A phase I study of single-agent BEZ235 (SDS sachet), once-or twice-daily, in Japanese patients with advanced solid tumors.

Background: BEZ235 is an oral, ATP-competitive inhibitor that targets class l PI3K and downstream effectors mTORC1/2. In previous phase I studies in mainly Western patients, the maximum tolerated dose (MTD) of single-agent BEZ235 solid dispersion system (SDS) sachet once daily (QD) was declared as 1200 mg and the recommended dose (RD) as 1000 mg; the MTD of the same formulation of BEZ235 twice daily (BID) was declared as 400 mg (Rodon EORTC-NCI-AACR 2012, Arkenau ASCO 2012). Here we present the results of a phase I, multicenter, open-label, dose escalation study of single-agent BEZ235 SDS sachet, administered QD or BID, in adult Japanese patients with advanced solid tumors (NCT01195376). Methods: Patients with histologically confirmed, unresectable advanced solid tumors not amenable to standard therapy, received continuous oral BEZ235, QD or BID in 28-day cycles. The primary objective was to determine the MTD/RD of single-agent BEZ235 in adult Japanese patients, based on dose-limiting toxicity (DLT) using a standard 3+3 method for dose escalation. MTD was defined as the highest dose causing DLT in no more than 1/6 patients in Cycle 1. Secondary objectives included preliminary antitumor activity (RECIST v1), safety profiles (CTCAE v3), and pharmacokinetics (PK). Results: As of Feb 10, 2013, 32 patients (mean age 58 yrs) were treated with BEZ235 at 2 dosing schedules; 27 patients received BEZ235 QD at 5 dose levels: 400, 800, 1000, 1200, or 1400 mg; and 5 patients received BEZ235 BID at 400 mg. 2 DLTs were reported with QD dosing: Grade 2 allergic reaction (1200 mg) and Grade 4 thrombocytopenia (1400 mg). Although equivalent DLT ratios were recorded at 1200 mg and 1400 mg (1/6 evaluable patients each), clinical observation led to 1200 mg being declared as the maximum, clinically tolerable dose and 1000 mg being declared as the RD of single-agent BEZ235 QD. The primary reason for discontinuation was disease progression (63%). Common suspected BEZ235-related AEs (≥40%) were diarrhea, decreased appetite, nausea, stomatitis, fatigue, vomiting, and rash; no difference in AE profile was observed between QD and BID schedules. Three patients experienced serious suspected BEZ235-related AEs: infectious enterocolitis, pneumonia, and diarrhea. No death related to treatment was reported. Best overall response was stable disease in 15/27 evaluable patients (56% disease control rate). After Feb 10, 2013, 3 additional patients were enrolled at 400 mg BID (8 in total) and 1 DLT (Grade 2 liver dysfunction) out of 6 evaluable patients was observed. PK data revealed a slow rate of absorption, less than dose-proportional exposure, and large interpatient variability for single-agent BEZ235 SDS sachet. Conclusions: The maximum, clinically tolerable dose of BEZ235 QD was declared as 1200 mg and the RD was declared as 1000 mg, in agreement with previous studies in Western populations. In addition, the tolerability of 400 mg BEZ235 BID was confirmed. The findings of this first-in-Japanese study suggest no major difference in BEZ235 tolerability and PK profile between Japanese and Western populations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A167. Citation Format: Koichiro Watanabe, Hironobu Minami, Satoshi Otsu, Yoshinori Hirashima, Ryotaro Morinaga, Kazuo Nishikawa, Yasushi Hisamatsu, Toru Mukohara, Naomi Kiyota, Naoko Chayahara, Masanori Toyoda, Yoshinori Imamura, Yutaka Fujiwara, Cornelia Quadt, Matthew Robson, Kazuto Natsume, Takuji Aoki, Kuniaki Shirao. A phase I study of single-agent BEZ235 (SDS sachet), once- or twice-daily, in Japanese patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A167.