Early 3+3 Trial Dose-Escalation Phase I Clinical Trial Design and Suitability for Immune Checkpoint Inhibitors.
Antibodies, Monoclonal, Humanized
/ adverse effects
Antineoplastic Agents, Immunological
/ adverse effects
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Carcinoma, Renal Cell
/ drug therapy
Clinical Trials, Phase I as Topic
/ methods
Dose-Response Relationship, Drug
Humans
Immune Checkpoint Inhibitors
/ adverse effects
Ipilimumab
/ adverse effects
Kidney Neoplasms
/ drug therapy
Lung Neoplasms
/ drug therapy
Melanoma
/ drug therapy
Neoplasms
/ drug therapy
Nivolumab
/ adverse effects
Outcome Assessment, Health Care
/ methods
Research Design
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 01 2021
15 01 2021
Historique:
received:
15
07
2020
revised:
21
09
2020
accepted:
16
10
2020
pubmed:
22
10
2020
medline:
11
1
2022
entrez:
21
10
2020
Statut:
ppublish
Résumé
Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation. We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3-5 adverse events (G3-5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models. A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3-5 AEs was 34% with a significant 27% reduced risk in lower doses ( Our analysis shows a lack of consistent dose-toxicity or dose-response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.
Identifiants
pubmed: 33082209
pii: 1078-0432.CCR-20-2669
doi: 10.1158/1078-0432.CCR-20-2669
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Antineoplastic Agents, Immunological
0
Immune Checkpoint Inhibitors
0
Ipilimumab
0
Nivolumab
31YO63LBSN
pembrolizumab
DPT0O3T46P
Types de publication
Journal Article
Meta-Analysis
Langues
eng
Sous-ensembles de citation
IM
Pagination
485-491Informations de copyright
©2020 American Association for Cancer Research.
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