Cancer Chemother Pharmacol (2011) 68:1377–1385
DOI 10.1007/s00280-011-1603-2
123
ORIGINAL ARTICLE
Lack of food eVect on single-dose pharmacokinetics of brivanib,
and safety and eYcacy following multiple doses in subjects
with advanced or metastatic solid tumors
Patricia LoRusso · GeoVrey I. Shapiro · Herbert Hurwitz ·
Mary Jo Pilat · Janice Chemidlin · Georgia Kollia ·
Shariq Syed · Bruce Fischer · Eric Masson
Received: 12 November 2010 / Accepted: 1 March 2011 / Published online: 3 April 2011
© Springer-Verlag 2011
Abstract
Purpose Brivanib alaninate, an orally available prodrug of
brivanib, is currently under evaluation for the treatment of
several malignancies. This study aimed to (1) investigate
eVects of a high-fat meal on single-dose pharmacokinetics of
brivanib in subjects with advanced/metastatic solid tumors
and (2) assess the safety and preliminary eYcacy of single
and multiple doses of brivanib alaninate in this population.
Methods A two-part study was conducted consisting of a
single-dose phase (Part A) and a multiple-dose phase (Part
B). In Part A, subjects received a single dose of brivanib
alaninate (800 mg) either in a fasting state or following
ingestion of a high-fat meal (approximately 951 kcal [15%
protein, 33% carbohydrate, 52% fat]); serial blood samples
were collected for pharmacokinetic analysis up to 48 h
post-dosing. In Part B, subjects received brivanib alaninate
(800 mg) once daily until discontinuation. Throughout both
phases, subjects were evaluated for adverse events (AEs)
and best clinical response.
Results No clinically signiWcant diVerences in brivanib
exposure were observed between fed and fasting subjects in
Part A; C
max
was unchanged and AUC
INF
decreased mar-
ginally when administered in a fed versus fasted state. In
Part A, the incidence of treatment-emergent AEs was
broadly similar in a fed or fasted state. Brivanib alaninate
was generally well tolerated throughout the study and
showed preliminary evidence of antitumor activity.
Conclusions Consumption of a high-fat meal had no sig-
niWcant eVect on brivanib pharmacokinetics. The study fur-
ther demonstrates the acceptable safety/tolerability proWle
and antitumor potential of brivanib in patients with
advanced malignancies.
Keywords Pharmacokinetics · Exposure · Food · Safety ·
Brivanib alaninate · Solid tumors
Introduction
Angiogenesis, the process by which new blood vessels are
formed, is critical for tumor growth and metastasis and is
mediated by several proangiogenic factors, such as vascular
endothelial growth factor A (VEGF-A) and Wbroblast
growth factors 1 (FGF-1) and 2 (FGF-2) [1]. A number
of antiangiogenic drugs that speciWcally inhibit VEGF
receptor (VEGFR) signaling pathways have demonstrated
survival beneWts, either as monotherapy or when co-admin-
istered with other chemotherapy agents, in subjects with
various advanced-stage malignancies, including renal cell
carcinoma (RCC), non-small-cell lung cancer, hepatocellular
carcinoma (HCC), and colorectal cancer [2–8]. Although
the use of these VEGF inhibitors represents a breakthrough
in the treatment of tumor angiogenesis, responses to date
have been modest and transient, and treatment with these
agents has varyingly been associated with signiWcant
toxicities [9, 10].
P. LoRusso (&) · M. J. Pilat
Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, USA
e-mail: lorussop@karmanos.org
G. I. Shapiro
Dana Farber Cancer Institute, 44 Binney Street,
Boston, MA 02115, USA
H. Hurwitz
Duke University Medical Center, DUMC 3052,
Durham, NC 27710, USA
J. Chemidlin · G. Kollia · S. Syed · B. Fischer · E. Masson
Bristol-Myers Squibb, Route 206 & Province Line Road,
Lawrenceville, NJ 08540, USA