A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors.
BACKGROUND
This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.


METHODS
Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD.


RESULTS
Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts.


CONCLUSIONS
In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.
Division of Medical Oncology, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Canada. Electronic address: djonker@ottawahospital.on.ca.
D J
DJ
Jonker
Department of Oncology, Premiere Oncology, Santa Monica, USA.
L S
LS
Rosen
Department of Oncology, Cross Cancer Institute, Edmonton, Canada.
M B
MB
Sawyer
Division of Clinical Pharmacology and New Drugs, Department of Medicine, European Institute of Oncology, Milan, Italy.
F
F
de Braud
Department of Oncology, University of Wisconsin Carbone Cancer Center, Madison.
G
G
Wilding
Department of Medicine, Dana-Farber Cancer Institute, Boston, USA.
C J
CJ
Sweeney
Department of Oncology, Christie Hospital, University of Manchester, Manchester, UK.
G C
GC
Jayson
Department of Medical Oncology, Peter MacCallum Cancer Center, East Melbourne, Australia.
G A
GA
McArthur
Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, Middlesex, UK.
G
G
Rustin
Division of Medical Oncology, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Canada.
G
G
Goss
Research and Development, Bristol-Myers Squibb, Princeton, USA.
J
J
Kantor
Research and Development, Bristol-Myers Squibb, Princeton, USA.
L
L
Velasquez
Research and Development, Bristol-Myers Squibb, Princeton, USA.
S
S
Syed
Research and Development, Bristol-Myers Squibb, Princeton, USA.
O
O
Mokliatchouk
Research and Development, Bristol-Myers Squibb, Princeton, USA.
D M
DM
Feltquate
Research and Development, Bristol-Myers Squibb, Princeton, USA.
G
G
Kollia
Research and Development, Bristol-Myers Squibb, Princeton, USA.
D S A
DSA
Nuyten
Research and Development, Bristol-Myers Squibb, Princeton, USA.
S
S
Galbraith
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality; D009389:Neovascularization, Pathologic; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D017468:Receptors, Fibroblast Growth Factor; D014227:Triazines; C509922:brivanib; D040262:Receptors, Vascular Endothelial Growth Factor; D000409:Alanine