Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies
| Autor: | Anna Durigova, Diego Tosi, Caroline Mollevi, Luca Gianni, Yassine Laghzali, Gianluca Del Conte, Nadia Hayaoui, Sophie Gourgou, Marie Alexandre, Krisztian Homicsko, Angelica Fasolo, Marie Vinches |
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| Přispěvatelé: | Institut du Cancer de Montpellier (ICM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), IRCCS Istituto Nazionale dei Tumori [Milano], Medical Oncology 1, Istituto dei Tumori di Milano |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
medicine.medical_specialty Maximum Tolerated Dose medicine.drug_class Antineoplastic Agents [SDV.CAN]Life Sciences [q-bio]/Cancer Monoclonal antibody Toxicology 03 medical and health sciences 0302 clinical medicine Planned Dose Neoplasms Internal medicine Dose escalation Humans Medicine 030304 developmental biology Clinical Trials as Topic 0303 health sciences Dose-Response Relationship Drug business.industry Antibodies Monoclonal First in human 3. Good health Oncology Research Design 030220 oncology & carcinogenesis Toxicity business |
| Zdroj: | Journal of Clinical Oncology Journal of Clinical Oncology, American Society of Clinical Oncology, 2015, 33 (19), pp.2158-2165. ⟨10.1200/JCO.2014.58.1082⟩ |
| ISSN: | 1527-7755 0732-183X |
| Popis: | Purpose We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. Methods We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. Results A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. Conclusion This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined. |
| Databáze: | OpenAIRE |
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