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) > 6 months. Archival tumor and circulating tumor DNA are being analyzed for presentation. Data will be updated.

Table 1 Study enrollment and results

Cohort N BKM120 N pt BKM120 interrupted/reduced (AE)* PD PR (Cycle completed) SD (Cycle completed) NE 
1A DL1 3 80 mg daily 2 (confusion, ALT) 1 0 1 (22) 1 (a) 
1A DL2 6 100 mg daily 3 (ALT, rash) 2 2 (13,3 (a)) 2 (9, 7) 0 
1A DL2b 2 100 mg intermittent 0 0 0 2 (6, 6) 0 
1B 10 100 mg intermittent 6 (AST, ALT, rash Hyperglycemia) 0 2 (15+, 12) 5 (16+, 9+, 9, 6, 6) 3 (a, a, b) 
C 10 100 mg daily 5 (rash, ALT, diarrhea, tremor) 2 3 (9+, 8+, 4+) 3 (3+, 3+, 3+)# 2 (1+, 2+) 
Total (N) 31   16 5 7 13 6 
Cohort N BKM120 N pt BKM120 interrupted/reduced (AE)* PD PR (Cycle completed) SD (Cycle completed) NE 
1A DL1 3 80 mg daily 2 (confusion, ALT) 1 0 1 (22) 1 (a) 
1A DL2 6 100 mg daily 3 (ALT, rash) 2 2 (13,3 (a)) 2 (9, 7) 0 
1A DL2b 2 100 mg intermittent 0 0 0 2 (6, 6) 0 
1B 10 100 mg intermittent 6 (AST, ALT, rash Hyperglycemia) 0 2 (15+, 12) 5 (16+, 9+, 9, 6, 6) 3 (a, a, b) 
C 10 100 mg daily 5 (rash, ALT, diarrhea, tremor) 2 3 (9+, 8+, 4+) 3 (3+, 3+, 3+)# 2 (1+, 2+) 
Total (N) 31   16 5 7 13 6 

*All occurred in C2+ except the diarrhea, CBR: 63%, NE: Not evaluable, a: off due to AE, b: withdrew consent, # NE for CBR

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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.