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

Our plain-English summary of 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, by D. Jamieson, M.J. Griffin, J. Sludden, et al (European Journal of Cancer, 2016).

The study

• Authors: D. Jamieson, M.J. Griffin, J. Sludden, Y. Drew, N. Cresti, K. Swales, M. Merriman, R. Allen, P. Bevan, M. Buerkle, C. Mala, V. Coyle, L. Rodgers, E. Dean, A. Greystoke, U. Banerji, R.H. Wilson, T.R. Evans, A. Anthoney, M. Ranson, A.V. Boddy, R. Plummer
• Journal: European Journal of Cancer
• Published: 2016;68:1-10
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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.

Copyright © 2016 Elsevier Ltd. All rights reserved.

In plain English

This was a phase I, open-label, dose-escalation trial of WX-554, an experimental oral cancer drug (a MEK inhibitor), run at five UK centres between March 2012 and March 2014. It did not study asbestos exposure. The trial recruited 41 patients with advanced solid tumours; six (15%) had mesothelioma, and colorectal cancer was most common. Mesothelioma results were not reported separately. Doses ranged from 25 to 150 mg once weekly and 25 to 75 mg twice weekly. No dose-limiting toxicities were recorded, and a maximum tolerated dose was not reached. Side effects considered drug-related occurred in 33 patients (80.5%), most often fatigue and diarrhoea. Four potentially drug-related serious adverse events occurred, all at higher doses. At 75 mg twice weekly, ERK phosphorylation, a marker of the drug's effect, in laboratory-stimulated blood cells was inhibited 60% before the day 8 dose and 70% six hours after it. Tumour ERK phosphorylation fell in all 5 paired biopsies, by a median of 68%. Of 34 patients assessed, none had an objective response; 20 (59%) had stable disease. The authors identified 75 mg twice weekly as the optimal biological dose.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I, open-label, dose-escalation drug trial (3 + 3 design), first study of WX-554 in cancer patients
• Who was studied: 41 patients with advanced solid tumours for whom no effective standard therapy was available, treated at five clinical centres in the UK, March 2012 to March 2014
• Exposure: No asbestos exposure was studied. The exposure was the oral MEK inhibitor WX-554: once-weekly dosing in five cohorts (25 to 150 mg) and twice-weekly dosing in three cohorts (25 to 75 mg)
• Main results:
  • Tumour types among the 41 patients: 6 (15%) had mesothelioma; colorectal cancer was the most common type (10, 24%). No results were given separately by tumour type, except for two individual cases.
  • No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached
  • All 41 patients had at least one adverse event; 33 (80.5%) had adverse events considered related to WX-554
  • Fatigue and diarrhoea were the most common adverse reactions
  • Four potentially drug-related serious adverse events occurred, all at higher doses: bowel perforation, grade 3 transaminitis, grade 4 anaemia and grade 2 QTc prolongation
  • In the 75 mg twice-weekly cohort, ERK phosphorylation in peripheral blood mononuclear cells stimulated ex vivo with PMA was inhibited 60% in the day 8 pre-dose samples and 70% in the 6-hour samples on day 8
  • In the 5 paired tumour biopsies (75 mg twice weekly), pERK was lower in all 5 at day 8 of cycle 1, with a median decrease of 68%
  • Of 34 patients eligible for response assessment, none had an objective response; 20 (59%) had stable disease, and 2 (6%) had prolonged disease stabilisation (one with cervical cancer, one with ampullary carcinoma)
  • The drug's mean half-life was 28 hours
• The authors' conclusion: The authors concluded that WX-554 was well tolerated and identified 75 mg twice weekly as the optimal biological dose for further study
• Limitations the authors state:
  • It is not known whether the degree of pERK inhibition in blood cells relates to the drug's effectiveness or toxicity
  • The lack of effectiveness may partly reflect that patients were not selected by tumour mutation; effectiveness must be tested in later phase II and III trials
  • Differences in assays, tissues and time points make comparison with other MEK inhibitor trials difficult

Topics

Medical terms in this study, explained in our Lexicon: Performance Status, Carcinoma.

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