Abstract A103: Preliminary results of a phase 1 study of FP-1039 (FGFR1:Fc), a novel antagonist of multiple fibroblast growth factor (FGF) ligands, in patients with advanced malignancies
Authors: Tolcher Anthony , Papadopoulos Kyri , Agnew Jim , Marshall John , Tanzola Carolyn , Zanghi Jim , Baker Kevin P. , Keer Harold N. , Patniak Amita 
Published: June 2012

Abstract
Background: The human fibroblast growth factor (FGF) axis is a complex system comprised of 22 ligands that bind to various combinations of 4 distinct cell surface receptors (FGFR1-4). FGFs have been demonstrated to be involved in tumor growth promotion, tumor angiogenesis, and in tumor stem cell maintenance. FP-1039 acts as a potent ligand “trap” that sequesters multiple FGF family ligands, neutralizing their ability to bind to and activate multiple FGF receptors. FP-1039 has anti-tumor activity in multiple xenograft models both as a single agent and in combination with other anticancer agents.
Study Design: We report preliminary results of a first-in-human study of FP-1039 as a single agent in patients with advanced solid malignancies. Objectives were to characterize the safety, pharmacokinetics (PK), and immunogeneicity profiles of FP-1039. Characterization of preliminary anti-tumor activity and pharmacodynamic biomarkers were exploratory objectives. Subjects received 4 once-weekly intravenous doses of FP-1039, followed by a two week observation period. In the absence of either unacceptable toxicity or progressive disease, patients were eligible to receive additional weekly doses of FP-1039.
Results: To date, a total of 15 subjects have received FP-1039 at doses ranging from 0.5–1.0 mg/kg. FP-1039 was generally well tolerated at doses of 0.5 and 0.75 mg/kg. A single dose limiting toxicity (DLT) was seen at 0.75 mg/kg and two at 1 mg/kg. The DLTs were clinically distinct, no consistent pattern related to drug exposure could be discerned and confounding factors were present. Further dose exploration is ongoing.
PK analysis revealed a linear, dose-dependent increase in drug exposure in the plasma compartment typical of a large protein. Cohort mean terminal half-lives ranged from 63 to 102 hours, and appeared to be similar on Day 1 and Day 22. There was accumulation after 4 weekly doses of FP-1039. Transient, weak anti-drug antibody responses were seen in 4 of 12 subjects (33%) which were not associated with changes in PK or clinical sequelae. Free plasma FGF2 levels were assessed prior to initial dosing and at multiple subsequent timepoints. All subjects had elevated FGF2 levels prior to FP-1039 treatment compared to published levels in normal individuals. Preliminary analysis demonstrated a decrease in plasma levels of free FGF2 following FP-1039 treatment at all doses.
Ten subjects completed the treatment period while 5 did not due to adverse events or rapidly progressive disease. By RECIST criteria, 6 subjects had stable disease. In one of these, a subject with castration-resistant prostate cancer and progressive disease despite docetaxel treatment, a reduction in FDG PET SUV on 2- and 6-week scans and a 20% decrease in tumor size by CT scan were demonstrated.
Conclusions: FP-1039 appears to be well tolerated at doses of 0.5–0.75 mg/kg, and exploration of higher doses is in progress. Preliminary PK and target engagement data (reduction in FGF2) support a weekly or longer dosing interval. Preliminary single agent activity is promising.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A103.