Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies.

S-CKD602 is a pegylated liposomal formulation of CKD-602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S-CKD602. S-CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD-602 in plasma were performed. The pharmacokinetic variability of S-CKD602 is associated with both linear and nonlinear clearances. Patients > or =60 years of age have a 2.7-fold higher exposure of S-CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S-CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2-fold higher exposure of S-CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1-2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S-CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.

Phase II study of topotecan and paclitaxel for patients with previously untreated extensive stage small-cell lung cancer.

BACKGROUND: This phase II study was conducted to evaluate the safety and efficacy of the combination of paclitaxel and topotecan for patients with extensive stage small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Previously untreated ED-SCLC patients with Eastern Coperative Oncology Group performance status <2 were eligible. Treatment consisted of topotecan 1 mg/m2 (first three patients received 1.25 mg/m2), on days 1-5, and paclitaxel 135 mg/m2 over 24 h on day 5, every 4 weeks. Prophylactic granulocyte colony-stimulating factor was administered to all patients. RESULTS: Thirty-two patients received a median of four cycles of chemotherapy. Grade 4 anemia, neutropenia and thrombocytopenia occurred in 13, 31 and 18 patients, respectively. Thirty episodes of febrile neutropenia occurred in 22 patients. Grade 3 fatigue, esophagitis, stomatitis and hypotension occurred in one patient each. Of 26 patients eligible for response evaluation, there were six complete and 12 partial responses (overall response rate 69%). The median survival was 54 weeks. The 1-, 2- and 3-year survival rates were 50%, 10% and 3%, respectively. CONCLUSIONS: The combination of topotecan and paclitaxel is active as initial therapy in SCLC, but the efficacy is similar to 'standard therapy'. This combination was associated with a high incidence of myelosuppression and febrile neutropenia, at the doses evaluated.