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|Ref Type||Journal Article|
|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|
|Date||2010 Sep 28|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|JNJ-26483327||BGB-102||EGFR Inhibitor (Pan) 47 HER2 Inhibitor 25 RET Inhibitor 39||JNJ-26483327 (BGB-102) 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).|
|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|
|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|