Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Mar:47:217-27.
doi: 10.1016/j.cct.2016.01.009. Epub 2016 Jan 26.

Innovations for phase I dose-finding designs in pediatric oncology clinical trials

Adelaide Doussau  1 , Birgit Geoerger  2 , Irene Jiménez  3 , Xavier Paoletti  4
Affiliations
Review

Innovations for phase I dose-finding designs in pediatric oncology clinical trials

Adelaide Doussau et al. Contemp Clin Trials. 2016 Mar.

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.

Keywords: Adaptive designs; Dose-finding clinical trials; Oncology; Pediatrics; Phase I; Review.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Designs used in pediatric phase I cancer clinical trials
Comprehensive review of published phase I trials conducted in children between 2009 and 2014: 88 publications, 90 trials, as 2 trials included 2 independent substudies. Search through Pubmed performed in December 2014.
Figure 2
Figure 2. Graphical depiction of dose escalation methods for phase I cancer clinical trials
Adapted from (57) with permission of the author. Each box represents a cohort comprising the indicated number of patients treated at a given dose level. A) Traditional 3+3 design. B) Rolling 6. C) Modified continual reassessment method. D) Escalation with overdose control. “Overdosing or excessive overdosing” refers to doses that exceed the MTD. DLT = dose-limiting toxicity; SD = starting dose; RD = recommended dose; DL = dose level; p(DLT at next DL) = probability of dose-limiting toxicity at the next dose level.
Figure 3
Figure 3. Distribution of the dose recommended in 8 simulations studies, when the 3rd dose level is the true MTD
Horizontal axis = True probability of dose-limiting toxicity of the dose level. Vertical axis = Proportion of simulated trials recommending this dose as recommended phase II dose (RP2D). Short dashed lines correspond to model-based designs. BSA: body surface area. CRM: Continual reassessment method. POMM: proportional odds mixed model. TiTE: Time to event. The scenarios are described in appendix. Reference: Skolnik 2008 (9), Onar 2009 (28), Onar-Thomas 2010 (19), Doussau 2012 (11), Zhao 2011 (14), Doussau 2013 (27), Broglio 2015 (26), O`Quigley 2014 (29).
Figure 4
Figure 4. Flow diagram: Designing a phase I dose-finding trial in pediatric oncology
See this image and copyright information in PMC

References

    1. Lee DP, Skolnik JM, Adamson PC. Pediatric phase I trials in oncology: an analysis of study conduct efficiency. J Clin Oncol. 2005;23(33):8431–8441. - PubMed
    1. Paoletti X, Geoerger B, Doz F, Baruchel A, Lokiec F, Le Tourneau C. A comparative analysis of paediatric dose-finding trials of molecularly targeted agent with adults' trials. Eur J Cancer. 2013;49(10):2392–2402. - PubMed
    1. Smith M, Ho PT. Pediatric drug development: a perspective from the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) Invest New Drugs. 1996;14(1):11–22. - PubMed
    1. Cousino MK, Zyzanski SJ, Yamokoski AD, Hazen RA, Baker JN, Noll RB, et al. Communicating and understanding the purpose of pediatric phase I cancer trials. J Clin Oncol. 2012;30(35):4367–4372. - PMC - PubMed
    1. Estlin EJ, Cotterill S, Pratt CB, Pearson AD, Bernstein M. Phase I trials in pediatric oncology: perceptions of pediatricians from the United Kingdom Children's Cancer Study Group and the Pediatric Oncology Group. J Clin Oncol. 2000;18(9):1900–1905. - PubMed

Substances

LinkOut - more resources