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

NCT ID: NCT02172872

Last Updated: 2023-02-15

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 606 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-11-28
• Study Completion Date: 2023-12-31

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.

Conditions

Acute Myeloid Leukemia (AML)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

standard combination chemotherapy

Group Type: ACTIVE_COMPARATOR

standard combination chemotherapy

Intervention Type: DRUG

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

decitabine

Group Type: EXPERIMENTAL

decitabine

Intervention Type: DRUG

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.

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

"3+7" induction chemotherapy; Intensive combined chemotherapy; Dacogen

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

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Gruppo Italiano Malattie EMatologiche dell'Adulto

OTHER

Sponsor Role: collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Luebbert, MD, PhD

Role: STUDY_CHAIR

Universitaetsklinikum Freiburg, Freiburg, Germany

Gerwin G Huls, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UMCG, Groningen, The Netherlands

Pierre W Wijermans, MD

Role: PRINCIPAL_INVESTIGATOR

HagaZiekenhuis, the Hague, The Netherlands

Locations

UZ Antwerpen

Edegem, Antwerpen, Belgium

UZ Brussel

Jette, Brussels Capital, Belgium

CHR Verviers

Verviers, Liège, Belgium

A.Z. St. Jan

Bruges, West-Vlaanderen, Belgium

Institut Jules Bordet

Brussels, , Belgium

C.H.U. Sart-Tilman

Liège, , Belgium

CHR De La Citadelle

Liège, , Belgium

National Specialized Hospital for Active Treatment of Haematological Diseases

Sofia, , Bulgaria

Clinical Hospital Merkur

Zagreb, , Croatia

University Hospital Rebro

Zagreb, , Croatia

CHU de Caen - Hôpital Côte de Nacre

Caen, , France

CHU de Nantes - Hôtel Dieu

Nantes, , France

Assistance Publique - Hôpitaux de Paris - Hôpital Saint Antoine

Paris, , France

Universitätsklinikum Aachen AÖR - Medizinische Fakultät der RWTH

Aachen, , Germany

Klinikum Augsburg

Augsburg, , Germany

Helios Kliniken - Helios Klinikum Berlin-Buch

Berlin, , Germany

Universitätsklinikum Essen

Essen, , Germany

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Universitaetklinikum Halle - Martin Luther Universitaet - Universitaetsklinikum Halle (Saale)

Halle, , Germany

Klinikum Der Phillips - Universität Marburg

Marburg, , Germany

Universitaet Rostock - Medizinische Fakultaet

Rostock, , Germany

Universitaetsklinikum Tuebingen-Uni Kliniken Berg

Tübingen, , Germany

Azienda Ospedaliero Universitaria - Ospedali Riuniti

Ancona, , Italy

Universita Degli Studi Di Bari - Policlinico

Bari, , Italy

Universita di Bologna

Bologna, , Italy

Ospedale Regionale A. Pugliese

Catanzaro, , Italy

Ospedali Riuniti Foggia

Foggia, , Italy

Azienda Ospedaliero - Universitaria Policlinico di Modena

Modena, , Italy

Amedeo Avogadro University of Eastern Piedmont-Ospedale Maggiore della Carita

Novara, , Italy

La Maddalena S.P.A.

Palermo, , Italy

Ospedale San Salvatore

Pesaro, , Italy

AUSL Romagna - Ospedale Santa Maria dell Croci

Ravenna, , Italy

Arcispedale Di S. Maria Nuova

Reggio Emilia, , Italy

AUSL Romagna - Ospedale Infermi di Rimini

Rimini, , Italy

H. San Giovanni - Addolorata

Roma, , Italy

Universita Degli Studi Di Roma La Sapienza - Ospedale Sant'Andrea

Roma, , Italy

Azienda Ospedallera Universitaria - Policlinico Tor Vergata

Rome, , Italy

Instituto Regina Elena / Instituti Fisioterapici Ospitalieri

Rome, , Italy

Ospedale San Eugenio

Rome, , Italy

Clinica Ematologica dell'Universita di Roma La Sapienza

Rome, , Italy

Ospedale Casa Sollievo Della Sofferenza

San Giovanni Rotondo, , Italy

Azienda Ospedaliera Città della Salute e della Scienza di Torino - Ospedale Molinette

Torino, , Italy

Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udine

Udine, , Italy

Vilnius University Hospital Santariskiu Clinics

Vilnius, , Lithuania

Rijnstate Hospital

Arnhem, , Netherlands

Reinier De Graaf Gasthuis

Delft, , Netherlands

Unversity Medical Center Groningen

Groningen, , Netherlands

Medisch Centrum Leeuwarden-Zuid

Leeuwarden, , Netherlands

Academisch Ziekenhuis Maastricht

Maastricht, , Netherlands

Radboud University Medical Center Nijmegen

Nijmegen, , Netherlands

Canisius-Wilhelmina Ziekenhuis

Nijmegen, , Netherlands

HagaZiekenhuis - locatie Leyweg

The Hague, , Netherlands

Hospital Escolar Soa Joao

Porto, , Portugal

Countries

Belgium; Bulgaria; Croatia; France; Germany; Italy; Lithuania; Netherlands; Portugal

References

Efficace F, Kicinski M, Coens C, Suciu S, van der Velden WJFM, Noppeney R, Chantepie S, Griskevicius L, Neubauer A, Audisio E, Luppi M, Fuhrmann S, Foa R, Crysandt M, Gaidano G, Vrhovac R, Venditti A, Posthuma EFM, Candoni A, Baron F, Legrand O, Mengarelli A, Fazi P, Vignetti M, Giraut A, Wijermans PW, Huls G, Lubbert M. Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial. Blood. 2024 Aug 1;144(5):541-551. doi: 10.1182/blood.2023023625.

Reference Type: DERIVED

PMID: 38717861 (View on PubMed)

Lubbert M, Wijermans PW, Kicinski M, Chantepie S, Van der Velden WJFM, Noppeney R, Griskevicius L, Neubauer A, Crysandt M, Vrhovac R, Luppi M, Fuhrmann S, Audisio E, Candoni A, Legrand O, Foa R, Gaidano G, van Lammeren-Venema D, Posthuma EFM, Hoogendoorn M, Giraut A, Stevens-Kroef M, Jansen JH, de Graaf AO, Efficace F, Ammatuna E, Vilque JP, Wasch R, Becker H, Blijlevens N, Duhrsen U, Baron F, Suciu S, Amadori S, Venditti A, Huls G; EORTC Leukemia Group, GIMEMA, and German MDS Study Group. 10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial. Lancet Haematol. 2023 Nov;10(11):e879-e889. doi: 10.1016/S2352-3026(23)00273-9.

Reference Type: DERIVED

PMID: 37914482 (View on PubMed)

Other Identifiers

2014-001486-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EORTC-1301

Identifier Type: -

Identifier Source: org_study_id