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. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

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

“…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 cell lines and primary patient samples.…”

Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy

“…There are no new clinical trials of BEZ235 developed on solid tumors. Some acute lymphoblastic leukemia patients may have some alterations in the PI3K/AKT/mTOR signaling pathway, and BEZ235 had promising effects in this small subset of patients [ 165 ]. AML did not benefit from BEZ235 treatment.…”

Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

“…Considering that most dose-limiting toxicities such as fatigue, diarrhea, nausea, and mucositis were noted with both PI3K and mTOR inhibitors, it is not unexpected that pan-PI3K and mTOR inhibition resulted in a high prevalence of adverse events at the dose of 400 mg/day. On the other hand, 300 mg/day was far better tolerated by the patients; therefore, this dose was established as recommended for phase II studies [ 115 ]. It is worth noting that dactolisib was found to increase the incidence of grade 3–4 adverse events in evaluable patients in several other clinical studies [ 116 ].…”