Josep Tabernero1, Rastislav Bahleda2, Rodrigo Dienstmann2, Jeffrey R Infante2, Alain Mita2, Antoine Italiano2, Emiliano Calvo2, Victor Moreno2, Barbara Adamo2, Anas Gazzah2, Bob Zhong2, Suso J Platero2, Johan W Smit2, Kim Stuyckens2, Moitreyee Chatterjee-Kishore2, Jordi Rodon2, Vijay Peddareddigari2, Feng R Luo2, Jean-Charles Soria2. 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.
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: Bruno Bockorny; Maria Rusan; Wankun Chen; Rachel G Liao; Yvonne Li; Federica Piccioni; Jun Wang; Li Tan; Aaron R Thorner; Tianxia Li; Yanxi Zhang; Changhong Miao; Therese Ovesen; Geoffrey I Shapiro; David J Kwiatkowski; Nathanael S Gray; Matthew Meyerson; Peter S Hammerman; Adam J Bass Journal: Mol Cancer Ther Date: 2018-04-13 Impact factor: 6.261
Authors: Milind Javle; Maeve Lowery; Rachna T Shroff; Karl Heinz Weiss; Christoph Springfeld; Mitesh J Borad; Ramesh K Ramanathan; Lipika Goyal; Saeed Sadeghi; Teresa Macarulla; Anthony El-Khoueiry; Robin Kate Kelley; Ivan Borbath; Su Pin Choo; Do-Youn Oh; Philip A Philip; Li-Tzong Chen; Thanyanan Reungwetwattana; Eric Van Cutsem; Kun-Huei Yeh; Kristen Ciombor; Richard S Finn; Anuradha Patel; Suman Sen; Dale Porter; Randi Isaacs; Andrew X Zhu; Ghassan K Abou-Alfa; Tanios Bekaii-Saab Journal: J Clin Oncol Date: 2017-11-28 Impact factor: 44.544
Authors: Niklas Schäfer; Gerrit H Gielen; Sied Kebir; Anja Wieland; Andreas Till; Frederic Mack; Christina Schaub; Theophilos Tzaridis; Roman Reinartz; Michael Niessen; Rolf Fimmers; Matthias Simon; Christoph Coch; Christine Fuhrmann; Ulrich Herrlinger; Björn Scheffler; Martin Glas Journal: J Cancer Res Clin Oncol Date: 2016-04-21 Impact factor: 4.553