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Clinical Trial
. 2012 Feb;69(2):505-14.
doi: 10.1007/s00280-011-1721-x. Epub 2011 Aug 18.

A phase I study of bortezomib and temozolomide in patients with advanced solid tumors

J Portnow  1 , P Frankel, S Koehler, P Twardowski, S Shibata, C Martel, R Morgan, M Cristea, W Chow, D Lim, V Chung, K Reckamp, L Leong, T W Synold
Affiliations
Clinical Trial

A phase I study of bortezomib and temozolomide in patients with advanced solid tumors

J Portnow et al. Cancer Chemother Pharmacol. 2012 Feb.

Abstract

Purpose: The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs).

Methods: Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not.

Results: Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (>8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL(sys)) on day 9 was 51% of the CL(sys) on day 2 (P < 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P < 0.01). The median bortezomib CL(sys) on days 2 and 9 was significantly higher (P < 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P < 0.04).

Conclusions: The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m(2), respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.

Trial registration: ClinicalTrials.gov NCT00544284.

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Conflict of interest statement

Conflicts of interest No financial conflict of interest exists for any of the authors.

Figures

Fig. 1
Fig. 1
Plasma bortezomib concentration versus time profiles for study patients taking (group A) and not taking (group B) concomitant HEIAs. Data points and error bars in panel B represent the means and standard deviations
See this image and copyright information in PMC

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