Phase I Trial of Poly-l-Glutamate Camptothecin (CT-2106) Administered Weekly in Patients with Advanced Solid Malignancies

Abstract

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-Lglutamate 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 highperformance 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/m 2 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 (t 1/2 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/m 2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.

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“…They are based on the traditional cytotoxic drugs (e.g. platinates [145,146], doxorubicin [147,148], camptothecin and analogues [149][150][151][152][153][154][155][156][157][158][159], paclitaxel/docetaxel [160][161][162][163][164], methotrexate [165], and irinotecan [166,167]). Xyotax (CT-2103 or OPAXIO), a PGA-paclitaxel conjugate, and NKTR-102, a polymer conjugate of irinotecan, are both currently in phase III clinical trials, being the conjugates closest to approval and market availability [164,[166][167][168].…”

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“…Four patients had stable disease (SD) for >9 weeks; 2 lung cancer patients (25 mg/m 2 ) had SD for >27 weeks. In a second Phase I trial in 26 patients, the MTD, toxicity, pharmacokinetics, and response rate of CT-21206 when administered weekly for 3 consecutive weeks of every 4-week cycle were determined [71]. With this schedule, the MTD was 75 mg/m 2 .…”

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“…Although the study showed favourable pharmacokinetics and slower urinary excretion, no objective response (neither partial nor complete) was observed. 33 In 2006, CT-2106 entered phase II clinical trials for the second-line treatment of ovarian cancer. Primary endpoints were to measure response rate and secondary measurements were of toxicity, response duration, time to progression (TTP), and survival (ClinicalTrials.gov identifier NCT00291837).…”