Abstract
2556 Background: EZN-2208 is a water-soluble, polyethylene glycol (PEG) conjugate of SN38 that is active in solid tumors and lymphoma preclinical models, including an in vivo CPT-11-resistant tumor model. EZN-2208 accumulates in tumors, where it releases SN38. Methods: Pts with advanced solid tumors were enrolled to determine the safety, tolerability, PK, maximum tolerated dose, recommended dose, and preliminary evidence of antitumor activity of EZN-2208 administered as a 1-hour intravenous infusion every 3 weeks in a 3+3 escalating dose design. Pts homozygous for UGT1A1*28 were eligible after safety was established in non-homozygous pts. Dose escalation was based on drug-related toxicities observed during the first cycle. Plasma concentrations of EZN-2208 and SN38 were determined by HPLC using fluorescence detection. Pharmacokinetic parameters were estimated using a non-compartmental model analysis. Results: Ten pts (2 males; median age = 59 yrs [34–79 yrs]) were treated at doses of 1.25 (3 pts), 2.5 (3 pts), 5.0 (3 pts), and 10 (1 pt) mg/m2. All 10 pts were pretreated (median number of prior regimens = 5). Tumor types included colorectal (7 pts), gastric (1 pt), anal (1 pt), and breast (1 pt) cancers. Adverse events included grade 2 fatigue and grade 2 neutropenia. No dose-limiting toxicities were observed. Stable disease was observed in 3 pts; 2 of the pts had previously progressed while receiving irinotecan. Plasma PK in the first 3 cohorts (9 pts) is provided in the table below. Conclusions: EZN-2208, a novel agent, was well tolerated in pretreated pts with solid tumors. A qualitative assessment of the data indicates a rough proportionality in AUC vs dose. PK data demonstrated high AUC and prolonged exposure to SN38. Dose escalation is ongoing. Dosea (mg/m2) EZN-2208 b SN38 b Cmaxa (μg/mL) AUC(0-∞)a (h·μg/mL) Terminal t½ (h) Cmax(ng/mL) AUC(0-t)c (h·μg/mL) 1.25 22.4±5.8 645±152 30.1±6.3 32.9±42.1 504±393 2.5 26.1±15.9 891±713 43.8±20.2 14.8±8.0 569±337 5.0 40.6±14.7 1,414±559 53.7±20.7 54.9±33.6 1,026±229 a = SN38 equivalents; b = Mean ± standard deviation; c = AUC(0-t), t is time of last measurable concentration. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Enzon Pharmaceuticals Enzon Pharmaceuticals Enzon Pharmaceuticals
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.