Abstract A100: Seamless phase I/II clinical trials in oncology: retrospective analysis of the last 7 years
Notice bibliographique
Résumé
Abstract Introduction: Drug development has evolved from the conventional sequence of three-phase clinical trial process to a seamless approach of adding cohorts to first-in-human trials to investigate both safety and efficacy in various cancers. In this retrospective study, we evaluated the prevalence of large early-phase studies in adult cancer patients; described the clinical characteristics, design, and statistical plan of these studies; and identified which investigational drugs using this seamless strategy were included in the accelerated approval program by the Food and Drug Administration (FDA). Methods: All abstracts presented at the American Society of Clinical Oncology (ASCO) annual meetings from 2010 to 2017 were reviewed. Clinical studies conducted in the pediatric population as well as abstracts reporting trials in progress were excluded. Seamless clinical trials were defined as any phase I/II studies with a sample size of 100 or more patients. The Center for Drug Evaluation and Research (CDER) drug approvals report was used to access the list of drugs included in the accelerated approval program by FDA. Results: We identified a total of 1786 early-phase trials enrolling more than 57,500 patients with malignant neoplasms. More frequently these studies included patients with advanced solid tumors (87%) and targeted therapy and immunotherapy agents were investigated in 64% and 15% of the cases, respectively. Of the 1786 trials, 51 were identified as seamless phase I/II with a sample size of 100 or more patients, representing only 3% of the total number of trials (n=1786) but 15% of the total number of patients (n=57,559). These seamless trials had a median number of 3 (1-13) expansion cohorts and a higher fraction (65%) were presented in the last 3 years (2014-2017), compared with 35% of the studies with results presented between 2010-2013. Fifty active investigational new drugs (67% targeted therapy, 18% immunotherapy, 10% antibody-drug conjugate, 2.0% chemotherapy, 3.9% other) were studied as single agents (53%) or in combination with other therapies (47%). Of the 51 identified large seamless phase I/II trials, only 29 (57%) studies had published results. Further, of these 29 studies, a planned statistical analysis for the calculation of the expansion cohorts’ sample-size was not available in 69% of the cases. The overall rate of significant (grade 3-4) adverse events was 49% (range, 0-100%), and at least one toxic death was reported in 5 of these studies. The pooled response rate (CR+PR) per study was 20% (range, 0.9-77). Considering the group of drugs studied in the 51-seamless phase I/II trials identified here, the FDA granted accelerated approval to 8 drugs and 1 other agent was given priority review. Conclusions: Approximately two-thirds of the studies identified were presented after the year 2014, suggesting an increased use of the seamless approach. While the high rate of accelerated approvals granted by the FDA endorses the observed preliminary clinical benefit of these drugs, the absence of a prespecified statistical plan is a weakness of most of the published studies. Citation Format: Pedro Barata, Brian Hobbs, Brian Rini, Channing Paller, Dan Normolle, Elizabeth Garrett-Mayer, Eric Rubin, Gary Rosner, Greg Pond, Jane Perlmutter, Lesley Seymour, Lillian Siu, Nolan Wages, Percy Ivy, Tatiana Prowell, Timothy Yap, David Hong. Seamless phase I/II clinical trials in oncology: retrospective analysis of the last 7 years [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A100.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,038 | 0,109 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,001 | 0,002 |
| Bibliométrie | 0,009 | 0,012 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,003 | 0,002 |
| Science ouverte | 0,001 | 0,002 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».