Original Article

Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 1, pp 151-158

First online:

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

  • Bhuvaneswari RamaswamyAffiliated withThe Ohio State University Email author 
  • , Tanios Bekaii-SaabAffiliated withThe Ohio State University
  • , Larry J. SchaafAffiliated withThe Ohio State University
  • , Gregory B. LesinskiAffiliated withThe Ohio State University
  • , David M. LucasAffiliated withThe Ohio State University
  • , Donn C. YoungAffiliated withThe Ohio State University
  • , Amy S. RuppertAffiliated withThe Ohio State University
  • , John C. ByrdAffiliated withThe Ohio State University
  • , Kristy CullerAffiliated withThe Ohio State University
    • , Diedre WilkinsAffiliated withThe Ohio State University
    • , John J. WrightAffiliated withThe Ohio State University
    • , Michael R. GreverAffiliated withThe Ohio State University
    • , Charles L. ShapiroAffiliated withThe Ohio State University

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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/m2) on days 2 and 9 and IV paclitaxel at 100 mg/m2 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.


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/m2 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.


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/m2.


Bortezomib Phase I Solid tumors Paclitaxel