A phase 1 first-in-human study of XMT-1107, a polymer-conjugated fumagillol derivative, in patients (pts) with advanced solid tumors.

Abstract

2526 Background: Fumagillol derivatives are novel anti-angiogenic agents that inhibit methionine aminopeptidase 2 (MetAP2) rather than directly inhibiting VEGF signaling. Clinical development of fumagillol derivatives (e.g. TNP-470) has been limited by CNS toxicities and short-half life. XMT-1107 is a small molecule fumagillol derivative (XMT-1191) conjugated to PHF (Fleximer), a 70 kDa biodegradable, hydrophilic polymer that does not cross the blood-brain barrier. XMT-1107 is hypothesized to decrease CNS exposure to XMT-1191 and lead to prolonged pharmacokinetic (PK) and pharmacodynamic (PD) effect. Methods: This study (NCT01011972) explored the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, PK, PD and antitumor activity of XMT-1107 as a single agent in pts with advanced solid tumors. XMT-1107 was given IV every 3 weeks at escalating doses using a 3+3 design. Results: 52 pts were enrolled in 14 dose cohorts ranging from 6-770 mg XMT-1191 equivalents/m2. MTD was not reached. Infus...