Phase I and pharmacokinetic study of SPI-77, a liposomal encapsulated dosage form of cisplatin

Purpose: To investigate the safety and pharmacokinetics of a new liposomal formulation of cisplatin, SPI-77, in patients with advanced malignancies. Patients and methods: Patients with histologically proven malignancies not amenable to other treatment were eligible for this study. The starting dose of SPI-77 (cisplatin in Stealth liposomes) was 40 mg/m(2) administered every 4 weeks in a 2-h infusion, and doses were escalated up to 420 mg/m(2). Pharmacokinetic monitoring was performed in all patients and samples were analysed for platinum content by atomic absorption spectroscopy. Platinum-DNA (Pt-DNA) adduct levels in leucocytes (white blood cells, WBC) and tumour tissue were quantified using a sensitive P-32-postlabelling assay. Results: A total of 27 patients were accrued. The main toxicities observed were infusion-related reactions, which could be prevented by lowering the initial infusion rate, and anaemia. The pharmacokinetics of SPI-77-derived platinum were strikingly different from standard cisplatin. Free platinum levels in plasma ultrafiltrate samples were undetectable at the lowest dose levels (40 and 80 mg/m2), and low but highly variable at higher doses of SPI-77. Plasma pharmacokinetics of total platinum were linear with small interpatient variability. The total body clearance of SPI-77 varied from 14 to 30 ml/h and was significantly lower than reported clearance values for cisplatin of 20 1/m(2) per h, due to the slow release of cisplatin from the liposomes. Pt-DNA adduct levels in WBC ranged from 0.02 to 4.13 fmol/ mug DNA for intrastrand Pt-GG (guanine-guanine) adducts and from 0.02 to 1.27 fmol/mug DNA for intrastrand Pt-AG (adenosine-guanine) adducts, which is more than tenfold lower than after administration of a comparable dose of non-liposomal cisplatin. In tumour samples obtained from two patients treated at the highest doselevels, relatively low levels of Pt-DNA adducts were observed. Conclusions: The results of this phase I trial show that the pharmacokinetic behaviour of cisplatin is significantly altered by its encapsulation in Stealth liposomes. The pharmacokinetics of SPI-77 are mainly dominated by the liposomal properties, resulting in high cholesterol concentrations and relatively low concentrations of (free) platinum in plasma, WBC and tumour tissue, which may explain the observed differences between the toxicity profiles of SPI-77 and cisplatin.