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/m2 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/m2 were evaluated. Two patients experienced grade 3 hypertension at 200 mg/m2, and additional grade 3 neutropenia events limited tolerability at this dose. An intermediate dose of 160 mg/m2 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 (Tmax 3–7.8 hours), a t1/2 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/m2 administered orally once daily with continuous dosing.

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

“…The toxicity profile observed in the MK-5108 CT group (i.e., Grade 3 and Grade 4 febrile neutropenia and Grade 3 infection) precluded escalation of MK-5108 doses to levels anticipated to provide adequate therapeutic exposure. Despite compelling preclinical findings showing the enhanced anti-tumor effects of AKIs and cytotoxic chemotherapies, it has been challenging to develop tolerable CT regimens because of the overlapping hematologic toxicities associated with both agents [18–20]. In the present study, the hematologic toxicity of neutropenia was observed only in the CT arm with docetaxel.…”

Predictive Biomarkers of Sensitivity to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Breast Cancer Models

“…ENMD-2076 has completed a phase I dose escalation study in patients with advanced solid tumors in which a patient with metastatic TNBC sustained clinically meaningful stabilization of disease lasting for 41 weeks (46). The drug had an acceptable safety profile, with predictable, mechanism-based side-effects including hypertension and mild neutropenia and is currently being evaluated in early phase clinical trials in hematologic malignancies (46).…”

Aurora-B protein expression is linked to initial response to taxane-based first-line chemotherapy in stage III ovarian carcinoma

“…This suggests that targeting Aurora kinases in ovarian carcinomas may be a potential future therapeutic approach, either alone or synergistically 18 29. Since Aurora-A and Aurora-B are similarly expressed in serous, FIGO stage III ovarian carcinomas, pan-Aurora kinase inhibitors24 30 31 44 rather than, for example, Aurora-A specific inhibitors (such as MLN8054 and MLN8237, currently still in clinical trials for the treatment of patients with ovarian, fallopian tube or peritoneal carcinoma) may eventually become the preferred choice.…”