title: A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma.
abstract: 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 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/m(2) 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  This trial is registered at www.Clinicaltrials.gov, Identifier: NCT00878904.
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: S
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: R
authors.initials: R
authors.lastname: Aggarwal
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: T
authors.initials: T
authors.lastname: Jahan
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ryan
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: T
authors.initials: T
authors.lastname: Troung
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Cripps
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: P
authors.initials: P
authors.lastname: Raha
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Thurn
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Grabowsky
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.
authors.forename: A
authors.initials: A
authors.lastname: Daud
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA pamela.munster@ucsf.edu.
authors.forename: P N
authors.initials: PN
authors.lastname: Munster
mesh_terms: D000328:Adult; D000368:Aged; D002843:Chromatin / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015251:Epirubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000077767:Panobinostat; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D059005:Topoisomerase II Inhibitors; D015251:Epirubicin; D000077767:Panobinostat
keywords: epirubicin; histone deacetylase; panobinostat; sarcoma; topoisomerase