Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer

Abstract

Purpose: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2.

Methods: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed.

Results: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%).

Conclusions: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.

Keywords: BEZ235; Breast cancer; Inhibitor; PI3K; mTORC1/2.

Fig. 1

Patients and treatments (to be re-drawn in high-res closer to submission). ^*Dose escalation started with SDS capsule A, and continued with SDS sachet. ^†MTD reached; however, the SDS capsule formulation was discontinued as it was difficult to swallow. HGC hard gelatin capsule, MTD maximum tolerated dose, SDS solid dispersion system

Fig. 2

Best percentage change and best overall response by investigator assessment. a Single-agent BEZ235 SDS sachet (to be re-drawn in high-res closer to submission). Patients with missing best percentage change from baseline and unknown overall response are not included. Missing line denotes a missing best percent change from baseline. UNK indicates patients not qualifying for confirmed CR or PR and without SD after more than 6 weeks or early progression within the first 12 weeks. b BEZ235 in combination with trastuzumab (to be re-drawn in high-res closer to submission). Patients with missing best percentage change from baseline and unknown overall response are not included. UNK indicates patients not qualifying for confirmed CR or PR and without SD after more than 6 weeks or early progression within the first 12 weeks