Phase I Study of BI 853520, an Inhibitor of Focal Adhesion Kinase, in Patients with Advanced or Metastatic Nonhematologic Malignancies

Abstract

Background: Overexpression/activation of focal adhesion kinase (FAK) in human malignancies has led to its evaluation as a therapeutic target. We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor.

Objective: Our objectives were to identify the maximum tolerated dose (MTD), and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker expression, and preliminary activity.

Patients and methods: The study comprised a standard 3 + 3 dose-escalation phase followed by an expansion phase in patients with selected advanced, nonhematologic malignancies.

Results: Thirty-three patients received BI 853520 in the dose-escalation phase; the MTD was 200 mg once daily (QD). Dose-limiting toxicities included proteinuria and fatigue, both of which were grade 3. Preliminary PK data supported QD dosing. In the expansion cohort, 63 patients received BI 853520 200 mg QD. Drug-related adverse events (AEs) in > 10% of patients included proteinuria (57%), nausea (57%), fatigue (51%), diarrhea (48%), vomiting (40%), decreased appetite (19%), and peripheral edema (16%). Most AEs were grade 1-2; grade 3 proteinuria, reported in 13 patients (21%), was generally reversible upon treatment interruption. Nineteen patients underwent dose reduction due to AEs, and three drug-related serious AEs were reported, none of which were fatal. Preliminary PD analysis indicated target engagement. Of 63 patients, 49 were evaluable; 17 (27%) achieved a best response of stable disease (4 with 150 + days), and 32 (51%) patients had progressive disease.

Conclusions: BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies. CLINICALTRIALS.

Gov identifier: NCT01335269.

Conflict of interest statement

Hal W. Hirte reports receiving honoraria from AstraZeneca, Roche and Merck; Albiruni R. Abdul Razak reports paid expert testimony for, and grants from, Boehringer Ingelheim; and Filip Y.F.L. De Vos reports paid expert testimony for Bristol Myers Squibb, and grants from Novartis. Remy B. Verheijen is an employee of AstraZeneca; David Schnell and Linda C. Pronk are employees of Boehringer Ingelheim; and Monique Jansen was an employee of Boehringer Ingelheim at the time of study conduct and manuscript preparation. Lillian L. Siu reports institutional clinical trial funding for this study provided by Boehringer Ingelheim. Maja J.A. de Jonge, Neeltje Steeghs, Martijn P. Lolkema, Sebastien J. Hotte, and Diane A.J. van der Biessen declare that they have no conflicts of interest.

Figures

Fig. 1

Plasma concentration–time profiles for BI 853520 after single- and multiple-dose administration in the first cycle. Pharmacokinetic profiles after single- and multiple-dose administration were assessed during the first treatment cycle, i.e. after the first dose on day 1 and after repeated dosing on day 28

Fig. 2

Individual (circle) and geometric mean (cross) PK parameters for BI 853520 after single- and multiple-dose administration in the first cycle. PK profiles after single- and multiple-dose administration were assessed during the first treatment cycle, i.e. after the first dose on day 1 and after repeated dosing on day 28. AUC area under the plasma concentration–time curve, Cmax maximum plasma concentration, gMean geometric mean, PK pharmacokinetic

Fig. 3

Change from baseline to end of the first cycle in levels of phosphorylated FAK/total FAK in tumor tissue (expansion cohort; 200 mg QD). FAK focal adhesion kinase, QD once daily

Fig. 4

Confirmed best overall tumor response and treatment duration by tumor type (expansion cohort; 200 mg QD). AE adverse event, QD once daily