Abstract P6-15-07: A Dose-Escalation Study with a Special Drug Delivery System (SDS) of BEZ235, a Novel Dual PI3K/mTOR Inhibitor, in Patients with Metastatic/Advanced Solid Tumors

Abstract

Abstract Background: The PI3K pathway plays a major role in cancer cell growth and survival and is the most frequently altered pathway in cancer. BEZ235 is a potent and highly specific oral PI3K/mTOR inhibitor. Administered as hard-gelatine capsule, BEZ235 was well tolerated with a favorable safety profile. Available data showed that BEZ235 led to PRs (1 patient (pt) with NSCLC [PTENnull], 1 pt with ER+ breast cancer [mutation unknown]) and prolonged disease stabilization (4 to >24 months) in pts with PI3K pathway dysregulated tumors (N=9/51), 5/9 with ER+, 1/9 with HER2+ breast cancer. Here, we present data from patients (pts) receiving treatment with a special drug delivery system of BEZ235 (SDS) with improved PK properties (Cao SABCS 2010). Results: 22 pts have been treated with BEZ235 SDS capsule at 3 dose levels (qd): 400 mg (5); 800 mg (6), 1000 mg (11). Median age was 56 years. The most common tumor types among pts enrolled were: breast cancer (4), CRC (4) and NSCLC (3). 2/22 pts were treated for >3 cycles, 16/22 pts progressed within the first three cycles of treatment. The maximum tolerated dose (MTD) is 1000 mg/d. Dose-limiting toxicities (DLTs) included: 2 Grade (G)3 fatigue (800 mg and 1000 mg) and 1 G3 skin rash (at 1000 mg). The most common treatment-related AEs included: fatigue, diarrhea, nausea, vomiting (G1-3). Preliminary PK data showed a slow absorption rate, Cmax at ∼6 h post-dose (range 2-8 h). The elimination halflife is ∼6 h across doses and visits. Steady state was reached after 8 days of treatment; the mean (SD) exposures at steady state (AUC, rss) for the dose of 400, 800, and 1000 mg/d were 8864 (12210), 19060 (19860), 46010 (36150) ng*h/mL, respectively. The exposure across dose levels (AUC0- 24, SS) was above the exposure required for tumor stasis in PI3K pathway dysregulated tumors, estimated based on CT measurements in patients(Bottino SABCS 2010). Currently, the efficacy of BEZ235 SDS, alone and in combination with trastuzumab, in patients with PIK3CA mutated breast cancer is investigated. As of today 1 clinical PR was observed with BEZ235+trastuzumab in a patient with breast cancer (HER2+, PIK3CA mutated, trastuzumab refractory) with brain and peripheral metastases. Conclusions: BEZ235 SDS treatment is well tolerated. The MTD is 1000 mg/d. Available PD and efficacy data show that BEZ235 is active in breast cancer (especially PI3K pathway dysregulated tumors). Phase II studies in breast cancer combining BEZ235 SDS with other agents will start soon. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-07.