A dose-finding and pharmacodynamic study of bortezomib in combination with weekly paclitaxel in patients with advanced solid tumors
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.
KeywordsBortezomib Phase I Solid tumors Paclitaxel
The project described was supported by Grant Number U01-CA76576 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer institute or the National Institutes of Health. The authors wish to thank the patients who participated in this trial; the many nurses, nurse practitioners, and patient care associates who assisted in the care of these patients in the Clinical Treatment Unit, JamesCare Dublin Clinic, and the Immediate Care Center; and acknowledge the contributions of Bill Riordan, Lisa O’Brien, and Jeannie Pierce at Millennium Pharmaceuticals in performing the 20S proteasome assay. The project described was supported by Grant Number U01-CA76576 from the National Cancer Institute.
- 11.Millennium Pharmaceuticals I. Velcade Full Prescribing Information. June 2008Google Scholar
- 19.Cresta SSC, Catapano CV, Gallerani E, Passalacqua D, Rinaldi A, Bertoni F, Vigano L, maur M, Capri G, Maccioni E, Tosi D, Gianni L (2008) Phase I study of bortezomib with weekly paclitaxel in patients with advanced solid tumors. Eur J Cancer. doi: 10.1016/j.ejca.2008.05.022
- 20.Ma C, Mandrekar SJ, Alberts SR et al (2007) A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies. Cancer Chemother Pharmacol 59:207–215CrossRefPubMedGoogle Scholar
- 25.Aron JL, Parthun MR, Marcucci G et al (2003) Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. Blood 102:652–658CrossRefPubMedGoogle Scholar
- 36.Ashamalla H, Zaki B, Mokhtar B et al. (2003) Hyperfractionated radiotherapy and paclitaxel for locally advanced/unresectable pancreatic cancer [erratum appears in Int J Radiat Oncol Biol Phys. Mar 15; 55(4):1158]. Int J Radiat Oncol Biol Phys 55: 679–687Google Scholar