Reference Detail

Ref Type Journal Article
PMID (20823884)
Authors Konings IR, de Jonge MJ, Burger H, van der Gaast A, van Beijsterveldt LE, Winkler H, Verweij J, Yuan Z, Hellemans P, Eskens FA
Title Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours.
Journal British journal of cancer
Vol 103
Issue 7
Date 2010 Sep 28
URL
Abstract Text JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327.Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood.JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27(kip1), phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%).JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.

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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
JNJ-26483327 JNJ-26483327 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
JNJ-26483327 EGFR Inhibitor (Pan) 42 HER2 Inhibitor 21 RET Inhibitor 36 JNJ-26483327 is a multi-kinase inhbitor, which inhibits wild-type and mutant EGFR, RET, and has activity against VEGFR3, ERBB2 (HER2), ERBB4, and SRC family members (PMID: 20823884).
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
Unknown unknown Advanced Solid Tumor not applicable JNJ-26483327 Phase I Actionable In a Phase I clinical trial, JNJ-26483327 was well-tolerated in patients with a range of advanced solid tumors, and demonstrated preliminary anti-tumor activity with 32% (6/19) of patients achieving stable disease for greater than 2 cycles (PMID: 20823884). 20823884