دورية أكاديمية
Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.
| العنوان: | Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours. |
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| المؤلفون: | Spicer, J, Baird, R, Suder, A, Cresti, N, Corbacho, J Garcia, Hogarth, L, Frenkel, E, Matsumoto, S, Kawabata, I, Donaldson, K, Posner, J, Sarker, D, Jodrell, D, Plummer, R |
| بيانات النشر: | Elsevier BV //dx.doi.org/10.1016/j.ejca.2014.11.003 Eur J Cancer |
| سنة النشر: | 2015 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | EGFR, HER2, HER4, Phase 1 clinical trial, Protein kinase inhibitor, Administration, Oral, Adult, Aged, Area Under Curve, Diarrhea, Dose-Response Relationship, Drug, Drug Administration Schedule, ErbB Receptors, Exanthema, Fatigue, Female, Humans, Male, Metabolic Clearance Rate, Middle Aged, Neoplasms, Protein Kinase Inhibitors, Quinazolines, Receptor, ErbB-2, Treatment Outcome, Young Adult |
| الوصف: | BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day. ; The authors acknowledge financial support from the UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (and NIHR Clinical Research Facility), and to The University of Cambridge and ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/247091Test |
| الإتاحة: | https://www.repository.cam.ac.uk/handle/1810/247091Test |
| رقم الانضمام: | edsbas.DEF77F6A |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |