Clinical pharmacokinetics (PK) of EZN-2208, a novel anticancer agent, in patients (pts) with advanced malignancies: A phase I, first-in-human, dose-escalation study

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