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

NCT01180322 | Completed Phase 2 DMC

• 1 other identifier: AMLSG 12-09
• Study Type: interventional
• Target: 277
• Locations: 2 countries
• Sites: 44

Brief Summary

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

Conditions

Acute Myeloid Leukemia (AML)

Keywords

azacitidine; Acute myeloid Leukemia (AML)

Outcome Measures

Primary Outcomes (1)

• Rates of complete remission (CR) after induction therapy

  To evaluate the impact of sequential or concurrent addition of 5-azacytidine to intensive induction chemotherapy with idarubicin and etoposide on the CR rate

  56 days

Secondary Outcomes (13)

• Event-free survival

  after two years of follow-up

• Relapse-free survival

  after two years of follow-up

• overall survival

  after two years of follow-up

• days in hospital during each cycle and during the whole intervention

  6 months

• Rate of early deaths or hypoplastic deaths (ED/HD)

  56 days

Study Arms (4)

Arm A

ACTIVE COMPARATOR

Standard Therapy

Drug: Cytarabine; Drug: Idarubicin; Drug: Etoposide; Drug: Lenograstim

Arm B

EXPERIMENTAL

Investigational Therapy "Azacitidine Prior"

Drug: Cytarabine; Drug: Idarubicin; Drug: Etoposide; Drug: Azacitidine; Drug: Lenograstim

Arm C

EXPERIMENTAL

Investigational Therapy "Azacitidine Concurrent"

Drug: Cytarabine; Drug: Idarubicin; Drug: Etoposide; Drug: Azacitidine; Drug: Lenograstim

Arm D

EXPERIMENTAL

Investigational Therapy "Azacitidine After"

Drug: Cytarabine; Drug: Idarubicin; Drug: Etoposide; Drug: Azacitidine; Drug: Lenograstim

Interventions

Cytarabine 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).

Arm A; Arm B; Arm C; Arm D

Idarubicin 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).

Arm A; Arm B; Arm C; Arm D

Etoposide 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.

Arm A; Arm B; Arm C; Arm D

Azacitidine 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)

Arm B; Arm C; Arm D

Lenograstim DRUG

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

Arm A; Arm B; Arm C; Arm D

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Ulm: lead

Study Sites (44)

Universitätsklinikum Innsbruck

Innsbruck, 6020, Austria

Location

Krankenhaus der Barmherzigen Schwestern

Linz, 4010, Austria

Location

Elisabethinen Krankenhaus Linz

Linz, 4020, Austria

Location

Landeskliniken Salzburg

Salzburg, 5020, Austria

Location

Hanuschkrankenhaus

Vienna, 1140, Austria

Location

Universitätsklinikum Charité Berlin

Berlin, 13353, Germany

Location

Knappschaftskrankenhaus Bochum-Langendreer

Bochum, 44892, Germany

Location

Universitätsklinikum Bonn

Bonn, 53111, Germany

Location

Städtisches Klinikum Braunschweig

Braunschweig, 38114, Germany

Location

Klinikum Bremen-Mitte

Bremen, 28177, Germany

Location

Klinikum Darmstadt

Darmstadt, 64283, Germany

Location

Universitätsklinikum Düsseldorf

Düsseldorf, 40225, Germany

Location

Kliniken Essen Süd, Evangelischs Krankenhaus

Essen, 45239, Germany

Location

Klinikum Esslingen

Esslingen am Neckar, 73730, Germany

Location

Klinikum Frankfurt-Höchst

Frankfurt, 65929, Germany

Location

Medizinisches Versorgungszentrum Fulda

Fulda, 36043, Germany

Location

Universitätsklinikum Gießen

Giessen, 35392, Germany

Location

Wilhelm-Anton-Hospital Goch

Goch, 47574, Germany

Location

Universitätsklinikum Göttingen

Göttingen, 37075, Germany

Location

Sklepios Klinik Hamburg-Altona

Hamburg, 22763, Germany

Location

Evangelisches Krankenhaus Hamm

Hamm, 59063, Germany

Location

Klinikum Hanau

Hanau, 63450, Germany

Location

KRH Klinikum Hannover-Siloah

Hanover, 30449, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

SLK-Kliniken Heilbronn

Heilbronn, 74078, Germany

Location

Städtisches Klinikum Karlsruhe

Karlsruhe, 76133, Germany

Location

Universitätsklinikum Schleswig-Holstein

Kiel, 24116, Germany

Location

Caritas-Krankenhaus Lebach

Lebach, 66822, Germany

Location

Klinikum Lippe

Lemgo, 32657, Germany

Location

Klinikum Lüdenscheid

Lüdenscheid, 58515, Germany

Location

Klinikum der Johannes-Guttenberg-Universität

Mainz, 55131, Germany

Location

Johannes Wesling Klinikum Minden

Minden, 32429, Germany

Location

Stauferklinikum Schwäbisch-Gmünd

Mutlangen, 73557, Germany

Location

Klinikum rechts der Isar

München, 81675, Germany

Location

Klinikum Passau

Passau, 94032, Germany

Location

Krankenhaus der Barmherzigen Brüder

Regensburg, 93049, Germany

Location

Caritas-Klinik St. Theresia

Saarbrücken, 66113, Germany

Location

Klinikum Stuttgart

Stuttgart, 70174, Germany

Location

Diakonie-Klinikum Stuttgart

Stuttgart, 70176, Germany

Location

Krankenhaus der Barmherzigen Brüder

Trier, 54292, Germany

Location

Universitätsklinikum Tübingen

Tübingen, 72076, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

Schwarzwald-Baar-Klinikum

Villingen-Schwenningen, 78050, Germany

Location

Helios Klinikum

Wuppertal, 42283, Germany

Location

Related Publications (1)

• 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.

  PMID: 37885041 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Cytarabine; Idarubicin; Etoposide; Azacitidine; Lenograstim

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Aza Compounds; Ribonucleosides; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Richard F Schlenk, MD

  University Hospital of Ulm

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PD Dr.

Study Record Dates

• First Submitted: August 2, 2010
• First Posted: August 12, 2010
• Study Start: November 1, 2010
• Primary Completion: June 1, 2012
• Study Completion: October 2, 2016
• Last Updated: December 31, 2020

Record last verified: 2020-12

Locations

AU (5); DE (39)