DOSE-ESCALATION OF THE HYPOXIC CELL SENSITIZER ETANIDAZOLE COMBINED WITH IFOSFAMIDE, CARBOPLATIN, ETOPOSIDE, AND AUTOLOGOUS HEMATOPOIETIC STEM-CELL SUPPORT

Multiple mechanisms of drug resistance contribute to treatment failure . Although high-dose therapy attempts to overwhelm these defenses phar macologically, this approach is only successful in a fraction of treat ed patients. Many drug resistance mechanisms are shared between malign ant and normal cells, but the expression of various drug resistance me chanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic ad vantage to the host. This study was designed to define the dose-limiti ng toxicities and maximum tolerated dose of etanidazole when it is giv en concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated dos es of high-dose ICE were administered concurrently with dose escalatio ns of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7, Mesna uroprotectio n was provided. Autologous marrow and cytokine mobilized peripheral bl ood progenitor cells were reinfused on day 0, Granulocyte colony-stimu lating factor was administered following reinfusion until the granuloc ytes recovered to >1000/mu l. Fifty-five adults with advanced malignan cies were enrolled in cohorts of five to nine patients. Four dose leve ls of etanidazole between 3 and 5.5 g/m(2)/day (12, 16, 20, and 22 g/m (2) total doses) and two doses of carboplatin (1600 and 1800 mg/m(2) t otal doses) were evaluated. Seven patients died of organ toxicity (13% ); two each from veno-occlusive disease of liver and sepsis; and one e ach from sudden death, renal failure, and refractory thrombocytopenic hemorrhage, Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricula r fibrillation and was resuscitated, Dose-dependent and largely revers ible peripheral neuropathy was observed consisting of two syndromes: s evere cramping myalgic/neuralgic pain, predominantly in stocking glove distribution, occurring between day -3 and day 0, and a sensory perip heral neuropathy with similar distribution peaking around day +60, The maximal achievable dose of etanidazole (16 g/m2 dose level) resulted in a mean serum level of 38 mu g/ml (25-55 mu g/ml). Etanidazole signi ficantly enhanced host toxicity of high-dose ICE. Effective modulatory doses of etanidazole could not be given with acceptable toxicity usin g this schedule.