INFORM2 NivEnt: The first trial of the INFORM2 biomarker driven phase I/II trial series: the combination of nivolumab and entinostat in children and adolescents with refractory high-risk malignancies.
Adolescent
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Bayes Theorem
Benzamides
/ administration & dosage
Biomarkers, Tumor
/ analysis
Child
Dose-Response Relationship, Drug
Drug Monitoring
/ methods
Drug Resistance, Neoplasm
Female
Humans
Male
Medical Futility
Mutation
Neoplasms
/ diagnosis
Nivolumab
/ administration & dosage
Precision Medicine
/ methods
Pyridines
/ administration & dosage
Treatment Outcome
Young Adult
Bayesian design
Biomarker
Checkpoint inhibition
Child
Entinostat
HDAC
Nivolumab
Phase I/II
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
05 Jun 2020
05 Jun 2020
Historique:
received:
05
03
2020
accepted:
27
05
2020
entrez:
7
6
2020
pubmed:
7
6
2020
medline:
20
1
2021
Statut:
epublish
Résumé
Pediatric patients with relapsed or refractory disease represent a population with a desperate medical need. The aim of the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) program is to translate next generation molecular diagnostics into a biomarker driven treatment strategy. The program consists of two major foundations: the INFORM registry providing a molecular screening platform and the INFORM2 series of biomarker driven phase I/II trials. The INFORM2 NivEnt trial aims to determine the recommended phase 2 dose (RP2D) of the combination treatment of nivolumab and entinostat (phase I) and to evaluate activity and safety (phase II). This is an exploratory non-randomized, open-label, multinational and multicenter seamless phase I/II trial in children and adolescents with relapsed / refractory or progressive high-risk solid tumors and CNS tumors. The phase I is divided in 2 age cohorts: 12-21 years and 6-11 years and follows a 3 + 3 design with two dose levels for entinostat (2 mg/m This trial intends to exploit the immune enhancing effects of entinostat on nivolumab using an innovative biomarker driven approach in order to maximize the chance of detecting signs of activity. It prevents exposure to unnecessary risks by applying the Bayesian adaptive design for early stopping for futility. The adaptive biomarker driven design provides an innovative approach accelerating drug development and reducing exposure to investigational treatments in these vulnerable children at the same time. ClinicalTrials.gov, NCT03838042. Registered on 12 February 2019.
Sections du résumé
BACKGROUND
BACKGROUND
Pediatric patients with relapsed or refractory disease represent a population with a desperate medical need. The aim of the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) program is to translate next generation molecular diagnostics into a biomarker driven treatment strategy. The program consists of two major foundations: the INFORM registry providing a molecular screening platform and the INFORM2 series of biomarker driven phase I/II trials. The INFORM2 NivEnt trial aims to determine the recommended phase 2 dose (RP2D) of the combination treatment of nivolumab and entinostat (phase I) and to evaluate activity and safety (phase II).
METHODS
METHODS
This is an exploratory non-randomized, open-label, multinational and multicenter seamless phase I/II trial in children and adolescents with relapsed / refractory or progressive high-risk solid tumors and CNS tumors. The phase I is divided in 2 age cohorts: 12-21 years and 6-11 years and follows a 3 + 3 design with two dose levels for entinostat (2 mg/m
DISCUSSION
CONCLUSIONS
This trial intends to exploit the immune enhancing effects of entinostat on nivolumab using an innovative biomarker driven approach in order to maximize the chance of detecting signs of activity. It prevents exposure to unnecessary risks by applying the Bayesian adaptive design for early stopping for futility. The adaptive biomarker driven design provides an innovative approach accelerating drug development and reducing exposure to investigational treatments in these vulnerable children at the same time.
TRIAL REGISTRATION
BACKGROUND
ClinicalTrials.gov, NCT03838042. Registered on 12 February 2019.
Identifiants
pubmed: 32503469
doi: 10.1186/s12885-020-07008-8
pii: 10.1186/s12885-020-07008-8
pmc: PMC7275428
doi:
Substances chimiques
Benzamides
0
Biomarkers, Tumor
0
Pyridines
0
entinostat
1ZNY4FKK9H
Nivolumab
31YO63LBSN
Banques de données
ClinicalTrials.gov
['NCT03838042']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
523Subventions
Organisme : Deutsches Krebsforschungszentrum
ID : NCT 3.0 POC
Organisme : Deutsche Krebshilfe
ID : #70112951 (ENABLE)
Références
Eur J Cancer. 2011 Jan;47(1):90-7
pubmed: 20970323
Lancet Oncol. 2015 Nov;16(15):e534-e542
pubmed: 26545842
J Clin Oncol. 2016 Sep 1;34(25):2980-7
pubmed: 27354485
Biom J. 2020 Mar;62(2):330-338
pubmed: 31608505
Eur J Cancer. 2019 Jun;114:27-35
pubmed: 31022591
PLoS One. 2012;7(1):e30815
pubmed: 22303460
Science. 2013 Dec 20;342(6165):1432-3
pubmed: 24357284
Lancet Oncol. 2017 Mar;18(3):e143-e152
pubmed: 28271869
Stat Med. 1994 Sep 30;13(18):1799-806
pubmed: 7997713
Mol Cancer Ther. 2017 Nov;16(11):2598-2608
pubmed: 28835386
J Clin Oncol. 2008 May 10;26(14):2384-9
pubmed: 18467730
Clin Cancer Res. 2016 Aug 15;22(16):4119-32
pubmed: 26964571
Biom J. 2019 May;61(3):488-502
pubmed: 30175405
Pediatr Blood Cancer. 2011 Oct;57(4):549-53
pubmed: 21442722
Nature. 2013 Jul 11;499(7457):214-218
pubmed: 23770567
Pediatr Blood Cancer. 2014 Jul;61(7):1195-201
pubmed: 24615997
J Clin Oncol. 2017 Jul 20;35(21):2439-2449
pubmed: 28640707
J Clin Oncol. 2016 Jul 1;34(19):2206-11
pubmed: 27001570
Neuro Oncol. 2011 Oct;13(10):1049-58
pubmed: 21784756
Science. 2013 Mar 29;339(6127):1546-58
pubmed: 23539594
Oncotarget. 2014 Aug 30;5(16):6558-72
pubmed: 25115382
J Clin Oncol. 2001 May 1;19(9):2390-6
pubmed: 11331317
Cancer Cell. 2016 Mar 14;29(3):311-323
pubmed: 26977882
Ann Oncol. 2018 Mar 1;29(3):766-771
pubmed: 29351570
Lancet Oncol. 2019 Jun;20(6):e336-e342
pubmed: 31162107
Science. 2016 Apr 8;352(6282):227-31
pubmed: 26966191
Am Soc Clin Oncol Educ Book. 2018 May 23;38:169-178
pubmed: 30231380
Nature. 2018 Mar 22;555(7697):469-474
pubmed: 29539639
J Pediatr Hematol Oncol. 2015 Mar;37(2):e102-10
pubmed: 25171452
Haematologica. 2014 Sep;99(9):1472-8
pubmed: 24763401
Nat Genet. 2017 Jul;49(7):1052-1060
pubmed: 28604729
Cancer Lett. 2012 May 1;318(1):42-52
pubmed: 22186300
Ann Oncol. 2015 Dec;26(12):2464-9
pubmed: 26410619
Acta Neuropathol Commun. 2015 Apr 03;3:22
pubmed: 25853389
Eur J Cancer. 2016 Sep;65:91-101
pubmed: 27479119
Biol Blood Marrow Transplant. 2012 Aug;18(8):1182-1190.e1
pubmed: 22698484
Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11774-9
pubmed: 25071169
Clin Trials. 2013 Oct;10(5):720-34
pubmed: 23983156
J Pediatr Hematol Oncol. 2009 Sep;31(9):651-63
pubmed: 19707161
Lancet Oncol. 2013 Nov;14(12):1200-7
pubmed: 24140199
J Clin Oncol. 2011 Aug 20;29(24):3286-92
pubmed: 21768459
J Clin Oncol. 2005 Jan 20;23(3):559-68
pubmed: 15659502