PMID- 30756308
OWN - NLM
STAT- MEDLINE
DCOM- 20200106
LR  - 20200309
IS  - 1776-260X (Electronic)
IS  - 1776-2596 (Print)
IS  - 1776-2596 (Linking)
VI  - 14
IP  - 1
DP  - 2019 Feb
TI  - Phase I Study of BI 853520, an Inhibitor of Focal Adhesion Kinase, in Patients 
      with Advanced or Metastatic Nonhematologic Malignancies.
PG  - 43-55
LID - 10.1007/s11523-018-00617-1 [doi]
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.
FAU - de Jonge, Maja J A
AU  - de Jonge MJA
AD  - Department of Internal Oncology, Erasmus Medical Centre Cancer Institute, Dr. 
      Molenwaterplein 40, 3015 GD, Rotterdam, The Netherlands. m.dejonge@erasmusmc.nl.
FAU - Steeghs, Neeltje
AU  - Steeghs N
AD  - Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer 
      Institute, Plesmanlaan 12, 11066 CX, Amsterdam, The Netherlands.
FAU - Lolkema, Martijn P
AU  - Lolkema MP
AD  - Department of Internal Oncology, Erasmus Medical Centre Cancer Institute, Dr. 
      Molenwaterplein 40, 3015 GD, Rotterdam, The Netherlands.
AD  - Department of Medical Oncology, University Medical Center Utrecht, Utrecht Cancer 
      Center, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
FAU - Hotte, Sebastien J
AU  - Hotte SJ
AD  - Division of Medical Oncology, Juravinski Cancer Centre, 3rd Floor, 699 Concession 
      Street, Hamilton, ON, L8V 5C2, Canada.
FAU - Hirte, Hal W
AU  - Hirte HW
AD  - Division of Medical Oncology, Juravinski Cancer Centre, 3rd Floor, 699 Concession 
      Street, Hamilton, ON, L8V 5C2, Canada.
FAU - van der Biessen, Diane A J
AU  - van der Biessen DAJ
AD  - Department of Internal Oncology, Erasmus Medical Centre Cancer Institute, Dr. 
      Molenwaterplein 40, 3015 GD, Rotterdam, The Netherlands.
FAU - Abdul Razak, Albiruni R
AU  - Abdul Razak AR
AD  - Division of Medical Oncology, Princess Margaret Cancer Centre, 610 University 
      Avenue, Suite 5-718, Toronto, ON, M5G 2M9, Canada.
FAU - De Vos, Filip Y F L
AU  - De Vos FYFL
AD  - Department of Medical Oncology, University Medical Center Utrecht, Utrecht Cancer 
      Center, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
FAU - Verheijen, Remy B
AU  - Verheijen RB
AD  - Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer 
      Institute, Plesmanlaan 12, 11066 CX, Amsterdam, The Netherlands.
FAU - Schnell, David
AU  - Schnell D
AD  - Department of Translational Medicine and Clinical Pharmacology, Boehringer 
      Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str 65, 88397, Biberach, Germany.
FAU - Pronk, Linda C
AU  - Pronk LC
AD  - Clinical Development Oncology, Boehringer Ingelheim Espana S.A., Parque 
      Empresarial Alvento, Via de los Poblados, 1 Planta Baja-Edif. B Ofic. A y C, 
      28033, Madrid, Spain.
FAU - Jansen, Monique
AU  - Jansen M
AD  - Medical Department, Boehringer Ingelheim BV, Comeniusstraat 6, 1817 MS Alkmaar, 
      PO Box 8037, 1802 KA, Aklmaar, The Netherlands.
FAU - Siu, Lillian L
AU  - Siu LL
AD  - Division of Medical Oncology, Princess Margaret Cancer Centre, 610 University 
      Avenue, Suite 5-718, Toronto, ON, M5G 2M9, Canada.
LA  - eng
SI  - ClinicalTrials.gov/NCT01335269
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - France
TA  - Target Oncol
JT  - Targeted oncology
JID - 101270595
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (PTK2 protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Female
MH  - Focal Adhesion Kinase 1/*antagonists & inhibitors
MH  - Follow-Up Studies
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasm Metastasis
MH  - Neoplasms/*drug therapy/pathology
MH  - Prognosis
MH  - Protein Kinase Inhibitors/*pharmacokinetics/*therapeutic use
MH  - Tissue Distribution
MH  - Young Adult
PMC - PMC6407740
COIS- 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.
EDAT- 2019/02/14 06:00
MHDA- 2020/01/07 06:00
PMCR- 2019/02/11
CRDT- 2019/02/14 06:00
PHST- 2019/02/14 06:00 [pubmed]
PHST- 2020/01/07 06:00 [medline]
PHST- 2019/02/14 06:00 [entrez]
PHST- 2019/02/11 00:00 [pmc-release]
AID - 10.1007/s11523-018-00617-1 [pii]
AID - 617 [pii]
AID - 10.1007/s11523-018-00617-1 [doi]
PST - ppublish
SO  - Target Oncol. 2019 Feb;14(1):43-55. doi: 10.1007/s11523-018-00617-1.