An open-label, dose escalation, safety, and pharmacokinetic study of ENMD-2076 administered orally to patients with advanced cancer.

Background:  ENMD-2076, a novel, orally-active antimitotic and antiangiogenic molecule inhibits Aurora A as well as tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and the FGF receptors. This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of ENMD-2076 administered once daily to patients (pts) with advanced cancer.  Methods:  The dose escalation scheme utilizes 3 (or 4) + 3 (or 2) design. Pts receive ENMD-2076 once daily in 28-day cycles (followed by 7–14 days of rest between cycles 1 and cycle 2 only).  Results:  14 pts have been enrolled in 3 dose cohorts (range 60 to 120 mg/m 2 /d). Median age/performance status is 62/1. The total number of treatment cycles to date is 45, with a median of 3 cycles (range <1 to 9 cycles). Most frequent, related toxicities (all grades, n=14) were hypertension (29%), fatigue (21%), proteinuria and diarrhea (both 14%). One pt experienced dose limiting toxicity of Grade 4 hypertension and Grade 3 cholecystitis in the first dose cohort of 60 mg/m 2 /d. Following drug interruption, the pt restarted at 30 mg/m 2 /d and continued for 4 additional cycles before being removed for progressive disease. Noncompartmental PK analysis of the first two dose levels shows that the plasma concentration of ENMD-981693 (the active free base of ENMD-2076) is dose- linear, as reflected in AUC and C max . The estimated terminal half-life (t 1/2 ) is unaltered regardless of dose; however, t 1/2  is approximately 50% greater at steady state than following single dose administration. Four ovarian cancer and 2 colon cancer pts have achieved decreases ranging from 11–61% in either CA125 or CEA, respectively (4 are associated with stable disease at Cycle 2 by modified RECIST criteria). Serum KDR concentrations assayed by ELISA decreased from baseline in all patients on treatment from a mean of 9153 pg/mL (SEM 464.2) at D1 to 6987 pg/mL (SEM 460.0) at D28 (p <0.05).  Conclusions:  ENMD-2076 is a small molecule kinase inhibitor with acceptable toxicity and preliminary evidence of antitumor activity in pts with ovarian and colorectal cancers.