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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.
- Source :
- British Journal of Cancer; 3/23/2016, Vol. 114 Issue 7, p723-730, 8p, 1 Diagram, 2 Charts, 3 Graphs
- Publication Year :
- 2016
-
Abstract
- <bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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).<bold>Conclusions: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- BREAST tumors
CLINICAL trials
COMPARATIVE studies
DRUG administration
DOSE-effect relationship in pharmacology
LONGITUDINAL method
RESEARCH methodology
MEDICAL cooperation
GENETIC mutation
OVARIAN tumors
PROGNOSIS
PROTEINS
RESEARCH
RESEARCH funding
TUMOR classification
EVALUATION research
GENETIC carriers
INDOLE compounds
THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 00070920
- Volume :
- 114
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- British Journal of Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 114080784
- Full Text :
- https://doi.org/10.1038/bjc.2016.41