A dose-escalation study with the novel formulation of the oral pan-class I PI3K inhibitor BEZ235, solid dispersion system (SDS) sachet, in patients with advanced solid tumors. z Y7 w# w' Q3 [' z4 z" n' F& }
Background: BEZ235 is a potent and highly specific oral dual mTOR/PI3K inhibitor. BEZ235 hard-gelatin capsule (Burris, ASCO 2010) and SDS capsule (Rodon, SABCS 2010) were reported previously. Here we present the dose escalation with the new BEZ235 formulation (BEZ235 SDS sachet). Methods: Phase I dose-escalation study of BEZ235 given orally once daily to adult patients with advanced solid tumors. A Bayesian logistic regression model with overdose control was used to guide dose escalation. Results: At the time of abstract submission, 25 patients have been treated with BEZ235 SDS sachet once daily at 4 dose levels: 800 mg (6); 1,000 mg (4), 1,400 mg (8), 1,600 mg (7). Tumor types enrolled included: colorectal (8), breast (4), NSCLC (3), renal (3) and sarcoma (3). 4/25 patients have been treated for >3 cycles, 10/25 patients progressed within the first three cycles of treatment and 8/25 are on treatment at time of abstract preparation. Maximum tolerated dose (MTD) for BEZ235 SDS sachet is 1,600 mg/d. Dose limiting toxicities (DLT) included: 2 cases of grade 3 fatigue/asthenia (at 1,400 mg) and 1 grade 3 thrombocytopenia (at 1,600 mg). Most common adverse events (AE) which are considered possibly treatment related included: nausea, diarrhea, vomiting and fatigue (G1-G3). At 1,600 mg, PK was evaluated in 7 patients. The absorption was slow with a tmax within 4 to 6 hours post-dose. The elimination half-life is ranging from 3.5 to 13.5 hours. At steady state, the median Cmax was 1,800 ng/mL (CV% = 38) and exposure was 22,375.5 ng.h/mL (CV% = 44). The accumulation ratio based on exposures between day 1 and steady state was estimated to be approximately 6 fold. Conclusions: BEZ235 SDS sachet was well tolerated with a favorable safety profile. Following the Bayesian model recommendation, the MTD for BEZ235 SDS sachet was determined as 1600 mg/d. Based on safety and pharmacology, this formulation is the chosen one for phase II clinical trials and it is being investigated in monotherapy in solid tumor patients with PI3K pathway alterations and in combination with trastuzumab for breast cancer. |
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