Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer

E. Berman, R. E. Wittes, B. Leyland-Jones, E. S. Casper, Richard J. Gralla, J. Howard, L. Williams, R. Baratz, C. W. Young

Research output: Contribution to journalArticle

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Abstract

4-Demethoxydaunorubicin (4-DMDR), an anthracycline analogue available in i.v. and p.o. form, has shown significant antitumor activity in murine tumor models while producing less cardiac toxicity than doxorubicin at equimyelotoxic doses. Phase I and clinical pharmacology studies of the i.v. and p.o. preparation were performed. With i.v. 4-DMDR, consistent myelosuppression was observed at a dose of 15 mg/sq m at a median Day 15; mild nausea and vomiting were observed in 9% of all treatment courses. In patients given p.o. 4-DMDR, myelosuppression occurred at median Day 14 in 10 of 12 patients given 50 mg/sq m. Nausea and vomiting occurred in 25% of all treatment courses, and dividing the dose over 3 days did not decrease the incidence. Alopecia occurred in 13% of evaluable patients treated with the i.v. preparation and 30% of evaluable patients treated p.o. No stomatitis was observed with either preparation, and no patient developed clinical signs of congestive heart failure. Pharmacokinetic studies were performed with both preparations and revealed prolonged plasma levels of the 13-hydroxy metabolite 4-DMDR-ol. The suggested starting dose for Phase II studies is 12.5 mg/sq m given every 21 days for i.v. 4-DMDR with dose escalation by 2.5 mg/sq m in the absence of myelotoxicity. For p.o. 4-DMDR, the suggested starting dose is 40 mg/sq m given every 21 days with escalation by 10 mg/sq m if no myelotoxicity is observed.

Original languageEnglish (US)
Pages (from-to)6096-6101
Number of pages6
JournalCancer Research
Volume43
Issue number12 I
StatePublished - 1983
Externally publishedYes

Fingerprint

Idarubicin
Clinical Pharmacology
Intravenous Administration
Oral Administration
Neoplasms
Nausea
Vomiting
Stomatitis
Anthracyclines
Alopecia
Doxorubicin
Clinical Studies
Heart Failure
Pharmacokinetics
Incidence
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Berman, E., Wittes, R. E., Leyland-Jones, B., Casper, E. S., Gralla, R. J., Howard, J., ... Young, C. W. (1983). Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer. Cancer Research, 43(12 I), 6096-6101.

Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer. / Berman, E.; Wittes, R. E.; Leyland-Jones, B.; Casper, E. S.; Gralla, Richard J.; Howard, J.; Williams, L.; Baratz, R.; Young, C. W.

In: Cancer Research, Vol. 43, No. 12 I, 1983, p. 6096-6101.

Research output: Contribution to journalArticle

Berman, E, Wittes, RE, Leyland-Jones, B, Casper, ES, Gralla, RJ, Howard, J, Williams, L, Baratz, R & Young, CW 1983, 'Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer', Cancer Research, vol. 43, no. 12 I, pp. 6096-6101.
Berman, E. ; Wittes, R. E. ; Leyland-Jones, B. ; Casper, E. S. ; Gralla, Richard J. ; Howard, J. ; Williams, L. ; Baratz, R. ; Young, C. W. / Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer. In: Cancer Research. 1983 ; Vol. 43, No. 12 I. pp. 6096-6101.
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N2 - 4-Demethoxydaunorubicin (4-DMDR), an anthracycline analogue available in i.v. and p.o. form, has shown significant antitumor activity in murine tumor models while producing less cardiac toxicity than doxorubicin at equimyelotoxic doses. Phase I and clinical pharmacology studies of the i.v. and p.o. preparation were performed. With i.v. 4-DMDR, consistent myelosuppression was observed at a dose of 15 mg/sq m at a median Day 15; mild nausea and vomiting were observed in 9% of all treatment courses. In patients given p.o. 4-DMDR, myelosuppression occurred at median Day 14 in 10 of 12 patients given 50 mg/sq m. Nausea and vomiting occurred in 25% of all treatment courses, and dividing the dose over 3 days did not decrease the incidence. Alopecia occurred in 13% of evaluable patients treated with the i.v. preparation and 30% of evaluable patients treated p.o. No stomatitis was observed with either preparation, and no patient developed clinical signs of congestive heart failure. Pharmacokinetic studies were performed with both preparations and revealed prolonged plasma levels of the 13-hydroxy metabolite 4-DMDR-ol. The suggested starting dose for Phase II studies is 12.5 mg/sq m given every 21 days for i.v. 4-DMDR with dose escalation by 2.5 mg/sq m in the absence of myelotoxicity. For p.o. 4-DMDR, the suggested starting dose is 40 mg/sq m given every 21 days with escalation by 10 mg/sq m if no myelotoxicity is observed.

AB - 4-Demethoxydaunorubicin (4-DMDR), an anthracycline analogue available in i.v. and p.o. form, has shown significant antitumor activity in murine tumor models while producing less cardiac toxicity than doxorubicin at equimyelotoxic doses. Phase I and clinical pharmacology studies of the i.v. and p.o. preparation were performed. With i.v. 4-DMDR, consistent myelosuppression was observed at a dose of 15 mg/sq m at a median Day 15; mild nausea and vomiting were observed in 9% of all treatment courses. In patients given p.o. 4-DMDR, myelosuppression occurred at median Day 14 in 10 of 12 patients given 50 mg/sq m. Nausea and vomiting occurred in 25% of all treatment courses, and dividing the dose over 3 days did not decrease the incidence. Alopecia occurred in 13% of evaluable patients treated with the i.v. preparation and 30% of evaluable patients treated p.o. No stomatitis was observed with either preparation, and no patient developed clinical signs of congestive heart failure. Pharmacokinetic studies were performed with both preparations and revealed prolonged plasma levels of the 13-hydroxy metabolite 4-DMDR-ol. The suggested starting dose for Phase II studies is 12.5 mg/sq m given every 21 days for i.v. 4-DMDR with dose escalation by 2.5 mg/sq m in the absence of myelotoxicity. For p.o. 4-DMDR, the suggested starting dose is 40 mg/sq m given every 21 days with escalation by 10 mg/sq m if no myelotoxicity is observed.

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