This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Voortman, J. Articles by Giaccone, G. Search for Related Content PubMed PubMed Citation Articles by Voortman, J. Articles by Giaccone, G.

A Parallel Dose-Escalation Study of Weekly and Twice-Weekly Bortezomib in Combination with Gemcitabine and Cisplatin in the First-Line Treatment of Patients with Advanced Solid Tumors

Authors' Affiliations: Departments of ¹ Medical Oncology and ² Pulmonology, VU University Medical Center, Amsterdam, the Netherlands; and ³ Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium

Requests for reprints: Giuseppe Giaccone, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, the Netherlands. Phone: 31-20-444-321; Fax: 31-20-444-079; E-mail: g.giaccone{at}vumc.nl.

Purpose: To establish maximum tolerated dose (MTD) and tolerability of two schedules of bortezomib in combination with cisplatin and gemcitabine as first-line treatment of patients with advanced solid tumors.

Experimental Design: Patients were assigned to increasing doses of bortezomib days 1 and 8 (weekly schedule) or days 1, 4, 8, and 11 (twice-weekly schedule), in addition to gemcitabine 1,000 mg/m² days 1 and 8 and cisplatin 70 mg/m² day 1, every 21 days. Maximum of six cycles. Plasma pharmacokinetics of cisplatin and gemcitabine were determined at MTD.

Results: Thirty-four patients were enrolled of whom 27 had non–small cell lung cancer (NSCLC). Diarrhea, neutropenia, and thrombocytopenia were dose-limiting toxicities leading to an MTD of bortezomib 1.0 mg/m² in the weekly schedule. Febrile neutropenia and thrombocytopenia with bleeding were dose-limiting toxicities in the twice-weekly schedule, leading to an MTD of bortezomib 1.0 mg/m² as well. Most common grade 3 treatment-related toxicities were thrombocytopenia and neutropenia. No grade 3 treatment-related sensory neuropathy was reported. Of 34 evaluable patients, 13 achieved partial responses, 17 stable disease, and 4 progressive disease. Response and survival of NSCLC patients treated with twice weekly or weekly bortezomib were similar. However, increased dose intensity of bortezomib led to increased gastrointestinal toxicity as well as myelosuppression. Pharmacokinetic profiles of cisplatin and gemcitabine were not significantly different in patients receiving either schedule.

Conclusions: Weekly bortezomib 1.0 mg/m² plus gemcitabine 1,000 mg/m² and cisplatin 70 mg/m² is the recommended phase 2 schedule, constituting a safe combination, with activity in NSCLC.

This article has been cited by other articles:

				R. Z. Orlowski and D. J. Kuhn Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade Clin. Cancer Res., March 15, 2008; 14(6): 1649 - 1657. [Abstract] [Full Text] [PDF]