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 Jens Voortman, 1 Egbert F. Smit, 2 Richard Honeywell, 1 Bart C. Kuenen, 1 Godefridus J. Peters, 1 Helgi van de Velde, 3 and Giuseppe Giaccone 1 Abstract 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/m 2 days 1and 8 and cisplatin 70 mg/m 2 day 1, every 21days. 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/m 2 in the weekly schedule. Febrile neutropenia and thrombocyto- penia with bleeding were dose-limiting toxicities in the twice-weekly schedule, leading to an MTD of bortezomib 1.0 mg/m 2 as well. Most common zgrade 3 treatment-related toxicities were thrombocytopenia and neutropenia. No grade z3 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 cis- platin and gemcitabine were not significantly different in patients receiving either schedule. Conclusions: Weekly bortezomib 1.0 mg/m 2 plus gemcitabine 1,000 mg/m 2 and cisplatin 70 mg/m 2 is the recommended phase 2 schedule, constituting a safe combination, with activity in NSCLC. The ubiquitin-proteasome pathway plays a pivotal role in the degradation of most intracellular proteins in eukaryotic cells, including those regulating apoptosis, cell cycle progression, transcription factor activation, and angiogenesis (1 – 3). Borte- zomib (VELCADE; Millennium Pharmaceuticals, Inc; Johnson & Johnson Pharmaceutical Research and Development, LLC), a dipeptide proteasome inhibitor, is a novel antineoplastic agent presently approved for the treatment of patients with relapsed and refractory multiple myeloma and relapsed mantle-cell lymphoma (4). Inhibition of the chymotryptic-like proteolytic activity of the proteasome by bortezomib suppresses tumor survival through multiple mechanisms, including induction of G 2 -M phase cell cycle arrest, cleavage of bcl-2, up-regulation and/or accumulation of BH3-only proteins, activation of caspases, and inhibition of nuclear factor-nB activation (5 – 9). In preclinical and clinical studies, it has shown a unique and promising cytotoxicity profile in a variety of solid tumors as well (10, 11). When the recommended schedule for multiple myeloma patients, twice-weekly administration of bortezomib 1.3 mg/m 2 , was administered as second-line treatment to non – small cell lung cancer (NSCLC) patients, 8% achieved a partial response (12, 13). Gemcitabine in combination with cisplatin is a widely used chemotherapeutic regimen for the treatment of advanced NSCLC, urothelial cell cancer, and other solid tumors (14, 15). Preclinical and clinical studies indicate synergistic or additive activity when bortezomib is combined with gemcitabine and/ or platinum agents (16 – 20). Inhibition of nuclear factor-nB activation, a factor thought to play a role in resistance to chemotherapy, and accumulation of proteins, misfolded or damaged by the effects of chemotherapy, might play important contributory roles (21, 22). A sequence-specific interaction of bortezomib and several chemotherapeutics has been shown in some preclinical studies, suggesting Cancer Therapy: Clinical 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 Received 1/11/07; revised 3/15/07; accepted 3/29/07. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: This study was presented in part at the American Society of Clinical Oncology 2005 (abstract no. 2103) and the European Cancer Conference 2005 (abstract no. 1468). 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@vumc.nl. F 2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-0061 www.aacrjournals.org Clin Cancer Res 2007;13(12) June 15, 2007 3642 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/13/12/3642/1969443/3642.pdf by guest on 06 July 2022