Abstract C124: Pharmacokinetics and safety of sorafenib in combination with capecitabine in advanced solid tumors
Authors: Infante Jeffrey R. , Jones Suzanne F. , Bendell Johanna C. , Greco F. Anthony , Yardley Denise A. , Woudenberg Janet , Lathia Chetan D. , Lane Cassie M. , Spigel David R. , Hainsworth John D. , Burris Howard A. 
Published: June 2012

Abstract
Background: This study had two primary objectives: first to address a possible increase in capecitabine (C) exposure when co-administered with sorafenib, and second, to further characterize the overall toxicity of this combination in both a 21 and a 14 day schedule.
Methods: Eligibility included patients (pts) with advanced solid tumors, ECOG 0–1, and adequate organ function. The study enrolled two simultaneous 21 day schedules of the combination: Cohort A received C 750 mg/m2 BID for 14 days of a 21-day cycle and Cohort B received C 1000 mg/m2 BID for 14 days of a 21-day cycle. In both Cohorts A and B, following a 7day lead in of C alone, sorafenib was dosed 400 mg BID daily for 21 days. Steady-state PK (pre, 30 min, 1, 2, 4, 6, 8, and 12 hr) was obtained following 7 days of exposure to C alone (both C and 5FU levels measured), sorafenib alone (both sorafenib levels and its metabolites), and both C and sorafenib in combination. Cohort C explored an alternate schedule without PK of 7 day on/7 day off flat dose C1000 mg BID in combination with continuous daily dosing of sorafenib 400 mg BID.
Results: 32 pts were enrolled between 2/08 and 4/09: median age 63 yrs (range 35–87); ECOG 0 75%; male 56%; and Caucasian 81%. HFSR was the primary toxicity with 16 (50%) of the 32 pts experiencing grade 3 events. Grade 3 HFSR by dose-level: C 750 mg/m2 was 33% and 1000 mg/m2 was 75%. Of the 16 pts that developed grade 3 HFSR, 75% of the time it occurred within the first 2 cycles. Grade 3 HFSR was also the DLT of Cohort C and defined the MTD at 1000 mg BID flat dose of C. Other grade 3 non-hematologic toxicities were rare: diarrhea 6%, mucositis 3%, and fatigue 3%. There were no grade 4 hematologic or non-hematologic toxicities. Upon co-administration with C (either 750 or 1000 mg/m2) there was no significant change in the Cmax or AUC(0–12) of sorafenib or its metabolites. Conversely, upon co-administration of sorafenib, at the C 750 mg/m2 dose-level (n=6 pts) there was a 15% increase C AUC(0–12) and no change in the 5FU AUC(0–12). At the C 1000 mg/m2 dose-level (n=12 pts), there was a 16% increase in C AUC(0–12) and an 8% increase in 5FU AUC(0–12). However these trends did not meet statistical significance, LS geometric means ratio for AUC(0–12) for C 750 mg/m2 1.15 (90%CI 0.90–1.46) and C 1000 mg/m2 1.16 (90%CI 0.94–1.43). G3 HFSR did not directly correlate with exposures of capecitabine, 5FU, or sorafenib. One pancreatic cancer patient had a PR and remains on study &gt; 9 months. 34% of pts had stable disease lasting ≥ 4 cycles.
Conclusions: Co-administration of sorafenib resulted in a mild increase in capecitabine AUC, though this increase did not reach statistical significance. Capecitabine did not affect the AUC of sorafenib or its metabolites. The rate of grade 3 HFSR is concerning and limits the feasibility of prolonged dosing with capecitabine 1000 mg/m2 on the 21 day schedule.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C124.