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|Authors||Rastislav Bahleda, Rodrigo Dienstmann, Barbara Adamo, Anas Gazzah, Jeffrey R. Infante, Bob Zhong, Suso J. Platero, Hans Smit, Timothy Perera, Kim Stuyckens, Jacqueline Bussolari, Vijay Peddareddigari, Jean-Charles Soria, Feng Roger Luo, Josep Tabernero|
|Title||Phase 1 study of JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced solid tumors.|
|Journal||J Clin Oncol 32:5s, 2014 (suppl; abstr 2501)|
|Abstract Text||Background: JNJ-42756493 is an orally bioavailable FGFR 1, 2, 3 and 4 inhibitor with nanomolar antitumor activity in cell lines and in vivo models with FGFR pathway aberration. Methods: This first in human study consists of 3 parts: dose escalation part 1to determine the recommended phase 2 dose (RP2D), dose confirmation part 2 with focus on pharmacodynamic effects, and dose expansion part 3 to evaluate the antitumor activity in selected solid tumors with FGFR gene amplification, mutation or translocation at the RP2D. Biomarkers include tumor tissue genomic profiling, skin/tumor biopsies and soluble serum markers. Toxicity is graded with CTCAE-4 and antitumor activity is assessed using RECIST 1.1. Results: As of 27 January 2014, 37 patients have been treated at 6 dose levels (0.5, 2, 4, 6, 9 and 12 mg daily continuously) in part 1. Most common (? 20% of patients) adverse events (AEs) were hyperphosphatemia (60%), asthenia (46%), dry mouth (30%), constipation (27%), abdominal pain (22%), stomatitis (22%), and vomiting (22%); all were ? Grade 2 in toxicity. Ten (27%) patients had ? Grade 3 AEs, and one dose limiting toxicity of Grade 3 AST/ALT elevation was noted at 12 mg dose. Daily 9 mg continuous dosing was declared the RP2D. Seven (19%) patients had serious AEs, including 1 death, but none were drug-related. Six (16%) patients had dose reductions due to drug-related hyperphosphatemia at 9 and 12 mg. Pharmacokinetics were linear, dose proportional and predictable with a half-life of 50 to 60 hours. Exposure dependent increases in phosphate blood levels were observed at doses up to 9 mg, thereafter reaching a plateau. Also a trend was seen for increase in FGF23 and decrease in PTH. Out of 8 patients enrolled to date with FGFR pathway aberration, we observed 1 partial response in a bladder cancer patient with FGFR3-TACC3 translocation and 1 near complete response in an urothelial cancer of renal pelvis harboring FGFR2 truncation at the RP2D. Four patients (2 lung cancer, 1 chondrosarcoma and 1 breast cancer patients with FGFR1 amplification) had stable disease. Conclusions: JNJ-42756493 has favorable pharmaceutical properties, with manageable side effects at the RP2D and evidence of antitumor activity. Clinical trial information: NCT01703481.|
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