Clinical trial NCT02172872: "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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Acute Myeloid Leukemia (AML)
Keywords: Newly diagnosed
AML
Elderly
Decitabine
Transplant
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Janssen Pharmaceuticals
name: Gruppo Italiano Malattie EMatologiche dell'Adulto
First posted: 2014-06-24
Enrollment: 606
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall survival (OS)
timeFrame: 4.9 years from first patient in
Secondary outcomes:
measure: Occurrence of adverse events (AEs)
timeFrame: 4.9 years from first patient in
measure: Progression-free survival (PFS) from randomization to the date of either first progression, first relapse or death, whichever occurs first
timeFrame: 4.9 years from first patient in
measure: Transplantation feasibility
timeFrame: 4.9 years from first patient in
measure: Outcome post-transplantation
timeFrame: 4.9 years from first patient in
measure: Health economics impact of each treatment arm
timeFrame: 4.9 years from first patient in
measure: Health Related Quality of Life (HRQoL) questionnaires
timeFrame: 4.9 years from first patient in
measure: Prognostic value of baseline physical and functional conditions on treatment outcome using geriatric assessment tools
timeFrame: 4.9 years from first patient in
measure: complete response (CR/CRi) rate
timeFrame: 4.9 years from first patient in
measure: Overall CR/CRi rate
timeFrame: 4.9 years from first patient in
measure: Disease-free survival (DFS) from CR or CRi
timeFrame: 4.9 years from first patient in
Other outcomes:
Locations:
city: Edegem
country: Belgium
facility: UZ Antwerpen
state: Antwerpen
city: Jette
country: Belgium
facility: UZ Brussel
state: Brussels
city: Verviers
country: Belgium
facility: CHR Verviers
state: Liège
city: Brugge
country: Belgium
facility: A.Z. St. Jan
state: West-Vlaanderen
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Liège
country: Belgium
facility: C.H.U. Sart-Tilman
city: Liège
country: Belgium
facility: CHR De La Citadelle
city: Sofia
country: Bulgaria
facility: National Specialized Hospital for Active Treatment of Haematological Diseases
city: Zagreb
country: Croatia
facility: Clinical Hospital Merkur
city: Zagreb
country: Croatia
facility: University Hospital Rebro
city: Caen
country: France
facility: CHU de Caen - Hôpital Côte de Nacre
city: Nantes
country: France
facility: CHU de Nantes - Hôtel Dieu
city: Paris
country: France
facility: Assistance Publique - Hôpitaux de Paris - Hôpital Saint Antoine
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen AÖR - Medizinische Fakultät der RWTH
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Berlin
country: Germany
facility: Helios Kliniken - Helios Klinikum Berlin-Buch
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Halle
country: Germany
facility: Universitaetklinikum Halle - Martin Luther Universitaet - Universitaetsklinikum Halle (Saale)
city: Marburg
country: Germany
facility: Klinikum Der Phillips - Universität Marburg
city: Rostock
country: Germany
facility: Universitaet Rostock - Medizinische Fakultaet
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen-Uni Kliniken Berg
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria - Ospedali Riuniti
city: Bari
country: Italy
facility: Universita Degli Studi Di Bari - Policlinico
city: Bologna
country: Italy
facility: Universita di Bologna
city: Catanzaro
country: Italy
facility: Ospedale Regionale A. Pugliese
city: Foggia
country: Italy
facility: Ospedali Riuniti Foggia
city: Modena
country: Italy
facility: Azienda Ospedaliero - Universitaria Policlinico di Modena
city: Novara
country: Italy
facility: Amedeo Avogadro University of Eastern Piedmont-Ospedale Maggiore della Carita
city: Palermo
country: Italy
facility: La Maddalena S.P.A.
city: Pesaro
country: Italy
facility: Ospedale San Salvatore
city: Ravenna
country: Italy
facility: AUSL Romagna - Ospedale Santa Maria dell Croci
city: Reggio nell'Emilia
country: Italy
facility: Arcispedale Di S. Maria Nuova
city: Rimini
country: Italy
facility: AUSL Romagna - Ospedale Infermi di Rimini
city: Roma
country: Italy
facility: H. San Giovanni - Addolorata
city: Roma
country: Italy
facility: Universita Degli Studi Di Roma La Sapienza - Ospedale Sant'Andrea
city: Rome
country: Italy
facility: Azienda Ospedallera Universitaria - Policlinico Tor Vergata
city: Rome
country: Italy
facility: Instituto Regina Elena / Instituti Fisioterapici Ospitalieri
city: Rome
country: Italy
facility: Ospedale San Eugenio
city: Rome
country: Italy
facility: Clinica Ematologica dell'Universita di Roma La Sapienza
city: San Giovanni Rotondo
country: Italy
facility: Ospedale Casa Sollievo Della Sofferenza
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino - Ospedale Molinette
city: Udine
country: Italy
facility: Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udine
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santariskiu Clinics
city: Arnhem
country: Netherlands
facility: Rijnstate Hospital
city: Delft
country: Netherlands
facility: Reinier De Graaf Gasthuis
city: Groningen
country: Netherlands
facility: Unversity Medical Center Groningen
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden-Zuid
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center Nijmegen
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Ziekenhuis
city: The Hague
country: Netherlands
facility: HagaZiekenhuis - locatie Leyweg
city: Porto
country: Portugal
facility: Hospital Escolar Soa Joao
Study officials:
affiliation: Universitaetsklinikum Freiburg, Freiburg, Germany
name: Michael Luebbert, MD, PhD
role: STUDY_CHAIR
affiliation: UMCG, Groningen, The Netherlands
name: Gerwin G Huls, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: HagaZiekenhuis, the Hague, The Netherlands
name: Pierre W Wijermans, MD
role: PRINCIPAL_INVESTIGATOR
References: