Phase I study of oral BKM120 and oral olaparib for high-grade serous ovarian cancer (HGSC) or triple-negative breast cancer (TNBC).

2510 Background: In vivo synergy of the PI3-kinase inhibitor BKM120 and the PARP inhibitor olaparib is seen using a mouse model of BRCA1-related breast cancer (BrCa) and sporadic TNBC (Juvekar et al and Ibrahim et al, Cancer Discovery 2012). The PI3kinase pathway is activated in both TNBC and HGSC (www.cancergenome.nih.gov). Olaparib is active in HGSC and germlineBRCA mutation (gBRCAm) ovarian cancer (OvCa) and gBRCAm BrCa. These data were the rationale for this phase I, multi-center study (NCT01623349) combining BKM120 and olaparib in patients (pts) with recurrent HGSC or TNBC. 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 are to determine the MTD and RP2D of daily oral olaparib (tablet formulation) and BKM120, assess toxicities, preliminary 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 OvCa or BrCa with presence of a gBRCAmut, PS 0-1, and measurable/evaluable cancer. Prior PARP inhibitor use was allowed. Results: 34 pts to date have received study drugs; 9 pts w/TNBC and 25 pts wHGSC. 26 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 as below. DL 6 was not feasible because of of grade 3 LFTs and grade 3 depression early in cycle 2. Evidence of clinical benefit by RECIST 1.1 was observed on all DL’s, and AEs seen were compatible with AE profile of BKM120 and olaparib. Expansion cohorts are accruing. Conclusions: Combined BKM120 and olaparib is feasible with evidence of clinical benefit seen at all DL’s. Further studies combining PARP and PI3kinase inhibitors are warranted. Clinical trial information: NCT01623349. Dose level Olaparib dose BID (mg) BKM120 dose qD (mg) # of patients 1 100 60 3 -1 50 40 6 2 100 40 7 3 150 50 3 4A 200 40 3 4B 150 50 3 5A 300 40 3 5B 200 50 3 6 (DLT dose) 300 60 3