Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03

• Jesus Garcia-Donas ^[9] ; Alicia Hurtado ^[1] ; Laia Garrigos ^[10] ; Ana Santaballa ^[2] ; Andres Redondo ^[3] ; Laura Vidal ^[11] ; Nuria Lainez ^[12] ; Eva Guerra ^[4] ; Victor Rodriguez ^[13] ; Juan Cueva ^[14] ; Isabel Bover ^[15] ; Isabel Palacio ^[16] ; Maria Jesus Rubio ^[5] ; Mario Prieto ^[17] ; Jose Antonio Lopez-Guerrero ^[6] ; Juan Francisco Rodriguez-Moreno ^[9] ; Zaida Garcia-Casado ^[6] ; Elena Garcia-Martinez ^[7] ; Alvaro Taus ^[10] ; Ignacio Pérez de Castro ^[8] ; Paloma Navarro ^[17] ; Enrique Grande ^[18] ; Grupo Español de Investigación en Tumores Huérfanos Infrecuentes GETHI
  1. [1] Fundación Hospital Alcorcón

     Fundación Hospital Alcorcón

     Alcorcón, España

     
  2. [2] Hospital Universitario La Fe

     Hospital Universitario La Fe

     Valencia, España

     
  3. [3] Hospital Universitario La Paz

     Hospital Universitario La Paz

     Madrid, España

     
  4. [4] Hospital Ramón y Cajal

     Hospital Ramón y Cajal

     Madrid, España

     
  5. [5] Hospital Universitario Reina Sofia

     Hospital Universitario Reina Sofia

     Cordoba, España

     
  6. [6] Instituto Valenciano de Oncologia

     Instituto Valenciano de Oncologia

     Valencia, España

     
  7. [7] Hospital Morales Meseguer

     Hospital Morales Meseguer

     Murcia, España

     
  8. [8] Instituto de Salud Carlos III

     Instituto de Salud Carlos III

     Madrid, España

     
  9. [9] HM Hospitales—Centro Integral Oncológico HM Clara Campal, Oña Street 10, 28050, Madrid, España
  10. [10] Hospital Universitario del Mar, Barcelona, España
  11. [11] Hospital Universitario Clinico de Barcelona, Barcelona, España
  12. [12] Hospital de Navarra, Pamplona, España
  13. [13] Hospital Universitario Valle Ebron, Barcelona, España
  14. [14] Complexo Hospital Universitario de Santiago de Compostela, Santiago de Compostela, España
  15. [15] Hospital Universitario Son Llatzer, Mallorca, España
  16. [16] Hospital Central de Asturias, Oviedo, España
  17. [17] HM Hospitales—Centro Integral Oncológico HM Clara Campal, Calle Oña 10, 28050, Madrid, España
  18. [18] Anderson Cancer Center, Madrid, España

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• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 25, Nº. 7 (July), 2023, págs. 2090-2098
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • Background Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole.

    Methods We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings.

    Results From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors” (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43–22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99–36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies.

    Conclusion Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857).

    ClinicalTrials.gov Identifier NCT01584297.