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. Infusion volume limited the maximum administered dose to 770 mg/m². One DLT of grade 4 thrombocytopenia was seen at 245 mg/m²; Grade 3 (n=4) and Grade 4 (n=3) thrombocytopenia were seen after Cycle 1 at 105 mg/m² and above. Grade 3 anemia was reported in 3 pts. 2 pts had Grade 3 transaminase elevation. There were 2 cases of ataxia: Grade 3 at 40 mg/m² in a pt with multiple CNS metastases evaluated as probably not related to study drug; and Grade 2 at 580 mg/m² evaluated as possibly related to study drug. Otherwise there were no CNS AEs. Free and conjugated XMT-1191 concentrations increased linearly with XMT-1107 dose. Evidence of MetAP2 inhibition was detectable in leukocytes at all dose levels, with complete inhibition throughout the 21 day cycle in 6/7 pts evaluated for PD at doses above 325 mg/m². 26 pts had a best response of stable disease with 12 pts stable for at least 4 cycles. Conclusions: XMT-1107 is well tolerated without significant CNS toxicity. The PK and PD profile supports once every 3 week intravenous dosing. The safety profile and preliminary antitumor effect supports further development in combination with chemotherapy and/or other anti-angiogenic agents. Clinical trial information: NCT01011972.