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. 1999 Nov;81(6):1022–1030. doi: 10.1038/sj.bjc.6690802

Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies

M Brada 1, I Judson 1, P Beale 1, S Moore 1, P Reidenberg 2, P Statkevich 3, M Dugan 3, V Batra 3, D Cutler 3
PMCID: PMC2362937  PMID: 10576660

Abstract

Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100–250 mg m−2 was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m−2 day−1. Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax ~1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m−2 day−1 for 5 days, every 28 days, is recommended for phase II studies. © 1999 Cancer Research Campaign

Keywords: oral, cytotoxic, chemotherapy, pharmacokinetics, dose escalation

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Selected References

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  1. Bleehen N. M., Newlands E. S., Lee S. M., Thatcher N., Selby P., Calvert A. H., Rustin G. J., Brampton M., Stevens M. F. Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol. 1995 Apr;13(4):910–913. doi: 10.1200/JCO.1995.13.4.910. [DOI] [PubMed] [Google Scholar]
  2. Bower M., Newlands E. S., Bleehen N. M., Brada M., Begent R. J., Calvert H., Colquhoun I., Lewis P., Brampton M. H. Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol. 1997;40(6):484–488. doi: 10.1007/s002800050691. [DOI] [PubMed] [Google Scholar]
  3. Catapano C. V., Broggini M., Erba E., Ponti M., Mariani L., Citti L., D'Incalci M. In vitro and in vivo methazolastone-induced DNA damage and repair in L-1210 leukemia sensitive and resistant to chloroethylnitrosoureas. Cancer Res. 1987 Sep 15;47(18):4884–4889. [PubMed] [Google Scholar]
  4. D'Atri S., Piccioni D., Castellano A., Tuorto V., Franchi A., Lu K., Christiansen N., Frankel S., Rustum Y. M., Papa G. Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: studies with blasts of leukaemic patients. Ann Oncol. 1995 Apr;6(4):389–393. doi: 10.1093/oxfordjournals.annonc.a059189. [DOI] [PubMed] [Google Scholar]
  5. Denny B. J., Wheelhouse R. T., Stevens M. F., Tsang L. L., Slack J. A. NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry. 1994 Aug 9;33(31):9045–9051. doi: 10.1021/bi00197a003. [DOI] [PubMed] [Google Scholar]
  6. Dhodapkar M., Rubin J., Reid J. M., Burch P. A., Pitot H. C., Buckner J. C., Ames M. M., Suman V. J. Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. Clin Cancer Res. 1997 Jul;3(7):1093–1100. [PubMed] [Google Scholar]
  7. Friedman H. S., Dolan M. E., Pegg A. E., Marcelli S., Keir S., Catino J. J., Bigner D. D., Schold S. C., Jr Activity of temozolomide in the treatment of central nervous system tumor xenografts. Cancer Res. 1995 Jul 1;55(13):2853–2857. [PubMed] [Google Scholar]
  8. Kim H. K., Lin C. C., Parker D., Veals J., Lim J., Likhari P., Statkevich P., Marco A., Nomeir A. A. High-performance liquid chromatographic determination and stability of 5-(3-methyltriazen-1-yl)-imidazo-4-carboximide, the biologically active product of the antitumor agent temozolomide, in human plasma. J Chromatogr B Biomed Sci Appl. 1997 Dec 5;703(1-2):225–233. doi: 10.1016/s0378-4347(97)00431-3. [DOI] [PubMed] [Google Scholar]
  9. Newlands E. S., Blackledge G. R., Slack J. A., Rustin G. J., Smith D. B., Stuart N. S., Quarterman C. P., Hoffman R., Stevens M. F., Brampton M. H. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer. 1992 Feb;65(2):287–291. doi: 10.1038/bjc.1992.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Newlands E. S., O'Reilly S. M., Glaser M. G., Bower M., Evans H., Brock C., Brampton M. H., Colquhoun I., Lewis P., Rice-Edwards J. M. The Charing Cross Hospital experience with temozolomide in patients with gliomas. Eur J Cancer. 1996 Dec;32A(13):2236–2241. doi: 10.1016/s0959-8049(96)00258-4. [DOI] [PubMed] [Google Scholar]
  11. O'Reilly S. M., Newlands E. S., Glaser M. G., Brampton M., Rice-Edwards J. M., Illingworth R. D., Richards P. G., Kennard C., Colquhoun I. R., Lewis P. Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours. Eur J Cancer. 1993;29A(7):940–942. doi: 10.1016/s0959-8049(05)80198-4. [DOI] [PubMed] [Google Scholar]
  12. Plowman J., Waud W. R., Koutsoukos A. D., Rubinstein L. V., Moore T. D., Grever M. R. Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res. 1994 Jul 15;54(14):3793–3799. [PubMed] [Google Scholar]
  13. Shen F., Decosterd L. A., Gander M., Leyvraz S., Biollax J., Lejeune F. Determination of temozolomide in human plasma and urine by high-performance liquid chromatography after solid-phase extraction. J Chromatogr B Biomed Appl. 1995 May 19;667(2):291–300. doi: 10.1016/0378-4347(95)00040-p. [DOI] [PubMed] [Google Scholar]
  14. Stevens M. F., Hickman J. A., Langdon S. P., Chubb D., Vickers L., Stone R., Baig G., Goddard C., Gibson N. W., Slack J. A. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res. 1987 Nov 15;47(22):5846–5852. [PubMed] [Google Scholar]
  15. Tsang L. L., Farmer P. B., Gescher A., Slack J. A. Characterisation of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity. Cancer Chemother Pharmacol. 1990;26(6):429–436. doi: 10.1007/BF02994094. [DOI] [PubMed] [Google Scholar]
  16. Wedge S. R., Porteous J. K., Glaser M. G., Marcus K., Newlands E. S. In vitro evaluation of temozolomide combined with X-irradiation. Anticancer Drugs. 1997 Jan;8(1):92–97. doi: 10.1097/00001813-199701000-00013. [DOI] [PubMed] [Google Scholar]
  17. Wedge S. R., Porteous J. K., Newlands E. S. 3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity. Br J Cancer. 1996 Oct;74(7):1030–1036. doi: 10.1038/bjc.1996.485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Wedge S. R., Porteous J. K., Newlands E. S. Effect of single and multiple administration of an O6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model. Cancer Chemother Pharmacol. 1997;40(3):266–272. doi: 10.1007/s002800050657. [DOI] [PubMed] [Google Scholar]

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