Phase i dose-escalation study of EZN-2208 (PEG-SN38), a novel conjugate of poly(ethylene) glycol and SN38, administered weekly in patients with advanced cancer

Purpose: This study evaluated the tolerability, pharmacokinetics, and preliminary antitumor activity of EZN-2208, a water-soluble poly(ethylene) glycol conjugate of SN38. Methods: Patients with advanced malignancies were enrolled in dose-escalating cohorts (3 + 3 design). EZN-2208 was administered as a 1-h intravenous infusion given weekly for 3 weeks per each 4-week cycle. Doses ranged from 1 to 12 mg/m². Results: Forty-one patients received EZN-2208. All patients had received prior cancer therapy (median = 2, range = 1-11). Twenty patients (49 %) had received prior irinotecan, and one patient had received prior topotecan. One patient in the 9-mg/m² cohort had dose-limiting toxicity (grade 3 febrile neutropenia), and one patient in the 12-mg/m² cohort had grade 3 neutropenia that resulted in the inability to deliver the third dose of EZN-2208. The most commonly reported drug-related adverse events were nausea (51 %), diarrhea (46 %), fatigue (41 %), alopecia (29 %), neutropenia (24 %), and vomiting (22 %). Administration of EZN-2208 results in prolonged exposure to SN38. Stable disease, sometimes prolonged, was observed as best response. Conclusions: EZN-2208 has an acceptable safety profile in previously treated patients with advanced malignancies. The recommended phase II dose of EZN-2208 administered according to this schedule was 9 mg/m².