Format

Send to

Choose Destination
J Clin Oncol. 2015 Oct 20;33(30):3401-8. doi: 10.1200/JCO.2014.60.7341. Epub 2015 Aug 31.

Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors.

Author information

1
Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey R. Infante, Sarah Cannon Research Institute, Nashville, TN; Alain Mita, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Bob Zhong, Suso J. Platero, Moitreyee Chatterjee-Kishore, Vijay Peddareddigari, and Feng R. Luo, Janssen Research and Development, Raritan, NJ; and Johan W. Smit and Kim Stuyckens, Janssen Research and Development, Beerse, Belgium. jtabernero@vhio.net.
2
Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey R. Infante, Sarah Cannon Research Institute, Nashville, TN; Alain Mita, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Bob Zhong, Suso J. Platero, Moitreyee Chatterjee-Kishore, Vijay Peddareddigari, and Feng R. Luo, Janssen Research and Development, Raritan, NJ; and Johan W. Smit and Kim Stuyckens, Janssen Research and Development, Beerse, Belgium.

Abstract

PURPOSE:

JNJ-42756493 is an orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. This first-in-human study evaluates the safety, pharmacokinetics, and pharmacodynamics and defines the recommended phase II dose (RP2D) of JNJ-42756493.

PATIENTS AND METHODS:

Eligible patients with advanced solid tumors received escalating doses of JNJ-42756493 from 0.5 to 12 mg administered continuously daily or JNJ-42756493 10 or 12 mg administered intermittently (7 days on/7 days off).

RESULTS:

Sixty-five patients were enrolled. The most common treatment-emergent adverse events included hyperphosphatemia (65%), asthenia (55%), dry mouth (45%), nail toxicity (35%), constipation (34%), decreased appetite (32%), and dysgeusia (31%). Twenty-seven patients (42%) experienced grade ≥ 3 treatment-emergent adverse events, and one dose-limiting toxicity of grade 3 ALT elevation was observed at 12 mg daily. Maximum-tolerated dose was not defined. Nine milligrams daily was considered as the initial RP2D; however, tolerability was improved with intermittent schedules, and 10 mg administered on a 7-days-on/7-days-off schedule was considered the final RP2D. Pharmacokinetics were linear, dose proportional, and predictable, with a half-life of 50 to 60 hours. Dose-dependent elevations in serum phosphate, a manifestation of pharmacodynamic effect, occurred in all patients starting at 4 mg daily. Among 23 response-evaluable patients with tumor FGFR pathway alterations, four confirmed responses and one unconfirmed partial response were observed in patients with glioblastoma and urothelial and endometrial cancer (all with FGFR2 or FGFR3 translocations); 16 patients had stable disease.

CONCLUSION:

JNJ-42756493 administered at 10 mg on a 7-days-on/7-days-off schedule achieved exposures at which clinical responses were observed, demonstrated pharmacodynamic biomarker activity, and had a manageable safety profile.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01703481.

PMID:
26324363
DOI:
10.1200/JCO.2014.60.7341
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center