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

Acute Myeloid Leukemia (AML) Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02172872
• Other study ID #: EORTC-1301
• Secondary ID: 2014-001486-27
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 28, 2014
• Est. completion date: December 2023

Study information

• Verified date: February 2023
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 606
• Est. completion date: December 2023
• Est. primary completion date: March 7, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Leukemia
• Leukemia, Myeloid, Acute

Intervention

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
• 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.

Locations

Country	Name	City	State
Belgium	A.Z. St. Jan	Brugge	West-Vlaanderen
Belgium	Institut Jules Bordet	Brussels
Belgium	UZ Antwerpen	Edegem	Antwerpen
Belgium	UZ Brussel	Jette	Brussels
Belgium	C.H.U. Sart-Tilman	Liège
Belgium	CHR De La Citadelle	Liège
Belgium	CHR Verviers	Verviers	Liège
Bulgaria	National Specialized Hospital for Active Treatment of Haematological Diseases	Sofia
Croatia	Clinical Hospital Merkur	Zagreb
Croatia	University Hospital Rebro	Zagreb
France	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
Germany	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
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	Tuebingen
Italy	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 nell'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	Clinica Ematologica dell'Universita di Roma La Sapienza	Rome
Italy	Instituto Regina Elena / Instituti Fisioterapici Ospitalieri	Rome
Italy	Ospedale San Eugenio	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
Lithuania	Vilnius University Hospital Santariskiu Clinics	Vilnius
Netherlands	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	Canisius-Wilhelmina Ziekenhuis	Nijmegen
Netherlands	Radboud University Medical Center Nijmegen	Nijmegen
Netherlands	HagaZiekenhuis - locatie Leyweg	The Hague
Portugal	Hospital Escolar Soa Joao	Porto

Sponsors (3)

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

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS)		4.9 years from first patient in
Secondary	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
Secondary	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
Secondary	Transplantation feasibility	Percentage of patients transplanted	4.9 years from first patient in
Secondary	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
Secondary	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
Secondary	Health Related Quality of Life (HRQoL) questionnaires	EORTC Quality of Life Questionnaire (QLQ-C30) Elderly module (ELD14)	4.9 years from first patient in
Secondary	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
Secondary	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
Secondary	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
Secondary	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