Phase I clinical and pharmacokinetic study of rebeccamycin analog NSC 655649 given daily for five consecutive days

Purpose: Rebeccamycin analog (NSC 655649) is active against a variety of bo th solid and nonsolid tumor cell lines. We performed a phase I trial to det ermine the maximum-tolerated dose (MTD) of rebeccamycin analog when given o n a daily x 5 schedule repeated every 3 weeks, characterize the toxicity pr ofile using this schedule, observe patients for antitumor response, and det ermine the pharmacokinetics of the agent and pharmacodynamic interactions. Patients and Methods: Thirty assessable patients received a total of 153 cy cles according to the following dose escalation schema: 60, 80, 106, 141, a nd 188 mg/m(2)/d x 5 days. Results: Grade 2 phlebitis occurred in all patients before the use of centr al venous access, placed at dose level 4 and higher. Dose-limiting toxicity (DLT), grade 4 neutropenia, occurred at 188 mg/m2/d x 5 days in both previ ously treated and chemotherapy-naive patients. Pharmacokinetic analysis rev ealed a three-compartmental model of drug elimination and a long terminal h alf-life (154 +/- 55 hours). The percentage drop in absolute neutrophil cou nt correlates with the area under the curve infinity. The presence of a sec ond peak during the elimination phase as well as a high concentration of NS C 655649 in biliary fluid compared with the corresponding plasma measuremen t tone patient) is suggestive of enterohepatic circulation. Two partial res ponses, two minor responses, and six prolonged (> 6 months) cases of stable disease were observed. Of these, three patients with gallbladder cancer an d one patient with cholangiocarcinoma experienced either a minor response o r a significant period of freedom from progression. Conclusion: The recommended phase II dose for NSC 665649 on a daily x 5 eve ry 3 weeks schedule is 141 and 165 mg/m(2)/d for patients with prior and no prior therapy, respectively, with DLT being neutropenia. During this phase I trial, encouraging antitumor activity was been observed. (C) 2001 by Ame rican Society of Clinical Oncology.