Abstract C221: EZN-2208, a novel anticancer agent, in patients (pts) with advanced malignancies: A phase 1 dose-escalation study
Authors: Patnaik Amita , Papadopoulos Kyriakos P. , Beeram Muralidhar , Kee Debbie , Tolcher Anthony W. , Schaaf Larry J. , Tahiri Sanaa , Bekaii-Saab Tanios , Buchbinder Aby 
Published: June 2012

Abstract
Background: SN38 is a potent topoisomerase I inhibitor and the active moiety of irinotecan. SN38 has poor solubility in any pharmaceutically acceptable excipient. The poor solubility of SN38 can be vastly improved by PEGylation. EZN-2208 (PEG-SN38) is a water-soluble, polyethylene glycol (PEG) drug conjugate of SN38 that enables increased solubility, parenteral delivery of SN38, longer circulating half-life, higher exposure of the active drug (SN38) in tumors, and greater preservation of the closed lactone ring (active form) in SN38 compared with SN38 derived from irinotecan. EZN-2208 is active in a broad spectrum of preclinical models of solid tumors and hematologic cancers, including an in vivo tumor model of CPT-11 resistance. EZN-2208 accumulates in tumors, where it releases SN38. EZN-2208 also down-modulates mRNA of hypoxia-inducible factor-1 α (HIF-1α) target genes.
Methods: Pts with advanced solid tumors were enrolled to determine the safety, tolerability, pharmacokinetics (PK), maximum tolerated dose (MTD), and evidence of preliminary antitumor activity of EZN-2208 administered as a 1-hour IV infusion, weekly × 3 per 4-week cycle, in a 3+3 escalating-dose design. Dose escalation was based on drug-related toxicities during Cycle 1. PK samples were obtained after the first and third doses. Plasma concentrations of EZN-2208, SN38, and SN38G were determined by HPLC using fluorescence detection. PK parameters were estimated using a noncompartmental model analysis.
Results: 41 pts (51% women; median age = 60 y [35-85]) were treated with EZN-2208 doses of 1 mg/m2 (n=3), 2 mg/m2 (n=5, including 2 pts homozygous for UGT1A1*28), 3.3 mg/m2 (n=3), 5 mg/m2 (n=6), 7 mg/m2 (n=8), 9 mg/m2 (n=10), and 12 mg/m2 (n=6). All pts had received prior therapies (median number of prior regimens = 2; range = 1–11). Tumor types included colorectal cancer (CRC) (n=24); breast and pancreatic cancers (n=3 each); esophageal cancer and NSCLC (n=2 each); anal, carcinoid, gallbladder, gastric, ovarian, and prostate cancers (n=1 each); and soft tissue sarcoma (n=1). Pts received 1 to 15 cycles. Dose-limiting toxicities (DLTs) were Grade 3 febrile neutropenia (1 pt, 9 mg/m2) and the inability to deliver the third week of therapy due to Grade 4 neutropenia (1 pt, 12 mg/m2). Most adverse events (AEs) were Grade 1 or 2. The most common AEs (in &gt;20% pts) considered likely related to study drug were nausea (49%), diarrhea and fatigue (44% each), alopecia (30%), and neutropenia and vomiting (28% each). Prolonged stable disease (SD) (&gt;90 days), sometimes associated with tumor shrinkage (), was observed as best response (duration on study) for 13 pts with CRC (485 , 240, 168, 162+, 113, 107, 92 days), NSCLC (127 days), breast (135, 118 days), esophageal (170, 120 days), and pancreatic (253 days) cancers. Five of the 7 pts with mCRC had received prior irinotecan.
Conclusions: EZN-2208, a novel agent, was well tolerated in previously treated pts with advanced malignancies. DLT was neutropenia ± fever, in distinction to the DLT of irinotecan. The MTD and recommended EZN-2208 dose for this regimen is 9 mg/m2. Prolonged periods of SD were observed. For some pts, the duration of EZN-2208 was longer than for their prior therapy. Enrollment is complete; final data, including PK, will be presented at the meeting. EZN-2208 is being evaluated in a Phase 2 clinical study in pts with CRC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C221.