtained. Treatment continued until progression or unacceptable toxicity. Drug plasma concentrations were measured by LC-MS/MS. Geometric mean ratios (GMR) and 90% confidence intervals (CI) of the sum concentration of sunitinib and SU12662 were estimated. Results:Twelve patients were included. Both intake regimens were not bioequivalent. The GMR (fed/fasted) of the AUC0-µ and Cmax were 1.33 (90% CI 1.03-1.70) and 1.30 (90% CI 1.02-1.65), respectively. Compared with the fasted state, a high-fat meal delayed time to maximum plasma concentration by 1.6 hours. The observed non bioequivalence and increase in drug exposure appeared to be mainly caused by 2 patients who suffered from early vomiting (~3hrs) after drug ingestion in the fasted state. After excluding them from the analysis, the GMR of the AUC0-µ and Cmax change to 1.09 (90% CI 0.98-1.22) and 1.09 (90% CI 0.96-1.23), respectively, indicating that both regimens were bioequivalent. The interpatient variability for AUC0-µ was reduced by the intake of food; 32.5% (fasted) to 29% (fed), while for Cmax the interpatient variability was similar 34.4% and 33.3%. Adverse events were similar to our prior phase I study with mainly grade I-II toxicities including fatigue (58%), nausea (50%) and anorexia (42%). Conclusions: Our study demonstrates that high dose sunitinib can be taken with or without food. For the patients without GI toxicity early after intake, the exposure to sunitinib was bioequivalent. Interpatient variability appeared to be modestly reduced by taken sunitinib with food. The results support the recommendation for administration of high dose sunitinib in a fed state to achieve more consistent therapeutic exposure and increased tolerance. Results from ongoing phase II trials with high dose intermittent sunitinib for patients with colorectal cancer and glioblastoma are eagerly awaited.

Citation Format: Sophie L. Gerritse, Mariette Labots, Maria Rovithi, Angela Colbers, Olaf J.L. Loosveld, Mikkjal Skardhamar, Nielka P. van Erp, Henk M.W. Verheul. Effect of food on the pharmacokinetics of high dose intermittent sunitinib in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C079. doi:10.1158/1535-7163.TARG-19-C079