Final results of a phase I and pharmacokinetic study of STEALTH liposomal CKD-602 (S-CKD602) in patients with advanced solid tumors

Abstract

2013 Background: S-CKD602 is a pegylated STEALTH liposomal formulation of CKD-602, a semi-synthetic analogue of camptothecin (CPT) and topoisomerase I inhibitor. Preclinical studies have shown that prolonged exposure to CPT achieves the greatest antitumor activity. STEALTH liposomes prolong the circulation time in plasma, achieve high and extended drug exposure in tumor, and provide a convenient dosing schedule. Methods: Patients (pts) were administered S-CKD602 IV over 1 h once every 3 wks. Modified Fibonacci escalation was used (3–6 pts/cohort), and dose levels ranged from 0.1–2.5 mg/m2. Serial plasma samples were obtained prior to administration to 96 h after administration, and on days 8 and 15 of cycle 1. Plasma samples were processed to measure concentrations of encapsulated (E), released (R), and sum total (E+R) CKD602 total (lactone + hydroxyl acid) by LC-MS/MS. Area under the plasma conc versus time curve (AUC0-∞) and t1/2 were estimated. Results: 45 pts (21 male) have been treated: median age 62 y (range: 33–79 y); ECOG status: 0 and 1 (43 pts), 2 (2 pts). The majority of reported adverse events were grade (G) 1 and 2. Frequent nonhematological toxicities were asthenia, nausea, diarrhea, vomiting, and anorexia. Dose-limiting toxicities of G3 mucositis occurred in 1/6 pts at 0.3 mg/m2, G3/4 bone marrow suppression in 2/3 pts at 2.5 mg/m2, and G3 febrile neutropenia in 1/6 pts at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Stable disease for ≥ 6 cycles occurred in 5 pts (hepatocellular carcinoma (CA), thyroid, prostate, 2 pts sarcoma). Partial responses occurred in 2 pts with ovarian CA (1.7 and 2.1 mg/m2). At 2.1 mg/m2, the mean ± SD AUC and t1/2 of sum total S-CKD602 were 44 ± 33 μg/mL·h and 18 ± 8 h, respectively. In all plasma samples, >90% of drug was encapsulated. Conclusions: S-CKD602 represents a promising new STEALTH liposomal CPT agent with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 IV once every 3 wks are planned. Prolonged plasma exposure over 1 to 2 wks is consistent with STEALTH liposomes and provides extended exposure compared with non-liposomal CPT. (Supported by ALZA and NIH/NCCR/GCRC #5M01 RR 00056). [Table: see text]