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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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References