A Phase I and Pharmacokinetic Study of Temozolomide and Cisplatin in Patients with Advanced Solid Malignancies1
- Carolyn D. Britten,
- Eric K. Rowinsky,
- Sharyn D. Baker,
- Sanjiv S. Agarwala,
- John R. Eckardt,
- Rebecca Barrington,
- Sami G. Diab,
- Lisa A. Hammond,
- Tom Johnson,
- Miguel Villalona-Calero,
- Uwe Fraass,
- Paul Statkevich,
- Daniel D. Von Hoff and
- S. Gail Eckhardt2
- Cancer Therapy and Research Center, Institute for Drug Development, and The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229 [C. D. B, E. K. R., S. D. B., J. R. E., R. B., S. G. D., L. A. H., M. V-C., D. D. V. H., S. G. E.]; The University of Pittsburgh Medical Center, Montefiore Hospital, Division of Medical Oncology, Pittsburgh, Pennsylvania 15213 [S. S. A.]; Brooke Army Medical Center, Fort Sam Houston, Texas 78234 [T. J.]; and Schering-Plough Research Institute, Kenilworth, New Jersey 07033 [U. F., P. S.]
Abstract
Temozolomide (TMZ) is an oral imidazotetrazinone that is spontaneously converted to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at physiological pH. MTIC methylates DNA at the O6 position of guanine, although this lesion may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (AGAT). In this study, TMZ was combined with cisplatin (CDDP), because both agents have single-agent activity against melanoma and other tumor types. Additionally, CDDP has been shown to inactivate AGAT, and subtherapeutic concentrations of CDDP have been shown to increase the sensitivity of leukemic blasts to TMZ. This Phase I study sought to determine the toxicities, recommended dose, and pharmacological profile of the TMZ/CDDP combination.
Patients were treated with oral TMZ daily for 5 consecutive days together with CDDP on day 1 (4 h after TMZ) every 4 weeks at the following TMZ (mg/m2/day)/CDDP (mg/m2) dose levels: 100/75, 150/75, 200/75, and 200/100. Plasma samples were obtained on days 1 and 2 to evaluate the pharmacokinetic parameters of TMZ alone and in combination with CDDP. Fifteen patients received a total of 44 courses of TMZ/CDDP. The principal toxicities of the regimen consisted of neutropenia, thrombocytopenia, nausea, and vomiting, which were intolerable in two of six new patients treated at the 200/100 mg/m2 dose level. Of five patients receiving 17 courses at the next lower dose level (200/75 mg/m2), none experienced dose-limiting toxicity. Antitumor activity was observed in patients with non-small cell lung cancer, squamous cell carcinoma of the tongue, and leiomyosarcoma of the uterus. Pharmacokinetic studies of TMZ revealed the following pertinent parameters (mean ± SD): time to maximum plasma concentration (Tmax) = 1.1 ± 0.6 h (day 1) and 1.7 ± 0.9 h (day 2); elimination half-life (t1/2) = 1.74 ± 0.22 h (day 1) and 2.35 ± 0.70 h (day 2); and clearance (Cls/F) = 115 ± 27 ml/min/m2 (day 1) and 141 ± 109 ml/min/m2 (day 2). TMZ drug exposure, described by the area under the plasma concentration-time curve (AUC∞) and the maximum plasma concentration (Cmax), was similar on days 1 and 2.
On the basis of these results, the recommended doses for Phase II clinical trials are TMZ 200 mg/m2/day for 5 days with 75 mg/m2 CDDP on day 1, every 4 weeks. The addition of CDDP did not affect the tolerable dose of single-agent TMZ (200 mg/m2/day × 5 days), nor did it substantially alter the pharmacokinetic behavior of TMZ.
Footnotes
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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.
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↵1 This work was supported in part by Schering-Plough Research Institute. Some patients in the study were treated at the Frederic C. Bartter Clinical Research Unit of The Audie Murphy Veterans Administration Hospital, supported in part by NIH Grant MO1 RR01346.
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↵2 To whom requests for reprints should be addressed, at Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Drive, Suite 700, San Antonio, Texas 78229. Phone: (210) 616-5834; Fax: (210) 692-7502; E-mail: geckhardt{at}saci.org
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↵3 The abbreviations used are: TMZ, temozolomide; DTIC, dacarbazine; MTIC, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide; AGAT, O6-alkylguanine-DNA alkyltransferase; DLT, dose-limiting toxicity; AUC, area under the plasma concentration-versus-time curve; CDDP, cisplatin; MTD, maximum tolerated dose; ECOG, Eastern Cooperative Oncology Group; ANC, absolute neutrophil count.
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- Accepted April 1, 1999.
- Received January 14, 1999.
- Revision received March 31, 1999.
