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A Phase I Dose-Escalation Study of the HIF-2 Alpha Inhibitor DFF332 in Patients with Advanced Clear-Cell Renal Cell Carcinoma

SK. Pal, A. Bernard-Tessier, P. Grell, X. Gao, RR. Kotecha, J. Picus, F. de Braud, S. Takahashi, A. Wong, C. Suárez, JA. Otero, N. Kundamal, X. Yang, S. Sharaby, M. Roy, P. Barzaghi-Rinaudo, NM. Tannir

. 2025 ; 31 (10) : 1847-1855. [pub] 20250515

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, klinické zkoušky, fáze I

Perzistentní odkaz   https://www.medvik.cz/link/bmc25015738

Grantová podpora
Novartis Pharmaceutical Corporation, USA

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.

Citace poskytuje Crossref.org

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