F Child1, P L Ortiz-Romero2, R Alvarez3, M Bagot4, R Stadler5, M Weichenthal6, R Alves7, P Quaglino8, M Beylot-Barry9, R Cowan10, L J Geskin11, A Pérez-Ferriols12, P Hellemans13, Y Elsayed14, C Phelps14, A Forslund15, M Kamida16, P L Zinzani17. 1. St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, U.K. 2. Department of Dermatology, 12 de Octubre Hospital, Institute i+12, Medical School, Complutense University, Madrid, Spain. 3. Portuguese Institute of Oncology, Lisbon, Portugal. 4. Department of Dermatology, Saint-Louis Hospital, Paris 7 University, Paris, France. 5. Department of Dermatology, Johannes Wesling Medical Center, Minden, Germany. 6. Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany. 7. Department of Dermatology, Hospital de Santo António - Centro Hospitalar do Porto, Porto, Portugal. 8. Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy. 9. Department of Dermatology, University Hospital of Bordeaux, Bordeaux, France. 10. Manchester Academic Health Science Centre, Christie Hospital, Manchester, U.K. 11. School of Medicine, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, U.S.A. 12. Department of Dermatology, University General Hospital, Valencia, Spain. 13. Janssen Research & Development, Beerse, Belgium. 14. Janssen Research & Development, Titusville, NJ, U.S.A. 15. Janssen Research & Development, Spring House, PA, U.S.A. 16. Janssen Pharmaceutical K.K., Tokyo, Japan. 17. Institute of Hematology 'Seràgnoli', University of Bologna, Bologna, Italy.
Abstract
BACKGROUND: Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. OBJECTIVES: To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL). METHODS: Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT). Secondary end points included global RR, duration of response (DOR) in skin, progression-free survival (PFS), pruritus relief, safety and pharmacodynamic markers. RESULTS:Eight of 26 (25 evaluable) patients achieved ≥ 50% reduction in mSWAT score at least once, with confirmed cutaneous response in six (RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 months. Median PFS was 5·1 months. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumour biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clinical cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhoea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalaemia and pyrexia. CONCLUSIONS: Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate.
RCT Entities:
BACKGROUND:Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. OBJECTIVES: To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL). METHODS:Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT). Secondary end points included global RR, duration of response (DOR) in skin, progression-free survival (PFS), pruritus relief, safety and pharmacodynamic markers. RESULTS: Eight of 26 (25 evaluable) patients achieved ≥ 50% reduction in mSWAT score at least once, with confirmed cutaneous response in six (RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 months. Median PFS was 5·1 months. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumour biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clinical cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhoea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalaemia and pyrexia. CONCLUSIONS:Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate.
Authors: Yemin Wang; Shary Yuting Chen; Shane Colborne; Galen Lambert; Chae Young Shin; Nancy Dos Santos; Krystal A Orlando; Jessica D Lang; William P D Hendricks; Marcel B Bally; Anthony N Karnezis; Ralf Hass; T Michael Underhill; Gregg B Morin; Jeffrey M Trent; Bernard E Weissman; David G Huntsman Journal: Mol Cancer Ther Date: 2018-09-19 Impact factor: 6.261