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Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma.

Authors :
Yust‐Katz, Shlomit
Liu, Diane
Yuan, Ying
Liu, Vivien
Kang, Sanghee
Groves, Morris
Puduvalli, Vinay
Levin, Victor
Conrad, Charles
Colman, Howard
Hsu, Sigmonid
Yung, W. K. Alfred
Gilbert, Mark R.
Source :
Cancer (0008543X); Aug2013, Vol. 119 Issue 15, p2747-2753, 8p
Publication Year :
2013

Abstract

BACKGROUND Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma. METHODS The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m<superscript>2</superscript> daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6). RESULTS Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths. CONCLUSIONS These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule. Cancer 2013;119:2747-2753. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
0008543X
Volume :
119
Issue :
15
Database :
Complementary Index
Journal :
Cancer (0008543X)
Publication Type :
Academic Journal
Accession number :
89149839
Full Text :
https://doi.org/10.1002/cncr.28031