PDF file - 45K, Summary of adverse events suspected to be study-drug related by grade (safety set).

PDF file - 42K, Summary of deaths and adverse events (safety set).

PDF file - 67K, Bayesian logistic regression model: dose-response curve and model inference results at the time of determination of the recommended Phase II dose.

PDF file - 48K, Exposure to buparlisib and trastuzumab (safety set).

PDF file - 38K, Patient disposition (full analysis set).

PDF file - 65K, Criteria for defining dose-limiting toxicities.

PDF file - 62K, Summary of buparlisib pharmacokinetic parameters.

Abstract Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy. Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways. Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935–45. ©2014 AACR.

Abstract Introduction: HER2 amplification can activate the phosphatidylinositol-3-kinase (PI3K) pathway in breast cancer. Furthermore, trastuzumab (T) resistance can be associated with loss/deregulation of PTEN, which also causes activation of PI3K pathway signaling. BKM120, a potent orally bioavailable pan-class I PI3K inhibitor, could reverse resistance to T in vitro. Furthermore, administration of BKM120 with T demonstrated synergistic activity in preclinical models. The potential for combining BKM120 with T in heavily pretreated HER2+ metastatic breast cancer (MBC) patients (pts) will be determined in this study to substantiate the hypothesis for future development. Methods: HER2+ MBC pts resistant to T-containing therapy (progression on or within 4 weeks since last T administration) received treatment in the dose-escalation portion of this multicenter trial. Prior anti-HER2−directed therapies were allowed. The primary objective was to determine the maximum tolerated dose (MTD) of BKM120 in combination with the standard dose of weekly T. A Bayesian logistic regression model with overdose control guided the dose escalation. Results: Seventeen pts with MBC have been enrolled: 5 at 50 mg/day and 12 at 100 mg/day dose of BKM120. Escalation was conducted up to the MTD level of single agent BKM120, 100 mg/day. Patient characteristics: median age 46 years (range 34–70); most pts were heavily pretreated (reported range of prior chemotherapy lines 1–4). In preliminary results (cut-off date 1st June 2011), 7 pts discontinued treatment. BKM120 in combination with T showed a mean peak drug concentration and half-life similar to single-agent BKM120. T trough levels remained above the single agent efficacy threshold. Only one dose-limiting toxicity (G3 asthenia) was reported at the BKM120 dose of 100 mg/day. The MTD was determined to be 100 mg/day. Reported G3 adverse events were asthenia, altered mood, rash, GGT increase, hypokalemia, and hypersensitivity in 1pt each. No G4 toxicity has been observed so far. With regards to activity, 2 partial responses (1 confirmed) and 3 occurrences of disease stabilization have been observed. Conclusions: BKM120 in combination with T in heavily pretreated HER2+ MBC pts with T-resistance has an acceptable safety profile and has shown encouraging preliminary activity. The Phase II portion of the study is ongoing. An updated analysis of efficacy, the potential correlation with PI3K pathway alteration status overlaying HER2 activation, and pharmacodynamics study will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-03.