A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia.
Adult
Aged
Aged, 80 and over
Antineoplastic Agents
/ pharmacokinetics
Drug Resistance, Neoplasm
Female
Humans
Imidazoles
/ pharmacokinetics
Leukemia
/ drug therapy
Male
Middle Aged
PTEN Phosphohydrolase
/ genetics
Phosphoinositide-3 Kinase Inhibitors
/ pharmacokinetics
Proto-Oncogene Proteins c-akt
/ genetics
Quinolines
/ pharmacokinetics
Recurrence
Ribosomal Protein S6 Kinases
/ metabolism
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Transcription Factors
/ genetics
Treatment Outcome
BEZ235
PI3K/mTor inhibition
Phase I clinical trial
Refractory ALL
Refractory AML
Journal
BMC pharmacology & toxicology
ISSN: 2050-6511
Titre abrégé: BMC Pharmacol Toxicol
Pays: England
ID NLM: 101590449
Informations de publication
Date de publication:
29 09 2020
29 09 2020
Historique:
received:
08
01
2020
accepted:
06
09
2020
entrez:
30
9
2020
pubmed:
1
10
2020
medline:
3
7
2021
Statut:
epublish
Résumé
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. 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. 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. 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. ClinicalTrials.gov , identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118 .
Sections du résumé
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 .
Identifiants
pubmed: 32993794
doi: 10.1186/s40360-020-00446-x
pii: 10.1186/s40360-020-00446-x
pmc: PMC7523358
doi:
Substances chimiques
Antineoplastic Agents
0
Imidazoles
0
PI3KCA protein, human
0
Phosphoinositide-3 Kinase Inhibitors
0
Quinolines
0
Transcription Factors
0
MTOR protein, human
EC 2.7.1.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Ribosomal Protein S6 Kinases
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
PTEN Phosphohydrolase
EC 3.1.3.67
PTEN protein, human
EC 3.1.3.67
dactolisib
RUJ6Z9Y0DT
Banques de données
ClinicalTrials.gov
['NCT01756118']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
70Subventions
Organisme : Goethe-Universität Frankfurt am Main
ID : n.a.
Pays : International
Organisme : Novartis Pharma
ID : n.a.
Pays : International
Organisme : Novartis Pharma
ID : n.a.
Pays : International
Organisme : Bristol-Myers Squibb Foundation
ID : n.a.
Pays : International
Organisme : José Carreras Leukämie-Stiftung
ID : n.a.
Pays : International
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