Abstract PD5-6: A phase I study of BKM120 and fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer
Authors: Ma Cynthia X , Luo Jingqin , Naughton Michael , Ademuyiwa Foluso , Suresh Rama , Pluard Timothy , Nagaraj Gayathri , Arnold Kaitlin , Lockhart Craig , Ellis Matthew J 
Published: May 2015

Abstract
Background
BKM120, an oral pan-Phosphatidylinositol-3-kinase (PI3K) inhibitor, plus fulvestrant (F) induced synergistic anti-tumor 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), tolerability and preliminary efficacy.
Methods
A 3+3 phase I design was chosen for phase IA with BKM120 administered orally to define MTD [Table 1]. Cycle (C) length was 28 days. F 500mg was administered intramuscularly on C1 day (D)1 and D15 then on D1 of each subsequent cycles. Two expansion cohorts, phase IB (intermittent dosing: 5 days on and 2 days off) and Cohort C (continuous dosing: daily) of BKM120 at MTD, 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 or Cohort C. Tumor measurement occurred every 3 cycles. Adverse events (AEs) were assessed by CTCAE 4.0 and response by RECIST 1.1.
Results
Thirty one pts, with median age of 58 (range: 34-71) years, prior exposure to a median of 1 (range: 0-9) endocrine and 0 (range: 0-2) chemo regimens, were enrolled. Majority of pts (83%) had visceral metastasis. Thirty, 25, and 22 pts were evaluable for AE, response and clinical benefit (CB), respectively. Most C1 AEs were grade (G)1 or 2, except 1 G3 diarrhea. No DLT occurred in C1. However, G2/3 AEs required BKM120 interruption and/or reduction in C2 or beyond occurred in 16 (53%) pts, including 9 ALT/AST elevation (G2 10%, G3 17%, G4 3%), 7 rash (G3 23%), and 1 pt each with G2 confusion, G3 hyperglycemia, G2 pneumonitis, and G3 tremor. As of June 3, 2014, 1 pt withdrew consent, 19 pts discontinued therapy due to progressive disease (PD) (n=15) or AE (n=4), 11 pts continue to receive BKM120/F. Fourteen (63.6%, 95% CI: 43.0 - 80.3%) of the 22 evaluable pts derived CB, including 7 partial response (PR) and 7 prolonged stable disease (SD) &gt; 6 months. Archival tumor and circulating tumor DNA are being analyzed for presentation. Data will be updated.
Table 1 Study enrollment and resultsCohortNBKM120N pt BKM120 interrupted/reduced (AE)*PDPR (Cycle completed)SD (Cycle completed)NE1A DL1380 mg daily2 (confusion, ALT)101 (22)1 (a)1A DL26100 mg daily3 (ALT, rash)22 (13,3 (a))2 (9, 7)01A DL2b2100 mg intermittent0002 (6, 6)01B10100 mg intermittent6 (AST, ALT, rash Hyperglycemia)02 (15+, 12)5 (16+, 9+, 9, 6, 6)3 (a, a, b)C10100 mg daily5 (rash, ALT, diarrhea, tremor)23 (9+, 8+, 4+)3 (3+, 3+, 3+)#2 (1+, 2+)Total (N)31 1657136*All occurred in C2+ except the diarrhea, CBR: 63%, NE: Not evaluable, a: off due to AE, b: withdrew consent, # NE for CBR
Conclusion
BKM120 100mg, administered daily or intermittently, plus F was tolerable without DLT during C1. Grade 2/3 AST/ALT and rash were common in both dosing schedules in subsequent cycles resulting in BKM120 interruption/reduction. Promising activity observed in this trial warrants further development of this combination in ER+ BC. Phase III studies are ongoing in pts with ER+ MBC progressed on aromoatase inhibitor.
Citation Format: Cynthia X Ma, Jingqin Luo, Michael Naughton, Foluso Ademuyiwa, Rama Suresh, Timothy Pluard, Gayathri Nagaraj, Kaitlin Arnold, Craig Lockhart, Matthew J Ellis. A phase I study of BKM120 and fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-6.