Abstract PD1-4: A phase I study of BKM120 and fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer
Authors: Ma CX , Wang J , Luo J , Naughton M , Nagaraj G , Bazzell N , Ellis MJ 
Published: August 2014

Abstract
Background
BKM120, a pan-Phosphatidylinositol-3-kinase (PI3K) inhibitor, in combination with fulvestrant (F) induced synergistic apoptotic effect in preclinical studies of estrogen receptor positive (ER+) breast cancer. We therefore conducted a phase I trial of BKM120 and F in postmenopausal women with ER+ metastatic breast cancer (MBC) to determine the maximum tolerated dose (MTD) and the tolerability of this combination.
Methods
A standard 3+3 phase I design was chosen for phase IA to determine the MTD. Upon completion of phase 1A, an expansion cohort phase IB was initiated to further assess the tolerability and efficacy. Patients (pts) with ER+ MBC with measurable disease were eligible. No more than 3 lines of systemic therapy in the metastatic setting were allowed in phase 1B. Cycle (C) length was 28 days. Adverse events (AEs) were assessed using CTCAE 4.0. Tumor measurement occurred every 3 cycles.
Results
Since November 2011, 18 pts (median age: 60 (range 48-71) years) were treated at 3 dose levels (DL) of BKM120 [Table 1]. Since none of the 3 pts enrolled at the starting dose of BKM120 (DL1: 80mg daily) experienced any DLT during C1, 3 pts were then enrolled at DL2 (BKM120 100 mg daily). No DLT was observed in C1, however 2 experienced grade (G) 3 ALT elevation during C2. Therefore, 3 pts were treated with BKM120 100mg 5 days on and 2 days off schedule (DL2b), without any significant AEs. Subsequently Phase IB enrolled 9 pts at this dose level.
Across different DLs, most AEs were G1. MTD was not reached based on C1 toxicity. However, asymptomatic ALT elevations occurred frequently during C2, resulting in dose interruption and dose reductions of BKM120 [Table 1]. Other AEs led to dose interruption and reductions include G2 confusion, G2 hyperglycemia and G3 rash. However, only 2 pts discontinued treatment due to AEs.
Table 1 Dose Level and Adverse EventsPhase IANBKM120No. pts dose reduced (AE, Cycle)No. pts discontinued (AE, Cycle)DL1380mg daily1 (G3 ALT, C2)1 (G2 confusion, C2)DL23100mg daily1 (G3 ALT, C2), 1 (G3 ALT, C2; G3 Rash, C7)0DL2b3*100mg daily, 5/700Phase IB (DL2b)9100mg daily, 5/71 (G3 ALT, C2; G3 Rash, C4), 1 (G2 ALT, G3 hyperglycemia, C2)1 (G4 ALT, C2)* 1 pt started DL2 in C1, then switched to DL2b following an amendment
Eleven pts with a median of 2 prior endocrine therapy (range 1-9) and 0-1 chemotherapy regimens in the metastatic setting were evaluable for response [Table 2]. Among these pts, 6 had prior disease progression on F. Clinical benefit was observed in 6 (54.5%) pts, including 1 partial response (PR) and 5 prolonged SD lasting for at least 6 cycles. Eight pts continue to receive treatment to date. Data will be updated at the time of presentation.
Table 2 ResponsePhaseDLEval. pts (N)Best responseDuration on study (mon)IA11PD3 1SD19+ 21PD1 2SD9, 7 2b1PR12IB2b5SD4+, 6, 6, 10+, 11++ treatment ongoing
Conclusion
BKM120 100mg, administered daily or intermittently, plus F was tolerable without DLT during C1. Grade 2/3 ALT elevation was common in C2, especially with daily dosing, but most pts continued treatment with reduced dose of BKM120. Promising activity was observed in this Phase I trial. Phase III studies of this combination have been started in ER+ MBC.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-4.