title: DECIDER: prospective randomized multicenter phase II trial of low-dose decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients >60 years with acute myeloid leukemia who are ineligible for induction chemotherapy.
abstract: BACKGROUND
  Acute myeloid leukemia (AML) is predominantly a disease of older patients with a poor long-term survival. Approval of decitabine (DAC) in the European Union (EU) in 2012 for the treatment of patients with AML ≥65 years marks the potential for hypomethylating agents in elderly AML. Nevertheless the situation is dissatisfactory and the quest for novel treatment approaches, including combination epigenetic therapy is actively ongoing. The given randomized trial should be helpful in investigating the question whether combinations of DAC with the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and/or all-trans retinoic acid (ATRA), which in vitro show a very promising synergism, are superior to the DAC monotherapy. The accompanying translational research project will contribute to find surrogate molecular end points for drug efficacy and better tailor epigenetic therapy. An additional aim of the study is to investigate the prognostic value of geriatric assessments for elderly AML patients treated non-intensively.
  
  
  METHODS
  DECIDER is a prospective, randomized, observer blind, parallel group, multicenter, Phase II study with a 2x2 factorial design. The primary endpoint is objective best overall response (complete remission (CR) and partial remission (PR)). The target population is AML patients aged 60 years or older and unfit for standard induction chemotherapy. Patients are randomized to one of the four treatment groups: DAC alone or in combination with VPA or ATRA or with both add-on drugs. One interim safety analysis was planned and carried out with the objective to stop early one or more of the treatment arms in case of an unacceptable death rate. This analysis showed that in all treatment arms the critical stopping rule was not reached. No important safety issues were observed. The Data Monitoring Committee (DMC) recommended continuing the study as planned. The first patient was included in December 2011. A total of 189 out of 200 planned patients were randomized since then (status 31.12.2014).
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00867672 (registration date 23.03.2009); German clinical trials registry number: DRKS00000733 (registration date 19.04.2011).
authors.affiliation: Clinical Trials Unit, Medical Center - University of Freiburg, Elsaesser Str. 2, 79110, Freiburg, Germany. olga.grishina@uniklinik-freiburg.de.
authors.forename: Olga
authors.initials: O
authors.lastname: Grishina
authors.affiliation: Clinical Trials Unit, Medical Center - University of Freiburg, Elsaesser Str. 2, 79110, Freiburg, Germany. claudia.schmoor@uniklinik-freiburg.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmoor
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert_Einstein-Allee 23, 89081, Ulm, Germany. konstanze.doehner@uniklinik-ulm.de.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Medicine, Division Hematology/Oncology/Stem-Cell Transplantation, Medical Center - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. bjoern.hackanson@uniklinik-freiburg.de.
authors.forename: Björn
authors.initials: B
authors.lastname: Hackanson
authors.affiliation: Pharmacy, Medical Center - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. beate.lubrich@uniklinik-freiburg.de.
authors.forename: Beate
authors.initials: B
authors.lastname: Lubrich
authors.affiliation: Department of Pathology, Institute of Clinical Pathology, Medical Center - University of Freiburg, Ludwig-Aschoff-Haus, Breisacher Str. 115a, 79106, Freiburg, Germany. annette.may@uniklinik-freiburg.de.
authors.forename: Annette M
authors.initials: AM
authors.lastname: May
authors.affiliation: Clinical Trials Unit, Medical Center - University of Freiburg, Elsaesser Str. 2, 79110, Freiburg, Germany. caroline.cieslik@uniklinik-freiburg.de.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cieslik
authors.affiliation: Department of Medicine, Division Hematology/Oncology/Stem-Cell Transplantation, Medical Center - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. michael.mueller@uniklinik-freiburg.de.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Müller
authors.affiliation: Department of Medicine, Division Hematology/Oncology/Stem-Cell Transplantation, Medical Center - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. michael.luebbert@uniklinik-freiburg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D002985:Clinical Protocols; D000077209:Decitabine; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D014212:Tretinoin / Q000008:administration & dosage; D014635:Valproic Acid / Q000008:administration & dosage
chemical_list: D014212:Tretinoin; D014635:Valproic Acid; D000077209:Decitabine; D001374:Azacitidine