Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study
| العنوان: | Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study |
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| المؤلفون: | Raoul Tibes, Daniel D. Von Hoff, Mitesh J. Borad, Larisa Reyderman, Corina E. Dutcus, Kevie Feit, Andrew Eisen, David Verbel |
| المصدر: | British Journal of Cancer |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Maximum Tolerated Dose, QT interval, Article, Papillary thyroid cancer, Lactones, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Neoplasms, Internal medicine, medicine, Humans, Dosing, Infusions, Intravenous, Adverse effect, Melanoma, neoplasms, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, business.industry, Middle Aged, medicine.disease, Regimen, 030104 developmental biology, 030220 oncology & carcinogenesis, Eye disorder, Female, business |
| الوصف: | Background This phase 1 first-in-human study aimed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and safety of E6201, and to establish recommended dosing in patients with advanced solid tumours, expanded to advanced melanoma. Methods Part A (dose escalation): sequential cohorts received E6201 intravenously (IV) over 30 min (once-weekly [qw; days (D)1 + 8 + 15 of a 28-day cycle]), starting at 20 mg/m2, increasing to 720 mg/m2 or the MTD. Part B (expansion): patients with BRAF-mutated or wild-type (WT) melanoma received E6201 320 mg/m2 IV over 60 minutes qw (D1 + 8 + 15 of a 28-day cycle) or 160 mg/m2 IV twice-weekly (D1 + 4 + 8 + 11 + 15 + 18 of a 28-day cycle; BRAF-mutated only). Results MTD in Part A (n = 25) was 320 mg/m2 qw, confirmed in Part B (n = 30). Adverse events included QT prolongation (n = 4) and eye disorders (n = 3). E6201 exposure was dose-related, with PK characterised by extensive distribution and fast elimination. One patient achieved PR during Part A (BRAF-mutated papillary thyroid cancer; 480 mg/m2 qw) and three during Part B (2 BRAF-mutated melanoma; 1 BRAF-WT melanoma; all receiving 320 mg/m2 qw). Conclusions An intermittent regimen of E6201 320 mg/m2 IV qw for the first 3 weeks of a 28-day cycle was feasible and reasonably well-tolerated in patients with advanced solid tumours, including melanoma with brain metastases, with evidence of clinical efficacy. |
| تدمد: | 1532-1827 0007-0920 |
| DOI: | 10.1038/s41416-018-0099-5 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::87f66ac1a9f12de379e88b4a4525aec3 https://doi.org/10.1038/s41416-018-0099-5 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....87f66ac1a9f12de379e88b4a4525aec3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15321827 00070920 |
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| DOI: | 10.1038/s41416-018-0099-5 |