A Phase I and Pharmacokinet ic Study of Pegy lated

Purpose: To assess the feasibility of administering camptothecin (CPT), the prototypic topoisomerase I inhibitor, as polyethylene glycol (PEG)-CPT, a macromolecule consisting of CPT conjugated to chemically modified PEG. The study also sought to determine the maximum-tolerated dose (MTD) of PEG-CPT, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of PEG-CPT as a 1-hour intravenous (IV) infusion every 3 weeks. A modified continual reassessment method was used for dose-level assignment to determine the MTD, which was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. Results: Thirty-seven patients were treated with 144 courses of PEG-CPT at seven dose levels ranging from 600 to 8,750 mg/m2. Severe myelosuppression was consistently experienced by heavily pretreated (HP) and minimally pretreated (MP) patients at the highest dose level evaluated, 8,750 mg/m2, whereas both HP and MP patients tolerated repetitive treatment at 7,000 mg/m2. Cystitis, nausea, vomiting, and diarrhea were also observed but were rarely severe. A partial response was noted in a patient with platinumand etoposide-resistant small-cell lung carcinoma, and minor responses were noted in one patient each with adenocarcinoma of unknown primary type and osteosarcoma. The pharmacokinetics of free CPT were dose proportional. Free CPT accumulated slowly in plasma, with maximal plasma concentrations achieved at 23 12.3 hours; the harmonic mean half-life (t1/2) of free CPT was long (t1/2, 77.46 36.77 hours). Conclusion: Clinically relevant doses of CPT can be delivered by administering PEG-CPT. The recommended dose for phase II studies in both MP and HP patients is 7,000 mg/m2 as 1-hour IV every 3 weeks. The characteristics of the myelosuppressive effects of PEG-CPT, the paucity of severe nonhematologic toxicities with repetitive treatment, the preliminary antitumor activity noted, and the slow clearance of CPT enabling simulation of desirable pharmacokinetic parameters with a convenient single-dosing regimen warrant further disease-directed evaluations. J Clin Oncol 21:148-157. © 2003 by American Society of Clinical Oncology.