Abstract A106: A phase 1 study of ENMD-2076 in patients with relapsed or refractory acute myeloid leukemia (AML)
Authors: Yee Karen W. , Brandwein Joseph , Minden Mark D. , Sanfelice Deborah , Chow Sue , Hedley David W. , Schimmer Aaron D. , Schuh Andre C. , Gupta Vikas , Sidor Carolyn F. , Arnott Jamie , Fletcher Graham , Bray Mark , Chen Hsiao-Wei Tina 
Published: June 2012

ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase as well as multiple receptor tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and FGFR. A phase 1 study was conducted to determine the maximum tolerated dose (MTD) and toxicities of ENMD-2076 in patients with refractory hematological malignancies. Fifteen patients with AML (cohorts of 6 patients per dose level) have been treated with 225 (n=7), 325 (n=2), and 375 (n=6) mg of ENMD-2076 administered orally once daily. Median age was 76 years (range, 60 to 82 years). Median ECOG status was 1 (range, 0 to 2). Fourteen patients had received prior therapy (median, 2 regimens; range, 0 to 4 regimens). A total of 17 cycles have been administered to date, with a median of 1 cycle (range, 0 to 3 cycles); 2 patients (14%) have received 3 or more cycles of therapy. The most common ENMD-2076-related adverse events were grade ≤ 2 and consisted of dizziness, petechiae, hypertension, nausea, fatigue, diarrhea, and reflux. Dose-limiting toxicity consisted of grade 3 fatigue in 2 patients at the 375 mg/day dose level. Therefore, the dose was decreased to 325 mg/day. Following a drug holiday, both patients who had experienced the grade 3 fatigue were restarted at the 325 mg/day dose level. No patient experienced grade 4 toxicities or death from ENMD-2076. Of the 13 evaluable patients, 1 patient achieved a morphologic leukemic free state (MLFS) with platelet transfusion independence. One patient achieved a HI-P. Two other patients had a 12% and 14% reduction in marrow blast count, respectively. At the time of analysis, 3 patients discontinued therapy due to disease progression. Peripheral blood and/or bone marrow were obtained at baseline for ex vivo drug sensitivity testing, and on Days 8 and 29 of cycle 1 for pharmacodynamic (PD) monitoring, using a whole blood flow cytometry protocol to measure ENMD-2076 effects on cell signalling pathways. This assay uses combined labelling for P-ERK, P-Akt, P-STAT5, and P-S6 as the readout, and tests the effects of acute stimulation with the ligands SCF and FL in the presence or absence of pathway inhibitors, including ENMD-2076. Pre-incubation with drug concentrations in the range 0.5 – 2 µM suppressed growth factor stimulation in the blast cells of all patients tested to date. Decreases in the ability to stimulate ERK,Akt, STAT5, and S6 were seen in the Day 8 and 29 samples, including a striking inhibition of cell signalling in one patient who achieved a MLFS. Assays are also in progress to monitor specific effects on Aurora kinase and the cell cycle in these patient samples. In conclusion, single agent ENMD-2076 has activity in a heavily pretreated group of AML patients that may correlate with inhibition of ERK,Akt, STAT5, and S6 activity. Enrollment, as well as PK and PD monitoring of this study, is ongoing.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A106.