Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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%).

CONCLUSION:

JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.

• Authors: I R H M Konings, M J A de Jonge, H Burger, A van der Gaast, L E C van Beijsterveldt, H Winkler, J Verweij, Z Yuan, P Hellemans, F A L M Eskens
• Journal: British journal of cancer (Br J Cancer) Vol. 103 Issue 7 Pg. 987-92 (Sep 28 2010) ISSN: 1532-1827 [Electronic] England
• PMID: 20823884 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• JNJ-26483327
• Macrocyclic Compounds
• Protein Kinase Inhibitors

Topics

• Administration, Oral
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Female
• Humans
• Macrocyclic Compounds (pharmacology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (adverse effects, pharmacokinetics, pharmacology, therapeutic use)