Individual PK-guided sunitinib dosing: A feasibility study in patients with advanced solid tumors.

Abstract

2596 Background: Sunitinib treatment shows a clear dose-efficacy relationship. However, due to large inter-individual variations in plasma exposure, target total trough levels (> 50 ng/mL) are frequently not reached with the current dosing schedule. Therefore, a prospective Phase I study was performed to determine the safety and feasibility of PK-guided dosing of sunitinib. Methods: Thirty patients with solid tumors with a potential benefit from sunitinib treatment were included. Patients were treated continuously with sunitinib 37.5 mg once daily. At day 15 and 29 of sunitinib treatment, plasma trough levels of sunitinib and its active metabolite (N-desethyl sunitinib) were measured. If the total trough level (TTL) was < 50 ng/mL and the patient did not show any ≥ grade 3 toxicity (CTCAE 4.02), the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from ≥ grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg. After 8 weeks a final TTL evaluation was performed. Results: All 30 patients started treatment and in 18 patients all 3 TTLs were measured at the time of this analysis. Given TTL < 50 ng/mL and < grade 3 toxicity, a first sunitinib dose increase could be applied in 10 patients and a second dose increase in 2 patients at day 15 and 29, respectively. At day 15, day 29 and 8 weeks of treatment, mean TTLs were 49.7 ng/mL (coefficient of variation (CV) 27.7%), 62.4 ng/mL (CV 35.5%) and 56.7 ng/mL (CV 47.8%), respectively. At day 15, using the sunitinib standard dose of 37.5 mg, target TTLs were reached in 8 patients (44%). At 8 weeks, the mean sunitinib daily dose intensity was increased to 40.3 mg (standard deviation (SD) ± 11.0). At the end of the 8 week study period, 5 out of 18 patients (28%) were still at an increased sunitinib dose level without additional side effects. In these patients the mean daily sunitinib dose was 55.0 mg (SD ± 6.8) and their final TTLs were all > 50 ng/mL (mean: 70.8 ng/mL (CV 29.8%)). Using PK-guided sunitinib dosing, target TTLs were reached in 10 out of 18 patients (56%) at the final TTL evaluation, compared to 44% at day 15 before any dose adjustment. Conclusions: Individual PK guided dosing is feasible and enables a significant increase in sunitinib dose intensity without causing additional toxicity.