Abstract C216: Phase 1, first‐in‐human, dose‐escalation study of EZN‐2208, a novel anticancer agent, in patients (pts) with advanced malignancies

Background: SN38, the active moiety of irinotecan, is a potent topoisomerase I inhibitor. Thus far, SN38 itself has not been used as an anticancer drug in humans due to its poor solubility in any pharmaceutically acceptable formulation. EZN‐2208 (PEG‐SN38) is a water‐soluble, polyethylene glycol drug conjugate of SN38 that is active in preclinical models of solid tumors/lymphoma, including an in vivo CPT‐11‐resistant tumor model. EZN‐2208 accumulates in tumors, where it releases SN38. EZN‐2208 also down‐modulates mRNA of hypoxia‐inducible factor‐1α (HIF‐1α) target genes, and has been shown to have anti‐angiogenic and anti‐apoptotic effects. Methods: Pts with advanced solid tumors were enrolled to determine the safety, tolerability, pharmacokinetics (PK), maximum tolerated dose (MTD), recommended dose, and preliminary evidence of antitumor activity of EZN‐2208 administered as a 1‐h IV infusion every 3 weeks. Dose escalation (3+3) 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. PK parameters were estimated using a noncompartmental model analysis. Results: 39 pts (59% women; median age = 58 y [24‐78 y]) received EZN‐2208 either without first‐cycle G‐CSF per the original protocol (n=27) or with first‐cycle G‐CSF per protocol amendment (n=12) after the dose‐limiting toxicity (DLT) was found to be neutropenic fever. Pts received EZN‐2208 doses of 1.25 mg/m 2 (n=3), 2.5 mg/m 2 (n=3), 5.0 mg/m 2 (n=5), 10 mg/m 2 (n=10), 16.5 mg/m 2 (n=6), 16.5 mg/m 2 with G‐CSF (n=6), and 25 mg/m 2 with G‐CSF (n=6). All pts had received previous treatment (median number of prior regimens = 3 (1–11). Tumor types included colorectal cancer (CRC) (n=14); breast, head & neck, and pancreatic cancers (n=3 each); ovarian, thyroid, and uterine cancers (n=2 each); cholangiocarcinoma (n=1); and anal, esophageal, fallopian tube, gallbladder, gastric, hepatocellular, SCLC, unknown primary, and vulvar cancers (n=1 each). Pts received 1 to 7 treatment cycles. The DLT was Grade 3 to 4 febrile neutropenia, which was reported in 2 pts who received 16.5 mg/m 2 EZN‐2208 without G‐CSF and in 2 pts who received 25 mg/m 2 EZN‐2208 with G‐CSF. Adverse events (AEs) were mostly Grade 1 or 2. The most common AEs (>20% of pts) considered likely related to study drug were fatigue (41%), nausea (36%), alopecia and diarrhea (33% each), neutropenia (23%), and vomiting (21%). Only 1 of all 39 pts had Grade 3 diarrhea in Cycle 1. Prolonged stable disease (>90 days), sometimes associated with tumor shrinkage (), was observed as best response (duration on study) for 9 pts with colorectal (214+ [ K‐RAS mutation], 148, 127, 127, 111 days), breast (135 days ↓), uterine (130 days ↓), cholangiocarcinoma (129 days ↓), and head and neck (262+ days) cancers. The 5 pts with mCRC had received prior irinotecan. Conclusions: EZN‐2208, a novel agent, was well tolerated in previously treated pts with advanced malignancies. No cumulative toxicities were reported. DLT was neutropenic fever, in distinction to the DLT of irinotecan. The MTD and recommended dose of EZN‐2208 for this regimen is 10 mg/m 2 without G‐CSF and 16.5 mg/m 2 with G‐CSF. For some pts, the duration of EZN‐2208 was longer than for their prior therapy. This study is closed to accrual; final results, including PK, will be presented at the meeting. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C216.