A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma
| Autor: | Thierry Jahan, T. Troung, Charles J. Ryan, Jennifer A. Grabowsky, Jeenah Park, Jimmy Hwang, Sharon Chen, Paromita Raha, Pamela N. Munster, Rahul Aggarwal, Scott Thomas, K. T. Thurn, Adil Daud, Amy Cripps |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Male sarcoma Indoles DNA Repair Pharmacology Hydroxamic Acids chemistry.chemical_compound 0302 clinical medicine Panobinostat Topoisomerase II Inhibitors 6.2 Cellular and gene therapies Cancer topoisomerase biology Sarcoma Hematology Middle Aged Chromatin 6.1 Pharmaceuticals 030220 oncology & carcinogenesis Combination Absolute neutrophil count HIV/AIDS Drug Therapy Combination Female Drug Epirubicin medicine.drug Adult panobinostat medicine.medical_specialty Maximum Tolerated Dose Clinical Trials and Supportive Activities Oncology and Carcinogenesis Dose-Response Relationship 03 medical and health sciences Rare Diseases Drug Therapy Clinical Research Internal medicine Genetics medicine Humans Oncology & Carcinogenesis Aged Dose-Response Relationship Drug business.industry Topoisomerase Evaluation of treatments and therapeutic interventions Original Articles medicine.disease Clinical trial Histone Deacetylase Inhibitors 030104 developmental biology chemistry histone deacetylase biology.protein Histone deacetylase business Febrile neutropenia |
| Zdroj: | Annals of oncology : official journal of the European Society for Medical Oncology, vol 27, iss 5 |
| Popis: | Background Treatment options for sarcoma are limited. Histone deacetylase inhibitors increase the efficacy of topoisomerase II inhibitors by promoting access to chromatin and by 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 of epirubicin on day 5 in 21-day cycles, with a dose expansion at maximum tolerated dose (MTD) in 20 sarcoma patients. Peripheral blood mononucleocyte histone acetylation was also evaluated. Results Forty patients received 20–60 mg panobinostat. Dose-limiting toxicities included thrombocytopenia, febrile neutropenia, and fatigue at 60 mg, defining a panobinostat MTD at 50 mg. Four responses were seen in 37 assessable patients, all after progression on prior topoisomerase II inhibitors. For those with sarcoma, 12 of 20 derived clinical benefit (1 partial response and 11 stable disease, median overall survival 8.3 months), including 8 of 14 previously progressed on topoisomerase II therapy. Treatment benefits correlated with increased histone acetylation and decreased neutrophil count on day 5. Conclusions 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. Clinical trial This trial is registered at www.Clinicaltrials.gov , Identifier: NCT00878904. |
| Databáze: | OpenAIRE |
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