Abstract CT324: Phase I of oral BKM120 or BYL719 and olaparib for high-grade serous ovarian cancer or triple-negative breast cancer: Final results of the BKM120 plus olaparib cohort
Authors: Matulonis Ursula A. , Wulf Gerburg , Barry William , Birrer Michael , Westin Shannon , Spagnoletti Tatum , Bell-McGuinn Katherine , Obermayer Elizabeth , Whalen Christin , Aghajanian Carol , Solit David , Mills Gordon , Cantley Lewis , Winer Eric 
Published: August 2015

Abstract
Background: Similarities exist between high grade serous ovarian cancer (HGSC) and triple negative breast cancer (TNBC); both often have gBRCA mutations, are sensitive to platinum agents, and have high copy number alterations per the TCGA. Preclinical data for both BKM120/olaparib and BYL719/olaparib combinations showed synergistic efficacy. These data served as the rationale for this study in pts with either recurrent HGSC or TNBC. The phase I study of BKM120 and olaparib has been completed, and the phase I study of BYL719 and olaparib is currently in dose escalation (NCT01623349).
Methods: This study has a 3 + 3 design, escalating dose levels (DL) if 0/3 or 1/6 pts have a dose limiting toxicity (DLT) during the first cycle (1st 28 days). Objectives were to determine the MTD and RP2D of daily oral olaparib (tablet formulation) and BKM120, assess toxicities, activity of this combination, and PK profiles of both drugs. Planned translational endpts include PI3kinase pathway effects, BRCA1 immunostaining/methylation, IL-8/circulating DNA levels, and somatic mutations in BRCA1/2 using FFPE tissue. Eligibility included: recurrent TNBC or HGSC or any histology of ovarian cancer (OvCa) or breast cancer (BrCa) with presence of a gBRCAmut, PS 0-1, and measurable/evaluable cancer. Prior PARP inhibitor use was allowed.
Results: 46 pts to date have received study drugs as part of the ph1 dose escalation of BKM120/olaparib (12 pts w/BrCa and 34 pts w/OvCa). 35 have known gBRCAm. Dosing started at DL1 (BKM120 60 mg and olaparib 100 mg BID); 2 DLTs were observed (1 gr 3 LFTs and 1 gr 3 hyperglycemia). A lower dose (-1) was pursued followed by re-escalation; MTD is BKM120 50 mg and olaparib 300 mg BID. Toxicities that defined DLTs included CNS toxicities (gr 3 depression) and grade 3 LFTs, early in cycle 2 (DL6). At the MTD of BKM120/olaparib, 11 pts with OvCa and 12 pts w BrCa were enrolled into a dose expansion cohort (DEC). Evidence of clinical benefit by RECIST 1.1 was observed on all DL's and in the DEC’s, in pts with a gBRCApos as well as gBRCAwt. AEs seen were compatible with AE profile of BKM120 and olaparib.
Conclusions: Combined BKM120 and olaparib is feasible, and evidence of clinical benefit was seen at all DL's both in gBRCApos and gBRCAwt pts. Toxicities that defined DLTs included CNS toxicities and LFT abnormalities. Clinical trial information: NCT01623349.
Citation Format: Ursula A. Matulonis, Gerburg Wulf, William Barry, Michael Birrer, Shannon Westin, Tatum Spagnoletti, Katherine Bell-McGuinn, Elizabeth Obermayer, Christin Whalen, Carol Aghajanian, David Solit, Gordon Mills, Lewis Cantley, Eric Winer. Phase I of oral BKM120 or BYL719 and olaparib for high-grade serous ovarian cancer or triple-negative breast cancer: Final results of the BKM120 plus olaparib cohort. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT324. doi:10.1158/1538-7445.AM2015-CT324