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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

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).


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Drug: standard combination chemotherapy Drug: decitabine Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : November 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Active Comparator: standard combination chemotherapy 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

Experimental: decitabine 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




Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: 4.9 years from first patient in ]

Secondary Outcome Measures :
  1. 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

  2. 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 ]
  3. Transplantation feasibility [ Time Frame: 4.9 years from first patient in ]
    Percentage of patients transplanted

  4. 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

  5. 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

  6. 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)

  7. 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)

  8. 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)

  9. 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)

  10. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02172872


Contacts
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Contact: EORTC HQ +32 2 774 16 11 1301@eortc.org

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Locations
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Belgium
UZ Antwerpen Recruiting
Edegem, Antwerpen, Belgium, 2650
Principal Investigator: Zwi Berneman, MD, PhD         
UZ Brussel Recruiting
Jette, Brussels, Belgium, 1090
Principal Investigator: Anne De Becker, MD         
CHR Verviers Recruiting
Verviers, Liège, Belgium, 4800
Principal Investigator: Gaetan Vanstraelen, MD         
A.Z. St. Jan Recruiting
Brugge, West-Vlaanderen, Belgium, 8000
Principal Investigator: Dominik Selleslag, MD         
Institut Jules Bordet Recruiting
Brussels, Belgium, 1000
Principal Investigator: Sebastian Wittnebel, MD         
Hôpitaux Universitaires Bordet-Erasme - Hôpital Universitaire Erasme Withdrawn
Brussels, Belgium, 1070
C.H.U. Sart-Tilman Recruiting
Liège, Belgium, 4000
Principal Investigator: Bernard De Prijck, MD         
CHR De La Citadelle Recruiting
Liège, Belgium, 4000
Principal Investigator: Beata Hodossy, MD         
Bulgaria
National Specialized Hospital for Active Treatment of Haematological Diseases Terminated
Sofia, Bulgaria, 1756
Croatia
Clinical Hospital Merkur Recruiting
Zagreb, Croatia, 10000
Principal Investigator: Simec N. Gredelj, MD         
University Hospital Rebro Recruiting
Zagreb, Croatia, 10000
Principal Investigator: Radovan Vrhovac, MD, PhD         
France
CHU de Caen - Hôpital Côte de Nacre Recruiting
Caen, France, 14033
Contact: Sylvain Chantepie, MD         
Principal Investigator: Sylvain Chantepie, MD         
CHU de Nantes - Hôtel Dieu Recruiting
Nantes, France, 44093
Principal Investigator: Patrice Chevallier, MD         
Assistance Publique - Hôpitaux de Paris - Hôpital Saint Antoine Recruiting
Paris, France, 75571
Principal Investigator: Ollivier Legrand, MD, PhD         
Germany
Universitätsklinikum Aachen AÖR - Medizinische Fakultät der RWTH Recruiting
Aachen, Germany, 52074
Principal Investigator: Martina Crysandt, MD         
Klinikum Augsburg Recruiting
Augsburg, Germany, 86156
Contact: Bjoern Hackanson         
Principal Investigator: Bjoern Hackanson, MD         
HELIOS Kliniken - Helios Klinikum Bad Saarow Recruiting
Bad Saarow, Germany, 15526
Contact: Daniel Schoendube         
Principal Investigator: Daniel Schoendube, MD         
Helios Kliniken - Helios Klinikum Berlin-Buch Recruiting
Berlin, Germany, 13125
Principal Investigator: Stephan Fuhrmann, MD         
Universitätsklinik Düsseldorf Recruiting
Düsseldorf, Germany, 40225
Principal Investigator: Ulrich Germing, MD         
Universitätsklinikum Essen Recruiting
Essen, Germany, 45147
Principal Investigator: Richard Noppeney, MD         
Universitätsklinikum Freiburg Recruiting
Freiburg, Germany, 79106
Principal Investigator: Michael Lübbert, MD, PhD         
Universitaetklinikum Halle - Martin Luther Universitaet - Universitaetsklinikum Halle (Saale) Recruiting
Halle, Germany, 06120
Contact: Haifa K Al-Ali         
Principal Investigator: Haifa K Al-Ali, MD         
Universtitätsklinikum Leipzig Recruiting
Leipzig, Germany, 04103
Principal Investigator: Uwe Platzbecker, MD         
Klinikum Der Phillips - Universität Marburg Recruiting
Marburg, Germany, 35043
Principal Investigator: Andreas Neubauer, MD         
Ortenau Klinikum St. Josefklinik Withdrawn
Offenburg, Germany, 77654
Universitaet Rostock - Medizinische Fakultaet Recruiting
Rostock, Germany, 18055
Contact: Christian Junghanss, MD, PhD         
Principal Investigator: Christian Junghanss, MD, PhD         
Sub-Investigator: Brigitte Kragl, MD         
Italy
Azienda Ospedaliero Universitaria - Ospedali Riuniti Recruiting
Ancona, Italy, 60020
Principal Investigator: Attilio Olivieri, MD         
A.O.R.N. San Giuseppe Moscati Recruiting
Avellino, Italy, 83100
Principal Investigator: Nicole Cantore, MD         
Universita Degli Studi Di Bari - Policlinico Recruiting
Bari, Italy, 70124
Principal Investigator: Giorgina Specchia, MD         
Universita di Bologna Recruiting
Bologna, Italy, 40138
Principal Investigator: Giovanni Martinelli, MD, PhD         
Ospedale Regionale A. Pugliese Recruiting
Catanzaro, Italy, 88100
Principal Investigator: Stefano Molica, MD         
Azienda Ospedaliero-Universitaria Careggi Recruiting
Firenze, Italy, 50134
Contact: Alberto Bosi, MD         
Principal Investigator: Alberto Bosi, MD         
Ospedali Riuniti Foggia Recruiting
Foggia, Italy, 71100
Contact: Silvana F Capalbo         
Principal Investigator: Silvana F Capalbo, MD         
Azienda Ospedaliera Vito Fazzi Recruiting
Lecce, Italy, 73100
Contact: Nicola Di Renzo, MD         
Principal Investigator: Nicola Di Renzo, MD         
Fondazione IRCCS Istituto Nazionale dei Tumori Withdrawn
Milano, Italy, 20133
Azienda Ospedaliero - Universitaria Policlinico di Modena Recruiting
Modena, Italy, 41124
Contact: Mario Luppi, MD, PhD         
Principal Investigator: Mario Luppi, MD, PhD         
Amedeo Avogadro University of Eastern Piedmont-Ospedale Maggiore della Carita Recruiting
Novara, Italy, 28100
Principal Investigator: Gianluca Gaidano, MD         
Policlinico P. Giaccone - Universita Di Palermo Recruiting
Palermo, Italy, 90127
Principal Investigator: Maria Enza Mitra, MD         
La Maddalena S.P.A. Recruiting
Palermo, Italy, 90146
Principal Investigator: Maurizio Musso, MD         
Ospedale Riuniti Villa Sofia-Cervello Recruiting
Palermo, Italy, 90146
Contact: Francesco Fabbiano, MD         
Principal Investigator: Francesco Fabbiano, MD         
Ospedale San Salvatore Recruiting
Pesaro, Italy, 61100
Contact: Giuseppe Visani, MD         
Principal Investigator: Giuseppe Visani, MD         
AUSL Romagna - Ospedale Santa Maria dell Croci Recruiting
Ravenna, Italy, 48121
Principal Investigator: Eliana Zuffa, MD         
Arcispedale Di S. Maria Nuova Recruiting
Reggio nell'Emilia, Italy, 42100
Contact: Annalisa Imovilli, MD         
Principal Investigator: Annalisa Imovilli, MD         
AUSL Romagna - Ospedale Infermi di Rimini Recruiting
Rimini, Italy, 47037
Principal Investigator: Anna Maria Mianulli, MD         
H. San Giovanni - Addolorata Recruiting
Roma, Italy, 00184
Principal Investigator: Anna Chierichini, MD         
Universita Degli Studi Di Roma La Sapienza - Ospedale Sant'Andrea Recruiting
Roma, Italy, 00189
Principal Investigator: Agustino Tafuri, MD, PhD         
Azienda Ospedallera Universitaria - Policlinico Tor Vergata Recruiting
Rome, Italy, 00133
Contact: Adriano Venditti, MD, PhD         
Sub-Investigator: Adriano Venditti, MD, PhD         
Instituto Regina Elena / Instituti Fisioterapici Ospitalieri Recruiting
Rome, Italy, 00144
Contact: Andrea Mengarelli, MD         
Principal Investigator: Andrea Mengarelli, MD         
Sub-Investigator: Antonio Spadea, MD         
Ospedale San Eugenio Recruiting
Rome, Italy, 00144
Contact: Paolo De Fabritiis, MD, PhD         
Principal Investigator: Paolo De Fabritiis, MD, PhD         
Clinica Ematologica dell'Universita di Roma La Sapienza Recruiting
Rome, Italy, 00161
Contact: Roberto Foa, MD, PhD         
Principal Investigator: Roberto Foa, MD, PhD         
Ospedale Casa Sollievo Della Sofferenza Recruiting
San Giovanni Rotondo, Italy, 71013
Principal Investigator: Nicola Cascavilla, MD         
Istituto Di Ematologia - Universita Di Sassari Recruiting
Sassari, Italy, 07100
Principal Investigator: Claudio Fozza, MD         
Azienda Ospedaliera Città della Salute e della Scienza di Torino - Ospedale Molinette Recruiting
Torino, Italy, 10126
Sub-Investigator: Stefano D'Ardia, MD         
Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udine Recruiting
Udine, Italy, 33100
Principal Investigator: Anna Candoni, MD         
Lithuania
Vilnius University Hospital Santariskiu Clinics Recruiting
Vilnius, Lithuania, 08661
Principal Investigator: Laimonas Griskevicius, MD, PhD         
Netherlands
Rijnstate Hospital Recruiting
Arnhem, Netherlands, 6815 AD
Principal Investigator: Marloes Cuijpers, MD         
Reinier De Graaf Gasthuis Recruiting
Delft, Netherlands, 2625 AD
Principal Investigator: E. Posthuma, MD         
Unversity Medical Center Groningen Recruiting
Groningen, Netherlands, 9713 GZ
Principal Investigator: Gerwin Huls, MD         
Medisch Centrum Leeuwarden-Zuid Recruiting
Leeuwarden, Netherlands, 8901 BR
Principal Investigator: Mels Hoogendoorn, MD         
Academisch Ziekenhuis Maastricht Recruiting
Maastricht, Netherlands, 6202 AZ
Principal Investigator: Marjolein van der Poel, MD         
Radboud University Medical Center Nijmegen Recruiting
Nijmegen, Netherlands, 6500 HB
Principal Investigator: Walter Van der Velden, MD         
Canisius-Wilhelmina Ziekenhuis Recruiting
Nijmegen, Netherlands, 6532 SZ
Principal Investigator: Susan de Jonge-Peeters, MD         
HagaZiekenhuis - locatie Leyweg Recruiting
The Hague, Netherlands, 2545 CH
Principal Investigator: Danielle van Lammeren - Venema, MD         
Portugal
Hospital Escolar Soa Joao Recruiting
Porto, Portugal, PT 4200 - 319
Contact: Jose E. Guimaraes         
Principal Investigator: Jose E. Guimaraes, MD, PhD         
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Janssen Pharmaceuticals
Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators
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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

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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT02172872     History of Changes
Other Study ID Numbers: EORTC-1301
2014-001486-27 ( EudraCT Number )
First Posted: June 24, 2014    Key Record Dates
Last Update Posted: August 8, 2019
Last Verified: August 2019
Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
Newly diagnosed
AML
Elderly
Decitabine
Transplant
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors