title: Innovations for phase I dose-finding designs in pediatric oncology clinical trials.
abstract: Phase I oncology clinical trials are designed to identify the optimal dose that will be recommended for phase II trials. In pediatric oncology, the conduct of those trials raises specific challenges, as the disease is rare with limited therapeutic options. In addition, the tolerance profile is known from adult trials. This paper provides a review of the major recent developments in the design of these trials, inspired by the need to cope with the specific challenges of dose finding in cancer pediatric oncology. We reviewed simulation studies comparing designs dedicated to address these challenges. We also reviewed the design used in published dose-finding trials in pediatric oncology over the period 2009-2014. Three main fields of innovation were identified. First, designs that were developed in order to relax the rules for more flexible inclusions. Second, methods to incorporate data emerging from adult studies. Third, designs accounting for toxicity evaluation at repeated cycles in pediatric oncology. In addition to this overview, we propose some further directions for designing pediatric dose-finding trials.
authors.affiliation: National Institutes of Health, Clinical Center, Department of Bioethics, Bethesda, MD, USA. Electronic address: adelaide.doussaudebazignan@nih.gov.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Doussau
authors.affiliation: Gustave Roussy, Pediatric and Adolescent Oncology, Villejuif, France; CNRS UMR8203, Univ. Paris-Sud, Univ. Paris-Saclay, Villejuif, France.
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.affiliation: Institut Curie, Pediatric, Adolescent and Young Adults Department, Paris, France.
authors.forename: Irene
authors.initials: I
authors.lastname: Jiménez
authors.affiliation: Gustave Roussy, Biostatistics and Epidemiology unit, Villejuif, France; INSERM U1018, CESP, Univ. Paris-Sud, Univ. Paris-Saclay, Villejuif, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Paoletti
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002648:Child; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D010372:Pediatrics; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents
keywords: Adaptive designs; Dose-finding clinical trials; Oncology; Pediatrics; Phase I; Review
references.citation: Biometrics. 1998 Mar;54(1):251-64
references.pmid: 9544520
references.citation: J Biopharm Stat. 2016;26(3):475-98
references.pmid: 26098782
references.citation: Clin Investig (Lond). 2013 Sep;3(9):null
references.pmid: 24273641
references.citation: Eur J Cancer. 2013 Jul;49(10):2392-402
references.pmid: 23540589
references.citation: Contemp Clin Trials. 2010 May;31(3):259-70
references.pmid: 20298812
references.citation: BMC Med Res Methodol. 2002 Dec 5;2:15
references.pmid: 12466027
references.citation: J Clin Oncol. 2011 May 1;29(13):1728-35
references.pmid: 21444876
references.citation: Contemp Clin Trials. 2015 Jul 11;44:56-63
references.pmid: 26173185
references.citation: Invest New Drugs. 1996;14(1):11-22
references.pmid: 8880389
references.citation: Stat Med. 1998 May 30;17(10):1103-20
references.pmid: 9618772
references.citation: Ann Oncol. 2015 Feb;26(2):422-8
references.pmid: 25403589
references.citation: Eur J Cancer. 2014 Aug;50(12):2040-9
references.pmid: 24880774
references.citation: Orphanet J Rare Dis. 2008;3:11
references.pmid: 18454853
references.citation: Contemp Clin Trials. 2015 Mar;41:139-45
references.pmid: 25638751
references.citation: Stat Med. 2015 Sep 30;34(22):2983-98
references.pmid: 26109523
references.citation: Biometrics. 2005 Mar;61(1):217-22
references.pmid: 15737096
references.citation: Clin Pharmacol Ther. 2008 Dec;84(6):729-33
references.pmid: 18923388
references.citation: Stat Biopharm Res. 2014 May 1;6(2):185-197
references.pmid: 25071878
references.citation: J Natl Cancer Inst. 2009 May 20;101(10):708-20
references.pmid: 19436029
references.citation: Stat Med. 2010 May 10;29(10):1096-106
references.pmid: 20082362
references.citation: Control Clin Trials. 2002 Jun;23(3):240-56
references.pmid: 12057877
references.citation: Lancet Oncol. 2013 Mar;14(3):e117-24
references.pmid: 23434337
references.citation: Biometrics. 1989 Sep;45(3):925-37
references.pmid: 2790129
references.citation: Stat Med. 2007 May 20;26(11):2317-30
references.pmid: 17016867
references.citation: Cancer Chemother Pharmacol. 2014 Dec;74(6):1191-8
references.pmid: 25257509
references.citation: Cancer. 2010 Jul 1;116(13):3244-50
references.pmid: 20564626
references.citation: Front Oncol. 2015 Jan 06;4:374
references.pmid: 25610810
references.citation: J Biopharm Stat. 2009;19(3):437-55
references.pmid: 19384687
references.citation: Pharm Stat. 2015 Jul-Aug;14(4):302-10
references.pmid: 25962576
references.citation: J Clin Oncol. 2008 Jan 10;26(2):190-5
references.pmid: 18182661
references.citation: Stat Med. 2009 Oct 30;28(24):3012-28
references.pmid: 19672839
references.citation: J Clin Oncol. 2012 Dec 10;30(35):4367-72
references.pmid: 23071225
references.citation: Biometrics. 1996 Jun;52(2):673-84
references.pmid: 8672707
references.citation: Biometrics. 2000 Dec;56(4):1177-82
references.pmid: 11129476
references.citation: Contemp Clin Trials. 2012 Jul;33(4):657-65
references.pmid: 22521954
references.citation: Clin Trials. 2011 Aug;8(4):361-9
references.pmid: 21610004
references.citation: Stat Med. 2010 May 10;29(10):1077-83
references.pmid: 20419760
references.citation: Stat Med. 2013 Dec 30;32(30):5430-47
references.pmid: 24018535
references.citation: Pharm Stat. 2016 Mar-Apr;15(2):123-34
references.pmid: 26685103
references.citation: Biometrics. 1990 Mar;46(1):33-48
references.pmid: 2350571
references.citation: Stat Med. 2014 Jul 10;33(15):2665-80
references.pmid: 24590816
references.citation: Biometrics. 2011 Dec;67(4):1555-63
references.pmid: 21361888
references.citation: J Natl Cancer Inst. 1997 Aug 6;89(15):1138-47
references.pmid: 9262252
references.citation: Clin Trials. 2004;1(6):499-508
references.pmid: 16279290
references.citation: J Clin Oncol. 2005 Nov 20;23(33):8431-41
references.pmid: 16293874
references.citation: Stat Med. 2011 Jun 15;30(13):1584-94
references.pmid: 21351289
references.citation: Br J Cancer. 2005 Sep 5;93(5):529-37
references.pmid: 16136028
references.citation: J Clin Oncol. 1998 Mar;16(3):966-78
references.pmid: 9508179
references.citation: Neuro Oncol. 2011 Jan;13(1):109-18
references.pmid: 20974795
references.citation: J Clin Oncol. 2003 Oct 15;21(20):3844-52
references.pmid: 14551303
references.citation: Stat Med. 2006 Jul 30;25(14):2365-83
references.pmid: 16220478
references.citation: Stat Med. 2008 Jun 15;27(13):2420-39
references.pmid: 18344187
references.citation: Comput Methods Programs Biomed. 2008 Jun;90(3):240-50
references.pmid: 18276034
references.citation: J Clin Oncol. 2000 May;18(9):1900-5
references.pmid: 10784630
references.citation: Contemp Clin Trials. 2011 Sep;32(5):694-703
references.pmid: 21554993