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

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.

• Authors: Josep Tabernero, Rastislav Bahleda, Rodrigo Dienstmann, Jeffrey R Infante, Alain Mita, Antoine Italiano, Emiliano Calvo, Victor Moreno, Barbara Adamo, Anas Gazzah, Bob Zhong, Suso J Platero, Johan W Smit, Kim Stuyckens, Moitreyee Chatterjee-Kishore, Jordi Rodon, Vijay Peddareddigari, Feng R Luo, Jean-Charles Soria
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 33 Issue 30 Pg. 3401-8 (Oct 20 2015) ISSN: 1527-7755 [Electronic] United States
• PMID: 26324363 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by American Society of Clinical Oncology.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyrazoles
• Quinoxalines
• Receptors, Fibroblast Growth Factor
• erdafitinib

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Humans
• Middle Aged
• Neoplasms (blood, drug therapy, metabolism)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrazoles (administration & dosage, adverse effects, pharmacokinetics)
• Quinoxalines (administration & dosage, adverse effects, pharmacokinetics)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors)