Results of a phase I trial of BAY 43–9006 in combination with doxorubicin in patients with refractory solid tumors

Abstract

3049 Background:BAY 43–9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. Previous single-agent phase I studies show BAY is well tolerated, with manageable and reversible side effects, most commonly hand-foot skin (HFS) reaction, rash, fatigue, and diarrhea. This phase I study was initiated to determine the safety and pharmacokinetics (PK) of BAY in combination with doxorubicin. Methods:Patients (pts) received a fixed dose of doxorubicin (60 mg/m2 q x 3weeks) starting on day 1 of cycle 1 (C1). BAY was given on days 4–21 in C1 and continuously thereafter. BAY doses were 100 mg bid (cohort 1) escalating to 200 mg bid (cohort 2) and 400 mg bid (cohorts 3 and 4). Results:34 pts (M:F, 21:13; median age 60 yrs range 33–73) were treated. Common tumor types were CRC (15%), pancreatic cancer (15%) and HCC (12%). Dose-limiting leuko/neutropenia was seen in cohort 1 (1/6 pts) and cohort 3 (6/22 pts); all were related to doxorubicin therapy. Dose-limiting grade 3 skin toxicity (HFS reaction) occurred in 4/22 pts in cohort 3, which was related to BAY therapy. Non-DLTs were doxorubicin-related leuko/neutropenia, occurring 3 times in cohort 1, 4 times in cohort 3, and 2 times in cohort 4, and BAY-related HFS reactions in 5 pts from cohort 3. Steady-state BAY PK was not significantly influenced by concomitant doxorubicin medication when C1 and C2 were compared. Multiple BAY dosing had no consistent effect on the PK of doxorubicin or its metabolite doxorubicinol. Seventeen (53%) pts had a best response according to RECIST of PR (1 pt with mesothelioma) or SD (16 pts); 11 of these pts were from the 400 mg bid cohort. Conclusions:The combination of BAY and doxorubicin appears to be well tolerated and an extension in pts with HCC is ongoing. Most frequent AEs were related to doxorubicin. Most BAY-related AEs were mild (grade 1/2). No clinically relevant PK interaction between BAY and doxorubicin was observed. The recommended dose of BAY for phase II studies in combination with doxorubicin is 400 mg bid BAY. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer AG, Wuppertal, Germany, Bayer Corp. Bayer AG, Wuppertal, Germany