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01-02-2012 | Original Article

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

Authors: J. Portnow, 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

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2012

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/m², 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.

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Title: A phase I study of bortezomib and temozolomide in patients with advanced solid tumors
Authors: J. Portnow
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
Publication date: 01-02-2012
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1721-x

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Abstract

Purpose

Methods

Results

Conclusions

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