A Phase I Dose-Escalation Study of the HIF-2 Alpha Inhibitor DFF332 in Patients with Advanced Clear-Cell Renal Cell Carcinoma
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| Název: | A Phase I Dose-Escalation Study of the HIF-2 Alpha Inhibitor DFF332 in Patients with Advanced Clear-Cell Renal Cell Carcinoma |
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| Autoři: | Sumanta K. Pal, Alice Bernard-Tessier, Peter Grell, Xin Gao, Ritesh R. Kotecha, Joel Picus, Filippo de Braud, Shunji Takahashi, Alvin Wong, Cristina Suárez, Javier A. Otero, Nicole Kundamal, Xin Yang, Sherif Sharaby, Mike Roy, Patrizia Barzaghi-Rinaudo, Nizar M. Tannir |
| Přispěvatelé: | Institut Català de la Salut, [Pal SK] Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California. [Bernard-Tessier A] Department of Cancer Medicine, Gustave Roussy, Paris Saclay University, Villejuif, France. [Grell P] Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic. [Gao X] Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts. [Kotecha RR] Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. [Picus J] Division of Oncology, Siteman Cancer Center, Washington University, St. Louis, Missouri. [Suárez C] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Zdroj: | Clin Cancer Res Scientia Scientia. Dipòsit d'Informació Digital del Departament de Salut instname |
| Informace o vydavateli: | American Association for Cancer Research (AACR), 2025. |
| Rok vydání: | 2025 |
| Témata: | Male, Adult, Maximum Tolerated Dose, Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia, Medicaments antineoplàstics - Ús terapèutic, Clinical Trials: Targeted Therapy, Antineoplastic Agents, ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias glandulares y epiteliales::carcinoma::adenocarcinoma::carcinoma de células renales, ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias urológicas::neoplasias renales, DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Carcinoma::Adenocarcinoma::Carcinoma, Renal Cell, Basic Helix-Loop-Helix Transcription Factors, Humans, DISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Urologic Neoplasms::Kidney Neoplasms, Other subheadings::Other subheadings::Other subheadings::/administration & dosage, Carcinoma, Renal Cell, Aged, Aged, 80 and over, Other subheadings::Other subheadings::Other subheadings::/drug therapy, Dose-Response Relationship, Drug, ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Diagnosis::Prognosis::Treatment Outcome, PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Dose-Response Relationship, Drug, Middle Aged, Posologia, Kidney Neoplasms, FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::relación dosis-respuesta de medicamentos, TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::diagnóstico::pronóstico::resultado del tratamiento, Treatment Outcome, COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos, Ronyons - Càncer - Tractament, Avaluació de resultats (Assistència sanitària), Otros calificadores::Otros calificadores::Otros calificadores::/administración & dosificación, Female, CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents |
| Popis: | Purpose: Mutations or silencing of the von Hippel–Lindau tumor suppressor gene accumulate hypoxia-inducible factors (HIF). HIF-2α is implicated in the oncogenesis of ∼50% of patients with clear-cell renal cell carcinoma (ccRCC) but has been considered “undruggable.” DFF332, an orally administered novel allosteric inhibitor of HIF-2α, showed dose-dependent antitumor efficacy in preclinical models of ccRCC. Patients and Methods: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles, are reported. Results: As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, two patients (5%) achieved a partial response, and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events occurring in 25 patients (63%). Only five patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious treatment-related adverse event, hypertension, was reported in one patient. The maximum tolerated dose was not reached. Conclusions: Although clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies. |
| Druh dokumentu: | Article Other literature type |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-24-2618 |
| Přístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/40043000 http://hdl.handle.net/11351/13354 |
| Rights: | CC BY NC ND URL: http://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
| Přístupové číslo: | edsair.doi.dedup.....856490b671b27765a3957c8ed5a37466 |
| Databáze: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstrakt: | Purpose: Mutations or silencing of the von Hippel–Lindau tumor suppressor gene accumulate hypoxia-inducible factors (HIF). HIF-2α is implicated in the oncogenesis of ∼50% of patients with clear-cell renal cell carcinoma (ccRCC) but has been considered “undruggable.” DFF332, an orally administered novel allosteric inhibitor of HIF-2α, showed dose-dependent antitumor efficacy in preclinical models of ccRCC. Patients and Methods: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles, are reported. Results: As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, two patients (5%) achieved a partial response, and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events occurring in 25 patients (63%). Only five patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious treatment-related adverse event, hypertension, was reported in one patient. The maximum tolerated dose was not reached. Conclusions: Although clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies. |
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| ISSN: | 15573265 10780432 |
| DOI: | 10.1158/1078-0432.ccr-24-2618 |