Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer Journal Article

   

Authors:	Matulonis, U. A.; Wulf, G. M.; Barry, W. T.; Birrer, M.; Westin, S. N.; Farooq, S.; Bell-McGuinn, K. M.; Obermayer, E.; Whalen, C.; Spagnoletti, T.; Luo, W.; Liu, H.; Hok, R. C.; Aghajanian, C.; Solit, D. B.; Mills, G. B.; Taylor, B. S.; Won, H.; Berger, M. F.; Palakurthi, S.; Liu, J.; Cantley, L. C.; Winer, E.
Article Title:	Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer
Abstract:	Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3+3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100mg b.i.d.). The MTD was determined to be BKM120 50mg q.d. and olaparib 300mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAmand gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone. © The Author 2016.
Keywords:	ovarian cancer; breast cancer; olaparib; bkm120; parp-inhibitors
Journal Title:	Annals of Oncology
Volume:	28
Issue:	3
ISSN:	0923-7534
Publisher:	Oxford University Press
Date Published:	2017-03-01
Start Page:	512
End Page:	518
Language:	English
DOI:	10.1093/annonc/mdw672
PROVIDER:	scopus
PUBMED:	27993796
PMCID:	PMC5834157
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85018277121&doi=10.1093%2fannonc%2fmdw672&partnerID=40&md5=c8c8997cddc874c2d8863640477b8cdf
Notes:	Article -- Export Date: 2 June 2017 -- Source: Scopus

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