Comparison Between Two Dose Levels of Daunorubicin and Between One vs. Two Induction Cycles for Adult Patients With AML

NCT ID: NCT02140242

Last Updated: 2023-09-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 721 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-16
• Study Completion Date: 2022-04-25

Brief Summary

The proposed trial will address two clinically important questions for younger patients with newly diagnosed acute myeloid leukemia (AML): the optimal dose of daunorubicin in induction therapy and the necessity of a second induction cycle in patients with a good response after the first induction. The primary endpoint is the rate of good responders. Secondary outcomes will be relapse-free survival, overall survival and minimal residual disease kinetics. Patients will be recruited in about 40 treatment centers of the Study Alliance Leukemia study group over a period of 40 months. The results will be of great clinical relevance: First, the study could facilitate the establishment or confirmation of the optimal daunorubicin dose.

Detailed Description

In the first part of the trial, patients will be randomly assigned to receive either 90 mg/m2 or 60 mg/m2 daunorubicin in the first induction cycle in addition to standard dosed cytarabine. Assuming a superiority of 90 mg/m2, 436 patients will be recruited. In the second part of the trial, good responders will be randomized to receive either a second or no further induction cycle. Assuming a non-inferiority of the single induction regarding the rate of complete remissions, a number of 360 patients will be included in the second part. Furthermore, in case of a non-inferiority of single versus double induction in good responders, about half of all younger AML patients could be spared a second induction cycle, leading to a reduction in treatment-related mortality, fewer days spent in hospital and improved quality of life.

As a result of the preplanned interim analysis of part I, the sponsor decided to suspend randomization in trial part I and to offer all patients the standard dose of 60 mg/m2 daunorubicin in both induction cycles (part I and II of the trial). Because of this an Amendment was sent to and approved by regulatories and ethics comitee.

The inclusion age was raised to 65 years based on the current German treatment guidelines in which patients up to the age of 65 are considered eligible for intensive induction chemotherapy with DA60 [Onkopedia-Leitlinie 2017].

Conditions

Leukemia, Myelocytic, Acute

Study Design

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

Study Groups

daunorubicin 60 mg/m2

study part 1 - dose daunorubicin standard dose daunorubicin in induction 1 (60 mg/m2) on days 3-5

Group Type: ACTIVE_COMPARATOR

study part 1 - dose daunorubicin

Intervention Type: DRUG

standard induction dose of daunorubicin 60 mg/m2 on days 3-5

Double induction

study part 2: induction cycles double induction (only patients with good response)

Group Type: ACTIVE_COMPARATOR

induction cycles

Intervention Type: PROCEDURE

single induction cycle versus double induction cycles (only patients with good response after first induction) Allocation is randomized for cytogenetic risk.

Single induction

study part 2: induction cycles single induction (only patients with good response)

Group Type: EXPERIMENTAL

induction cycles

Intervention Type: PROCEDURE

single induction cycle versus double induction cycles (only patients with good response after first induction) Allocation is randomized for cytogenetic risk.

Interventions

study part 1 - dose daunorubicin

standard induction dose of daunorubicin 60 mg/m2 on days 3-5

Intervention Type: DRUG

induction cycles

single induction cycle versus double induction cycles (only patients with good response after first induction) Allocation is randomized for cytogenetic risk.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Newly diagnosed AML other than acute promyelocytic leukemia (APL) according to WHO criteria, i.e. bone marrow aspirate or biopsy must contain ≥20% blasts of all nucleated cells or differential blood count must contain ≥20% blasts. In acute erythroid leukemia, ≥20% blasts in all non-erythroid bone marrow cells. In AML defined by cytogenetic aberrations, the rate of blasts may be <20%. Secondary AMLs are eligible for inclusion.
• Age 18- inkl.65 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Adequate liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:

• Total bilirubin ≤ 1.5 times the upper limit of normal
• alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 times upper limit of normal

Exclusion Criteria

• Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by transthoracic two-dimensional echocardiography ("M Mode") or multiple gated acquisition scan (MUGA scan)
• Signed informed consent
• Women must fulfill at least one of the following criteria in order to be eligible for trial inclusion:

• Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum follicle stimulating hormone (FSH) > 40 U/ml)
• Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
• Continuous and correct application of a contraception method with a Pearl Index of <1% (e.g. implants, depots, oral contraceptives, intrauterine device - IUD).
• Sexual abstinence
• Vasectomy of the sexual partner

• Patients who are not eligible for standard chemotherapy as assessed by the treating physician
• Central nervous system manifestation of AML
• Cardiac disease: i.e. heart failure New York Heart Association (NYHA) III or IV; unstable coronary artery disease (MI more than 6 months prior to study entry is permitted); serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
• Patients undergoing renal dialysis
• Chronic pulmonary disease with clinical relevant hypoxia
• Known HIV or Hepatitis infection
• Uncontrolled active infection
• Medical conditions other than AML with an estimated life expectancy below 6 months
• Previous treatment of AML except hydroxyurea up to 5 days
• Relapsed or primary refractory AML
• Acute promyelocytic leukemia
• Previous anthracycline-containing chemotherapy
• Treatment with any known non-marketed drug substance or experimental therapy within 4 weeks prior to enrollment
• Incapability of understanding purpose and possible consequences of the trial
• Pregnant or breastfeeding women
• Evidence suggesting that the patient is not likely to follow the study protocol (e.g. lacking compliance)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital Dresden

OTHER

Sponsor Role: collaborator

Masaryk University

OTHER

Sponsor Role: collaborator

Technische Universität Dresden

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christoph Röllig, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I

Locations

Interní klinika LF Masarykovy univerzity a Fakultní nemocnice Brno

Brno, , Czechia

Faculty Hospital Hradec Králové, II. Clinic of international medicine

Hradec Králové, , Czechia

Fakultní nemocnice Olomouc

Olomouc, , Czechia

Fakultní nemocnice Královské Vinohrady

Prague, , Czechia

Ústav hematologie a krevní transfuze (ÚHKT)

Prague, , Czechia

Uniklinik RWTH Aachen

Aachen, , Germany

Klinikum Altenburger Land GmbH

Altenburg, , Germany

Klinikum Augsburg

Augsburg, , Germany

Sozialstiftung Bamberg Klinikum am Bruderwald

Bamberg, , Germany

Charite Campus Benjamin Franklin

Berlin, , Germany

Helios Klinikum Berlin-Buch

Berlin, , Germany

Klinikum Bielefeld

Bielefeld, , Germany

Augusta Kliniken Bochum Hattingen

Bochum, , Germany

Ev. Diakonie-Krankenhaus gGmbH Bremen

Bremen, , Germany

Klinikum Chemnitz GmbH

Chemnitz, , Germany

Carl.Thiem-Klinikum Cottbus gGmbH

Cottbus, , Germany

Universitätsklinikum Carl Gustav Carus Dresden

Dresden, , Germany

Krankenhaus Düren gem. GmbH

Düren, , Germany

Marienhospital Düsseldorf GmbH

Düsseldorf, , Germany

Universitätsklinikum Erlangen

Erlangen, , Germany

Universitätsklinikum Essen

Essen, , Germany

Johann Wolfgang Goethe-Universität Frankfurt am Main

Frankfurt am Main, , Germany

Universitätsklinikum Halle (Saale)

Halle, , Germany

Asklepios Klinik St. Georg

Hamburg, , Germany

St. Marien-Hospital Hamm

Hamm, , Germany

Universitätsklinikum Heidelberg

Heidelberg, , Germany

St. Bernward Krankenhaus Hildesheim

Hildesheim, , Germany

Universitätsklinikum Jena

Jena, , Germany

Westpfalz-Klinikum GmbH

Kaiserslautern, , Germany

Städtisches Krankenhaus Kiel

Kiel, , Germany

Gemeinschaftsklinikum Mittelrhein GmbH

Koblenz, , Germany

Universitätsklinikum Leipzig

Leipzig, , Germany

Universitätsklinikum Gießen und Marburg

Marburg, , Germany

Universitätsklinikum Münster

Münster, , Germany

Klinikum Nürnberg-Nord

Nuremberg, , Germany

Diakonie-Klinikum Schwäbisch Hall gGmbH

Schwäbisch Hall, , Germany

Robert-Bosch-Krankenhaus

Stuttgart, , Germany

Rems-Murr-Klinikum Winnenden

Winnenden, , Germany

Countries

Czechia; Germany

Related Links

https://www.aml-germany.com/

study alliance

http://www.uniklinikum-dresden.de/

University Hospital

https://www.czecrin.cz/

czech ECRIN center

Other Identifiers

TUD-2DAUNO-058

Identifier Type: -

Identifier Source: org_study_id