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

Leukemia, Myelocytic, Acute Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02140242
• Other study ID #: TUD-2DAUNO-058
• Status: Completed
• Phase: Phase 3
• Start date: April 16, 2014
• Est. completion date: April 25, 2022

Study information

• Verified date: September 2023
• Source: Technische Universität Dresden
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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].

Recruitment information / eligibility

• Status: Completed
• Enrollment: 721
• Est. completion date: April 25, 2022
• Est. primary completion date: April 25, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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)

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelocytic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, 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.

Locations

Country	Name	City	State
Czechia	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	Praha
Czechia	Ústav hematologie a krevní transfuze (ÚHKT)	Praha
Germany	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	Nürnberg
Germany	Diakonie-Klinikum Schwäbisch Hall gGmbH	Schwäbisch Hall
Germany	Robert-Bosch-Krankenhaus	Stuttgart
Germany	Rems-Murr-Klinikum Winnenden	Winnenden

Sponsors (3)

Lead Sponsor	Collaborator
Technische Universität Dresden	Masaryk University, University Hospital Dresden

Countries where clinical trial is conducted

Czechia,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	day 15
Primary	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.	day 35 after final induction
Secondary	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.	day 35
Secondary	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.	5 years
Secondary	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.	5 years
Secondary	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.	5 years
Secondary	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.	day 35
Secondary	Rate of induction deaths	Rate of induction deaths (until day 60 or beginning of consolidation treatment - whichever occurs first)	day 60
Secondary	Incidence of serious infectious complications	Incidence of serious infectious complications Grades 3-4 (Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0	day 35
Secondary	Sonographic cardiac left ventricular ejection fraction	Sonographic cardiac left ventricular ejection fraction	day 35
Secondary	Serum levels of pro-brain natriuretic peptide (por-BNP) and Troponin-T	Serum levels of pro-BNP and Trop-T	day 35
Secondary	Incidence of CTCAE grade =3 cardiac complications	Incidence of CTCAE grade =3 cardiac complications	day 35
Secondary	Rate of early deaths	Rate of early deaths (2 weeks)	week 2

External Links

•   czech ECRIN center
•   study alliance
•   University Hospital