Phase I trial of 6-hour infusion of glufosfamide, a new alkylating agent with potentially enhanced selectivity for tumors that overexpress transmembrane glucose transporters: A study of the European Organization for Researchand Treatment of Cancer Early Clinical Studies Group

Purpose: To determine the maximum-tolerated dose (MTD), the principal toxic ities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-D- glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with t he potential to target the glucose transporter system. Patients and Methods: Twenty-one patients (10 women and 11 men; median age, 56 years) with refractory solid tumors were treated with doses ranging fro m 800 to 6,000 mg/m(2). Glufosfamide wets administered every 3 weeks as a t wo-step (fast/slow) intravenous infusion over a 6-hour period. All patients underwent pharmacokinetic sampling at the first course. Results: The MTD was 6,000 mg/m(2). At this dose, two of six patients devel oped a reversible, dose-limiting renal tubular acidosis and a slight increa se in serum creatinine the week after the second and third courses of treat ment, respectively, whereas three of six patients experienced short-lived g rade 4 neutropenia/leukopenia. Other side effects were generally mild. Phar macokinetics indicated linearity of area under the time-versus-concentratio n curve against dose over the dose range studied and a short elimination ha lf-life. There was clear evidence of antitumor activity, with a long-lastin g complete response of an advanced pancreatic adenocarcinoma and minor tumo r shrinkage of two refractory colon carcinomas and one heavily pretreated b reast cancer. Conclusion: The principal toxicity of 6-hour infusion of glufosfamide is re versible renal tubular acidosis, the MTD is 6,000 mg/m(2), and the recommen ded phase II dose is 4,500 mg/m(2). Close monitoring of serum potassium and creatinine levels is suggested for patients receiving glufosfamide for ear ly detection of possible renal toxicity. Evidence of antitumor activity in resistant carcinomas warrants further clinical exploration of glufosfamide in phase II studies. (C) 2000 by American Society of Clinical Oncology.