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

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ClinicalTrials.gov Identifier: NCT02172872
Recruitment Status : Recruiting
First Posted : June 24, 2014
Last Update Posted : August 8, 2019
Sponsor:
Collaborators:
Janssen Pharmaceuticals
Gruppo Italiano Malattie EMatologiche dell'Adulto
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Tracking Information
First Submitted Date  ICMJE June 19, 2014
First Posted Date  ICMJE June 24, 2014
Last Update Posted Date August 8, 2019
Study Start Date  ICMJE November 2014
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 23, 2014)
Overall survival (OS) [ Time Frame: 4.9 years from first patient in ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02172872 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2014)
  • Occurrence of adverse events (AEs) [ Time Frame: 4.9 years from first patient in ]
    The events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
  • 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 ]
  • Transplantation feasibility [ Time Frame: 4.9 years from first patient in ]
    Percentage of patients transplanted
  • Outcome post-transplantation [ Time Frame: 4.9 years from first patient in ]
    PFS, incidence of relapse or progression, and incidence of non-relapse or progression related mortality
  • Health economics impact of each treatment arm [ Time Frame: 4.9 years from first patient in ]
    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
  • Health Related Quality of Life (HRQoL) questionnaires [ Time Frame: 4.9 years from first patient in ]
    EORTC Quality of Life Questionnaire (QLQ-C30) Elderly module (ELD14)
  • Prognostic value of baseline physical and functional conditions on treatment outcome using geriatric assessment tools [ Time Frame: 4.9 years from first patient in ]
    Short physical performance battery (SPPB) and activities of daily living (ADL)
  • complete response (CR/CRi) rate [ Time Frame: 4.9 years from first patient in ]
    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)
  • Overall CR/CRi rate [ Time Frame: 4.9 years from first patient in ]
    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)
  • Disease-free survival (DFS) from CR or CRi [ Time Frame: 4.9 years from first patient in ]
    The time between the date of CR or CRi and the date of first relapse or death (whatever the cause), whichever occurs first
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE "InDACtion" vs "3+7" Induction in AML
Official Title  ICMJE 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
Brief Summary

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia (AML)
Intervention  ICMJE
  • Drug: standard combination chemotherapy
    1. Cycle 1

      1. daunorubicin (60 mg/m²) infusion (15-30 min) for 3 days
      2. cytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days.
    2. Cycle 2

      1. daunorubicin (45 mg/m²) infusion (15-30 min) for 3 days
      2. cytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days.
    3. Cycle 3 (mini-ICE)

      1. idarubicin (8 mg/m²) infusion (15-30 min) for 3 days
      2. cytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 days
      3. etoposide (100 mg/m²) infusion (1 hr) for 3 days
    4. Cycle 4 (mini-ICE) (optional)

      1. idarubicin (8 mg/m²) infusion (15-30 min) for 3 days
      2. cytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 days
      3. etoposide (100 mg/m²) infusion (1 hr) for 3 days
    Other Names:
    • "3+7" induction chemotherapy
    • Intensive combined chemotherapy
  • Drug: decitabine
    1. Cycle 1: decitabine (20 mg/m²) infusion (1 hr) for 10 days
    2. Cycle 2

      1. if bone marrow (BM) blasts < 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 days
      2. if BM blasts >= 5%: decitabine (20 mg/m²) infusion (1 hr) for 10 days
    3. Cycle 3

      1. if BM blasts < 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 days
      2. if BM blasts >= 5%: decitabine (20 mg/m²) infusion (1 hr) for 10 days
    4. Cycle 4-6: decitabine (20 mg/m²) infusion (1 hr) for 5 days
    5. Continuation therapy from Cycle 7 and until 'progression or toxicity': decitabine (20 mg/m²) infusion (1 hr) for 5 days or 3 days

    Note: All patients considered eligible for transplant should be consolidated with alloHCT once donor is available.

    Other Name: Dacogen
Study Arms  ICMJE
  • Active Comparator: standard combination chemotherapy
    Intervention: Drug: standard combination chemotherapy
  • Experimental: decitabine
    Intervention: Drug: decitabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 23, 2014)
600
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: EORTC HQ +32 2 774 16 11 1301@eortc.org
Listed Location Countries  ICMJE Belgium,   Bulgaria,   Croatia,   France,   Germany,   Italy,   Lithuania,   Netherlands,   Portugal
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02172872
Other Study ID Numbers  ICMJE EORTC-1301
2014-001486-27 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party European Organisation for Research and Treatment of Cancer - EORTC
Study Sponsor  ICMJE European Organisation for Research and Treatment of Cancer - EORTC
Collaborators  ICMJE
  • Janssen Pharmaceuticals
  • Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators  ICMJE
Study Chair: Michael Luebbert, MD, PhD Universitaetsklinikum Freiburg, Freiburg, Germany
Principal Investigator: Gerwin G Huls, MD, PhD UMCG, Groningen, The Netherlands
Principal Investigator: Pierre W Wijermans, MD HagaZiekenhuis, the Hague, The Netherlands
PRS Account European Organisation for Research and Treatment of Cancer - EORTC
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP