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

BackgroundAcute 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/DesignDECIDER 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 registrationClinicalTrials.gov identifier: NCT00867672 (registration date 23.03.2009); German clinical trials registry number: DRKS00000733 (registration date 19.04.2011).

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

“…In a phase I case study, a patient who suffered from relapsed stage 4 NB received AZA treatment combined with dendritic cell vaccine, which resulted in complete remission (34). In addition, clinical studies combining AZA with RA for treating Acute Myeloid Leukemia are underway (35,36). However, despite the well-known demethylating effects of AZA and the clinical efficacy, no single definitive mechanism through which AZA confers its antitumorigenic effects has been proven.…”

Efficacy and safety of decitabine in treatment of elderly patients with acute myeloid leukemia: A systematic review and meta-analysis

“…The incidence of AML increases progressively with age, and advanced age is an adverse prognostic factor in AML patients [2, 3]. Poor prognosis of elderly AML patients is due to several different factors, including comorbid conditions, decreased organ function, poor performance status and a higher incidence of adverse karyotypes [4, 5].…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…Given the clinical efficacy of approved HDAC inhibitors in AML, the sparsity of prospective studies of VPA in AML is surprising. The result of a prospective study investigating the combination of VPA with decitabine in AML is awaited with interest …”

“…The result of a prospective study investigating the combination of VPA with decitabine in AML is awaited with interest. 135 As discussed above regarding metformin and its analogue, phenformin, AN446 is a prodrug of VPA which is >60-fold more potent than VPA in killing cancer cells in vitro. Tarasenko et al 136 was the only HDAC inhibitor tested that exhibited selective HDAC inhibitory activity that was high in cancer cells and low in noncancerous cells.…”