Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia
Stein, Eytan M. (Memorial Sloan Kettering Cancer Center (New York))
DeAngelo, Daniel J. (Dana-Farber Cancer Institute (Boston, Massachusetts))
Chromik, Jörg (Goethe University Frankfurt)
Chatterjee, Manik (University Hospital of Würzburg)
Bauer, Sebastian (German Consortium of Translational Cancer Research (DKTK))
Lin, Chia-Chi (National Taiwan University Hospital (Taipei, Taiwan))
Suárez, Cristina (Vall d'Hebron Institut d'Oncologia)
de Vos, Filip (University Medical Center Utrecht)
Steeghs, Neeltje (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
Cassier, Philippe A. (Léon Bérard Center)
Tai, David (National Cancer Center Singapore)
Kiladjian, Jean-Jacques (Université de Paris)
Yamamoto, Noboru (National Cancer Center Hospital (Tokyo, Japó))
Mous, Rogier (University Medical Center Utrecht)
Esteve Reyner, Jordi (Hospital Clínic i Provincial de Barcelona)
Minami, Hironobu (Kobe University Graduate School of Medicine and Hospital (Japó))
Ferretti, Stephane (Novartis Institutes for Biomedical Research)
Guerreiro, Nelson (Novartis Institutes for Biomedical Research)
Meille, Christophe (Novartis Institutes for Biomedical Research)
Radhakrishnan, Rajkumar (Novartis Healthcare Private Limited (Hyderabad, India))
Pereira, Bernard (Novartis Institutes for BioMedical Research (Cambridge, Massachusetts))
Mariconti, Luisa (Novartis Institutes for Biomedical Research)
Halilovic, Ensar (Novartis Institutes for BioMedical Research (Cambridge, Massachusetts))
Fabre, Claire (Novartis Institutes for Biomedical Research)
Carpio Segura, Cecilia del Carmen (Vall d'Hebron Institut d'Oncologia)
Universitat Autònoma de Barcelona

Fecha:	2021
Resumen:	This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53-MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers. Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12. 5-350 mg) and 2A (days 1-14; 28-day cycle; dose 1-20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1-7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1. Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10. 3% [95% confidence interval (CI), 2. 2-27. 4] in solid tumors and 4. 2% (95% CI, 0. 1-21. 1), 20% (95% CI, 4. 3-48. 1), and 22. 2% (95% CI, 8. 6-42. 3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively. A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	Clinical Cancer Research, Vol. 28 (december 2021) , p. 870-881, ISSN 1557-3265

DOI: 10.1158/1078-0432.CCR-21-1295
PMID: 34862243

12 p, 506.4 KB

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