A randomized phase II and pharmacokinetic study of dacarbazine in patients with recurrent glioma

S Vincent Rajkumar, Joel M Reid, P. J. Novotny, S. L. Safgren, B. W. Scheithauer, Steven P. Johnson, S. Nair, R. F. Morton, A. K. Hatfield, J. E. Krook, M. M. Ames, Jan Craig Buckner

Research output: Contribution to journalArticle

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Abstract

We conducted a randomized phase II study to determine the efficacy of dacarbazine (DTIC) in recurrent gliomas. Patients were randomly assigned to receive either DTIC 750 mg/m2 IV day 1 every 28 days (Arm A) or DTIC 200 mg/m2 IV days 1-5 every 28 days (Arm B). Pharmacokinetics were studied in 6 patients on each arm using HPLC analysis. Thirty-nine patients (30 male, 9 female), ages 27-67 years (median 53) were entered on the study (20 on Arm A, 19 on Arm B). No objective responses were seen. Median time to progression was 3 months. Median survival was 8 months. Treatment was generally well tolerated. Major toxicities were grade 1-2 nausea (33%), lethargy (28%), diarrhea (15%), alopecia (15%), and grade 3 neutropenia (8%). Four patients on Arm A had mild self-limited episodes of intravascular hemolysis occurring immediately after drug infusion, the mechanism of which is unknown. Mean AUC for DTIC, HMMTIC (5-[3-hydroxymethyl-3-methyl-1-triazeno] imidazole-4-carboxamide), and MTIC (5-[3-methyl-1-triazeno] imidazole-4-carboxamide), in Arm A were 14.8, 0.17, and 1.15 mM min, respectively. Corresponding values for Arm B (on day 1 of 5) were 1.7, 0.06, and 0.29 mM min, respectively. The predicted HMMTIC and MTIC exposure over 5 days for Arm B, based on the day 1 data, is higher than with Arm A. We conclude that DTIC is well tolerated but does not have activity in patients with recurrent gliomas. The 5-day schedule appears less toxic, and pharmacokinetics studies show that it provides greater exposure to MTIC and HMMTIC compared to the one-day schedule.

Original languageEnglish (US)
Pages (from-to)255-261
Number of pages7
JournalJournal of Neuro-Oncology
Volume49
Issue number3
DOIs
StatePublished - 2000

Fingerprint

Dacarbazine
5-(3-methyl-1-triazeno)imidazole-4-carboxamide
Glioma
Pharmacokinetics
Appointments and Schedules
Lethargy
Poisons
Alopecia
Hemolysis
Neutropenia
Nausea
Area Under Curve
Diarrhea
High Pressure Liquid Chromatography
Survival
Pharmaceutical Preparations
5-(3-hydroxymethyl-3-methyl-1-triazeno)imidazole-4-carboxamide

Keywords

  • Brain tumors
  • Chemotherapy
  • Dacarbazine
  • DTIC
  • Glioblastoma
  • Recurrent gliomas

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neuroscience(all)

Cite this

A randomized phase II and pharmacokinetic study of dacarbazine in patients with recurrent glioma. / Rajkumar, S Vincent; Reid, Joel M; Novotny, P. J.; Safgren, S. L.; Scheithauer, B. W.; Johnson, Steven P.; Nair, S.; Morton, R. F.; Hatfield, A. K.; Krook, J. E.; Ames, M. M.; Buckner, Jan Craig.

In: Journal of Neuro-Oncology, Vol. 49, No. 3, 2000, p. 255-261.

Research output: Contribution to journalArticle

Rajkumar, SV, Reid, JM, Novotny, PJ, Safgren, SL, Scheithauer, BW, Johnson, SP, Nair, S, Morton, RF, Hatfield, AK, Krook, JE, Ames, MM & Buckner, JC 2000, 'A randomized phase II and pharmacokinetic study of dacarbazine in patients with recurrent glioma', Journal of Neuro-Oncology, vol. 49, no. 3, pp. 255-261. https://doi.org/10.1023/A:1006454427026
Rajkumar, S Vincent ; Reid, Joel M ; Novotny, P. J. ; Safgren, S. L. ; Scheithauer, B. W. ; Johnson, Steven P. ; Nair, S. ; Morton, R. F. ; Hatfield, A. K. ; Krook, J. E. ; Ames, M. M. ; Buckner, Jan Craig. / A randomized phase II and pharmacokinetic study of dacarbazine in patients with recurrent glioma. In: Journal of Neuro-Oncology. 2000 ; Vol. 49, No. 3. pp. 255-261.
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abstract = "We conducted a randomized phase II study to determine the efficacy of dacarbazine (DTIC) in recurrent gliomas. Patients were randomly assigned to receive either DTIC 750 mg/m2 IV day 1 every 28 days (Arm A) or DTIC 200 mg/m2 IV days 1-5 every 28 days (Arm B). Pharmacokinetics were studied in 6 patients on each arm using HPLC analysis. Thirty-nine patients (30 male, 9 female), ages 27-67 years (median 53) were entered on the study (20 on Arm A, 19 on Arm B). No objective responses were seen. Median time to progression was 3 months. Median survival was 8 months. Treatment was generally well tolerated. Major toxicities were grade 1-2 nausea (33{\%}), lethargy (28{\%}), diarrhea (15{\%}), alopecia (15{\%}), and grade 3 neutropenia (8{\%}). Four patients on Arm A had mild self-limited episodes of intravascular hemolysis occurring immediately after drug infusion, the mechanism of which is unknown. Mean AUC for DTIC, HMMTIC (5-[3-hydroxymethyl-3-methyl-1-triazeno] imidazole-4-carboxamide), and MTIC (5-[3-methyl-1-triazeno] imidazole-4-carboxamide), in Arm A were 14.8, 0.17, and 1.15 mM min, respectively. Corresponding values for Arm B (on day 1 of 5) were 1.7, 0.06, and 0.29 mM min, respectively. The predicted HMMTIC and MTIC exposure over 5 days for Arm B, based on the day 1 data, is higher than with Arm A. We conclude that DTIC is well tolerated but does not have activity in patients with recurrent gliomas. The 5-day schedule appears less toxic, and pharmacokinetics studies show that it provides greater exposure to MTIC and HMMTIC compared to the one-day schedule.",
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