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Background: In vivo synergy of the PI3-kinase inhibitor BKM120 with the PARP inhibitor olaparib has been observed using a mouse model of BRCA1-related breast cancer and sporadic TNBC (Juvekar et al and Ibrahim et al, Cancer Discovery 2012). In addition, olaparib has single agent activity in both HGSC and BRCA-associated breast cancer. The PI3kinase pathway is activated in both TNBC and HGSC (www.cancergenome.nih.gov). These preclinical and clinical data have served as the rationale for this phase I, multi-center study (NCT01623349) combining the oral PARP inhibitor olaparib with the oral PI3-kinase inhibitor BKM120 in patients with recurrent HGSC or recurrent TNBC. This study is being conducted through the Stand Up to Cancer (SU2C)'s Targeting PI3-kinase in Women's Cancers Dream Team. Study Design: This study has a 3 + 3 design, escalating if 0/3 or 1/6 participants have a dose limiting toxicity (DLT) during the first cycle of therapy (first 28 days). The study objectives are to determine the recommended phase II dose (RP2D) of daily continuous oral olaparib (using the tablet formulation) and BKM120, assess toxicities, safety, and preliminary activity of this combination, and determine pharmacokinetic profiles of both agents. In addition, there are several translational endpoints including elucidation of downstream signaling effects of the PI3-kinase pathway, examination of BRCA1 immunostaining, and assessment of BRCA1 promoter hypermethylation and somatic mutations in BRCA1 and BRCA2 using archived formalin fixed paraffin embedded (FFPE) tissue. Serial IL-8 and circulating DNA levels are also being monitored as well. Eligibility includes a diagnosis of recurrent TNBC or HGSC, PS 0 or 1, measurable or evaluable cancer, and normal lab values and organ function. Prior PARP inhibitor exposure is allowed. In addition, breast cancer or ovarian cancer patients with any histologic subtype are eligible if they have a known germline BRCA1 or BRCA2 mutation. At the RP2D, 10 pts each with a diagnosis of TNBC or HGSC will be enrolled to further determine safety and efficacy profiles in addition to more thoroughly studying translational endpoints. As of June 7, 2013, 16 patients have been enrolled into this study with a planned accrual of approximately 50 patients which may change based on number of dose levels tested during dose escalation. In addition, an amendment is pending that will add a second cohort studying the combination of olaparib and BYL719 based on robust pre-clinical activity observed in murine models which will increase our total accrual. Once this new cohort is open, both arms will enroll simultaneously. For further information, contact Ursula Matulonis at: umatulonis@partners.org. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-02.