Initial results of a first-in-man phase I study of EPC2407, a novel small molecule microtubule inhibitor anticancer agent with tumor vascular endothelial disrupting activity

Abstract

2531 Background: EPC2407 is a 4-aryl-chromene single isomer microtubulin inhibitor which in preclinical models showed antitumor effects due both to direct tumor apoptosis and to tumor vascular endothelium disruption. Through Dec. 2007, 17 patients with advanced cancers received from 1 to 18 doses of EPC2407. Methods: The 17 patients included advanced adenocarcinomas of the prostate (4), G.I. tract (2), breast, pancreas, unknown origin, NSCLC (2), melanoma, neuroendocrine, anaplastic thyroid, parotid gland carcinoma, VIPoma, and leiomyosarcoma. All patients met enrollment criteria: ECOG PS of 0–1, three month expected survival and confirmed tumor progression on prior therapy. EPC2407 was infused over 1 hour on 3 consecutive days in 21 day cycles. A modified Fibonacci dose escalation started at 4 mg/m2. Results: The primary objective was to define DLT. At the fourth dose level of 21 mg/m2 anticipated transient vasoconstrictive effects were seen in 2 of 2 patients: one patient had cardiac ischemia and severe pain in the tumor bed and one patient had pain at the site of a pre-existing DVT. The MTD was determined to be 13 mg/m2. Most patients at all dose levels had transient increases in BP during infusion and for 1–4 hours after. QTc increased up to 50 msec and correlated temporally and quantitatively with dose and with BP changes. Several patients received 4 or more cycles and had stable disease for 3+ months. There was minimal nausea/vomiting or other acute symptoms; one patient had moderate alopecia. Two patients reported transient decrease in mental status and two reported dysphoria or anxiety. There were no dermal or pulmonary AE’s and no clinically significant myelosuppression, hepatic or renal toxicities. The PK profile for EPC2407 is similar to that predicted in toxicokinetic analyses. The T1/2 in plasma is 2–3 hours. The AUC is dose-proportional up to MTD. Conclusions: EPC2407 appears to be an effective new anticancer agent with an acceptable side effect profile. Based on this study and results from preclinical studies showing additive or synergistic activity with antiangiogenic or chemotherapeutic agents, further clinical development of EPC2407 is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Epicept Corp Epicept Corp Epicept Corp Epicept Corp