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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.

Grishina O, Schmoor C, Döhner K, Hackanson B, Lubrich B, May AM, Cieslik C, Müller MJ, Lübbert M - BMC Cancer (2015)

Bottom Line: 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.No important safety issues were observed.The first patient was included in December 2011.

View Article: PubMed Central - PubMed

Affiliation: Clinical Trials Unit, Medical Center - University of Freiburg, Elsaesser Str. 2, 79110, Freiburg, Germany. olga.grishina@uniklinik-freiburg.de.

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/design: 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).

Trial registration: ClinicalTrials.gov identifier: NCT00867672 (registration date 23.03.2009); German clinical trials registry number: DRKS00000733 (registration date 19.04.2011).

No MeSH data available.


Related in: MedlinePlus

Trial flow. *If WBC ≥ 30.000/μl: Hydroxyurea (HU) or Ara-C until WBC < 30.000/μl. CR = complete remission; PR = partial remission; ALE = antileukemic effect; SD = stable disease
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Fig1: Trial flow. *If WBC ≥ 30.000/μl: Hydroxyurea (HU) or Ara-C until WBC < 30.000/μl. CR = complete remission; PR = partial remission; ALE = antileukemic effect; SD = stable disease

Mentions: Study treatment in the four study arms Fig. 1 is as follows: (DAC) intravenous decitabine 20 mg/m2 over 1 h, 5 days (total dose 100 mg/m2), repeated every 4 weeks; (DAC + VPA) intravenous decitabine 20 mg/m2 over 1 h, 5 days (total dose 100 mg/m2), repeated every 4 weeks, and VPA (p.o.) from day 6 of first cycle continuously throughout all treatment cycles in a dose to achieve a VPA serum level between 50 to 110 mg/l; (DAC + ATRA) intravenous decitabine 20 mg/m2 over 1 h, 5 days (total dose 100 mg/m2), repeated every 4 weeks and ATRA (45 mg/m2 p.o.) from day 6 to day 28 of each treatment cycle; (DAC + VPA + ATRA) intravenous decitabine 20 mg/m2 over 1 h, 5 days (total dose 100 mg/m2), repeated every 4 weeks and VPA (p.o.) from day 6 continuously throughout all treatment cycles in a dose to achieve a VPA serum level between 50 to 110 mg/l and ATRA (45 mg/m2 p.o.) from day 6 to day 28 of each treatment cycle. Treatment cycles are repeated until relapse/progression, hematopoietic stem-cell transplantation, ongoing cytopenia, other unacceptable toxicity or patient’s death. Response assessment is performed at the end of the cycles 2, 4 and 6, and thereafter every third cycle. Study visits are carried out at least once a month during the treatment and every three months after treatment discontinuation until 12 months after randomization of the last patient.Fig. 1


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.

Grishina O, Schmoor C, Döhner K, Hackanson B, Lubrich B, May AM, Cieslik C, Müller MJ, Lübbert M - BMC Cancer (2015)

Trial flow. *If WBC ≥ 30.000/μl: Hydroxyurea (HU) or Ara-C until WBC < 30.000/μl. CR = complete remission; PR = partial remission; ALE = antileukemic effect; SD = stable disease
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4443550&req=5

Fig1: Trial flow. *If WBC ≥ 30.000/μl: Hydroxyurea (HU) or Ara-C until WBC < 30.000/μl. CR = complete remission; PR = partial remission; ALE = antileukemic effect; SD = stable disease
Mentions: Study treatment in the four study arms Fig. 1 is as follows: (DAC) intravenous decitabine 20 mg/m2 over 1 h, 5 days (total dose 100 mg/m2), repeated every 4 weeks; (DAC + VPA) intravenous decitabine 20 mg/m2 over 1 h, 5 days (total dose 100 mg/m2), repeated every 4 weeks, and VPA (p.o.) from day 6 of first cycle continuously throughout all treatment cycles in a dose to achieve a VPA serum level between 50 to 110 mg/l; (DAC + ATRA) intravenous decitabine 20 mg/m2 over 1 h, 5 days (total dose 100 mg/m2), repeated every 4 weeks and ATRA (45 mg/m2 p.o.) from day 6 to day 28 of each treatment cycle; (DAC + VPA + ATRA) intravenous decitabine 20 mg/m2 over 1 h, 5 days (total dose 100 mg/m2), repeated every 4 weeks and VPA (p.o.) from day 6 continuously throughout all treatment cycles in a dose to achieve a VPA serum level between 50 to 110 mg/l and ATRA (45 mg/m2 p.o.) from day 6 to day 28 of each treatment cycle. Treatment cycles are repeated until relapse/progression, hematopoietic stem-cell transplantation, ongoing cytopenia, other unacceptable toxicity or patient’s death. Response assessment is performed at the end of the cycles 2, 4 and 6, and thereafter every third cycle. Study visits are carried out at least once a month during the treatment and every three months after treatment discontinuation until 12 months after randomization of the last patient.Fig. 1

Bottom Line: 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.No important safety issues were observed.The first patient was included in December 2011.

View Article: PubMed Central - PubMed

Affiliation: Clinical Trials Unit, Medical Center - University of Freiburg, Elsaesser Str. 2, 79110, Freiburg, Germany. olga.grishina@uniklinik-freiburg.de.

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/design: 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).

Trial registration: ClinicalTrials.gov identifier: NCT00867672 (registration date 23.03.2009); German clinical trials registry number: DRKS00000733 (registration date 19.04.2011).

No MeSH data available.


Related in: MedlinePlus