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

  • 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.

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Author:Fabian LangORCiDGND, Lydia WunderleGND, Susanne BaduraGND, Eberhard SchleyerGND, Monika BrüggemannORCiDGND, Hubert ServeORCiDGND, Susanne SchnittgerGND, Nicola GökbugetGND, Heike PfeiferGND, Sebastian Alexander WagnerORCiDGND, Kevin AshelfordORCiD, Gesine BugORCiDGND, Oliver G. OttmannORCiDGND
Parent Title (English):BMC pharmacology & toxicology
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Date of Publication (online):2020/09/29
Date of first Publication:2020/09/29
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/11/07
Tag:BEZ235; PI3K/mTor inhibition; Phase I clinical trial; Refractory ALL; Refractory AML
Issue:art. 70
Article Number:70
Page Number:14
First Page:1
Last Page:14
We also thank High Throughput Sequencing Unit of the Genomics & Proteomics Core Facility, DKFZ, for providing excellent whole genome and RNA sequencing services. The One Touch Pipeline (OTP) framework was used for organization and processing of sequencing data. This service was supported by the BMBF-funded Heidelberg Center for Human Bioinformatics (HD-HuB) within the German Network for Bioinformatics Infrastructure (de.NBI) (#031A537A, #031A537C).
This research was funded and supported by Novartis, the Deutsche Krebshilfe Verbundprojekt 108690. OO holds an endowed professorship of the DJCLS (H06/06). Open Access funding enabled and organized by Projekt DEAL.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
The peer review history for this article is available at https://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/s40360-020-00446-x/peer-review.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International