A phase I and pharmacokinetic study with 21-day continuous infusion of XXXX .

@entity1 @entity137 @entity4264 @entity417 @entity295 @entity1259 @entity33 @entity2688 @entity1431 @entity8566 @entity236
A phase I study with continuous administration of @entity1259 for 21 days using a venous access port and a portable pump was performed. The first dose step was 2 mg/m2/d for 21 days. Interval between courses was 3 weeks. Dose increment per step was 1 mg/m2/d. Twenty-two @entity1 entered the study and received a total of 58 courses with a median of two (range, one to nine). Up to 5 mg/m2/d no @entity137 (according to World Health Organization [WHO] criteria) occurred. At 6 mg/m2/d (six pts), one @entity1 had @entity1431 grade 3. Two others had some hair loss. At 7 mg/m2/d (four @entity1 ), all @entity1 developed @entity33 (two grade 3). Three @entity1 had @entity236 (one grade 3 @entity417 , one grade 4 @entity1431 ), and one @entity1 developed the @entity8566 . No other @entity137 occurred in the @entity1 . One @entity1 obtained a partial response (18 weeks), ten had stable disease (12 to 54 weeks), seven had progressive disease, and four were not evaluable for response. One @entity1 developed @entity2688 around the port, responding to antibiotic treatment; one @entity1 developed a @entity4264 that resolved with urokinase and removal of the access port. No @entity295 occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with fluorometric detection. Plasma steady state was reached after 57 hours. During steady state there was a linear relationship between @entity1259 dose administered and @entity1259 level in plasma (r = .58, P less than .05), whole blood (r = .75, P less than .005), and in leukocytes (r = .68, P less than .05). The area under the curve in leukocytes was higher with continuous infusion of 6 mg/m2 for 21 days compared with bolus injection of 80 mg/m2. This method of continuous infusion with @entity1259 may be a way to increase intracellular drug-uptake as expressed by intracellular area under curve (AUC). We recommend 6 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.
