Abstract P6-11-08: A multicenter, open-label Ph IB/II study of BEZ235, an oral dual PI3K/mTOR inhibitor, in combination with paclitaxel in patients with HER2-negative, locally advanced or metastatic breast cancer
Authors: Campone M , Fumoleau P , Gil-Martin M , Isambert N , Beck JT , Becerra C , Shtivelband M , Duval V , di Tomaso E , Roussou P , Urban P , Urruticoechea A 
Published: August 2014

Abstract
Background: The PI3K/AKT/mTOR pathway is frequently altered in breast cancer (BC). Alterations in PIK3CA or inactivation of PTEN are observed in 10–40% and in up to 50% of breast tumors, respectively. The PI3K/AKT/mTOR pathway can be further activated through various receptor classes or cross-talk with other pathways, making it a rational target for therapeutic intervention in BC. BEZ235 is an oral dual inhibitor of mTOR and PI3K. It has demonstrated anti-proliferative activity, substantial growth inhibition, and induction of apoptosis in preclinical studies. In a Ph I study, single-agent BEZ235 (600 mg BID) was shown to have less toxicity than the equivalent once-daily dosing, and have preliminary evidence of activity in advanced solid tumors (Arkenau, et al. ASCO 2012:#3097).
Methods: This is a multicenter, open-label Ph IB/II study of continuous, oral BEZ235 twice daily (BID) in combination with paclitaxel (80 mg/m2; IV weekly [QW]) in women with HER2-negative (HER2–), metastatic or inoperable locally advanced BC (NCT01495247).
For the Ph IB part, women with HER2–, metastatic or inoperable locally advanced BC, who are suitable for treatment with paclitaxel, are eligible for enrollment. The primary objective is to determine the maximum tolerated dose (MTD)/recommended Ph II dose (RP2D) of BEZ235 in combination with paclitaxel based on dose-limiting toxicities (DLTs) using an adaptive 5-parameter Bayesian logistic regression model with overdose control. The MTD is defined as the highest drug dosage not causing medically unacceptable DLTs in more than 35% of the treated patients during Cycle 1 (1 cycle = 28 days). Secondary objectives include safety (CTCAE), preliminary activity (RECIST), and pharmacokinetics (PK). Estimated enrollment is 15–30 patients into the Ph IB part.
Results: As of June 2012, 13 pts have been enrolled into the Ph IB part of the trial. The first cohort (n = 7 pts) received BEZ235 200 mg BID + 80 mg/m2 QW paclitaxel. Of these 7 pts, 3 are ongoing, with 2 pts having received treatment for more than 12 weeks so far, and 4 pts have discontinued (2 due to an adverse event [AE]; 1 due to an AE/pt's decision; and 1 due to disease progression). Of the 6 evaluable pts in the first cohort, 2 experienced DLTs: Grade 3 stomatitis (1 pt) and Grade 2/3 neutropenia (1 pt). Most common AEs included stomatitis and GI toxicity (e.g. diarrhea, nausea/vomiting). To date, reported Grade 3 AEs related to study drug were stomatitis (2 pts), neutropenia (1 pt), and skin rash (1 pt). Among the 3 pts with at least one tumor evaluation, 1 pt with a triple-negative metastatic BC, who had previously been treated with paclitaxel, experienced a RECIST partial response which was confirmed on second tumor evaluation. PK analysis is ongoing.
Conclusions: Additional patients have been enrolled at BEZ235 200 mg BID/paclitaxel 80 mg/m2 QW to provide further information on the safety and activity profile of this combination. Updated safety and efficacy results will be presented. Upon determination of the MTD/RP2D, the randomized Ph II part will begin to compare weekly paclitaxel given with or without BEZ235 BID as the first-line treatment of HER2– metastatic BC.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-08.