• Francisco Bautista, Lucas Moreno, Lynley Marshall, PearsonAndrew D JADJPediatric Drug Development Team, The Royal Marsden Hospital, Division of Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK. Electronic address: andy1pearson@btinternet.com., Birgit Geoerger, and Xavier Paoletti.
• Clinical Research Unit, Pediatric Oncology, Hematology and Stem Cell Transplant Department, Hospital Infantil Universitario Niño Jesús, Avenida Menéndez Pelayo, 65, 28009, Madrid, Spain. Electronic address: franciscojose.bautista@salud.madrid.org.
• Eur. J. Cancer. 2017 Nov 1; 86: 275-284.

BackgroundDose-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.MethodsThe 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.ResultsThirteen 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.ConclusionDLTs 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.Copyright © 2017 Elsevier Ltd. All rights reserved.

36 keywords...

hide…