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

Sponsor

Technische Universität Dresden (Other)

Overall Status

Recruiting

CT.gov ID

NCT02140242

Collaborator

Universitätsklinikum Dresden, Nationales Centrum für Tumorerkrankungen Dresden (NCT/UCC) (Other), Masaryk University (Other)

600

Enrollment

Locations

Arms

96.5

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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.

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].

Study Design

Study Type:

Interventional

Anticipated 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 :

Apr 16, 2014

Anticipated Primary Completion Date :

May 1, 2022

Anticipated Study Completion Date :

May 1, 2022

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

response rate after first induction [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 [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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts 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)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Interní klinika LF Masarykovy univerzity a Fakultní nemocnice Brno	Brno	Czechia
2	Faculty Hospital Hradec Králové, II. Clinic of international medicine	Hradec Králové	Czechia
3	Fakultní nemocnice Olomouc	Olomouc	Czechia
4	Fakultní nemocnice Královské Vinohrady	Praha	Czechia
5	Ústav hematologie a krevní transfuze (ÚHKT)	Praha	Czechia
6	Uniklinik RWTH Aachen	Aachen	Germany	52074
7	Klinikum Altenburger Land GmbH	Altenburg	Germany
8	Klinikum Augsburg	Augsburg	Germany
9	Sozialstiftung Bamberg Klinikum am Bruderwald	Bamberg	Germany
10	Charite Campus Benjamin Franklin	Berlin	Germany
11	Helios Klinikum Berlin-Buch	Berlin	Germany
12	Klinikum Bielefeld	Bielefeld	Germany
13	Augusta Kliniken Bochum Hattingen	Bochum	Germany	44791
14	Ev. Diakonie-Krankenhaus gGmbH Bremen	Bremen	Germany
15	Klinikum Chemnitz GmbH	Chemnitz	Germany
16	Carl.Thiem-Klinikum Cottbus gGmbH	Cottbus	Germany
17	Universitätsklinikum Carl Gustav Carus Dresden	Dresden	Germany
18	Krankenhaus Düren gem. GmbH	Düren	Germany
19	Marienhospital Düsseldorf GmbH	Düsseldorf	Germany
20	Universitätsklinikum Erlangen	Erlangen	Germany
21	Universitätsklinikum Essen	Essen	Germany
22	Johann Wolfgang Goethe-Universität Frankfurt am Main	Frankfurt am Main	Germany
23	Universitätsklinikum Halle (Saale)	Halle	Germany
24	Asklepios Klinik St. Georg	Hamburg	Germany
25	St. Marien-Hospital Hamm	Hamm	Germany
26	Universitätsklinikum Heidelberg	Heidelberg	Germany
27	St. Bernward Krankenhaus Hildesheim	Hildesheim	Germany
28	Universitätsklinikum Jena	Jena	Germany	07740
29	Westpfalz-Klinikum GmbH	Kaiserslautern	Germany
30	Städtisches Krankenhaus Kiel	Kiel	Germany
31	Gemeinschaftsklinikum Mittelrhein GmbH	Koblenz	Germany
32	Universitätsklinikum Leipzig	Leipzig	Germany
33	Universitätsklinikum Gießen und Marburg	Marburg	Germany
34	Universitätsklinikum Münster	Münster	Germany
35	Klinikum Nürnberg-Nord	Nürnberg	Germany
36	Agaplesion Diakoniekrankenhaus Rotenburg	Rotenburg	Germany
37	Diakonie-Klinikum Schwäbisch Hall gGmbH	Schwäbisch Hall	Germany
38	Klinikum Sindelfingen-Böblingen	Sindelfingen	Germany
39	Robert-Bosch-Krankenhaus	Stuttgart	Germany
40	Rems-Murr-Klinikum Winnenden	Winnenden	Germany