Phase I trial of BAY 43–9006 (sorafenib) combined with dacarbazine (DTIC) in metastatic melanoma patients

Abstract

7508 Background: BAY 43–9006 (BAY) prevents tumor cell proliferation and angiogenesis via blockade of the RAF/MEK/ERK pathway at the level of RAF (RAF-1, wild-type B-RAF, V599E B-RAF) kinase and inhibition of the receptor tyrosine kinases VEGFR-2 and PDGFR-β. In phase I/II trials, BAY was generally well tolerated as a single agent or with concomitant chemotherapy. Methods: This single-centre, open-label, phase I, dose-escalation study was performed to determine the safety profile and maximum tolerated dose (MTD) of BAY administered at 200 (cohort 1) or 400 (cohort 2) mg bid in combination with repeated 21-day cycles of DTIC 1000 mg/m2. In an extension phase (cohort 3), patients (pts) received the MTD of BAY plus DTIC 1000 mg/m2. Results: Pts with metastatic melanoma were enrolled (ECOG PS 0–1) into cohorts 1 (n=3) 2 (n=6) and 3 (n=3). 1 pt died due to PD. The most common drug-related AEs were dermatologic (rash, flushing, hand-foot skin reaction [HFS]); gastrointestinal (nausea, diarrhoea, constipation, vomiting), constitutional (fatigue/lethargy) or blood/bone-marrow-related, and were generally grade (gr) 1–2 in severity and transient. 1 pt in cohort 2 experienced dose-limiting toxicity of gr 3 HFS. No drug-related gr 3/4 AEs occurred in cohort 1. Gr 3/4 drug-related AEs in cohort 2 were mostly resolved and included gr 4 hypercalcemia; gr 3 low hemoglobin; gr 3 pancreatic hemorrhage; gr 3 pancreatitis; gr 3 leucopenia that occurred in 1 pt each and gr 3/4 neutropenia in 2 pts. Gr 3/4 laboratory abnormalities were rare. According to RECIST, of the 11 evaluable pts after cycle 2, 2 pts had PR; 2 pts had response not reaching PR; 1 pt had SD; and 6 pts had PD. Conclusions: Continuous BAY 400 mg bid is safe and well tolerated and shows preliminary anti-tumor activity in combination with DTIC 1000 mg/m2. The MTD of BAY is 400 mg bid in combination with DTIC 1000 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Bayer Healthcare Bayer, CFSB, Deutsche Bank, Medacorp AstraZeneca, Bayer AG Bayer Bayer