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.

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. [ABSTRACT FROM AUTHOR]