Phase I trial of poly-L-glutamate camptothecin (CT-2106) administered weekly in patients with advanced solid malignancies.

PURPOSE: CT-2106 is a 20(S)-camptothecin poly-L-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-L-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies. EXPERIMENTAL DESIGN: CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively. RESULTS: Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively. CONCLUSIONS: CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.

Phase I study of paclitaxel poliglumex administered weekly for patients with advanced solid malignancies.

BACKGROUND: Paclitaxel poliglumex (PPX, also called Xyotax or CT-2103) is a water soluble macromolecular drug conjugate that links paclitaxel with a biodegradable polymer, poly-L-glutamic acid. The recommended phase II dose of PPX every 3 week is 235 mg/m(2) administered over a 10-min infusion without premedication. This study was designed to determine the MTD and pharmacology of PPX administered weekly to patients with solid malignancies. METHODS: The starting dose of weekly PPX was 20 mg/m(2). Each cycle consists of 6 weekly treatments with pharmacokinetics of PPX (the conjugated paclitaxel) and unconjugated paclitaxel obtained after the first and sixth dose. Three to six patients were enrolled at each dose level. Toxicity and response were assessed by the NCI Common Toxicity criteria version 2 and RECIST criteria, respectively. RESULTS: Twenty-six patients were treated with PPX at the following dose levels: 20 mg/m(2) (five patients), 40 mg/m(2) (four patients), 60 mg/m(2) (four patients), 70 mg/m(2) (eight patients) and 80 mg/m(2) (five patients). Dose-limiting toxicities, consisting of grade 3 neutropenia, occurred in the 80 mg/m(2) cohort during cycle 1. Therefore, the dose recommended for phase II studies was 70 mg/m(2). In this cohort, a single dose-limiting event, consisting of diarrhea, was seen. Neuropathy and fatigue were the most common toxicities. No objective responses were noted. Pharmacokinetics was dose-proportional, and the degree of neutropenia related to drug exposure, but not to peak plasma concentration. There was no significant accumulation of conjugated or unconjugated paclitaxel with this dosing schedule. CONCLUSIONS: The recommended dose of PPX for subsequent disease-directed studies is 70 mg/m(2) weekly.