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Clinical Therapy Trials—Drug |
University of Texas Southwestern Medical Center, Dallas, TX 75214 (S.C.S., K.L.F.); University of Texas Health Science Center at San Antonio, San Antonio, TX 78284 (J.G.K.); University of California School of Medicine, San Francisco, CA 94143 (S.M.C., M.D.P.); University of Pittsburgh, Pittsburgh, PA 15213 (M.E.B.); University of Wisconsin, Madison, WI 53792 (H.I.R., M.P.M.); University of Washington, Seattle, WA 98195 (A.M.S.); and Cross Cancer Institute, Alberta, T6B 1Z2 Canada (D.F.)
2 Address correspondence and reprint requests to S. Clifford Schold, Jr., M.D., Duke University Medical Center, Room 201B Bryan Research Building, P.O. Box 2900, Durham, NC 27710.
Abstract
The North American Brain Tumor Consortium conducted a phase I trial of the combination 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide. Eligibility included a patient with a cancer type that was considered refractory to standard therapy. Prior nitrosourea treatments were not permitted. There were parallel dose escalations in two treatment schedules. Forty-five patients were enrolled during an 18-month period. The maximum tolerated doses (MTDs) when temozolomide followed BCNU (Arm A) were temozolomide at 550 mg/m2/p.o. and BCNU at 150 mg/m2/i.v.), whereas the MTD when temozolomide preceded BCNU (Arm B) was temozolomide at 400 mg/m2/p.o. and BCNU at 100 mg/m2/i.v. Toxicity was predominantly hematologic, although there were three instances of pulmonary toxicity, which in one case could have represented potentiation of nitrosourea-induced pulmonary fibrosis. The half-life of temozolomide was 1.86 (±0.31) h. There was a moderate relationship between dose and peak concentration and a strong relationship between dose and plasma concentration time curve. Pharmacokinetic parameters of temozolomide were unaffected by the treatment schedule, so the difference in MTD between the schedules is likely due to a biologic rather than a pharmacokinetic sequence interaction. There were 9 partial responses among 43 patients evaluable for response, including 5 of 25 with a histologic diagnosis of glioblastoma. The recommended dose and schedule for phase II trials of this regimen are BCNU 150 mg/m2/i.v. followed in 2 h by temozolomide 550 mg/m2/p.o. repeated every 6 weeks. We are also recommending screening and periodic pulmonary function testing during treatment to assess the possible potentiation of nitrosourea-induced pulmonary fibrosis.
References
Felker, G.M., Friedman, H.S., Dolan, M.E., Moschel, R.C., and Schold, C. (1993) Treatment of subcutaneous and intracranial brain tumor xenografts with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother. Pharmacol. 32,471 -476.[CrossRef][ISI][Medline]
Friedman, H.S., Dolan, M.E., Moschel, R.C., Pegg, A.E., Felker,
G.M., Rich, J., Bigner, D.D., and Schold, S.C., Jr. (1992)
Enhancement of nitrosourea activity in medulloblastoma and glioblastoma
multiforme. J. Natl. Cancer Inst.
84,1926
-1931.
Friedman, H.S., Dolan, E.E., Pegg, A.E., Marcelli, S., Keir, S.,
Catino, J.J., Bigner, D.D., and Schold, S.C., Jr. (1995) Activity
of temozolomide in the treatment of central nervous system tumor xenografts.
Cancer Res. 55,2853
-2857.
Friedman, H.S., Johnson, S.P., Doug, Q., Schold, S.C., Rasheed,
B.K., Bigner, S.H., Ali-Osman, F., Dolan, E., Colvin, O.M., Houghton, P.,
Germain, G., Drummond, J.T., Keir, S., Marcelli, S., Bigner, D.D., and
Modrich, P. (1997) Methylator resistance mediated by mismatch
repair deficiency in a glioblastoma multiforme xenograft. Cancer
Res. 57,2933
-2936.
Gibaldi, M. (Ed.) (1984) Biopharmaceutics and Clinical Pharmacokinetics. Third edition. Philadelphia, Penn.: Lea & Febiger.
Hundley, R.F., and Lukens, J.N. (1979) Nitrosourea-associated pulmonary fibrosis. Cancer Treat. Rep. 63,2128 -2130.[ISI][Medline]
Mitchell, R.B., and Dolan, M.E. (1993) Effect of temozolomide and dacarbazine on O6-alkylguanine-DNA alkyltransferase activity and sensitivity of human tumor cells and xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother. Pharmacol. 32,59 -63.[CrossRef][ISI][Medline]
Newlands, E.S., Blackledge, G.R.P., Slack, J.A., Rustin, G.J., Smith, D.B., Stuart, N.S., Quarterman, C.P., Hoffman, R., Stevens, M.F., and Brampton, M.H. (1992) Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br. J. Cancer 65,287 -291.[ISI][Medline]
Newlands, E.S., Stevens, M.F.G., Wedge, S.R., Wheelhouse, R.T., and Brock, C. (1997) Temozolomide: A review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat. Rev. 23,35 -61.[CrossRef][ISI][Medline]
Plowman, J., Waud, W.R., Koutsoukos, A.D., Rubinstein, L.V., Moore,
T.D., and Grever, M.R. (1994) 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. 54,3793
-3799.
Schold, S.C., Jr., Brent, T.P., von Hofe, E., Friedman, H.S., Mitra, S., Bigner, D.D., Swenberg, J.A., and Kleihues, P. (1989) O6-alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain tumor xenografts. J. Neurosurg. 70,573 -577.[ISI][Medline]
Tsang, L.L.H., Farmer, P.B., Gescher, A., and Slack, J.A. (1990) Characterization of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity. Cancer Chemother. Pharmacol. 26,429 -436.[ISI][Medline]
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