Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies: a phase I...

Area of Science:

• Pharmacology
• Oncology
• Clinical Trials

Background:

• Preclinical data suggest intermittent high-dose protein kinase inhibitors may enhance treatment efficacy.
• This phase I trial investigated the safety and tolerability of pulsatile, high-dose sorafenib.

Purpose of the Study:

• To evaluate the safety of high-dose, once-weekly sorafenib administration in patients with advanced malignancies.
• To determine if drug monitoring could achieve target plasma concentrations (AUC) of sorafenib.
• To assess the effect of cola beverage on sorafenib absorption.

Main Methods:

• A 3+3 dose escalation design was used for once-weekly high-dose sorafenib administration.
• Drug monitoring guided dose adjustments to reach a target AUC(0-12 h).
• Patients consumed either water or cola with sorafenib to assess beverage effects.

Main Results:

• Seventeen patients with advanced malignancies were enrolled.
• High-dose sorafenib achieved twofold higher Cmax compared to standard dosing, but dose-limiting toxicities (perforations, organ failure) occurred.
• Drug monitoring significantly improved the accuracy of achieving target AUC, while cola did not enhance exposure.
• Two patients experienced stable disease as their best response.

Conclusions:

• High-dose, once-weekly sorafenib administration is associated with dose-limiting toxicities, precluding escalation beyond 125-150 mg/L/h AUC.
• Drug monitoring is an effective strategy for achieving target sorafenib exposure in this dosing regimen.