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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: standard combination chemotherapy; Drug: decitabine

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: Interventional
• Enrollment (Actual): 606
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Liège, Belgium, 4000
    • CHR de la CITADELLE
  • Liège, Belgium, 4000
    • C.H.U. Sart-Tilman
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • UZ Antwerpen
  • Brussels
    • Jette, Brussels, Belgium, 1090
      • UZ Brussel
  • Liège
    • Verviers, Liège, Belgium, 4800
      • CHR Verviers
  • West-Vlaanderen
    • Brugge, West-Vlaanderen, Belgium, 8000
      • A.Z. St. Jan
• Bulgaria
  • Sofia, Bulgaria, 1756
    • National Specialized Hospital for Active Treatment of Haematological Diseases
• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital Rebro
  • Zagreb, Croatia, 10000
    • Clinical Hospital Merkur
• France
  • Caen, France, 14033
    • CHU de Caen - Hopital Cote de Nacre
  • Nantes, France, 44093
    • CHU de Nantes - Hotel Dieu
  • Paris, France, 75571
    • Assistance Publique - Hopitaux de Paris - Hopital Saint Antoine
• Germany
  • Aachen, Germany, 52074
    • Universitätsklinikum Aachen AÖR - Medizinische Fakultät der RWTH
  • Augsburg, Germany, 86156
    • Klinikum Augsburg
  • Berlin, Germany, 13125
    • Helios Kliniken - Helios Klinikum Berlin-Buch
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Freiburg, Germany, 79106
    • Universitatsklinikum Freiburg
  • Halle, Germany, 06120
    • Universitaetklinikum Halle - Martin Luther Universitaet - Universitaetsklinikum Halle (Saale)
  • Marburg, Germany, 35043
    • Klinikum Der Phillips - Universität Marburg
  • Rostock, Germany, 18055
    • Universitaet Rostock - Medizinische Fakultaet
  • Tuebingen, Germany, 72076
    • Universitaetsklinikum Tuebingen-Uni Kliniken Berg
• Italy
  • Ancona, Italy, 60020
    • Azienda Ospedaliero Universitaria - Ospedali Riuniti
  • Bari, Italy, 70124
    • Universita Degli Studi Di Bari - Policlinico
  • Bologna, Italy, 40138
    • Universita di Bologna
  • Catanzaro, Italy, 88100
    • Ospedale Regionale A. Pugliese
  • Foggia, Italy, 71100
    • Ospedali Riuniti Foggia
  • Modena, Italy, 41124
    • Azienda Ospedaliero - Universitaria Policlinico di Modena
  • Novara, Italy, 28100
    • Amedeo Avogadro University of Eastern Piedmont-Ospedale Maggiore della Carita
  • Palermo, Italy, 90146
    • La Maddalena S.P.A.
  • Pesaro, Italy, 61100
    • Ospedale San Salvatore
  • Ravenna, Italy, 48121
    • AUSL Romagna - Ospedale Santa Maria dell Croci
  • Reggio nell'Emilia, Italy, 42100
    • Arcispedale Di S. Maria Nuova
  • Rimini, Italy, 47037
    • AUSL Romagna - Ospedale Infermi di Rimini
  • Roma, Italy, 00184
    • H. San Giovanni - Addolorata
  • Roma, Italy, 00189
    • Universita Degli Studi Di Roma La Sapienza - Ospedale Sant'Andrea
  • Rome, Italy, 00144
    • Ospedale San Eugenio
  • Rome, Italy, 00133
    • Azienda Ospedallera Universitaria - Policlinico Tor Vergata
  • Rome, Italy, 00144
    • Instituto Regina Elena / Instituti Fisioterapici Ospitalieri
  • Rome, Italy, 00161
    • Clinica Ematologica dell'Universita di Roma La Sapienza
  • San Giovanni Rotondo, Italy, 71013
    • Ospedale Casa Sollievo della Sofferenza
  • Torino, Italy, 10126
    • Azienda Ospedaliera Citta della Salute e della Scienza di Torino - Ospedale Molinette
  • Udine, Italy, 33100
    • Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udine
• Lithuania
  • Vilnius, Lithuania, 08661
    • Vilnius University Hospital Santariskiu Clinics
• Netherlands
  • Arnhem, Netherlands, 6815 AD
    • Rijnstate Hospital
  • Delft, Netherlands, 2625 AD
    • Reinier de Graaf Gasthuis
  • Groningen, Netherlands, 9713 GZ
    • Unversity Medical Center Groningen
  • Leeuwarden, Netherlands, 8901 BR
    • Medisch Centrum Leeuwarden-Zuid
  • Maastricht, Netherlands, 6202 AZ
    • Academisch Ziekenhuis Maastricht
  • Nijmegen, Netherlands, 6532 SZ
    • Canisius-Wilhelmina Ziekenhuis
  • Nijmegen, Netherlands, 6500 HB
    • Radboud University Medical Center Nijmegen
  • The Hague, Netherlands, 2545 CH
    • HagaZiekenhuis - Locatie Leyweg
• Portugal
  • Porto, Portugal, PT 4200 - 319
    • Hospital Escolar Soa Joao

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: standard combination chemotherapy	Drug: standard combination chemotherapy; Cycle 1daunorubicin (60 mg/m²) infusion (15-30 min) for 3 dayscytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days.; Cycle 2daunorubicin (45 mg/m²) infusion (15-30 min) for 3 dayscytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days.; Cycle 3 (mini-ICE)idarubicin (8 mg/m²) infusion (15-30 min) for 3 dayscytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 daysetoposide (100 mg/m²) infusion (1 hr) for 3 days; Cycle 4 (mini-ICE) (optional)idarubicin (8 mg/m²) infusion (15-30 min) for 3 dayscytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 daysetoposide (100 mg/m²) infusion (1 hr) for 3 days; Other Names: "3+7" induction chemotherapy; Intensive combined chemotherapy
Experimental: decitabine	Drug: decitabine; Cycle 1: decitabine (20 mg/m²) infusion (1 hr) for 10 days; Cycle 2if bone marrow (BM) blasts < 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 daysif BM blasts >= 5%: decitabine (20 mg/m²) infusion (1 hr) for 10 days; Cycle 3if BM blasts < 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 daysif BM blasts >= 5%: decitabine (20 mg/m²) infusion (1 hr) for 10 days; Cycle 4-6: decitabine (20 mg/m²) infusion (1 hr) for 5 days; 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 Names: Dacogen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival (OS)	4.9 years from first patient in

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of adverse events (AEs)	The events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0	4.9 years from first patient in
Progression-free survival (PFS) from randomization to the date of either first progression, first relapse or death, whichever occurs first		4.9 years from first patient in
Transplantation feasibility	Percentage of patients transplanted	4.9 years from first patient in
Outcome post-transplantation	PFS, incidence of relapse or progression, and incidence of non-relapse or progression related mortality	4.9 years from first patient in
Health economics impact of each treatment arm	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	4.9 years from first patient in
Health Related Quality of Life (HRQoL) questionnaires	EORTC Quality of Life Questionnaire (QLQ-C30) Elderly module (ELD14)	4.9 years from first patient in
Prognostic value of baseline physical and functional conditions on treatment outcome using geriatric assessment tools	Short physical performance battery (SPPB) and activities of daily living (ADL)	4.9 years from first patient in
complete response (CR/CRi) rate	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)	4.9 years from first patient in
Overall CR/CRi rate	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)	4.9 years from first patient in
Disease-free survival (DFS) from CR or CRi	The time between the date of CR or CRi and the date of first relapse or death (whatever the cause), whichever occurs first	4.9 years from first patient in

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: Janssen Pharmaceuticals; Gruppo Italiano Malattie EMatologiche dell'Adulto

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2014
• Primary Completion (Actual): March 7, 2022
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: June 19, 2014
• First Submitted That Met QC Criteria: June 23, 2014
• First Posted (Estimate): June 24, 2014

Study Record Updates

• Last Update Posted (Actual): February 15, 2023
• Last Update Submitted That Met QC Criteria: February 14, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Elderly; AML; Decitabine; Transplant; Newly diagnosed
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia, Myeloid; Leukemia; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine
• Other Study ID Numbers: EORTC-1301; 2014-001486-27 (EudraCT Number)