Clinical trial NCT02140242: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia, Myelocytic, Acute
Keywords: AML
leukemia
induction treatment
daunorubicin
7+3
Lead sponsor: Technische Universität Dresden
Sponsor class: OTHER
Collaborators: name: University Hospital Dresden
name: Masaryk University
First posted: 2014-05-16
Enrollment: 721
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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 \[Onkopedia-Leitlinie 2017\].

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)

Primary outcomes:
measure: response rate after first induction
timeFrame: day 15
measure: Rate complete remissions
timeFrame: day 35 after final induction
Secondary outcomes:
measure: rate cytogenetic and molecular complete remissions
timeFrame: day 35
measure: event-free survival (EFS)
timeFrame: 5 years
measure: relapse-free survival (RFS)
timeFrame: 5 years
measure: overall survival (OS)
timeFrame: 5 years
measure: Correlation between Minimal Residual Disease (MRD) and EFS, RFS, OS
timeFrame: day 35
measure: Rate of induction deaths
timeFrame: day 60
measure: Incidence of serious infectious complications
timeFrame: day 35
measure: Sonographic cardiac left ventricular ejection fraction
timeFrame: day 35
measure: Serum levels of pro-brain natriuretic peptide (por-BNP) and Troponin-T
timeFrame: day 35
measure: Incidence of CTCAE grade ≥3 cardiac complications
timeFrame: day 35
measure: Rate of early deaths
timeFrame: week 2
Other outcomes:
Locations:
city: Brno
country: Czechia
facility: Interní klinika LF Masarykovy univerzity a Fakultní nemocnice Brno
city: Hradec Králové
country: Czechia
facility: Faculty Hospital Hradec Králové, II. Clinic of international medicine
city: Olomouc
country: Czechia
facility: Fakultní nemocnice Olomouc
city: Praha
country: Czechia
facility: Fakultní nemocnice Královské Vinohrady
city: Praha
country: Czechia
facility: Ústav hematologie a krevní transfuze (ÚHKT)
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
city: Altenburg
country: Germany
facility: Klinikum Altenburger Land GmbH
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bamberg
country: Germany
facility: Sozialstiftung Bamberg Klinikum am Bruderwald
city: Berlin
country: Germany
facility: Charite Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Bielefeld
country: Germany
facility: Klinikum Bielefeld
city: Bochum
country: Germany
facility: Augusta Kliniken Bochum Hattingen
city: Bremen
country: Germany
facility: Ev. Diakonie-Krankenhaus gGmbH Bremen
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz GmbH
city: Cottbus
country: Germany
facility: Carl.Thiem-Klinikum Cottbus gGmbH
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Düren
country: Germany
facility: Krankenhaus Düren gem. GmbH
city: Düsseldorf
country: Germany
facility: Marienhospital Düsseldorf GmbH
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt am Main
country: Germany
facility: Johann Wolfgang Goethe-Universität Frankfurt am Main
city: Halle
country: Germany
facility: Universitätsklinikum Halle (Saale)
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg
city: Hamm
country: Germany
facility: St. Marien-Hospital Hamm
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Hildesheim
country: Germany
facility: St. Bernward Krankenhaus Hildesheim
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH
city: Kiel
country: Germany
facility: Städtisches Krankenhaus Kiel
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Mittelrhein GmbH
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Marburg
country: Germany
facility: Universitätsklinikum Gießen und Marburg
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg-Nord
city: Schwäbisch Hall
country: Germany
facility: Diakonie-Klinikum Schwäbisch Hall gGmbH
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus
city: Winnenden
country: Germany
facility: Rems-Murr-Klinikum Winnenden
Study officials:
affiliation: Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I
name: Christoph Röllig, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: