A Phase I/II Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib for Relapsed Refractory Acute Myeloid Leukemia.
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Boron Compounds
/ administration & dosage
Cytarabine
/ administration & dosage
Drug Resistance, Neoplasm
/ drug effects
Etoposide
/ administration & dosage
Female
Glycine
/ administration & dosage
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Maximum Tolerated Dose
Middle Aged
Mitoxantrone
/ administration & dosage
Neoplasm Recurrence, Local
/ drug therapy
Patient Safety
Remission Induction
Salvage Therapy
Treatment Outcome
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 07 2019
15 07 2019
Historique:
received:
13
12
2018
revised:
01
03
2019
accepted:
11
04
2019
pubmed:
18
4
2019
medline:
23
9
2020
entrez:
18
4
2019
Statut:
ppublish
Résumé
The prognosis of patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) remains poor, and novel therapies are needed. The proteasome pathway represents a potential therapeutic target. A phase I trial of the second-generation proteasome inhibitor ixazomib in combination with MEC (mitoxantrone, etoposide, and cytarabine) was conducted in patients with R/R AML. Dose escalation of ixazomib was performed using a standard 3 × 3 design. Gene-expression profiling was performed on pretreatment and posttreatment bone marrow or blood samples. The maximum tolerated dose of ixazomib in combination with MEC was 1.0 mg. The dose limiting toxicity was thrombocytopenia. Despite a poor risk population, the response rate [complete remission (CR)/CR with incomplete count recovery (CRi)] was encouraging at 53%. Gene-expression analysis identified two genes, IFI30 (γ-interferon inducible lysosomal thiol reductase) and RORα (retinoic orphan receptor A), which were significantly differentially expressed between responding and resistant patients and could classify CR. These results are encouraging, but a randomized trial is needed to address whether the addition of ixazomib to MEC improves outcome. Gene-expression profiling also helped us identify predictors of response and potentially novel therapeutic targets.
Identifiants
pubmed: 30992301
pii: 1078-0432.CCR-18-3886
doi: 10.1158/1078-0432.CCR-18-3886
pmc: PMC6635077
mid: NIHMS1527399
doi:
Substances chimiques
Boron Compounds
0
Cytarabine
04079A1RDZ
Etoposide
6PLQ3CP4P3
ixazomib
71050168A2
Mitoxantrone
BZ114NVM5P
Glycine
TE7660XO1C
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4231-4237Subventions
Organisme : NCI NIH HHS
ID : K12 CA076917
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA043703
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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