Highlights
- •A new set of dose-limiting toxicities (DLTs) and recommended phase II dose (RP2D) definitions have been issued for molecularly targeted agents' adult phase I trials.
- •We analysed the Innovative Therapies for Children with Cancer Consortium dose-finding trials and conducted a survey with among expert pediatricians.
- •Several proposals for adult dose-finding trials are translated in paediatric studies.
- •DLTs should be homogeneously defined across trials.
- •Definition of RP2D should include delayed toxicities and supported by pharmacokinetics/pharmacodynamics data.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusion
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.
Keywords
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Article info
Publication history
Published online: October 19, 2017
Accepted:
September 13,
2017
Received:
August 1,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
