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Trial Evaluating Induction Therapy With Idarubicin and Etoposide Plus Sequential or Concurrent Azacitidine and Maintenance Therapy With Azacitidine

NCT ID: NCT01180322

Last Updated: 2020-12-31

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

277 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-11-30

Study Completion Date

2016-10-02

Brief Summary

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This is a randomized phase II, four-arm, open-label, multi-center study in adult patients with acute myeloid leukemia (AML) as defined in inclusion/exclusion criteria.

The primary efficacy objective is to evaluate the impact of sequential or concurrent addition of 5-azacytidine to intensive induction chemotherapy with idarubicin and etoposide on the complete remission (CR) rate

Sample size: 336 patients

The treatment duration of an individual patient randomized into one of the three experimental arms (Arm B, C, D) (in case of application of induction, consolidation and maintenance therapy with Azacitidine) is about 30 months.

The treatment duration for patients randomized into the standard arm of the study (Arm A) is about 7 months (in case of application of induction, consolidation and 2-yrs observation as maintenance (without treatment with Azacitidine)).

In case of induction followed by consolidation with allogeneic Stem cell transplantation (SCT) the treatment duration per patient is about 6 months.

Every patient will be followed until month 54 after inclusion into the study. Duration of the study for an individual patient including treatment (induction, consolidation \[chemotherapy or allogeneic SCT\], maintenance \[experimental arm with Azacitidine or observation\]) and follow-up period: 54 months

Detailed Description

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Conditions

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Acute Myeloid Leukemia (AML)

Keywords

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azacitidine Acute myeloid Leukemia (AML)

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm A

Standard Therapy

Group Type ACTIVE_COMPARATOR

Cytarabine

Intervention Type DRUG

Induction therapy:100 mg/m2/day by continuous intravenous (IV) infusion on days 1-7 (total dose 700 mg/m2)

Consolidation therapy:

Younger adults (18 to 65 years): 3 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 18 g/m2).

Elderly patients (\>65 years): 1 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 6 g/m2).

Idarubicin

Intervention Type DRUG

First induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1,3,5 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 1+3.

Arm B:

12 mg/m2/day by IV push on days 6, 8 10 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 6+8.

Second induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1 and 3 (total dose 24 mg/m2; for all age groups)

Arm B:

12 mg/m2/day by IV push on days 6 and 8 (total dose 24 mg/m2; for all age groups).

Etoposide

Intervention Type DRUG

Induction therapy:

Arm A, C, D:

100 mg/m²/day by 1-hour IV infusion on days 1,2,3 (total dose 300 mg/m2). On days 1 and 3 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 1+3.

Arm B:

100 mg/m²/day by 1-hour IV infusion on days 6,7,8 (total dose 300 mg/m2). On days 6 and 8 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 6+8.

Lenograstim

Intervention Type DRUG

Consolidation therapy:

subcutaneously daily beginning on day 10 until neutrophil count \> 0.5 x 109/l.

Arm B

Investigational Therapy "Azacitidine Prior"

Group Type EXPERIMENTAL

Cytarabine

Intervention Type DRUG

Induction therapy:100 mg/m2/day by continuous intravenous (IV) infusion on days 1-7 (total dose 700 mg/m2)

Consolidation therapy:

Younger adults (18 to 65 years): 3 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 18 g/m2).

Elderly patients (\>65 years): 1 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 6 g/m2).

Idarubicin

Intervention Type DRUG

First induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1,3,5 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 1+3.

Arm B:

12 mg/m2/day by IV push on days 6, 8 10 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 6+8.

Second induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1 and 3 (total dose 24 mg/m2; for all age groups)

Arm B:

12 mg/m2/day by IV push on days 6 and 8 (total dose 24 mg/m2; for all age groups).

Etoposide

Intervention Type DRUG

Induction therapy:

Arm A, C, D:

100 mg/m²/day by 1-hour IV infusion on days 1,2,3 (total dose 300 mg/m2). On days 1 and 3 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 1+3.

Arm B:

100 mg/m²/day by 1-hour IV infusion on days 6,7,8 (total dose 300 mg/m2). On days 6 and 8 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 6+8.

Azacitidine

Intervention Type DRUG

Induction therapy:

Arm B and C:

100 mg/m2/day by subcutaneous (SC) injection or 15-minute IV infusion on day 1 to day 5 (total dose 500 mg/m2). Azacitidine is always given prior to idarubicin and etoposide.

Arm D:

100 mg/m2/day by SC injection or 15-minute IV infusion on days 4-8 (total dose 500 mg/m2). Azacitidine is always given prior to idarubicin and etoposide.

Maintenance therapy:

Arm B, C, D:

50 mg/m2/day by SC injection on days 1-5 (total dose 250 mg/m2) every 4 weeks. (Maintenance therapy is scheduled for a total duration of 2 years in patients with continuous CR)

Lenograstim

Intervention Type DRUG

Consolidation therapy:

subcutaneously daily beginning on day 10 until neutrophil count \> 0.5 x 109/l.

Arm C

Investigational Therapy "Azacitidine Concurrent"

Group Type EXPERIMENTAL

Cytarabine

Intervention Type DRUG

Induction therapy:100 mg/m2/day by continuous intravenous (IV) infusion on days 1-7 (total dose 700 mg/m2)

Consolidation therapy:

Younger adults (18 to 65 years): 3 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 18 g/m2).

Elderly patients (\>65 years): 1 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 6 g/m2).

Idarubicin

Intervention Type DRUG

First induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1,3,5 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 1+3.

Arm B:

12 mg/m2/day by IV push on days 6, 8 10 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 6+8.

Second induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1 and 3 (total dose 24 mg/m2; for all age groups)

Arm B:

12 mg/m2/day by IV push on days 6 and 8 (total dose 24 mg/m2; for all age groups).

Etoposide

Intervention Type DRUG

Induction therapy:

Arm A, C, D:

100 mg/m²/day by 1-hour IV infusion on days 1,2,3 (total dose 300 mg/m2). On days 1 and 3 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 1+3.

Arm B:

100 mg/m²/day by 1-hour IV infusion on days 6,7,8 (total dose 300 mg/m2). On days 6 and 8 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 6+8.

Azacitidine

Intervention Type DRUG

Induction therapy:

Arm B and C:

100 mg/m2/day by subcutaneous (SC) injection or 15-minute IV infusion on day 1 to day 5 (total dose 500 mg/m2). Azacitidine is always given prior to idarubicin and etoposide.

Arm D:

100 mg/m2/day by SC injection or 15-minute IV infusion on days 4-8 (total dose 500 mg/m2). Azacitidine is always given prior to idarubicin and etoposide.

Maintenance therapy:

Arm B, C, D:

50 mg/m2/day by SC injection on days 1-5 (total dose 250 mg/m2) every 4 weeks. (Maintenance therapy is scheduled for a total duration of 2 years in patients with continuous CR)

Lenograstim

Intervention Type DRUG

Consolidation therapy:

subcutaneously daily beginning on day 10 until neutrophil count \> 0.5 x 109/l.

Arm D

Investigational Therapy "Azacitidine After"

Group Type EXPERIMENTAL

Cytarabine

Intervention Type DRUG

Induction therapy:100 mg/m2/day by continuous intravenous (IV) infusion on days 1-7 (total dose 700 mg/m2)

Consolidation therapy:

Younger adults (18 to 65 years): 3 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 18 g/m2).

Elderly patients (\>65 years): 1 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 6 g/m2).

Idarubicin

Intervention Type DRUG

First induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1,3,5 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 1+3.

Arm B:

12 mg/m2/day by IV push on days 6, 8 10 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 6+8.

Second induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1 and 3 (total dose 24 mg/m2; for all age groups)

Arm B:

12 mg/m2/day by IV push on days 6 and 8 (total dose 24 mg/m2; for all age groups).

Etoposide

Intervention Type DRUG

Induction therapy:

Arm A, C, D:

100 mg/m²/day by 1-hour IV infusion on days 1,2,3 (total dose 300 mg/m2). On days 1 and 3 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 1+3.

Arm B:

100 mg/m²/day by 1-hour IV infusion on days 6,7,8 (total dose 300 mg/m2). On days 6 and 8 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 6+8.

Azacitidine

Intervention Type DRUG

Induction therapy:

Arm B and C:

100 mg/m2/day by subcutaneous (SC) injection or 15-minute IV infusion on day 1 to day 5 (total dose 500 mg/m2). Azacitidine is always given prior to idarubicin and etoposide.

Arm D:

100 mg/m2/day by SC injection or 15-minute IV infusion on days 4-8 (total dose 500 mg/m2). Azacitidine is always given prior to idarubicin and etoposide.

Maintenance therapy:

Arm B, C, D:

50 mg/m2/day by SC injection on days 1-5 (total dose 250 mg/m2) every 4 weeks. (Maintenance therapy is scheduled for a total duration of 2 years in patients with continuous CR)

Lenograstim

Intervention Type DRUG

Consolidation therapy:

subcutaneously daily beginning on day 10 until neutrophil count \> 0.5 x 109/l.

Interventions

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Cytarabine

Induction therapy:100 mg/m2/day by continuous intravenous (IV) infusion on days 1-7 (total dose 700 mg/m2)

Consolidation therapy:

Younger adults (18 to 65 years): 3 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 18 g/m2).

Elderly patients (\>65 years): 1 g/m2/day by IV infusion over 3 hours every 12 hours on days 1, 2, and 3 (total dose 6 g/m2).

Intervention Type DRUG

Idarubicin

First induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1,3,5 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 1+3.

Arm B:

12 mg/m2/day by IV push on days 6, 8 10 (total dose 36 mg/m2). For elderly (\>65 yrs) patients only two doses of idarubicin are foreseen on days 6+8.

Second induction therapy:

Arm A, C, D:

12 mg/m2/day by IV push on days 1 and 3 (total dose 24 mg/m2; for all age groups)

Arm B:

12 mg/m2/day by IV push on days 6 and 8 (total dose 24 mg/m2; for all age groups).

Intervention Type DRUG

Etoposide

Induction therapy:

Arm A, C, D:

100 mg/m²/day by 1-hour IV infusion on days 1,2,3 (total dose 300 mg/m2). On days 1 and 3 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 1+3.

Arm B:

100 mg/m²/day by 1-hour IV infusion on days 6,7,8 (total dose 300 mg/m2). On days 6 and 8 start after idarubicin push. For elderly (\>65 yrs) patients only two doses of etoposide are foreseen on days 6+8.

Intervention Type DRUG

Azacitidine

Induction therapy:

Arm B and C:

100 mg/m2/day by subcutaneous (SC) injection or 15-minute IV infusion on day 1 to day 5 (total dose 500 mg/m2). Azacitidine is always given prior to idarubicin and etoposide.

Arm D:

100 mg/m2/day by SC injection or 15-minute IV infusion on days 4-8 (total dose 500 mg/m2). Azacitidine is always given prior to idarubicin and etoposide.

Maintenance therapy:

Arm B, C, D:

50 mg/m2/day by SC injection on days 1-5 (total dose 250 mg/m2) every 4 weeks. (Maintenance therapy is scheduled for a total duration of 2 years in patients with continuous CR)

Intervention Type DRUG

Lenograstim

Consolidation therapy:

subcutaneously daily beginning on day 10 until neutrophil count \> 0.5 x 109/l.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* Patients with suspected diagnosis of acute myeloid leukemia or related precursor neoplasm, or acute leukemia of ambiguous lineage (classified according to the World Health Organization (WHO) classification)
* Patients considered eligible for intensive chemotherapy
* WHO performance status of ≤ 2
* Age ≥ 18 years. There is no upper age limit.
* No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis
* Non-pregnant and non-nursing. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration. "Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months.
* Female patients in the reproductive age and male patients must agree to avoid getting pregnant or to father a child while on therapy and for 3 month after the last dose of chemotherapy.
* Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin one acceptable method of birth control (IUD, tubal ligation, or partner's vasectomy). Hormonal contraception is an inadequate method of birth control.
* Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy. (while on therapy and for 3 month after the last dose of chemotherapy)
* Signed written informed consent.

Exclusion Criteria

-AML with other recurrent genetic abnormalities (according to WHO 2008): AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 AML with t(15;17)(q22;q12); PML-RARA (or variant translocations with other RARA gene fusions)

* AML with NPM1 mutation
* AML with FLT3 mutation
* Performance status WHO \>2
* Patients with ejection fraction \< 50% by Multi Gated Acquisition Scan (MUGA) or echocardiogram (ECHO scan) within 14 days of day 1
* Organ insufficiency (creatinine \>1.5x upper normal serum level; bilirubin, AST or ALP \>2.5x upper normal serum level, not attributable to AML; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)
* Uncontrolled infection
* Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
* Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.
* Known positive for Human immunodeficiency virus (HIV)
* Bleeding disorder independent of leukemia
* No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation.
* No consent for biobanking.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Ulm

OTHER

Sponsor Role lead

Responsible Party

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Prof. Dr. Richard Schlenk

PD Dr.

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Richard F Schlenk, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Ulm

Locations

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Universitätsklinikum Innsbruck

Innsbruck, , Austria

Site Status

Krankenhaus der Barmherzigen Schwestern

Linz, , Austria

Site Status

Elisabethinen Krankenhaus Linz

Linz, , Austria

Site Status

Landeskliniken Salzburg

Salzburg, , Austria

Site Status

Hanuschkrankenhaus

Vienna, , Austria

Site Status

Universitätsklinikum Charité Berlin

Berlin, , Germany

Site Status

Knappschaftskrankenhaus Bochum-Langendreer

Bochum, , Germany

Site Status

Universitätsklinikum Bonn

Bonn, , Germany

Site Status

Städtisches Klinikum Braunschweig

Braunschweig, , Germany

Site Status

Klinikum Bremen-Mitte

Bremen, , Germany

Site Status

Klinikum Darmstadt

Darmstadt, , Germany

Site Status

Universitätsklinikum Düsseldorf

Düsseldorf, , Germany

Site Status

Kliniken Essen Süd, Evangelischs Krankenhaus

Essen, , Germany

Site Status

Klinikum Esslingen

Esslingen am Neckar, , Germany

Site Status

Klinikum Frankfurt-Höchst

Frankfurt, , Germany

Site Status

Medizinisches Versorgungszentrum Fulda

Fulda, , Germany

Site Status

Universitätsklinikum Gießen

Giessen, , Germany

Site Status

Wilhelm-Anton-Hospital Goch

Goch, , Germany

Site Status

Universitätsklinikum Göttingen

Göttingen, , Germany

Site Status

Sklepios Klinik Hamburg-Altona

Hamburg, , Germany

Site Status

Evangelisches Krankenhaus Hamm

Hamm, , Germany

Site Status

Klinikum Hanau

Hanau, , Germany

Site Status

KRH Klinikum Hannover-Siloah

Hanover, , Germany

Site Status

Medizinische Hochschule Hannover

Hanover, , Germany

Site Status

SLK-Kliniken Heilbronn

Heilbronn, , Germany

Site Status

Städtisches Klinikum Karlsruhe

Karlsruhe, , Germany

Site Status

Universitätsklinikum Schleswig-Holstein

Kiel, , Germany

Site Status

Caritas-Krankenhaus Lebach

Lebach, , Germany

Site Status

Klinikum Lippe

Lemgo, , Germany

Site Status

Klinikum Lüdenscheid

Lüdenscheid, , Germany

Site Status

Klinikum der Johannes-Guttenberg-Universität

Mainz, , Germany

Site Status

Johannes Wesling Klinikum Minden

Minden, , Germany

Site Status

Stauferklinikum Schwäbisch-Gmünd

Mutlangen, , Germany

Site Status

Klinikum rechts der Isar

München, , Germany

Site Status

Klinikum Passau

Passau, , Germany

Site Status

Krankenhaus der Barmherzigen Brüder

Regensburg, , Germany

Site Status

Caritas-Klinik St. Theresia

Saarbrücken, , Germany

Site Status

Klinikum Stuttgart

Stuttgart, , Germany

Site Status

Diakonie-Klinikum Stuttgart

Stuttgart, , Germany

Site Status

Krankenhaus der Barmherzigen Brüder

Trier, , Germany

Site Status

Universitätsklinikum Tübingen

Tübingen, , Germany

Site Status

Universitätsklinikum Ulm

Ulm, , Germany

Site Status

Schwarzwald-Baar-Klinikum

Villingen-Schwenningen, , Germany

Site Status

Helios Klinikum

Wuppertal, , Germany

Site Status

Countries

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Austria Germany

References

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Schmutz M, Zucknick M, Schlenk RF, Mertens D, Benner A, Weichenhan D, Mucke O, Dohner K, Plass C, Bullinger L, Claus R. Predictive value of DNA methylation patterns in AML patients treated with an azacytidine containing induction regimen. Clin Epigenetics. 2023 Oct 26;15(1):171. doi: 10.1186/s13148-023-01580-z.

Reference Type DERIVED
PMID: 37885041 (View on PubMed)

Other Identifiers

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AMLSG 12-09

Identifier Type: -

Identifier Source: org_study_id