Reference Detail

Ref Type

Journal Article

PMID

(27693888)

Authors

Jamieson D, Griffin MJ, Sludden J, Drew Y, Cresti N, Swales K, Merriman M, Allen R, Bevan P, Buerkle M, Mala C, Coyle V, Rodgers L, Dean E, Greystoke A, Banerji U, Wilson RH, Evans TR, Anthoney A, Ranson M, Boddy AV, Plummer R

Title

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours.

Journal	Vol	Issue	Date	Pages	Journal Short Title
European journal of cancer (Oxford, England : 1990)	68		2016 11	1-10	Eur J Cancer

URL

Abstract Text

We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials.Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules.Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma.WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.

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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
WX-554	WX-554	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
WX-554			MEK inhibitor (Pan) 24 MEK1 Inhibitor 26 MEK2 Inhibitor 24	WX-554 inhibits the activity of MEK1/2, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation (PMID: 27837257, PMID: 27693888).

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