Phase I study of streptozocin- and carmustine-sequenced administration in patients with advanced cancer

K. C. Micetich, B. Futscher, D. Koch, R. I. Fisher, L. C. Erickson

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Background: Fewer than 20% of patients with nonhematologic malig-nancies treated with chloroethylnitrosoureas (CENUs) respond, but streptozocin (STZ), which depletes O6-methylguanine-DNA-methyltransferase (MGMT), has been shown to reverse resistance to CENUs in vitro. Purpose: The purpose of this phase I study was to determine (a) the maximum toler-ated dose (MTD) of carmustine (BCNU), a CENU, plus a fixed dose of STZ; (b) the toxic effects of the drugs; and (c) the effects on peripheral blood mononuclear cells (PBMC). Methods: A clinical phase I study of STZ fol-lowed by BCNU was designed to simu-late conditions that produce maximal sensitization of CENU-resistant HT-29 cells in vitro. Patients received a 20minute infusion of the MTD of STZ (2 g/m2) followed 1 hour later with a 60-minute infusion of BCNU (100, 125, 137.5, or 150 mg/m2). Treatment was repeated after 6 weeks. Twenty-four patients with advanced malignancies received 32 courses of therapy (range, 1-2 courses). Results: The MTD of BCNU was 125 mg/m2. The dose-limit-ing toxic effect was thrombocytopenia occurring about 22 days after treat-ment, with recovery between days 28 and 35. Transient hypophosphatemia and proteinuria were common, and serum creatinine was elevated in 9% of the courses. Two patients who received therapy died-one due to pulmonary toxic effects and one due to hepatic toxic effects. Two patients with pre-viously untreated carcinoid achieved partial response. In three patients, MGMT levels in PBMC were more than 85% depleted after STZ ad-ministration and more than 90% depleted after BCNU infusion. Con-clusions: These results show that the magnitude of MGMT depletion by STZ in PBMC is in the range necessary to produce sensitivity to CENUs in resis-tant cell lines but also that, when BCNU is combined with STZ, the MTD of BCNU is about 50% that of BCNU as a single agent and that platelet count suppression occurs earlier. Implica-tions: We plan to conduct phase II studies of STZ plus BCNU in tumor types with low response to CENUs. One of the major goals will be to demonstrate that depletion of MGMT is greater in tumor cells than in normal cells. [J Natl Cancer Inst 84:256-260, 1992]

Original languageEnglish (US)
Pages (from-to)256-261
Number of pages6
JournalJournal of the National Cancer Institute
Volume84
Issue number4
DOIs
StatePublished - Feb 19 1992
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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