Clinical Trials /

"InDACtion" vs "3+7" Induction in AML

NCT02172872

Description:

Older patients with acute myeloid leukemia (AML) have a small (< 10%) chance of long-term survival. Despite the treatment of elderly AML patients with intensive chemotherapy, the survival has not been improved during the last decades. The purpose of this study is to determine whether frontline therapy with a 10-day decitabine schedule provides a better survival than standard intensive combination chemotherapy in elderly AML patients (>= 60 years).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: "InDACtion" vs "3+7" Induction in AML
  • Official Title: 10-day Decitabine Versus Conventional Chemotherapy ("3+7") Followed by Allografting in AML Patients ≥ 60 Years: a Randomized Phase III Study of the EORTC Leukemia Group, CELG, GIMEMA and German MDS Study Group

Clinical Trial IDs

  • ORG STUDY ID: EORTC-1301
  • SECONDARY ID: 2014-001486-27
  • NCT ID: NCT02172872

Conditions

  • Acute Myeloid Leukemia (AML)

Interventions

DrugSynonymsArms
standard combination chemotherapy"3+7" induction chemotherapy, Intensive combined chemotherapystandard combination chemotherapy
decitabineDacogendecitabine

Purpose

Older patients with acute myeloid leukemia (AML) have a small (< 10%) chance of long-term survival. Despite the treatment of elderly AML patients with intensive chemotherapy, the survival has not been improved during the last decades. The purpose of this study is to determine whether frontline therapy with a 10-day decitabine schedule provides a better survival than standard intensive combination chemotherapy in elderly AML patients (>= 60 years).

Detailed Description

      -  The overall survival (OS) of older AML patients has not been improved during the last
           decades with intensive chemotherapy based on cytarabine combined with an anthracycline
           ("3+7").

        -  Next generation sequencing technology reveals that mutations in genes involved in
           epigenetics are frequently mutated in AML (e.g. DNMT3a), suggesting an important role of
           epigenetics in the pathophysiology of AML. Decitabine (given in a 5-day schedule) has
           been shown to be superior to low-dose Ara-C.

        -  A retrospective analysis revealed that epigenetic therapy (either azacitidine or
           decitabine) is associated with similar survival rates as intensive chemotherapy in older
           patients (n=671) with newly diagnosed AML.

        -  The recently published encouraging phase 2 data with the 10-day decitabine schedule
           suggests that decitabine results in similar CR rates compared with intensive
           chemotherapy. Allogeneic transplantation (alloHCT) also offers the opportunity for cure
           among older AML patients, therefore treatment strategies should aim to allograft older
           AML patients.

        -  Decitabine treatment can lead to very interesting cure rates when used as "bridging" to
           allografting.

      Based on the data summarized above, we hypothesize that decitabine at a daily dose of 20
      mg/m² starting with the 10-day schedule followed by an alloHCT or by continuation of 5-days
      decitabine cycles is superior to conventional intensive chemotherapy in older AML patients.
    

Trial Arms

NameTypeDescriptionInterventions
standard combination chemotherapyActive Comparator
  • standard combination chemotherapy
decitabineExperimental
  • decitabine

Eligibility Criteria

        Inclusion criteria:

          1. Age ≥ 60 years

          2. WHO Performance status ≤ 2

          3. Eligible for standard intensive chemotherapy

          4. Newly diagnosed AML cytopathologically confirmed to the WHO classification (up to 2
             months prior to randomization)

          5. De novo or secondary AML is allowed

          6. White blood cell (WBC) count is ≤ 30x10E9/L (measured within 72 hours prior to
             randomization).

          7. Laboratory assessments (measured prior to randomization):

               1. serum glutamate oxaloacetate transaminase (SGOT / ASAT) and serum glutamate
                  pyruvate transaminase (SGPT / ALAT) < 2.5 x the upper limit of normal range
                  unless considered AML-related

               2. Total serum bilirubin < 2.5 x the upper limit of normal range unless considered
                  AML-related or due to Gilbert's syndrome

               3. Serum creatinine < 2.5 x the upper limit of normal range unless considered
                  AML-related

          8. Patients of reproductive potential should use adequate birth control measures, as
             defined by investigator, during the study treatment period and for at least 3 months
             after the last study treatment.

          9. Before patient registration/randomization, written informed consent must be given
             according to the International Conference of Harmonization good clinical practice (ICH
             GCP) and national/local regulations

        Exclusion criteria:

          1. Presence of acute promyelocytic leukemia (APL, i.e. AML-M3 with t(15;17)(q22;q12);
             promyelocytic leukemia - retinoic acid receptor-alpha (PML-RARA) fusion gene and
             cytogenetic variants)

          2. Presence of blast crisis of chronic myeloid leukemia

          3. Presence of active central nervous system (CNS) leukemia

          4. Patients did not receive any prior treatment for AML (relapsed AML is not allowed),
             such as any antileukemic therapy including investigational agents and hypomethylating
             agents (decitabine, 5-azacytidine). Treatment with hydroxyurea (HU) is allowed to
             control the leukocytosis if given preferably for less than 5 days and is stopped at
             least two days prior to the start of any of the protocol regimens

          5. Patients received any prior treatment for myelodysplastic syndrome (MDS) or
             myeloproliferative neoplasms (MPN) with:

               1. hypomethylating agents (decitabine, 5-azacytidine), OR

               2. with intensive chemotherapy or transplantation within the last three years

               3. NOTE: The following treatments for previous MDS or MPN are allowed (up to one
                  month before inclusion):

                    -  Growth factors, thrombomimetics, immunosuppression (cyclosporin A, steroids,
                       antithymocyte globulin etc.), chelation, interferons, anagrelide

                    -  Lenalidomide, low-dose chemotherapy (low-dose melphalan, HU, low-dose
                       cytarabine etc.), tyrosine-kinase inhibitors, histone deacetylase inhibitors
                       (e.g. valproic acid, panobinostat etc.), mammalian target of rapamycin
                       (mTOR) inhibitors, other experimental treatment that is not based on
                       inhibition of deoxyribonucleic acid (DNA) methyltransferase

          6. Presence of concomitant severe cardiovascular disease which would make intensive
             chemotherapy impossible, i.e. uncontrolled arrhythmias requiring chronic treatment,
             congestive heart failure or symptomatic ischemic heart disease, reduced left
             ventricular function assessed by multigated acquisition (MUGA) scan or echocardiogram

          7. Presence of any malignancy (except basal and squamous cell carcinoma of the skin) for
             which the patient received systemic anticancer treatment within 6 months prior to
             randomization NOTE: Diagnosis of any previous or concomitant malignancy is thus not an
             exclusion criterion.

          8. Presence of active uncontrolled infection

          9. Presence of any psychological, familial, sociological or geographical condition in the
             opinion of the investigator potentially hampering compliance with the study protocol
             and follow-up schedule; those conditions should be discussed with the patient before
             registration in the trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:4.9 years from first patient in
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Occurrence of adverse events (AEs)
Time Frame:4.9 years from first patient in
Safety Issue:
Description:The events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Measure:Progression-free survival (PFS) from randomization to the date of either first progression, first relapse or death, whichever occurs first
Time Frame:4.9 years from first patient in
Safety Issue:
Description:
Measure:Transplantation feasibility
Time Frame:4.9 years from first patient in
Safety Issue:
Description:Percentage of patients transplanted
Measure:Outcome post-transplantation
Time Frame:4.9 years from first patient in
Safety Issue:
Description:PFS, incidence of relapse or progression, and incidence of non-relapse or progression related mortality
Measure:Health economics impact of each treatment arm
Time Frame:4.9 years from first patient in
Safety Issue:
Description:At the end of each cycle, duration of hospitalization and number of visits (planned or related to event), number of transfusions, growth factor support and intravenous anti-infective are collected
Measure:Health Related Quality of Life (HRQoL) questionnaires
Time Frame:4.9 years from first patient in
Safety Issue:
Description:EORTC Quality of Life Questionnaire (QLQ-C30) Elderly module (ELD14)
Measure:Prognostic value of baseline physical and functional conditions on treatment outcome using geriatric assessment tools
Time Frame:4.9 years from first patient in
Safety Issue:
Description:Short physical performance battery (SPPB) and activities of daily living (ADL)
Measure:complete response (CR/CRi) rate
Time Frame:4.9 years from first patient in
Safety Issue:
Description:All patients who reached complete response (CR) or complete response with incomplete marrow recovery (CRi) after the administration of protocol treatment ("3+7" or decitabine)
Measure:Overall CR/CRi rate
Time Frame:4.9 years from first patient in
Safety Issue:
Description:All patients who reached CR or CRi, after administration of the protocol treatment ("3+7" or decitabine) or following another salvage/new treatment for AML (other than transplant)
Measure:Disease-free survival (DFS) from CR or CRi
Time Frame:4.9 years from first patient in
Safety Issue:
Description:The time between the date of CR or CRi and the date of first relapse or death (whatever the cause), whichever occurs first

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:European Organisation for Research and Treatment of Cancer - EORTC

Trial Keywords

  • Newly diagnosed
  • AML
  • Elderly
  • Decitabine
  • Transplant

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