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

Fabian Lang,Hubert Serve,Oliver G Ottmann,Kevin Ashelford,Heike Pfeifer,Monika Brüggemann,Lydia Wunderle,Susanne Badura,Eberhard Schleyer,Sebastian Wagner,Nicola Gökbuget,Susanne Schnittger,Gesine Bug

doi:10.1186/s40360-020-00446-x

Abstract

BackgroundCombined 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.MethodsHerein 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.ResultsTwenty-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.ConclusionsCombined 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 registrationClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

Highlights

Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin complexes may be an efficient treatment for acute leukemia
In Philadelphia chromosome positive (Ph+) BCP-Acute lymphoblastic leukemia (ALL) PI3K signaling has been shown to be involved in mutation-independent resistance to ABLdirected tyrosine kinase inhibitors [14] and recent preclinical data suggest a role in Philadelphia chromosome negative (Ph-) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) [14, 15]
While mutations of the PI3KCA gene are rare in leukemia, events upstream of PI3K are commonly implicated in causing aberrant activation of this pathway, e.g. activating mutations of the receptor tyrosine kinases (RTKs), Fms-like tyrosine kinase 3 (FLT3) and KIT receptor tyrosine kinase, BCRABL1 fusion gene, or activating mutations in NRas and KRas [17,18,19,20]

Summary

Introduction

Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The phosphatidylinositol 3-kinase (PI3K) / Akt / mammalian target of rapamycin (mTOR) signaling axis plays an important physiologic role in protein synthesis, gene transcription, cell growth and apoptosis [1, 2]. PI3K/Akt/mTOR network upregulation has been detected in leukemia stem cells (LSCs) transplanted in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, where it exerted a powerful pro-survival effect [23, 24]. Taken together, these observations lent compelling weight to the clinical exploration of PI3K inhibitors in the therapy of acute leukemia

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