Phase I study of BAY 43–9006 (sorafenib), a Raf kinase and VEGFR inhibitor, combined with irinotecan (CPT-11) in advanced solid tumors

Abstract

3115 Background: BAY 43–9006 (BAY), a Raf kinase and VEGFR inhibitor, inhibits tumor cell proliferation and angiogenesis. In preclinical studies BAY and irinotecan (CPT-11) had improved anti-tumor activity over single agents. Methods: This phase I study investigated the safety and pharmacokinetics (PK) of continuous oral BAY plus CPT-11 administered weekly for 4 weeks followed by a 2-week break. In an initial dose-escalation phase, patients (pts) with advanced, refractory solid tumors received CPT-11 125 mg/m2 and BAY 100, 200 and 400 mg bid (cohorts 1–3). In an extended phase, colorectal cancer (CRC) pts received fixed-dose CPT-11 140 mg and BAY 400 mg bid (cohort 4). Results: 32 pts (ECOG 0:1:2=10:21:1) were valid for safety. 20 pts were enrolled in the dose-escalation phase (common tumor types: CRC [n=9] and gastric cancer [n=4]) and 12 pts in the CRC extension. MTD was not reached. The most common drug-related AEs were diarrhea, alopecia, fatigue, nausea and vomiting. The most common ≥grade 3 AEs were blood/bone marrow related and gastrointestinal. 12/20 pts in cohorts 1–3 and 5/7 evaluable pts in cohort 4 had SD as best response. BAY 100 or 200 mg bid and CPT-11 125 mg/m2 had no marked impact on the PK of either drug. BAY 400 mg bid plus CPT-11 125 mg/m2 or 140 mg increased exposure to CPT-11 and the metabolite SN 38, but did not appear to increase clinical toxicity. CPT-11 140 mg had a negligible effect on the PK of BAY. Conclusions: MTD was not reached for BAY 400 mg bid plus CPT-11 125 mg/m2 or 140 mg. BAY 400 mg bid and CPT-11 125 mg/m2or 140 mg increased exposure to CPT-11 and SN 38. CPT-11 140 mg had a negligible effect on the PK of BAY. As patients are still being treated with 140 mg CPT-11 and BAY 400 mg bid, the recommended dose for CPT-11 in combination with BAY 400 mg bid will be made when these data are presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer