A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor–Positive Metastatic Breast Cancer

Abstract

Purpose This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive breast cancer (ER+BC). Experimental Design Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts evaluated intermittent (5 of 7 day dosing) and continuous buparlisib (100mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in Phase IB and Cohort C. Results Thirty one patients were enrolled. MTD was defined as buparlisib 100mg daily plus fulvestrant. Common adverse events (AEs) included fatigue (38.7 %), transaminases elevation (35.5 %), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared to intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI 40.7–74.5%). Response was not associated with PIK3CA mutation or treatment cohort, however loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was commoner in resistant cases and mutations in AKT1 and ESR1 did not exclude treatment response. Conclusion Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER+BC. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features.

Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE)

“…The overall safety profile (elevated liver enzymes, rash, hyperglycaemia, psychiatric disorders [i.e. depression and anxiety]) was consistent with that expected for buparlisib [22–24,26,36]. However, the frequency of these in this study was much higher than previously reported [26,37].…”

The PI3K Pathway in Human Disease

“…In a phase I trial of the pan-PI3K inhibitor, buparlisib, an intermittent five days on, two days off schedule produced fewer early onset adverse events, at the same daily dose of buparlisib (Ma et al, 2016). Intermittent dosing may also permit more pronounced pathway inhibition with equivalent toxicity for less toxic inhibitors such as the isoform-selective PI3K inhibitors.…”

New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer

“…Another phase 1 study evaluated buparlisib in combination with fulvestrant demonstrating antitumor activity in 31 patients with HR+ MBC with a CBR of 58.6%. Also in this case, response was not associated with PIK3CA mutation; however, loss of PTEN, PR expression, or mutation in TP53 was most common in resistant cases, and mutations in AKT1 and ESR1 did not preclude treatment response [70]. The MTD of buparlisib was confirmed at 100 mg daily even with fulvestrant.…”