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.

• Authors: Jennifer R Diamond, Bruno R Bastos, Ryan J Hansen, Daniel L Gustafson, S Gail Eckhardt, Eunice L Kwak, Shuchi S Pandya, Graham C Fletcher, Todd M Pitts, Gillian N Kulikowski, Mark Morrow, Jamie Arnott, Mark R Bray, Carolyn Sidor, Wells Messersmith, Geoffrey I Shapiro
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 4 Pg. 849-60 (Feb 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21131552 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• ENMD 2076
• Histones
• Pyrazoles
• Pyrimidines
• Vascular Endothelial Growth Factor Receptor-2
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Adult
• Aged
• Angiogenesis Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Aurora Kinases
• Dose-Response Relationship, Drug
• Female
• Histones (metabolism)
• Humans
• Hypertension (chemically induced)
• Keratinocytes (drug effects, metabolism)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Neutropenia (chemically induced)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyrazoles (administration & dosage, adverse effects, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Tumor Burden (drug effects)
• Vascular Endothelial Growth Factor Receptor-2 (blood)