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

Overview

Journal Ann Oncol

Publisher Elsevier

Specialty Oncology

Date 2010 Dec 7

PMID 21131369

Citations 32

Authors

D J Jonker

L S Rosen

M B Sawyer

F de Braud

G Wilding

C J Sweeney

G C Jayson

G A McArthur

G Rustin

G Goss

J Kantor

L Velasquez

S Syed

O Mokliatchouk

D M Feltquate

G Kollia

D S A Nuyten

S Galbraith

Affiliations

Soon will be listed here.

Abstract

Background: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.

Patients And 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.

Conclusion: 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.

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