Safety, pharmacokinetics, and activity of EZN‐2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies

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Abstract
BACKGROUND: EZN‐2208 is a water‐soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN‐2208 in adult patients with advanced solid tumors.METHODS: Patients in sequential cohorts (3 + 3 design) received intravenous EZN‐2208 at doses between 1.25 mg/m2 and 25 mg/m2 once every 21 days.RESULTS: Thirty‐nine patients received EZN‐2208. The median number of prior therapies was 2 (range, 0‐10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN‐2208 with (16.5 mg/m2) and without (10 mg/m2) granulocyte‐colony–stimulating factor (G‐CSF). The dose‐limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m2 with G‐CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m2). PK analysis indicated a mean terminal half‐life of 19.4 ± 3.4 hours. Sixteen patients (41%) achieved stable disease, including 6 of 39 patients (15%) who had stable disease that lasted ≥4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short‐lived 32% tumor regression. Among 6 patients who had stable disease that lasted for ≥4 months, 3 had received prior irinotecan, and 1 had KRAS‐positive colorectal cancer.CONCLUSIONS: EZN‐2208 was well tolerated and produced stable disease that lasted for ≥4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18%) with advanced solid tumors, including those who had failed prior irinotecan therapy. Cancer 2012. © 2012 American Cancer Society.

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