TY - JOUR
T1 - Phase I Study of BI 853520, an Inhibitor of Focal Adhesion Kinase, in Patients with Advanced or Metastatic Nonhematologic Malignancies
AU - de Jonge, Maja J A
AU - Steeghs, Neeltje
AU - Lolkema, Martijn P
AU - Hotte, Sebastien J
AU - Hirte, Hal W
AU - van der Biessen, Diane A J
AU - Abdul Razak, Albiruni R
AU - De Vos, Filip Y F L
AU - Verheijen, Remy B
AU - Schnell, David
AU - Pronk, Linda C
AU - Jansen, Monique
AU - Siu, Lillian L
N1 - Funding Information:
The authors thank all patients and their families, and investigators and staff at all clinical sites, for their valuable contributions to this study. The authors acknowledge Emma Landers, PhD, of GeoMed, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this manuscript, which was funded by Boehringer Ingelheim.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Female
KW - Focal Adhesion Kinase 1/antagonists & inhibitors
KW - Follow-Up Studies
KW - Humans
KW - Male
KW - Maximum Tolerated Dose
KW - Middle Aged
KW - Neoplasm Metastasis
KW - Neoplasms/drug therapy
KW - Prognosis
KW - Protein Kinase Inhibitors/pharmacokinetics
KW - Tissue Distribution
KW - Young Adult
UR - http://www.scopus.com/inward/record.url?scp=85061198711&partnerID=8YFLogxK
U2 - 10.1007/s11523-018-00617-1
DO - 10.1007/s11523-018-00617-1
M3 - Article
C2 - 30756308
SN - 1776-2596
VL - 14
SP - 43
EP - 55
JO - Targeted Oncology
JF - Targeted Oncology
IS - 1
ER -