Abstract 1957


Despite recent improvements, MM remains incurable, indicating the need for continued investigation of novel agents. ENMD-2076 is a novel, orally active molecule that has been shown to have significant activity against Aurora and multiple receptor tyrosine kinases. Recently, we demonstrated that ENMD-2076 has significant pre-clinical in vitro and in vivo activity against MM cell lines and primary myeloma cells (Wang et al., Br J Haematol, 2010). Furthermore, ENMD-2076 inhibited critical pathways for MM cell survival and proliferation, including PI3K/AKT pathway with downregulation of survivin and XIAP, and Aurora A and B kinases, inducing G2/M cell cycle arrest, angiogenesis, and the FGFR3 pathway. We present the interim results of a phase I clinical trial of ENMD-2076 in patients with relapsed and refractory MM.


An open label, single agent, dose-escalation dose safety and tolerability trial of ENMD-2076 is currently conducted in heavily pre-treated, relapsed and refractory MM patients who have previously failed standard therapy. Using a 3+3 design, dose escalation with ENMD-2076 is currently being studied at the doses: 150, 225, 325, 400 mg PO daily in 28 day cycles. Patients receive 28-day cycles according to safety and tolerability and absence of progression. Pharmacokinetics and pharmacodynamic studies, including effect on phosphorylated histone 3 (pH3) in purified bone marrow MM cells, effect on the PI3K pathway in peripheral blood mononuclear cells (PBMC), and circulating endothelial cell precursors are being investigated.


Currently, dose-escalation for the first three dose levels has been completed. Nine patients of median age 54 (range, 48–76) years were treated. There were 5 males and 4 females. The median number of prior regimens was 3 (range, 2–5), with 8 patients having failed high-dose melphalan and autologous stem cell transplantation. The most commonly observed toxicities included grades 1–2 anorexia (n=2), nausea (n=2), diarrhea (n=3), fatigue (n=3), asymptomatic elevation of amylase (n=3) and lipase (n=1), leucopenia (n=1), and heavy proteinuria (n=1). Grades 3 toxicities included hypertension (n=1), asymptomatic elevation of lipase (n=2), and thrombocytopenia (n=1). No dose-limiting toxicity was observed with all toxicities resolving promptly upon interruption or discontinuation of dosing. All patients treated on dose level 1 had progression of disease on treatment, 1 patient in dose level 2 had stabilization of disease, and 2 patients on dose level 3 had stable disease although with 21% and 19% reduction in serum M-protein after the first cycle. Significant increases in pH3 in MM cells were observed in 4 of 5 patients tested in dose levels 2 and 3. p-STAT3 and pGSK-beta were downregulated in PBMC in one patient, who also had a 19% reduction in M-protein.


In the ongoing phase I clinical trial, ENMD-2076 appears safe and well –tolerated at the doses tested to date. Additional schedules are under investigation based on tolerability and correlative analyses. ENMD-2076 may hold promise as a treatment for MM and further study is warranted.


Farag:EntreMed, Inc: Research Funding. Bray:EntreMed, Inc.: Employment. Sidor:EntreMed, Inc: Employment.

Author notes


Asterisk with author names denotes non-ASH members.