A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma
Mené sur 40 patients atteints d'une tumeur solide de stade avancé (dont 20 patients atteints d'un sarcome réfractaire), cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale d'un traitement combinant panobinostat et épirubicine
Background : Treatment options for sarcoma are limited. Histone deacetylase inhibitors increase the efficacy of topoisomerase II inhibitors by promoting access to chromatin and down-regulating DNA repair. Thus, combined panobinostat and epirubicin therapy was evaluated to treat refractory sarcoma. Patients and methods : Patients with advanced solid tumors were enrolled in a 3+3 dose escalation phase I trial of panobinostat given on days 1, 3, and 5 followed by 75 mg/m2 epirubicin on day 5 in 21-day cycles, with a dose expansion at MTD in 20 sarcoma patients. Peripheral blood mononucleocyte histone acetylation was also evaluated. Results : Forty patients received 20 to 60 mg panobinostat. Dose-limiting toxicities included thrombocytopenia, febrile neutropenia and fatigue at 60mg, defining a panobinostat MTD at 50 mg. Four responses were seen in 37 evaluable patients, all after progression on prior topoisomerase II inhibitors. For those with sarcoma, 12/20 benefited (1 PR, 11 SD, median OS 8.3 months), including 8/14 previously progressed on topoisomerase II therapy. Treatment benefits correlated with increased histone acetylation and decreased day 5 neutrophil count. Conclusion : Panobinostat and epirubicin treatment is well tolerated and may reverse anthracycline resistance. Changes in histone acetylation and associated decrease in neutrophil count correlated with clinical benefit and warrant investigation as predictive biomarkers.