Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer
| العنوان: | Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer |
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| المؤلفون: | Gordon C Jayson, Gary Acton, Jonathan A. Ledermann, Geoff Hall, Sarah Halford, Martin Highley, Nicola J. Curtin, Ruth Plummer, Julieann Sludden, R.M. Glasspool, David Jamieson, Alan V. Boddy, Zoe Backholer, Daniel Rea, Raffaella Mangano, Yvette Drew, James W. Murray |
| المساهمون: | Drew, Yvette, Ledermann, Jonathan, Hall, Geoff, Rea, Daniel, Glasspool, Ros, Highley, Martin, Jayson, Gordon, Sludden, Julieann, Murray, James, Jamieson, David, Halford, Sarah, Acton, Gary, Backholer, Zoe, Mangano, Raffaella, Boddy, Alan, Curtin, Nicola, Plummer, Ruth |
| المصدر: | British Journal of Cancer Drew, Y, Ledermann, J, Hall, G, Rea, D, Glasspool, R, Highley, M, Jayson, G, Sludden, J, Murray, J, Jamieson, D, Halford, S, Acton, G, Blackholer, Z, Mangano, R, Boddy, A, Curtin, N & Plummer, R 2016, ' Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer ', Br J Cancer, vol. 114, e21 . https://doi.org/10.1038/bjc.2016.41 |
| بيانات النشر: | UK : Nature Publishing Group, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Indoles, Poly (ADP-Ribose) Polymerase Inhibitor, Cohort Studies, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, Tissue Distribution, mutation carriers, Ovarian Neoplasms, Manchester Cancer Research Centre, BRCA1 Protein, Middle Aged, Prognosis, poly(ADP-ribose) polymerase, polymerase, ovarian cancer, Oncology, 030220 oncology & carcinogenesis, Female, Corrigendum, Adult, Heterozygote, Poly ADP ribose polymerase, Breast Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Drug Administration Schedule, Olaparib, Young Adult, 03 medical and health sciences, Germline mutation, Breast cancer, breast cancer, medicine, Humans, Rucaparib, Germ-Line Mutation, Aged, Neoplasm Staging, BRCA2 Protein, Dose-Response Relationship, Drug, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, PARP inhibition, BRCA mutation, medicine.disease, rucaparib, 030104 developmental biology, chemistry, Immunology, Cancer research, business, Follow-Up Studies |
| الوصف: | Background: Rucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers. Methods: Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0–1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles. Results: Rucaparib was well tolerated in patients up to doses of 480 mg per day and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, with a median duration of response of 179 days (range 84–567 days). Conclusions: Rucaparib is well tolerated and results in high levels of PARP inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is active in gBRCA-mutant ovarian cancer and this activity correlates with platinum-free interval. The key lessons learned from this study is that continuous rucaparib dosing is required for optimal response, the recommended phase 2 dose (RP2D) for continuous oral scheduling has not been established and requires further exploration and, thirdly, the use of a PD biomarker to evaluate dose–response has its limitations. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd5e00f287a35b93593ae9c8ca970c12 https://hdl.handle.net/11541.2/133063 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....dd5e00f287a35b93593ae9c8ca970c12 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |