David Jamieson1, Melanie J Griffin1, Julieann Sludden1, Yvette Drew2, Nicola Cresti3, Karen Swales4, Mark Merriman5, Rodger Allen5, Paul Bevan6, Markus Buerkle6, Carola Mala6, Vicky Coyle7, Lisa Rodgers8, Emma Dean9, Alastair Greystoke2, Udai Banerji4, Richard H Wilson7, T R Jeffery Evans8, Alan Anthoney10, Malcolm Ranson9, Alan V Boddy1, Ruth Plummer11. 1. Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. 2. Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK. 3. Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK. 4. Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK. 5. UCB, 216 Bath Road, Slough, SL1 4EN, UK. 6. WILEX AG, Grillparzerstr. 18, 81675, Munich, Germany. 7. Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK; Northern Ireland Cancer Center, Belfast City Hospital, Belfast, UK. 8. Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, G12 OYN, UK. 9. The Christie NHS Foundation Trust, The University of Manchester, Manchester, M20 4BX, UK. 10. St. James's Institute of Oncology, Beckett Street, Leeds, LS9 7TF, UK. 11. Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK. Electronic address: ruth.plummer@ncl.ac.uk.
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.
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.