A phase I study of the raf kinase/VEGF-R inhibitor sorafenib in combination with bortezomib in patients with advanced malignancy.

2569 Background: This phase I study was undertaken to define the toxicity and the maximum tolerated dose of the combination of sorafenib (BAY43-9006; a Raf kinase /VEGFR2 inhibitor) with bortezomib (a proteasome inhibitor) in patients (pts) with advanced solid tumors. The study also has an expanded cohort at MTD that will enroll pts with myeloma/ CLL to evaluate the pharmacodynamic/ pharmacokinetic parameters of therapy.,Pts over 18 yrs with cytologic or histologic proof of unresectable solid tumors were enrolled to determine the MTD of the combination. Pts were treated with daily sorafenib and bortezomib on days 1, 4, 8 and 11 of a 3-week cycle. Toxicities were graded by the NCI CTC v.3. Pts are followed for a maximum of 3 mos after they go off treatment. The dose-escalation schema is in the table below.,Twelve pts (7 females, median age 63) have been enrolled on this study (6 each at dose level and 2). Tumor types included renal (3), lung (3), pancreas (2), breast (1), adrenal gland (1), melanoma (1) and spindle cell tumor (1). All pts are off treatment. Eight of these pts went off treatment due to disease progression (5 pts were treated at dose level 1 and 3 pts were treated at dose level 2). All 12 pts were evaluable for dose-limiting toxicity (DLT) analysis. DLT was seen in two pts at dose level 2 (one pt had grade 3 pain-abdominal and grade 4 lipase; and one pt had grade 3 vomiting). As a result, dose level 1 was declared as MTD. No grade 4 hematologic toxicities or grade 5 toxicities were seen. One grade 4 fatigue and lipase were reported in cycle 1. A median of 2 cycles of therapy (range 1-5) were administered. One pt had a partial response (renal), 4 had stable disease, 5 had progression and two pts were too early to evaluate for response.,The combination of sorafenib and bortezomib appear to have antitumor activity and based on this study we recommend a dose of sorafenib at 200 mg twice daily continuously with bortezomib 1 mg/m2 on days 1, 4, 8, 11 of a 21 day cycle for further studies. [Table: see text] No significant financial relationships to disclose.