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

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02172872

Collaborator

Janssen Pharmaceuticals (Industry), Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

606

Enrollment

Locations

Arms

120.1

Anticipated Duration (Months)

11.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

606 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

Actual Study Start Date :

Nov 28, 2014

Actual Primary Completion Date :

Mar 7, 2022

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: standard combination chemotherapy	Drug: standard combination chemotherapy Cycle 1 daunorubicin (60 mg/m²) infusion (15-30 min) for 3 days cytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days. Cycle 2 daunorubicin (45 mg/m²) infusion (15-30 min) for 3 days cytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days. Cycle 3 (mini-ICE) idarubicin (8 mg/m²) infusion (15-30 min) for 3 days cytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 days etoposide (100 mg/m²) infusion (1 hr) for 3 days Cycle 4 (mini-ICE) (optional) idarubicin (8 mg/m²) infusion (15-30 min) for 3 days cytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 days etoposide (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 2 if bone marrow (BM) blasts < 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 days if BM blasts >= 5%: decitabine (20 mg/m²) infusion (1 hr) for 10 days Cycle 3 if BM blasts < 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 days if 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

Arm

Intervention/Treatment

Active Comparator: standard combination chemotherapy

Drug: standard combination chemotherapy

Cycle 1 daunorubicin (60 mg/m²) infusion (15-30 min) for 3 days cytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days. Cycle 2 daunorubicin (45 mg/m²) infusion (15-30 min) for 3 days cytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days. Cycle 3 (mini-ICE) idarubicin (8 mg/m²) infusion (15-30 min) for 3 days cytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 days etoposide (100 mg/m²) infusion (1 hr) for 3 days Cycle 4 (mini-ICE) (optional) idarubicin (8 mg/m²) infusion (15-30 min) for 3 days cytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 days etoposide (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 2 if bone marrow (BM) blasts < 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 days if BM blasts >= 5%: decitabine (20 mg/m²) infusion (1 hr) for 10 days Cycle 3 if BM blasts < 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 days if 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

Outcome Measures

Primary Outcome Measures

Overall survival (OS) [4.9 years from first patient in]

Secondary Outcome Measures

Occurrence of adverse events (AEs) [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 [4.9 years from first patient in]
Transplantation feasibility [4.9 years from first patient in]
Percentage of patients transplanted
Outcome post-transplantation [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 [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 [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 [4.9 years from first patient in]
Short physical performance battery (SPPB) and activities of daily living (ADL)
complete response (CR/CRi) rate [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 [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 [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Age ≥ 60 years
WHO Performance status ≤ 2
Eligible for standard intensive chemotherapy
Newly diagnosed AML cytopathologically confirmed to the WHO classification (up to 2 months prior to randomization)
De novo or secondary AML is allowed
White blood cell (WBC) count is ≤ 30x10E9/L (measured within 72 hours prior to randomization).
Laboratory assessments (measured prior to randomization):
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
Total serum bilirubin < 2.5 x the upper limit of normal range unless considered AML-related or due to Gilbert's syndrome
Serum creatinine < 2.5 x the upper limit of normal range unless considered AML-related
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.
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:

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)
Presence of blast crisis of chronic myeloid leukemia
Presence of active central nervous system (CNS) leukemia
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
Patients received any prior treatment for myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN) with:
hypomethylating agents (decitabine, 5-azacytidine), OR
with intensive chemotherapy or transplantation within the last three years
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

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
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.
Presence of active uncontrolled infection
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UZ Antwerpen	Edegem	Antwerpen	Belgium	2650
2	UZ Brussel	Jette	Brussels	Belgium	1090
3	CHR Verviers	Verviers	Liège	Belgium	4800
4	A.Z. St. Jan	Brugge	West-Vlaanderen	Belgium	8000
5	Institut Jules Bordet	Brussels		Belgium	1000
6	C.H.U. Sart-Tilman	Liège		Belgium	4000
7	CHR De La Citadelle	Liège		Belgium	4000
8	National Specialized Hospital for Active Treatment of Haematological Diseases	Sofia		Bulgaria	1756
9	Clinical Hospital Merkur	Zagreb		Croatia	10000
10	University Hospital Rebro	Zagreb		Croatia	10000
11	CHU de Caen - Hôpital Côte de Nacre	Caen		France	14033
12	CHU de Nantes - Hôtel Dieu	Nantes		France	44093
13	Assistance Publique - Hôpitaux de Paris - Hôpital Saint Antoine	Paris		France	75571
14	Universitätsklinikum Aachen AÖR - Medizinische Fakultät der RWTH	Aachen		Germany	52074
15	Klinikum Augsburg	Augsburg		Germany	86156
16	Helios Kliniken - Helios Klinikum Berlin-Buch	Berlin		Germany	13125
17	Universitätsklinikum Essen	Essen		Germany	45147
18	Universitätsklinikum Freiburg	Freiburg		Germany	79106
19	Universitaetklinikum Halle - Martin Luther Universitaet - Universitaetsklinikum Halle (Saale)	Halle		Germany	06120
20	Klinikum Der Phillips - Universität Marburg	Marburg		Germany	35043
21	Universitaet Rostock - Medizinische Fakultaet	Rostock		Germany	18055
22	Universitaetsklinikum Tuebingen-Uni Kliniken Berg	Tuebingen		Germany	72076
23	Azienda Ospedaliero Universitaria - Ospedali Riuniti	Ancona		Italy	60020
24	Universita Degli Studi Di Bari - Policlinico	Bari		Italy	70124
25	Universita di Bologna	Bologna		Italy	40138
26	Ospedale Regionale A. Pugliese	Catanzaro		Italy	88100
27	Ospedali Riuniti Foggia	Foggia		Italy	71100
28	Azienda Ospedaliero - Universitaria Policlinico di Modena	Modena		Italy	41124
29	Amedeo Avogadro University of Eastern Piedmont-Ospedale Maggiore della Carita	Novara		Italy	28100
30	La Maddalena S.P.A.	Palermo		Italy	90146
31	Ospedale San Salvatore	Pesaro		Italy	61100
32	AUSL Romagna - Ospedale Santa Maria dell Croci	Ravenna		Italy	48121
33	Arcispedale Di S. Maria Nuova	Reggio nell'Emilia		Italy	42100
34	AUSL Romagna - Ospedale Infermi di Rimini	Rimini		Italy	47037
35	H. San Giovanni - Addolorata	Roma		Italy	00184
36	Universita Degli Studi Di Roma La Sapienza - Ospedale Sant'Andrea	Roma		Italy	00189
37	Azienda Ospedallera Universitaria - Policlinico Tor Vergata	Rome		Italy	00133
38	Instituto Regina Elena / Instituti Fisioterapici Ospitalieri	Rome		Italy	00144
39	Ospedale San Eugenio	Rome		Italy	00144
40	Clinica Ematologica dell'Universita di Roma La Sapienza	Rome		Italy	00161
41	Ospedale Casa Sollievo Della Sofferenza	San Giovanni Rotondo		Italy	71013
42	Azienda Ospedaliera Città della Salute e della Scienza di Torino - Ospedale Molinette	Torino		Italy	10126
43	Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udine	Udine		Italy	33100
44	Vilnius University Hospital Santariskiu Clinics	Vilnius		Lithuania	08661
45	Rijnstate Hospital	Arnhem		Netherlands	6815 AD
46	Reinier De Graaf Gasthuis	Delft		Netherlands	2625 AD
47	Unversity Medical Center Groningen	Groningen		Netherlands	9713 GZ
48	Medisch Centrum Leeuwarden-Zuid	Leeuwarden		Netherlands	8901 BR
49	Academisch Ziekenhuis Maastricht	Maastricht		Netherlands	6202 AZ
50	Radboud University Medical Center Nijmegen	Nijmegen		Netherlands	6500 HB
51	Canisius-Wilhelmina Ziekenhuis	Nijmegen		Netherlands	6532 SZ
52	HagaZiekenhuis - locatie Leyweg	The Hague		Netherlands	2545 CH
53	Hospital Escolar Soa Joao	Porto		Portugal	PT 4200 - 319

Sponsors and Collaborators

European Organisation for Research and Treatment of Cancer - EORTC
Janssen Pharmaceuticals
Gruppo Italiano Malattie EMatologiche dell'Adulto

Investigators

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