A Randomized Placebo-controlled Phase 2 Study of Decitabine With or Without Eltrombopag in AML Patients

Acute myeloid leukemia (AML) is a disease with a poor prognosis including a 5-year overall survival (OS) of app. 20% for the entire population. In particular, the outcome of elderly patients with AML is dismal and the majority of patients die within the first year after diagnosis. This is also because treatment options for elderly patients with AML significantly differ from patients of younger age. In fact, comorbid conditions are common among the elderly such as heart disease, renal insufficiency and vascular disease thus influencing the ability to withstand intensive therapy. Elderly patients are also more likely than younger patients to develop severe, life threatening infections during the course of treatment. In addition to infectious complications, hemorrhages due to severe thrombocytopenia are responsible for morbidity and mortality in a considerable amount of patients. Compared with younger AML patients, elderly individuals with AML display a higher incidence of poor-prognosis karyotypes, of a preceding myelodysplastic syndrome (MDS), and greater expression of proteins involved in intrinsic resistance to chemotherapeutic agents. As a result conventional anthracycline based chemotherapy is only infrequently used in patients above the age of 65 years. Based on a recent randomized trial (Kantarjian et al. 2012) low-intensity epigenetic therapy with decitabine (DAC) has become the first-line standard of care in most European countries including Germany. Nevertheless, even with this treatment the 1-year OS is approximately 30 % only. Furthermore, severe thrombocytopenia is a main side effect of this therapy and can prevent adequate continuation of treatment being crucially for treatment success. Supportive care with platelet transfusions is effective primarily only over short periods and often requires hospitalization and therefore lowers the quality of life of these patients in their palliative situation. Therefore, patients could benefit from an approach aiming at an increase of platelet counts through combined use of Azacitidine (AZA) or DAC with an oral thrombopoietin receptor agonist like eltrombopag (EPAG). This could allow for a better adherence to DAC/AZA therapy by preventing dose delays due to prolonged thrombocytopenia. Additionally, the potential antileukemic effect of EPAG could also be beneficial for these AML patients.

The DELTA-trial is designed as a two-arm, double-blind, multicenter randomized-controlled phase- II study of EPAG or placebo in combination with standard-dose DAC/AZA treatment as concomitant medication in subjects at least 65 years of age with AML not eligible for intensive chemotherapy and planned therapy with Decitabine (DAC)/Azacitidine(AZA). Patients will be randomized 1:1 into the experimental study arm and the control study arm. EPAG 200 mg (100 mg for East Asian patients) once daily has been selected as the starting dose for this study because this regimen has been investigated to be safe and potentially effective in increasing platelet counts in patients with AML. Concomitant medication with DAC/AZA will be according to the european label and the summary of product characteristics. There will be a dose adjustment of EPAG depending on the platelet counts obtained on day 1 of a planned DAC/AZA cycle. EPAG or placebo will be taken for 14 days in each treatment cycle starting on day 12 with a minimum treatment gab of 2 days before and after each DAC/AZA course.

Concomitant medication will be either Decitabine (DAC) 20 mg/m2 body surface i.v. over 30 minutes on days 1-5 of each cycle or Azacitidine (AZA) 75 mg/m2 body surface sc. on days 1-7. One cycle lasts 28 days.

Patients will receive medication as long as they benefit from treatment and in the absence of relevant adverse events indicating a treatment discontinuation; but for a maximum of 12 cycles. During Follow Up (up to 4 years) patient survival and first treatment change will be observed.

Eligibility Criteria:
Inclusion Criteria:

* Newly diagnosed AML (including therapy-related or with antecedent MDS) other than acute promyelocytic leukemia (APL) according to WHO criteria, i.e. bone marrow aspirate / biopsy or peripheral blood must contain ≥20% blasts in AML defined by cytogenetic aberrations according to WHO the proportion of blasts may be \<20%
* Age ≥ 65 years
* Eastern Cooperative Oncology Group performance status (ECOG) 0-3
* patients not eligible for intensive induction therapy (according to investigator's decision)
* planned therapy with DAC/AZA
* platelet count \<75 Gpt/L taken within 4 weeks prior to randomization
* adequate liver function as assessed by the following laboratory requirements during screening (within 4 weeks prior to study inclusion):

  * Total bilirubin ≤ 3 times the upper limit of normal (except for Gilbert's Syndrome)
  * Alanine transaminase (ALAT) and Aspartate transaminase (ASAT) ≤ 3 times upper limit of normal
* signed Informed Consent

Exclusion Criteria:

* acute promyelocytic leukemia (APL)
* history of higher-risk MDS or AML treatment with thrombopoietin receptor (TPO-R) agonists, hypomethylating agents or intensive chemotherapy
* substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
* treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding to first dose of study mediation
* uncontrolled active infection
* New York Heart Association (NYHA) stage ≥ 2 due to heart insufficiency
* positive Human Immunodeficiency Virus (HIV) or Hepatitis B / C serology
* patients unable to swallow medication
* known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to EPAG or DAC or excipients that contraindicates their participation