A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors

Abstract

Introduction The PI3 kinase (PI3K) pathway is a commonly dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective dual PI3K/mTOR inhibitor. Methods Patients were enrolled in a 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetics (PK) of BEZ235 when administered twice-daily as an oral sachet. For intrapatient PK comparison, patients were to receive a lead in of the total daily dose in a QD schedule for the first 8 days of the initial 28 day cycle. Patients continued treatment until unacceptable toxicity or disease progression occurred. Results Thirty-three patients received BEZ235. Initial dose levels of 200 and 400 mg BID had no DLTs. At the 600 mg BID dose level with 1200 mg QD lead in dose two DLTs of grade 3 mucositis occurred early in the first treatment cycle, the lead-in QD dosing was eliminated. Fatigue and mucositis limited dosing at 600 mg BID in subsequent patients. The 400 mg BID dose level was re-explored, with DLTs of grade 3 hyperglycemia, dehydration, fatigue, and grade 3 thrombocytopenia. Twelve patients were enrolled at an intermediate dose of 300 mg BID; a grade 3 mucositis DLT was reported in 1 patient, and this dose was declared the MTD. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. Fifteen patients experienced stable disease as their best response, including 10 (colorectal [4 patients], endometrial [3 patients], carcinoid NOS, pancreas, and melanoma) who had disease control for ≥16 weeks. Conclusions The recommended dose of BEZ235 administered BID as an oral sachet formulation is 300 mg BID. Toxicities seen have been reported for other dual PI3K/mTOR inhibitors.

Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication

“…Conventional cancer treatment utilizes chemotherapy at the maximally tolerated dose (MTD), or the highest dose shown to be both cytotoxic and tolerable for the patient. Clinical studies including trials of dactolisib alone in pancreatic neuroendocrine tumors (70) and bladder cancers (71) showed that dactolisib was poorly tolerated as the MTD was 300 mg in the phase I study (72). These studies did demonstrate limited clinical efficacy with several patients with stable disease but given the poor tolerability, these trials did not advance.…”

NVP-BEZ235, a novel dual PI3K–mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells

“…Recently, Choi and colleagues used PI-103, a novel of PI3Kα and mTOR dual inhibitor, showed that treatment with PI-103 increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells [32]. NVP-BEZ235 has shown great promise in controlling solid tumors in preclinical mouse models [33] and has been reported to increase sensitivity to radiotherapy [15,23] and gefitinib [34]. To our knowledge, effects of NVP-BEZ235 on the cytotoxicity of TMZ have not been studied in glioma cells.…”

The PI3K Pathway in Human Disease

“…Mucositis is also one of the main dose-limiting toxicities of the TORKi compounds (Table S1) AZD2014 (Basu et al, 2015) and CC-223 (Bendell et al, 2015a), and occurred frequently in a phase I trial of TAK-228 (Ghobrial et al, 2016). Mucositis was reported in phase I studies of pan-PI3K inhibitor buparlisib (BKM120) (Bendell et al, 2012; Ragon et al, 2017) and the dual PI3K/mTOR inhibitor BEZ235 (Bendell et al, 2015b; Carlo et al, 2016). The p110δ inhibitor idelalisib is associated with autoimmune colitis as discussed below, but also with lung and liver inflammation (Coutré et al, 2015) that might arise from increased innate immune stimulation.…”