Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies

A Phase I dose escalation and pharmacokinetic study of the alkylating cytot oxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies res cued by autologous peripheral blood stem cell transplantation. Twenty-two p atients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused ove r 2 h at escalating doses from 20 to 56 g/m(2), and pharmacokinetic paramet ers were analyzed. At 56 g/m(2), three of six patients experienced dose-lim iting toxicities: diarrhea grade III/IV in three patients; mucositis/stomat itis grade III in one patient; toxic epidermal necrolysis in one patient; a nd grade III acidosis In one patient. Other low-grade side effects, includi ng erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patient s died within 4 weeks after treatment because of rapid tumor progression an d fungal infection, respectively. Plasma half-life, distribution volume, an d renal elimination of treosulfan were independent of dose, whereas the inc rease in area under the curve was linear up to 56 g/m(2) treosulfan, The ma ximum tolerated dose of high-dose treosulfan is 47 g/m(2). A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclus ion of high-dose treosulfan in combination protocols with autologous periph eral blood stem cell transplantation seems worthwhile.