Reference Detail

Ref Type

PMID

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	Vol	Issue	Date	Pages	Journal Short Title
J Clin Oncol 32:5s, 2014 (suppl; abstr 2501)

URL

http://meetinglibrary.asco.org/content/126428-144

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