A phase I study of a dual PI3-Kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

Abstract

Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort -1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3+3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase.Results Twenty-four patients with ALL (n=11) or AML (n=12) or CML-BP (n=1) were enrolled. All patients had failed one (n=5) or more lines of therapy (n=5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML.Trial registration ClinicalTrials.gov, identifier NCT01756118. registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118

TAL1 cooperates with PI3K/AKT pathway activation in T-cell acute lymphoblastic leukemia

“…With several PI3K/AKT pathway inhibitors in development, [37][38][39][40][41] these data could find clinical applications for high risk T-ALL patients with PI3K/AKT pathway activation in whom stardard treatment does not lead to MRD negativity. Dactolisib (BEZ235) is a dual pan-PI3K and mTOR inhibitor for which a phase I study in acute leukemia showed positive effect in a subset of ALL patients.…”

“…Pharmacologic inhibition of PI3K-AKT signaling showed pronounced anti-proliferative effects and induced apoptosis in preclinical models using leukemia cell lines or primary leukemia samples. [37][38][39][40][41] Given the negative effect of TAL1 on cell growth and the key role of PI3K signaling in TAL1 positive T-ALL, we examined the effect of PI3K-AKT inhibitors in our different models. In agreement with the negative effect of TAL1 on cell growth, we show that inactivation of PI3K/AKT pathway has a stronger effect on viability in TAL1+AKT E17K cells compared to AKT cells.…”

“…Dactolisib (BEZ235) is a dual pan-PI3K and mTOR inhibitor for which a phase I study in acute leukemia showed positive effect in a subset of ALL patients. 39 However, digestive toxicity (mostly dose dependent) remains an important problem. MK2206, an allosteric pan-AKT inhibitor, has been shown to induce apoptosis and autophagy in T-ALL cellines and primary patient samples.…”

Studies on the mode of action of synthetic diindolylmethane derivatives against triple negative breast cancer cells

“…Several compounds targeting this pathway are in clinical trials combined with targeted therapy, endocrine therapy, or cytotoxic agents. 8,9 Silibinin, the main component of silymarin, the natural substance from milk thistle seeds, influences oestrogen receptors and blocks PI3K/Akt/mTOR and Ras/ERK signalling. 10 The anticancer activity of cruciferous vegetables is mainly due to the presence of the phytochemical indole 3 carbinol (I3C).…”

“…PI3K/Akt/mTOR signalling pathway is a major focus of interest in breast cancer and is identified as a novel target for drug discovery. Several compounds targeting this pathway are in clinical trials combined with targeted therapy, endocrine therapy, or cytotoxic agents 8,9 . Silibinin, the main component of silymarin, the natural substance from milk thistle seeds, influences oestrogen receptors and blocks PI3K/Akt/mTOR and Ras/ERK signalling 10 …”