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Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium.

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Date
2017-11
ICR Author
Marsden,
Author
Bautista, F
Moreno, L
Marshall, L
Pearson, ADJ
Geoerger, B
Paoletti, X
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Type
Journal Article
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Abstract
Dose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children.The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members.Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III-IV haematologic toxicities that were transient or asymptomatic and grade III-IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition.DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials.
URI
https://repository.icr.ac.uk/handle/internal/1405
DOI
https://doi.org/10.1016/j.ejca.2017.09.015
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Subject
Humans
Neoplasms
Antineoplastic Agents
Maximum Tolerated Dose
Medical Oncology
Pediatrics
Age Factors
Dose-Response Relationship, Drug
Models, Theoretical
Research Design
Adolescent
Adult
Child
Child, Preschool
Infant
Terminology as Topic
Clinical Trials, Phase I as Topic
Drug Dosage Calculations
Language
eng
Date accepted
2017-09-13
License start date
2017-11
Citation
European journal of cancer (Oxford, England : 1990), 2017, 86 pp. 275 - 284

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