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

• ClinicalTrials.gov Identifier: NCT02140242
• Recruitment Status: Recruiting
• First Posted: May 16, 2014
• Last Update Posted: August 6, 2020
• Sponsor: Technische Universität Dresden
• Collaborators: Nationales Centrum für Tumorerkrankungen Dresden (NCT/UCC); Masaryk University
• Information provided by (Responsible Party): Technische Universität Dresden

Tracking Information

• First Submitted Date: May 9, 2014
• First Posted Date: May 16, 2014
• Last Update Posted Date: August 6, 2020
• Actual Study Start Date: April 16, 2014
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 14, 2014)

• 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.
• 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 14, 2014)

• 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.
• 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.
• 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.
• 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.
• 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.
• Rate of induction deaths [ Time Frame: day 60 ]
  Rate of induction deaths (until day 60 or beginning of consolidation treatment - whichever occurs first)
• 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
• Sonographic cardiac left ventricular ejection fraction [ Time Frame: day 35 ]
  Sonographic cardiac left ventricular ejection fraction
• Serum levels of pro-brain natriuretic peptide (por-BNP) and Troponin-T [ Time Frame: day 35 ]
  Serum levels of pro-BNP and Trop-T
• Incidence of CTCAE grade ≥3 cardiac complications [ Time Frame: day 35 ]
  Incidence of CTCAE grade ≥3 cardiac complications
• Rate of early deaths [ Time Frame: week 2 ]
  Rate of early deaths (2 weeks)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Comparison Between Two Dose Levels of Daunorubicin and Between One vs. Two Induction Cycles for Adult Patients With AML
• 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
• 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].

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Leukemia, Myelocytic, Acute

Intervention

• Drug: study part 1 - dose daunorubicin
  standard induction dose of daunorubicin 60 mg/m2 on days 3-5
• Procedure: induction cycles
  single induction cycle versus double induction cycles (only patients with good response after first induction) Allocation is randomized for cytogenetic risk.

Study Arms

• Active Comparator: daunorubicin 60 mg/m2
  study part 1 - dose daunorubicin standard dose daunorubicin in induction 1 (60 mg/m2) on days 3-5
  Intervention: Drug: study part 1 - dose daunorubicin
• Active Comparator: Double induction
  study part 2: induction cycles double induction (only patients with good response)
  Intervention: Procedure: induction cycles
• Experimental: Single induction
  study part 2: induction cycles single induction (only patients with good response)
  Intervention: Procedure: induction cycles

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 14, 2014): 600
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 2021
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Annett Haake; +049 - 0351 458 3965; annett.haake@ukdd.de

Contact: Frank Fiebig; +049 - 0351 458 5198; frank.fiebig@ukdd.de

• Listed Location Countries: Germany, Czechia

Administrative Information

• NCT Number: NCT02140242
• Other Study ID Numbers: TUD-2DAUNO-058
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Technische Universität Dresden
• Study Sponsor: Technische Universität Dresden

Collaborators

• Nationales Centrum für Tumorerkrankungen Dresden (NCT/UCC)
• Masaryk University

Investigators

• Principal Investigator: Christoph Röllig, Prof. Dr.; Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I

• PRS Account: Technische Universität Dresden
• Verification Date: August 2020