A dose-finding and pharmacodynamic study of bortezomib in combination with weekly paclitaxel in patients with advanced solid tumors

作者：Ramaswamy Bhuvaneswari^*; Bekaii Saab Tanios; Schaaf Larry J; Lesinski Gregory B; Lucas David M; Young Donn C; Ruppert Amy S; Byrd John C; Culler Kristy; Wilkins Diedre; Wright John J; Grever Michael R; Shapiro Charles L

来源：Cancer Chemotherapy and Pharmacology, 2010, 66(1): 151-158.

DOI：10.1007/s00280-009-1145-z

• Bortezomib
• Phase I
• Solid tumors
• Paclitaxel

Purpose A phase I study to determine the maximum tolerated dose(MTD) of bortezomib (B) when combined with weekly paclitaxel in patients with advanced solid tumors.
Patients and methods Eligible patients received escalating doses of intravenous (IV) bortezomib (0.6-2 mg/m(2)) on days 2 and 9 and IV paclitaxel at 100 mg/m(2) on days 1 and 8 of a 21-day cycle. Dose escalation was based on two end-points: not exceeding 80% 20S-proteasome inhibition (20-S PI) and the development of dose-limiting toxicity defined as grade 3 or greater non-hematologic or grade 4 hematologic toxicities.
Results Forty-five patients with advanced solid tumors and a median of 3 prior chemotherapy regimens (range 0-9), received 318 doses (median 5, range 1-34) of bortezomib and paclitaxel. Dose-related inhibition of 20-S PI was observed with a maximum inhibition of 70-80% at the MTD of 1.8 mg/m(2) of bortezomib. At the MTD (N = 9) the following toxicities were observed: grade 4 neutropenia without fever (n = 2) and cerebrovascular ischemia (n = 1); grade 3 neutropenia (n = 3), diarrhea (n = 2), nausea (n = 1), and fatigue (n = 1); grade 2 fatigue (n = 5), diarrhea (n = 4), and dyspnea (n = 2). There was one partial response in a patient with an eccrine porocarcinoma. Stabilization of disease was observed in 7 (16%) patients, 3 of whom had advanced pancreatic cancer.
Conclusion Sequential paclitaxel and bortezomib in previously treated patients with advanced solid tumors resulted in acceptable toxicity and no evidence of interaction. The recommended phase II dose of bortezomib in combination with weekly paclitaxel was 1.8 mg/m(2).

• 出版日期2010-5