Phase II trial of dose-escalated sorafenib in advanced solid tumors.

Abstract

3055 Background: Sorafenib is a multitargeted tyrosine-kinase inhibitor active in several tumor types. The dose-efficacy relationship of sorafenib has not been fully explored. A phase II trial in kidney cancer (Amato, ASCO 2007) reported a 52% CR/PR rate with acceptable toxicity above its recommended dose (400 mg PO BID). Here we report a phase II trial designed to explore sorafenib dose-escalation in (1) patients (pts) tolerating 400 mg BID for 28 days or (2) dose re-escalation in pts initially requiring a dose reduction but subsequently tolerating 400 mg QD. Methods: Pts started at 400 mg PO BID; doses were escalated to 600 mg BID for the second cycle and 800 mg BID for the third cycle if there were no grade 3+ adverse events (AEs) in the preceding cycle. If reduction to 400 mg QD was required in cycle 1 but tolerated for at least 28 days, sorafenib was re- escalated to 400 mg BID for cycle 3. Dose escalation was not allowed after cycle 3. The primary endpoint was the sum of the % tolerating a dose escalation to 600 mg BID for 28 days plus the % tolerating a re-escalation to 400 mg BID in cycle 3. With 90% power and 5% significance, 51 pts were needed to differentiate a dose escalation/re-escalation rate of 70% vs. the null rate of 50%. Results: Of 51 pts enrolled, 48 are evaluable with median age: 62 years; median prior regimens: 3; most common tumor types: non-small cell lung (32%) and colorectal (10%). Only 10 pts (21%) tolerated the primary endpoint of dose escalation or re-escalation and only 3 (6%) tolerated 2 successive dose escalations. Dose reduction in cycle 1 was required by 29 pts (62%) of which 4 attempted re-escalation and 3 tolerated it for 28+ days. Seven of 13 pts tolerated dose escalation to 600 mg BID for 28+ days. The most common reasons for escalation failure were AEs (34%) and progression (30%). Grade 3+ hand-foot, allergic reaction, hypophosphatemia, and abdominal pain were reasons for failure in 2+ pts. There were no RECIST responses but tumor necrosis was seen in 2 pts with head and neck cancer. Conclusions: In contrast to a prior report in kidney cancer pts, sorafenib dose escalation and/or re-escalation after a dose reduction were not feasible in this cohort of heavily pretreated solid tumor pts. Toxicities were substantial. Sorafenib dose escalation remains an investigational approach. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer