Clinical efficacy of the optimal biological dose in early-phase trials of anti-cancer targeted therapies.
Anti-neoplastic agents
Antibodies
Dose-response relationship
Drug
Maximum tolerated dose
Monoclonal
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
04
07
2019
revised:
26
07
2019
accepted:
02
08
2019
pubmed:
4
9
2019
medline:
10
6
2020
entrez:
4
9
2019
Statut:
ppublish
Résumé
Determining the optimal biological dose (OBD) has been described as an alternative strategy to the maximum tolerated doses (MTDs) for identifying the recommended phase II trial doses (RP2Ds) of phase I anti-cancer therapies. However, the clinical relevance is still unknown. An extensive review was performed to assess if the OBDs defined in early-phase trials were useful for subsequent drug development and approvals. All the molecular targeted therapies approved by the Food and Drug Administration (FDA) in solid oncology or in haematological malignancies before July 2018 were listed through the National Cancer Institute Database. The early-phase trial publications investigating these drugs as single agents were retrieved and analysed to identify the drugs for which OBDs were reported. The publications of subsequent pivotal efficacy clinical trials leading to the approvals were retrieved, and OBDs compared with the final labelled doses and dosing schedules. A total of 87 early-phase trial publications were analysed, corresponding to 81 FDA-approved targeted therapies. OBDs were reported for 40% (32/81) of these drugs (19 small molecules, 13 monoclonal antibodies). MTDs were not identified for 59% (19/32) of molecules. When the OBDs were selected as the RP2Ds (18/32 molecules), the final FDA-approved doses were consistent with the OBDs for 83% of the drugs, which is much higher than the previously reported 58% rate when MTDs were chosen as the RP2Ds. Although still poorly investigated, the OBD may be a relevant and complementary end-point for early-phase trials of targeted therapies.
Sections du résumé
BACKGROUND
Determining the optimal biological dose (OBD) has been described as an alternative strategy to the maximum tolerated doses (MTDs) for identifying the recommended phase II trial doses (RP2Ds) of phase I anti-cancer therapies. However, the clinical relevance is still unknown. An extensive review was performed to assess if the OBDs defined in early-phase trials were useful for subsequent drug development and approvals.
METHODS
All the molecular targeted therapies approved by the Food and Drug Administration (FDA) in solid oncology or in haematological malignancies before July 2018 were listed through the National Cancer Institute Database. The early-phase trial publications investigating these drugs as single agents were retrieved and analysed to identify the drugs for which OBDs were reported. The publications of subsequent pivotal efficacy clinical trials leading to the approvals were retrieved, and OBDs compared with the final labelled doses and dosing schedules.
RESULTS
A total of 87 early-phase trial publications were analysed, corresponding to 81 FDA-approved targeted therapies. OBDs were reported for 40% (32/81) of these drugs (19 small molecules, 13 monoclonal antibodies). MTDs were not identified for 59% (19/32) of molecules. When the OBDs were selected as the RP2Ds (18/32 molecules), the final FDA-approved doses were consistent with the OBDs for 83% of the drugs, which is much higher than the previously reported 58% rate when MTDs were chosen as the RP2Ds.
CONCLUSION
Although still poorly investigated, the OBD may be a relevant and complementary end-point for early-phase trials of targeted therapies.
Identifiants
pubmed: 31479946
pii: S0959-8049(19)30442-3
doi: 10.1016/j.ejca.2019.08.002
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
40-46Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.