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


METHODS
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.
University of Colorado at Denver, Aurora, Colorado, USA.
Jennifer R
JR
Diamond
Bruno R
BR
Bastos
Ryan J
RJ
Hansen
Daniel L
DL
Gustafson
S Gail
SG
Eckhardt
Eunice L
EL
Kwak
Shuchi S
SS
Pandya
Graham C
GC
Fletcher
Todd M
TM
Pitts
Gillian N
GN
Kulikowski
Mark
M
Morrow
Jamie
J
Arnott
Mark R
MR
Bray
Carolyn
C
Sidor
Wells
W
Messersmith
Geoffrey I
GI
Shapiro
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D064127:Aurora Kinases; D004305:Dose-Response Relationship, Drug; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C551397:ENMD 2076; D006657:Histones; D011720:Pyrazoles; D011743:Pyrimidines; D040301:Vascular Endothelial Growth Factor Receptor-2; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases