Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies

Merry L. Tetef, Timothy W. Synold, Warren Chow, Lucille Leong, Kim Margolin, Robert Morgan, James Raschko, Stephen Shibata, George Somlo, Yun Yen, James H. Doroshow, Susan Groshen, Kay Johnson, Heinz Josef Lenz, David Gandara

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Dexrazoxane is a bidentate chelator of divalent cations. Pretreatment with short infusions of dexrazoxane prior to bolus doxorubicin has been shown to lessen the incidence and severity of anthracycline-associated cardiac toxicity. However, because of rapid, diffusion-mediated cellular uptake and the short plasma half-life of dexrazoxane, combined with prolonged cellular retention of doxorubicin, dexrazoxane may be more effective when administered as a continuous infusion. Thus, a Phase I pharmacokinetic trial of a 96-h infusion of dexrazoxane was performed. Dexrazoxane doses were escalated in cohorts of 3 to 6 patients per dose level. All patients received granulocyte-colony stimulating factor at a dose of 5 μg/kg/day starting 24 h after completion of the dexrazoxane infusion. Plasma samples were collected and analyzed for dexrazoxane by highperformance liquid chromatography. Urine collections were performed at baseline and during the infusion to determine the renal clearance of dexrazoxane and the excretion rate of divalent cations. Twenty-two patients were enrolled at doses ranging from 125 to 250 mg/m2/day. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 2 patients treated at 250 mg/m2/day, grade 3 thrombocytopenia and grade 4 nausea and vomiting in 1 patient treated at 221 mg/m2/day, grade 4 diarrhea and grade 3 nausea and vomiting in 1 patient treated at 221 mg/m2/day, and grade 3 hypertension in 1 patient treated at 166.25 mg/m2/day. Steady-state dexrazoxane levels ranged from 496 μg/l (2.2 μM) to 1639 μg/l (7.4 μM). Dexrazoxane plasma CLss and elimination t1/2 were 7.2 ± 1.6 l/h/m2 and 2.0 ± 0.8 h, respectively. The mean percentage of administered dexrazoxane recovered in the urine at steady state was 30% (range, 10-66%). Urinary iron and zinc excretion during the dexrazoxane infusion increased in 12 of 18 and 19 of 19 patients by a median of 3.7- and 2.4-fold, respectively. These results suggest that dexrazoxane as a 96-h infusion can be safely administered with granulocyte-colony stimulating factor at doses that achieve plasma levels that have been demonstrated previously to inhibit topoisomerase II activity and to induce apoptosis in vitro. Additional studies will be required to determine whether the combination of continuous infusions of dexrazoxane and doxorubicin would provide enhanced cardioprotection compared with the currently recommended bolus or short infusion schedules.

Original languageEnglish
Pages (from-to)1569-1576
Number of pages8
JournalClinical Cancer Research
Volume7
Issue number6
Publication statusPublished - Jan 1 2001
Externally publishedYes

Fingerprint

Dexrazoxane
Neoplasms
Doxorubicin
Divalent Cations
Granulocyte Colony-Stimulating Factor
Nausea
Vomiting
Type II DNA Topoisomerase
Urine Specimen Collection

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tetef, M. L., Synold, T. W., Chow, W., Leong, L., Margolin, K., Morgan, R., ... Gandara, D. (2001). Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies. Clinical Cancer Research, 7(6), 1569-1576.

Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies. / Tetef, Merry L.; Synold, Timothy W.; Chow, Warren; Leong, Lucille; Margolin, Kim; Morgan, Robert; Raschko, James; Shibata, Stephen; Somlo, George; Yen, Yun; Doroshow, James H.; Groshen, Susan; Johnson, Kay; Lenz, Heinz Josef; Gandara, David.

In: Clinical Cancer Research, Vol. 7, No. 6, 01.01.2001, p. 1569-1576.

Research output: Contribution to journalArticle

Tetef, ML, Synold, TW, Chow, W, Leong, L, Margolin, K, Morgan, R, Raschko, J, Shibata, S, Somlo, G, Yen, Y, Doroshow, JH, Groshen, S, Johnson, K, Lenz, HJ & Gandara, D 2001, 'Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies', Clinical Cancer Research, vol. 7, no. 6, pp. 1569-1576.
Tetef ML, Synold TW, Chow W, Leong L, Margolin K, Morgan R et al. Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies. Clinical Cancer Research. 2001 Jan 1;7(6):1569-1576.
Tetef, Merry L. ; Synold, Timothy W. ; Chow, Warren ; Leong, Lucille ; Margolin, Kim ; Morgan, Robert ; Raschko, James ; Shibata, Stephen ; Somlo, George ; Yen, Yun ; Doroshow, James H. ; Groshen, Susan ; Johnson, Kay ; Lenz, Heinz Josef ; Gandara, David. / Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignancies. In: Clinical Cancer Research. 2001 ; Vol. 7, No. 6. pp. 1569-1576.
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