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

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.

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

“…Likewise, the MAG-CPT gave released CPT dynamics of the same type (35,36). However, the polymeric micelle of SN-38 shows the same behavior for released SN-38 in animals (37) and humans (28), as does PEG-bound SN-38 in animals (38) and humans (39). When CPT binding to albumin is properly accounted for, the PK parameters of the unconjugated CPT in animals and humans can be correlated.…”

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38

“…The potency of EZN-2208 was 10 to 245-times higher than CPT-11 in different human cancer cell lines [16]. The macromolecule also inhibited HIF-1α protein expression in tumours and thus provides potential treatment against CPT-11 refractory tumours in patients with advanced malignancies [33,77]. Importantly, the severe dose-limiting diarrhoea was absent during EZN-2208 therapy, although other side effects such as neutropenia was also noticed in 28% patients receiving treatment.…”

“…A fraction of SN38G is also eliminated via renal excretion [30,31]. The elimination half-life of SN38 is 10 to 209 h from the blood [20,32,33].…”

In vitro and in vivo evaluation of SN-38 nanocrystals with different particle sizes

“…To exploit the full therapeutic potential of SN-38, a variety of drug delivery systems have been extensively investigated, including polymeric implants, 11 micelles, [12][13][14] liposomes, 15,16 polymer conjugates, 7,17 and nanoparticles. 9,18 Unfortunately, although these techniques enhanced the solubility of SN-38, there are also many inherent drawbacks, such as low encapsulation efficiency and low drug loading, 10,15 poor stability during conjugation process, and low final yield of polymer conjugates.…”