Phase I safety, pharmacokinetic, and pharmacodynamic study of ENMD-2076, a novel angiogenic and Aurora kinase inhibitor, in patients with advanced solid tumors

Abstract

Purpose: ENMD-2076 is a unique orally bioavailable Aurora kinase and VEGFR inhibitor. The purpose of this phase 1 study of ENMD-2076 was to determine the MTD, pharmacokinetic, and pharmacodynamic profiles and preliminary antitumor activity.

Experimental design: Patients with refractory advanced solid malignancies were treated with ENMD-2076 orally with continuous once daily dosing. Doses from 60 to 200 mg/m(2) were evaluated using a standard 3 (to 4) + 3 design. Pharmacokinetic parameters were studied on days 1, 28, and 30 to 35 of cycle 1. Expanded MTD cohorts included patients with ovarian cancer, colorectal cancer, and refractory solid tumors.

Results: A total of 67 patients (46 F, 21M; ages 30-76) entered the study. Dose levels of 60, 80, 120, 200, and 160 mg/m(2) were evaluated. Two patients experienced grade 3 hypertension at 200 mg/m(2), and additional grade 3 neutropenia events limited tolerability at this dose. An intermediate dose of 160 mg/m(2) was determined to be the MTD. The most common drug-related adverse events included hypertension, nausea/vomiting, and fatigue. The pharmacokinetics of ENMD-2076 were characterized by a rapid absorption phase (T(max) 3-7.8 hours), a t(1/2) of 27.3 to 38.3 hours after a single dose, and dose proportional exposure. Decreased plasma sVEGFR2 was observed posttreatment. Two patients with platinum refractory/resistant ovarian cancer had RECIST partial responses.

Conclusions: ENMD-2076 was well tolerated, had a linear pharmacokinetic profile, and showed promising antitumor activity, particularly in ovarian cancer. The recommended phase 2 dose of ENMD-2076 is 160 mg/m(2) administered orally once daily with continuous dosing.

Trial registration: ClinicalTrials.gov NCT00658671.

Figure 1

Plasma ENMD-2076 and ENMD-2060 concentrations and relationship of drug exposure to dose level. Points represent mean concentration for ENMD-2076 on day 1 (A) and day 28 (B) and for ENMD-2060 on day 28 (C) at the indicated dose level. Relationship of ENMD-2076 exposure (AUC_0-inf) on day 1 (D) and day 28 (E) with actual dose of ENMD-2076 received, and ENMD-2060 exposure (AUC_0-inf) on day 28 with actual dose of ENMD-2076 received (F). Points represent individual patients and lines represent linear regression of data. The r²s for D, E, and F are 0.627, 0.401, and 0.118, respectively.

Figure 2

A, Plasma sVEGFR2 was assayed at baseline (cycle 1, day 1) and at cycle 1, day 28 (*P < 0.001). B, Plasma sVEGFR2 on day 1 and day 28 after continuous dosing during cycle 1 by dosing cohort (*P < 0.001 compared to day 1 in same dosing cohort, **P < 0.05 compared to day 1 in same dosing cohort). (Inset) Percent decrease in plasma sVEGFR2 on day 28 compared to day 1 after continuous dosing during cycle 1 by dosing cohort. Differences in percent change between dosing cohorts are not statistically significant by one-way ANOVA (P = 0.23).

Figure 3

Waterfall plot of the change in the sum of the longest diameters of target lesions observed at the time of best response. Not shown, n = 9, due to unavailable tumor measurements. Dose cohorts are shown in parentheses. White bars and/or *s represent patients who remained on ENMD-2076 at least 6 months.