A phase I pharmacokinetic (PK) study of MBP-426, a novel liposome encapsulated oxaliplatin.

2535 Background: MBP-426 is a novel liposome encapsulated oxaliplatin (L-OHP) formulation bound to human transferrin, developed to improve the safety and efficacy of L -OHP through the prolongation of circulation time and by targeting transferrin receptors on tumor cells. In vitro, MBP-426 is effective against various human cancer cell lines. This study assessed the toxicity and safety of intravenously (IV) administered MBP-426, including defining the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). METHODS Patients (pts) with advanced/ metastatic solid tumors refractory to conventional therapy received MBP-426 as 2-4 hrs IV infusion every 3 weeks in cohorts of 3 to 6 pts. Enrollment required age > 18 yrs, ECOG Performance Status 0-2 and adequate organ functions. Tumor response was assessed by RECIST. Plasma was sampled for PK. RESULTS 39 pts were dosed, median age 59 (range 27-79), 25 (64%) male. The common tumor types were colorectal 23 (60%), pancreas 3 (8%), and neuroendocrine 3 (8%). Most pts were heavily pretreated with chemotherapy or chemoradiation. 77% pts had received oxaliplatin or cisplatin. Eleven dose levels ranging from 6 to 400 mg/m2 were evaluated. At 400 mg/m2, 2/3 pts had DLT as grade 4 thrombocytopenia and prolonged thrombocytopenia (1 pt each). The recommended phase II dose is 226 mg/m2 where 1/6 pts had grade 4 thrombocytopenia. Grade 3-4 toxicities included fatigue (3 pts), hypercholesterolemia (3 pts), anemia (2 pts) and constipation (1 pt). Common grade 1-2 toxicities were nausea and/or vomiting (59%), fatigue (43%), infusion reaction (15%), thrombocytopenia (15%), anemia (13%) and peripheral neuropathy (13%). 15 pts had stable disease after 2 cycles. 3 pts with colon carcinoma refractory to conventional oxaliplatin had stable disease for 4, 5 and 6 cycles respectively, one of them had 25% decrease in target lesions. PKs of MBP-426 were dose-proportional. Main PK parameters at 226 mg/m2 were AUC 2141+419 μg.hr/ml, and t½ 89+92 hr, comparing favorably with intact L-OHP. CONCLUSIONS MBP-426 has a favorable safety profile with thrombocytopenia as main DLT. The PK target concentration of L-OHP was exceeded at higher doses. Based on PK and toxicity profiles, the recommended dose is 226 mg/m2. [Table: see text].