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

Primary Purpose

Leukemia, Myelocytic, Acute

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
study part 1 - dose daunorubicin
induction cycles
Sponsored by
Technische Universität Dresden
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myelocytic, Acute focused on measuring AML, leukemia, induction treatment, daunorubicin, 7+3

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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
    • Creatinine ≤ 1.5 times upper limit of normalExclusion 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

Exclusion criteria:

  • 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)

Sites / Locations

  • Interní klinika LF Masarykovy univerzity a Fakultní nemocnice Brno
  • Faculty Hospital Hradec Králové, II. Clinic of international medicine
  • Fakultní nemocnice Olomouc
  • Fakultní nemocnice Královské Vinohrady
  • Ústav hematologie a krevní transfuze (ÚHKT)
  • Uniklinik RWTH Aachen
  • Klinikum Altenburger Land GmbH
  • Klinikum Augsburg
  • Sozialstiftung Bamberg Klinikum am Bruderwald
  • Charite Campus Benjamin Franklin
  • Helios Klinikum Berlin-Buch
  • Klinikum Bielefeld
  • Augusta Kliniken Bochum Hattingen
  • Ev. Diakonie-Krankenhaus gGmbH Bremen
  • Klinikum Chemnitz GmbH
  • Carl.Thiem-Klinikum Cottbus gGmbH
  • Universitätsklinikum Carl Gustav Carus Dresden
  • Krankenhaus Düren gem. GmbH
  • Marienhospital Düsseldorf GmbH
  • Universitätsklinikum Erlangen
  • Universitätsklinikum Essen
  • Johann Wolfgang Goethe-Universität Frankfurt am Main
  • Universitätsklinikum Halle (Saale)
  • Asklepios Klinik St. Georg
  • St. Marien-Hospital Hamm
  • Universitätsklinikum Heidelberg
  • St. Bernward Krankenhaus Hildesheim
  • Universitätsklinikum Jena
  • Westpfalz-Klinikum GmbH
  • Städtisches Krankenhaus Kiel
  • Gemeinschaftsklinikum Mittelrhein GmbH
  • Universitätsklinikum Leipzig
  • Universitätsklinikum Gießen und Marburg
  • Universitätsklinikum Münster
  • Klinikum Nürnberg-Nord
  • Diakonie-Klinikum Schwäbisch Hall gGmbH
  • Robert-Bosch-Krankenhaus
  • Rems-Murr-Klinikum Winnenden

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Experimental

Arm Label

daunorubicin 60 mg/m2

Double induction

Single induction

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

response rate after first induction
To investigate whether a higher dose of daunorubicin in induction chemotherapy leads to an increase in hematological good responders defined as having <5% myeloid blasts on day 15 after start of induction therapy.
Rate complete remissions
To investigate whether the rate of complete remissions (CR) after single induction is similar to that after double induction in patients with good response to induction I.

Secondary Outcome Measures

rate cytogenetic and molecular complete remissions
To investigate whether a higher dose of daunorubicin in induction chemotherapy will lead to an increase in cytogenetic and molecular complete remissions.
event-free survival (EFS)
To investigate whether a higher dose of daunorubicin will lead to improved event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). To investigate whether EFS, RFS and OS are similar after single versus double induction in patients with good response to induction I.
relapse-free survival (RFS)
To investigate whether a higher dose of daunorubicin will lead to improved event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). To investigate whether EFS, RFS and OS are similar after single versus double induction in patients with good response to induction I.
overall survival (OS)
To investigate whether a higher dose of daunorubicin will lead to improved event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). To investigate whether EFS, RFS and OS are similar after single versus double induction in patients with good response to induction I.
Correlation between Minimal Residual Disease (MRD) and EFS, RFS, OS
To correlate the level of cytogenetic and molecular minimal residual disease after induction treatment with survival outcomes EFS, RFS and OS.
Rate of induction deaths
Rate of induction deaths (until day 60 or beginning of consolidation treatment - whichever occurs first)
Incidence of serious infectious complications
Incidence of serious infectious complications Grades 3-4 (Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0
Sonographic cardiac left ventricular ejection fraction
Sonographic cardiac left ventricular ejection fraction
Serum levels of pro-brain natriuretic peptide (por-BNP) and Troponin-T
Serum levels of pro-BNP and Trop-T
Incidence of CTCAE grade ≥3 cardiac complications
Incidence of CTCAE grade ≥3 cardiac complications
Rate of early deaths
Rate of early deaths (2 weeks)

Full Information

First Posted
May 9, 2014
Last Updated
September 13, 2023
Sponsor
Technische Universität Dresden
Collaborators
University Hospital Dresden, Masaryk University
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1. Study Identification

Unique Protocol Identification Number
NCT02140242
Brief Title
Comparison Between Two Dose Levels of Daunorubicin and Between One vs. Two Induction Cycles for Adult Patients With AML
Acronym
DaunoDouble
Official Title
Randomized Comparison Between Two Dose Levels of Daunorubicin and Between One Versus Two Cycles of Induction Therapy for Adult Patients With Acute Myeloid Leukemia ≤65 Years
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
April 16, 2014 (Actual)
Primary Completion Date
April 25, 2022 (Actual)
Study Completion Date
April 25, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Technische Universität Dresden
Collaborators
University Hospital Dresden, Masaryk University

4. Oversight

Data Monitoring Committee
No

5. Study Description

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].

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myelocytic, Acute
Keywords
AML, leukemia, induction treatment, daunorubicin, 7+3

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
721 (Actual)

8. Arms, Groups, and Interventions

Arm Title
daunorubicin 60 mg/m2
Arm Type
Active Comparator
Arm Description
study part 1 - dose daunorubicin standard dose daunorubicin in induction 1 (60 mg/m2) on days 3-5
Arm Title
Double induction
Arm Type
Active Comparator
Arm Description
study part 2: induction cycles double induction (only patients with good response)
Arm Title
Single induction
Arm Type
Experimental
Arm Description
study part 2: induction cycles single induction (only patients with good response)
Intervention Type
Drug
Intervention Name(s)
study part 1 - dose daunorubicin
Intervention Description
standard induction dose of daunorubicin 60 mg/m2 on days 3-5
Intervention Type
Procedure
Intervention Name(s)
induction cycles
Intervention Description
single induction cycle versus double induction cycles (only patients with good response after first induction) Allocation is randomized for cytogenetic risk.
Primary Outcome Measure Information:
Title
response rate after first induction
Description
To investigate whether a higher dose of daunorubicin in induction chemotherapy leads to an increase in hematological good responders defined as having <5% myeloid blasts on day 15 after start of induction therapy.
Time Frame
day 15
Title
Rate complete remissions
Description
To investigate whether the rate of complete remissions (CR) after single induction is similar to that after double induction in patients with good response to induction I.
Time Frame
day 35 after final induction
Secondary Outcome Measure Information:
Title
rate cytogenetic and molecular complete remissions
Description
To investigate whether a higher dose of daunorubicin in induction chemotherapy will lead to an increase in cytogenetic and molecular complete remissions.
Time Frame
day 35
Title
event-free survival (EFS)
Description
To investigate whether a higher dose of daunorubicin will lead to improved event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). To investigate whether EFS, RFS and OS are similar after single versus double induction in patients with good response to induction I.
Time Frame
5 years
Title
relapse-free survival (RFS)
Description
To investigate whether a higher dose of daunorubicin will lead to improved event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). To investigate whether EFS, RFS and OS are similar after single versus double induction in patients with good response to induction I.
Time Frame
5 years
Title
overall survival (OS)
Description
To investigate whether a higher dose of daunorubicin will lead to improved event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). To investigate whether EFS, RFS and OS are similar after single versus double induction in patients with good response to induction I.
Time Frame
5 years
Title
Correlation between Minimal Residual Disease (MRD) and EFS, RFS, OS
Description
To correlate the level of cytogenetic and molecular minimal residual disease after induction treatment with survival outcomes EFS, RFS and OS.
Time Frame
day 35
Title
Rate of induction deaths
Description
Rate of induction deaths (until day 60 or beginning of consolidation treatment - whichever occurs first)
Time Frame
day 60
Title
Incidence of serious infectious complications
Description
Incidence of serious infectious complications Grades 3-4 (Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0
Time Frame
day 35
Title
Sonographic cardiac left ventricular ejection fraction
Description
Sonographic cardiac left ventricular ejection fraction
Time Frame
day 35
Title
Serum levels of pro-brain natriuretic peptide (por-BNP) and Troponin-T
Description
Serum levels of pro-BNP and Trop-T
Time Frame
day 35
Title
Incidence of CTCAE grade ≥3 cardiac complications
Description
Incidence of CTCAE grade ≥3 cardiac complications
Time Frame
day 35
Title
Rate of early deaths
Description
Rate of early deaths (2 weeks)
Time Frame
week 2

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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 Creatinine ≤ 1.5 times upper limit of normalExclusion 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 Exclusion criteria: 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christoph Röllig, Prof. Dr.
Organizational Affiliation
Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I
Official's Role
Principal Investigator
Facility Information:
Facility Name
Interní klinika LF Masarykovy univerzity a Fakultní nemocnice Brno
City
Brno
Country
Czechia
Facility Name
Faculty Hospital Hradec Králové, II. Clinic of international medicine
City
Hradec Králové
Country
Czechia
Facility Name
Fakultní nemocnice Olomouc
City
Olomouc
Country
Czechia
Facility Name
Fakultní nemocnice Královské Vinohrady
City
Praha
Country
Czechia
Facility Name
Ústav hematologie a krevní transfuze (ÚHKT)
City
Praha
Country
Czechia
Facility Name
Uniklinik RWTH Aachen
City
Aachen
ZIP/Postal Code
52074
Country
Germany
Facility Name
Klinikum Altenburger Land GmbH
City
Altenburg
Country
Germany
Facility Name
Klinikum Augsburg
City
Augsburg
Country
Germany
Facility Name
Sozialstiftung Bamberg Klinikum am Bruderwald
City
Bamberg
Country
Germany
Facility Name
Charite Campus Benjamin Franklin
City
Berlin
Country
Germany
Facility Name
Helios Klinikum Berlin-Buch
City
Berlin
Country
Germany
Facility Name
Klinikum Bielefeld
City
Bielefeld
Country
Germany
Facility Name
Augusta Kliniken Bochum Hattingen
City
Bochum
ZIP/Postal Code
44791
Country
Germany
Facility Name
Ev. Diakonie-Krankenhaus gGmbH Bremen
City
Bremen
Country
Germany
Facility Name
Klinikum Chemnitz GmbH
City
Chemnitz
Country
Germany
Facility Name
Carl.Thiem-Klinikum Cottbus gGmbH
City
Cottbus
Country
Germany
Facility Name
Universitätsklinikum Carl Gustav Carus Dresden
City
Dresden
Country
Germany
Facility Name
Krankenhaus Düren gem. GmbH
City
Düren
Country
Germany
Facility Name
Marienhospital Düsseldorf GmbH
City
Düsseldorf
Country
Germany
Facility Name
Universitätsklinikum Erlangen
City
Erlangen
Country
Germany
Facility Name
Universitätsklinikum Essen
City
Essen
Country
Germany
Facility Name
Johann Wolfgang Goethe-Universität Frankfurt am Main
City
Frankfurt am Main
Country
Germany
Facility Name
Universitätsklinikum Halle (Saale)
City
Halle
Country
Germany
Facility Name
Asklepios Klinik St. Georg
City
Hamburg
Country
Germany
Facility Name
St. Marien-Hospital Hamm
City
Hamm
Country
Germany
Facility Name
Universitätsklinikum Heidelberg
City
Heidelberg
Country
Germany
Facility Name
St. Bernward Krankenhaus Hildesheim
City
Hildesheim
Country
Germany
Facility Name
Universitätsklinikum Jena
City
Jena
ZIP/Postal Code
07740
Country
Germany
Facility Name
Westpfalz-Klinikum GmbH
City
Kaiserslautern
Country
Germany
Facility Name
Städtisches Krankenhaus Kiel
City
Kiel
Country
Germany
Facility Name
Gemeinschaftsklinikum Mittelrhein GmbH
City
Koblenz
Country
Germany
Facility Name
Universitätsklinikum Leipzig
City
Leipzig
Country
Germany
Facility Name
Universitätsklinikum Gießen und Marburg
City
Marburg
Country
Germany
Facility Name
Universitätsklinikum Münster
City
Münster
Country
Germany
Facility Name
Klinikum Nürnberg-Nord
City
Nürnberg
Country
Germany
Facility Name
Diakonie-Klinikum Schwäbisch Hall gGmbH
City
Schwäbisch Hall
Country
Germany
Facility Name
Robert-Bosch-Krankenhaus
City
Stuttgart
Country
Germany
Facility Name
Rems-Murr-Klinikum Winnenden
City
Winnenden
Country
Germany

12. IPD Sharing Statement

Links:
URL
https://www.aml-germany.com/
Description
study alliance
URL
http://www.uniklinikum-dresden.de/
Description
University Hospital
URL
https://www.czecrin.cz/
Description
czech ECRIN center

Learn more about this trial

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

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