Rationale: Preclinical research showed improved efficacy of sorafenib when given in a high-dose, pulsatile schedule compared with conventional (lower dose) continuous scheduling as a result of higher peak concentrations in the tumor. In this phase I study patients will be treated with high-dose, pulsatile sorafenib in exposure escalation cohorts. Exposure escalations cohorts are based on a target plasma AUC0-12h (area under the curve) and are used instead of conventional dose escalation cohorts because the effect of a drug is dependent of its AUC levels and large differences in plasma sorafenib AUC0-12h have previously been shown between patients treated at the same dose level.~Primary Objectives:~To determine the maximum tolerated plasma AUC0-12h of high-dose sorafenib administered in a weekly, pulsatile schedule.~To assess the safety and tolerability of high-dose, pulsatile sorafenib.~Secondary Objectives:~To determine the pharmacokinetic behaviour of sorafenib and its major active metabolite pyridine N-oxide when administered in a weekly, pulsatile schedule.~To determine a recommended phase II plasma AUC0-12h of high-dose sorafenib in a weekly pulsatile schedule.~Preliminary assessment of the efficacy of high-dose, pulsatile sorafenib administered at the maximum tolerated plasma AUC0-12h.~To determine skin and intratumoral concentrations of sorafenib and their correlation with plasma and whole blood concentrations.~To select 1-2 optimal time points from the AUC0-12h data to determine sorafenib exposure using a finger puncture.~Study design: A single center, open-label, phase I study of high-dose, pulsatile sorafenib administered in exposure escalation cohorts.~Study population: Adult patients with locally advanced or metastatic disease for whom no standard therapy exists.~Treatment: Patients will be treated in exposure escalation cohorts with high-dose sorafenib administered in a weekly pulsatile schedule. Using pharmacokinetic monitoring, the sorafenib dose will be adjusted to a target plasma AUC0-12h. The escalation cohorts consist of 3-6 patients per exposure level starting with a target plasma sorafenib AUC0-12h level of 25-50 mg/L/h. After the determination of the maximum tolerated AUC0-12h, 10 additional patients will be entered into an expansion cohort. In the expansion cohort the patients will be treated with a weekly pulse of sorafenib at the maximum tolerated AUC0-12h for further assessment of safety and preliminary exploration of efficacy.
Sorafenib is an oral anticancer drug and inhibits multiple protein kinases important for tumor growth and metastases, including VEGFR, PDGFR, and RAF kinases. In daily clinical practice it is currently used at a dose of 400 mg twice daily in a continuous schedule. In this phase I study patients will be treated with a new dosing schedule of sorafenib: i.e. a high-dose, pulsatile schedule. The tolerability and safety of this new schedule is examined in exposure escalation cohorts based on a target plasma AUC0-12h (area under the curve). Exposure escalation cohorts are used instead of conventional dose escalation cohorts because the effect of a drug is dependent of its AUC levels and large differences in plasma sorafenib AUC0-12h have previously been shown between patients treated at the same dose level. Using pharmacokinetic monitoring, the sorafenib dose will be adjusted to a target plasma AUC0-12h. The escalation cohorts consist of 3-6 patients per exposure level starting with a target plasma sorafenib AUC0-12h level of 25-50 mg/L/h. After the determination of the maximum tolerated AUC0-12h, 10 additional patients will be entered into an expansion cohort. In the expansion cohort the patients will be treated with a weekly pulse of sorafenib at the maximum tolerated AUC0-12h for further assessment of safety and preliminary exploration of efficacy.