Feasibility study of intra-patient sorafenib dose-escalation or re-escalation in patients with previously treated advanced solid tumors

Abstract

Purpose: To determine if intra-patient dose escalation of the multi-targeted kinase inhibitor sorafenib is feasible in patients with advanced pretreated solid malignancies.

Methods: An intra-patient dose escalation scheme starting at 400 mg BID was employed in this prospective trial. Doses were escalated to 600 mg BID for the second cycle and to 800 mg BID for the third cycle in the absence of grade 3+ adverse events. In the event of grade 3+ adverse events during cycle 1, doses were reduced to 400 mg daily through cycle 2. Dose re-escalation for cycle 3 was allowed in the absence of grade 3+ adverse events during cycle 2. Further dose escalation was prohibited. The primary endpoint was the overall percentage of patients tolerating dose escalation to 600 mg BID through cycle 2 or tolerating re-escalation to 400 mg BID through cycle 3.

Results: Fifty eligible patients with various solid tumors and a median of 3 prior therapies were enrolled. Eleven patients (22%) tolerated primary dose escalation or re-escalation. Only 14 patients (28%) completed cycle 1 without dose modification or discontinuing treatment. Seven of 13 patients tolerated primary dose escalation through cycle 2. Four of 5 patients tolerated dose re-escalation through cycle 3. Reasons for escalation failure included tumor progression (42%) and adverse events (26%). Common grade 3+ adverse events included hand-foot skin reaction, hypertension, and hypophosphatemia.

Conclusions: Intra-patient dose escalation and/or re-escalation of sorafenib were not feasible in pretreated solid tumor patients. Sorafenib dose escalation remains an investigational approach.

Trial registration: ClinicalTrials.gov NCT00810394.

Fig. 1

Study Schema. Patients were treated at the dose levels described with cycle length defined as four weeks. Dashed arrows refer to dose de-escalation as the result of grade 3 or higher toxicity. Solid arrows refer to dose escalation which was performed during the first 3 cycles if a patient tolerated a dose level for 28 or more days without grade 3 or higher toxicity

Fig. 2

Flow of patients through the first two cycles of treatment on the study. Reasons for treatment failure at a given dose level are noted