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

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ClinicalTrials.gov Identifier: NCT02140242
Recruitment Status : Unknown
Verified August 2017 by Technische Universität Dresden.
Recruitment status was:  Recruiting
First Posted : May 16, 2014
Last Update Posted : August 11, 2017
Sponsor:
Collaborators:
Universitätskrebszentrum des Universitätsklinikums
Masaryk University
Information provided by (Responsible Party):
Technische Universität Dresden

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.

Condition or disease Intervention/treatment Phase
Leukemia, Myelocytic, Acute Drug: study part 1 - dose daunorubicin Procedure: induction cycles Phase 3

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].


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 16, 2014
Estimated Primary Completion Date : May 2018
Estimated Study Completion Date : August 2018


Arm Intervention/treatment
Active Comparator: daunorubicin 60 mg/m2
study part 1 - dose daunorubicin standard dose daunorubicin in induction 1 (60 mg/m2) on days 3-5
Drug: study part 1 - dose daunorubicin
standard induction dose of daunorubicin 60 mg/m2 on days 3-5

Active Comparator: Double induction
study part 2: induction cycles double induction (only patients with good response)
Procedure: induction cycles
single induction cycle versus double induction cycles (only patients with good response after first induction) Allocation is randomized for cytogenetic risk.

Experimental: Single induction
study part 2: induction cycles single induction (only patients with good response)
Procedure: induction cycles
single induction cycle versus double induction cycles (only patients with good response after first induction) Allocation is randomized for cytogenetic risk.




Primary Outcome Measures :
  1. response rate after first induction [ Time Frame: day 15 ]
    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.

  2. Rate complete remissions [ Time Frame: day 35 after final induction ]
    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 :
  1. rate cytogenetic and molecular complete remissions [ Time Frame: day 35 ]
    To investigate whether a higher dose of daunorubicin in induction chemotherapy will lead to an increase in cytogenetic and molecular complete remissions.

  2. event-free survival (EFS) [ Time Frame: 5 years ]
    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.

  3. relapse-free survival (RFS) [ Time Frame: 5 years ]
    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.

  4. overall survival (OS) [ Time Frame: 5 years ]
    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.

  5. Correlation between Minimal Residual Disease (MRD) and EFS, RFS, OS [ Time Frame: day 35 ]
    To correlate the level of cytogenetic and molecular minimal residual disease after induction treatment with survival outcomes EFS, RFS and OS.

  6. Rate of induction deaths [ Time Frame: day 60 ]
    Rate of induction deaths (until day 60 or beginning of consolidation treatment - whichever occurs first)

  7. Incidence of serious infectious complications [ Time Frame: day 35 ]
    Incidence of serious infectious complications Grades 3-4 (Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0

  8. Sonographic cardiac left ventricular ejection fraction [ Time Frame: day 35 ]
    Sonographic cardiac left ventricular ejection fraction

  9. Serum levels of pro-brain natriuretic peptide (por-BNP) and Troponin-T [ Time Frame: day 35 ]
    Serum levels of pro-BNP and Trop-T

  10. Incidence of CTCAE grade ≥3 cardiac complications [ Time Frame: day 35 ]
    Incidence of CTCAE grade ≥3 cardiac complications

  11. Rate of early deaths [ Time Frame: week 2 ]
    Rate of early deaths (2 weeks)



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02140242


Contacts
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Contact: Frank Staps +049 - 0351 458 5198 frank.staps@uniklinikum-dresden.de
Contact: Annett Haake +049 - 0351 458 3965 annett.haake@uniklinikum-dresden.de

Locations
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Czechia
Interní klinika LF Masarykovy univerzity a Fakultní nemocnice Brno Recruiting
Brno, Czechia
Contact: Jirí Mayer, MD         
Faculty Hospital Hradec Králové, II. Clinic of international medicine Recruiting
Hradec Králové, Czechia
Contact: Pavel Zák, doc. MUDr.         
Fakultní nemocnice Olomouc Recruiting
Olomouc, Czechia
Contact: Tomas Szotkowski, Doc. Dr.         
Fakultní nemocnice Královské Vinohrady Recruiting
Praha, Czechia
Contact: Jan Novák, MD         
Ústav hematologie a krevní transfuze (ÚHKT) Recruiting
Praha, Czechia
Contact: Jolana Mertová, MUDr.         
Germany
Uniklinik RWTH Aachen Recruiting
Aachen, Germany, 52074
Contact: Edgar Jost, MD         
Klinikum Altenburger Land GmbH Recruiting
Altenburg, Germany
Contact: Armin Schulz-Abelius, MD         
Klinikum Augsburg Enrolling by invitation
Augsburg, Germany
Sozialstiftung Bamberg Klinikum am Bruderwald Recruiting
Bamberg, Germany
Contact: Martina Teichmann, MD         
Charite Campus Benjamin Franklin Recruiting
Berlin, Germany
Contact: Claudia Baldus, Prof.         
Klinikum Bielefeld Recruiting
Bielefeld, Germany
Contact: Martin Görner, MD         
Augusta Kliniken Bochum Hattingen Recruiting
Bochum, Germany, 44791
Contact: Dirk Behringer, Prof.         
Ev. Diakonie-Krankenhaus gGmbH Bremen Recruiting
Bremen, Germany
Contact: Johannes Kullmer, MD         
Klinikum Chemnitz GmbH Recruiting
Chemnitz, Germany
Contact: Mathias Hänel, MD         
PD Dr. Christoph Röllig Recruiting
Dresden, Germany
Principal Investigator: Christoph Röllig, MD         
Krankenhaus Düren gem. GmbH Recruiting
Düren, Germany
Contact: Michael Flaßhove, MD         
Marienhospital Düsseldorf GmbH Recruiting
Düsseldorf, Germany
Contact: Aristoteles Giagounidis, MD         
Universitätsklinikum Erlangen Recruiting
Erlangen, Germany
Contact: Stefan Krause, Prof.         
Universitätsklinikum Essen Recruiting
Essen, Germany
Contact: Richard Noppeney, MD         
Johann Wolfgang Goethe-Universität Frankfurt am Main Recruiting
Frankfurt am Main, Germany
Contact: Björn Steffen, MD         
Universitätsklinikum Halle (Saale) Recruiting
Halle, Germany
Contact: Maxi Wass, MD         
Asklepios Klinik St. Georg Terminated
Hamburg, Germany
St. Marien-Hospital Hamm Recruiting
Hamm, Germany
Contact: Heinz Albert Dürk, MD         
Universitätsklinikum Heidelberg Recruiting
Heidelberg, Germany
Contact: Alwin Krämer, Prof.         
St. Bernward Krankenhaus Hildesheim Recruiting
Hildesheim, Germany
Contact: Ulrich Kaiser, Prof.         
Universitätsklinikum Jena Recruiting
Jena, Germany, 07740
Contact: Sebastian Scholl, MD         
Westpfalz-Klinikum GmbH Recruiting
Kaiserslautern, Germany
Contact: Stefan Mahlmann, MD         
Städtisches Krankenhaus Kiel Recruiting
Kiel, Germany
Contact: Sebastian Buske, MD         
Gemeinschaftsklinikum Mittelrhein GmbH Recruiting
Koblenz, Germany
Contact: Dirk Niemann, MD         
Universitätsklinikum Gießen und Marburg Recruiting
Marburg, Germany
Contact: Andreas Neubauer, Prof.         
Universitätsklinikum Münster Recruiting
Münster, Germany
Contact: Christoph Schliemann, MD         
Klinikum Nürnberg-Nord Recruiting
Nürnberg, Germany
Contact: Kerstin Schäfer-Eckart, MD         
Agaplesion Diakoniekrankenhaus Rotenburg Recruiting
Rotenburg, Germany
Contact: Frank Heits, MD         
Diakonie-Klinikum Schwäbisch Hall gGmbH Recruiting
Schwäbisch Hall, Germany
Contact: Thomas Geer, MD         
Klinikum Sindelfingen-Böblingen Recruiting
Sindelfingen, Germany
Contact: Markus Ritter, MD         
Robert-Bosch-Krankenhaus Recruiting
Stuttgart, Germany
Contact: Martin Kaufmann, MD         
Rems-Murr-Klinikum Winnenden Recruiting
Winnenden, Germany
Contact: Stefani Parmentier, MD         
Sponsors and Collaborators
Technische Universität Dresden
Universitätskrebszentrum des Universitätsklinikums
Masaryk University
Investigators
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Principal Investigator: Christoph Röllig, PD Dr. med. Universitätsklinikum Dresden Carl Gustav Carus

Additional Information:
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Responsible Party: Technische Universität Dresden
ClinicalTrials.gov Identifier: NCT02140242     History of Changes
Other Study ID Numbers: TUD-2DAUNO-058
First Posted: May 16, 2014    Key Record Dates
Last Update Posted: August 11, 2017
Last Verified: August 2017
Keywords provided by Technische Universität Dresden:
AML
leukemia
induction treatment
daunorubicin
7+3
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Daunorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action