A phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) in patients with advanced malignancies

BACKGROUND, A Phase I study of cis-malonato [(4R,5R)-4,5-bis(aminomethyl)-1 ,3-dioxolane] platinum(II) (SKI 2053R), a new platinum derivative, was perf ormed to determine the maximum tolerated dose (MTD), the dose limiting toxi cities (DLTs), and the pharmacokinetic profile of SKI 2053R in patients wit h advanced, refractory malignancies. METHODS. Twenty-one patients were entered into the study. SKI 2053R was adm inistered with an intravenous infusion over 1 hour every 4 weeks. The SKI 2 053R dose was escalated from 40 mg/m(2) up to 480 mg/m(2) using a modified Fibonacci scheme. Pharmacokinetic analysis was done in all patients to dete rmine the total and ultrafiltrable platinum concentrations in both the plas ma and the urine. RESULTS. All patients were evaluable for toxicity and response. There was n o significant toxicity with dosages up to 360 mg/m(2). At 480 mg/m(2), two of three patients developed Grade 4 hepatotoxicity, Grade 3 leukopenia and thrombocytopenia, and Grade 2 azotemia and proteinuria. Other toxicity incl uded nausea and emesis, but it was controlled with antiemetics. SKI 2053R d id not cause significant neurotoxicity or mucositis. There were 4 patients with stable disease among the 21 patients. Plasma decay of the total and fr ee platinum concentrations was best fitted by using a two-compartment, open model. The terminal plasma half-life of the total platinum after SKI 2053R administration ranged from 63.4 hours to 114.1 hours in dosages ranging fr om 40 mg/m(2) to 480 mg/m(2) without significant dose dependency. However, the terminal plasma half-life of the free platinum concentration showed a s ignificant dose dependent, incremental pattern. The renal excretion of SKI 2053R measured as platinum ranged from 49% to 75% of the administered dose. CONCLUSIONS, The MTD of SKI 2053R was 480 mg/m(2). The major DLTs were hepa totoxicity, nephrotoxicity, and myelosuppression, The recommended starting dose for a subsequent Phase II study is 360 mg/m(2) once every 4 weeks. Can cer 2001;91:1549-56. (C) 2001 American Cancer Society.