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

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 toxi city. However, because of rapid, diffusion-mediated cellular uptake and the short plasma half-life of dexrazoxane, combined with prolonged cellular re tention of doxorubicin, dexrazoxane may be more effective when administered as a continuous infusion. Thus, a Phase I pharmacokinetic trial of a 96-11 infusion of dexrazoxane was performed. Dexrazoxane doses were escalated in cohorts of 3 to 6 patients per dose level. All patients received granulocy te-colony stimulating factor at a dose of 5 mug/kg/day starting 24 h after completion of the dexrazoxane infusion. Plasma samples were collected and a nalyzed for dexrazoxane by highperformance liquid chromatography. Urine col lections were performed at baseline and during the infusion to determine th e renal clearance of dexrazoxane and the excretion rate of divalent cations , Twenty-two patients were enrolled at doses ranging from 125 to 250 mg/m(2 )/day, Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 2 pati ents 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 gr ade 3 nausea and vomiting in 1 patient treated at 221 mg/m(2)/day, and grad e 3 hypertension in 1 patient treated at 166.25 mg/m(2)/day. Steady-state d exrazoxane levels ranged from 496 mug/l (2.2 muM) to 1639 mug/l (7.4 muM) D exrazoxane plasma CLss and elimination t(1/2) were 7.2 +/- 1.6 1/h/m(2) and 2.0 +/- 0.8 h, respectively. The mean percentage of administered dexrazoxa ne 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. Th ese results suggest that dexrazoxane as a 96-h infusion can be safely admin istered with granulocyte-colony stimulating factor at doses that achieve pl asma levels that have been demonstrated previously to inhibit topoisomerase IT activity and to induce apoptosis in vitro. Additional studies will be r equired to determine whether the combination of continuous infusions of dex razoxane and doxorubicin would provide enhanced cardioprotection compared w ith the currently recommended bolus or short infusion schedules.