Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies.

Background: Sorafenib (a VEGFR and multi-targeted kinase inhibitor) and Bortezomib (a proteasome inhibitor) have clinical antineoplastic activities as single agents, and combine synergistically in preclinical models.

Methods: This Phase I study was undertaken to define the toxicity and the maximum tolerated doses (MTD) of the combination in patients with advanced solid tumors. Patients with cytologic or histologic proof of unresectable solid tumors were treated with escalating doses of sorafenib (twice daily) and bortezomib (days 1, 4, 8 and 11 intravenously) with 21-day cycles.

Results: Fourteen patients (7 males, median age 65, range 24-74), with renal (3), lung (3), pancreas (2), and breast, adrenal gland, melanoma, spindle cell tumor, chronic lymphocytic leukemia and multiple myeloma (1 each) were enrolled. All patients are off treatment, 10 due to disease progression. DLT was seen in two patients (one grade 3 abdominal pain and grade 4 lipase elevation; one with grade 3 vomiting) at sorafenib 200 mg twice daily and bortezomib 1.3 mg/m(2), establishing the MTD. No grade 4 hematologic or grade 5 toxicities were seen. One patient with renal cell cancer had a partial response and 5 patients attained stable disease.

Conclusions: The combination of sorafenib and bortezomib was tolerated well. The recommended phase 2 doses are sorafenib 200 mg twice daily continuously with bortezomib 1 mg/m(2) on days 1, 4, 8, 11 (21 day cycles). The combination shows preliminary signs of efficacy, supporting phase 2 studies.