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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Dr. Richard Schlenk, University of Ulm
ClinicalTrials.gov Identifier:
NCT01180322
First received: August 2, 2010
Last updated: August 30, 2013
Last verified: August 2013
  Purpose

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


Condition Intervention Phase
Acute Myeloid Leukemia (AML)
Drug: Cytarabine
Drug: Idarubicin
Drug: Etoposide
Drug: Azacitidine
Drug: Lenograstim
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase-II Trial Evaluating Induction Therapy With Idarubicin and Etoposide Plus Sequential or Concurrent Azacitidine and Maintenance Therapy With Azacitidine

Resource links provided by NLM:


Further study details as provided by University of Ulm:

Primary Outcome Measures:
  • Rates of complete remission (CR) after induction therapy [ Time Frame: 56 days ] [ Designated as safety issue: No ]
    To evaluate the impact of sequential or concurrent addition of 5-azacytidine to intensive induction chemotherapy with idarubicin and etoposide on the CR rate


Secondary Outcome Measures:
  • Event-free survival [ Time Frame: after two years of follow-up ] [ Designated as safety issue: No ]
  • Relapse-free survival [ Time Frame: after two years of follow-up ] [ Designated as safety issue: No ]
  • overall survival [ Time Frame: after two years of follow-up ] [ Designated as safety issue: No ]
  • days in hospital during each cycle and during the whole intervention [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Rate of early deaths or hypoplastic deaths (ED/HD) [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
  • type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 3.0), timing and relatedness of non-hematological toxicity observed during different treatment cycles [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • quality of life [ Time Frame: at the end of therapy (in average 6 months) and once a year in the follow-up ] [ Designated as safety issue: No ]
    quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics according to Messerer et al [35].

  • duration of leukopenia after each consolidation cycle [ Time Frame: 42 days ] [ Designated as safety issue: No ]
  • duration of neutropenia after each consolidation cycle [ Time Frame: 42 days ] [ Designated as safety issue: No ]
  • duration of thrombocytopenia after each consolidation cycle [ Time Frame: 42 days ] [ Designated as safety issue: No ]
  • duration of leukopenia after each induction cycle [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • duration of neutropenia after each induction cycle [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • duration of thrombocytopenia after each induction cycle [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 336
Study Start Date: November 2010
Estimated Study Completion Date: October 2016
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A
Standard Therapy
Drug: 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).

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).

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.

Drug: Lenograstim

Consolidation therapy:

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

Experimental: Arm B
Investigational Therapy "Azacitidine Prior"
Drug: 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).

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).

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.

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)

Drug: Lenograstim

Consolidation therapy:

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

Experimental: Arm C
Investigational Therapy "Azacitidine Concurrent"
Drug: 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).

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).

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.

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)

Drug: Lenograstim

Consolidation therapy:

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

Experimental: Arm D
Investigational Therapy "Azacitidine After"
Drug: 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).

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).

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.

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)

Drug: Lenograstim

Consolidation therapy:

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


  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01180322

Locations
Austria
Universitätsklinikum Innsbruck
Innsbruck, Austria, 6020
Elisabethinen Krankenhaus Linz
Linz, Austria, 4020
Krankenhaus der Barmherzigen Schwestern
Linz, Austria, 4010
Landeskliniken Salzburg
Salzburg, Austria, 5020
Hanuschkrankenhaus
Wien, Austria, 1140
Germany
Universitätsklinikum Charité Berlin
Berlin, Germany, 13353
Knappschaftskrankenhaus Bochum-Langendreer
Bochum, Germany, 44892
Universitätsklinikum Bonn
Bonn, Germany, 53111
Städtisches Klinikum Braunschweig
Braunschweig, Germany, 38114
Klinikum Bremen-Mitte
Bremen, Germany, 28177
Klinikum Darmstadt
Darmstadt, Germany, 64283
Universitätsklinikum Düsseldorf
Düsseldorf, Germany, 40225
Kliniken Essen Süd, Evangelischs Krankenhaus
Essen, Germany, 45239
Klinikum Esslingen
Esslingen, Germany, 73730
Klinikum Frankfurt-Höchst
Frankfurt, Germany, 65929
Medizinisches Versorgungszentrum Fulda
Fulda, Germany, 36043
Universitätsklinikum Gießen
Gießen, Germany, 35392
Wilhelm-Anton-Hospital Goch
Goch, Germany, 47574
Universitätsklinikum Göttingen
Göttingen, Germany, 37075
Sklepios Klinik Hamburg-Altona
Hamburg, Germany, 22763
Evangelisches Krankenhaus Hamm
Hamm, Germany, 59063
Klinikum Hanau
Hanau, Germany, 63450
KRH Klinikum Hannover-Siloah
Hannover, Germany, 30449
Medizinische Hochschule Hannover
Hannover, Germany, 30625
SLK-Kliniken Heilbronn
Heilbronn, Germany, 74078
Städtisches Klinikum Karlsruhe
Karlsruhe, Germany, 76133
Universitätsklinikum Schleswig-Holstein
Kiel, Germany, 24116
Caritas-Krankenhaus Lebach
Lebach, Germany, 66822
Klinikum Lippe
Lemgo, Germany, 32657
Klinikum Lüdenscheid
Lüdenscheid, Germany, 58515
Klinikum der Johannes-Guttenberg-Universität
Mainz, Germany, 55131
Johannes Wesling Klinikum Minden
Minden, Germany, 32429
Stauferklinikum Schwäbisch-Gmünd
Mutlangen, Germany, 73557
Klinikum rechts der Isar
München, Germany, 81675
Klinikum Passau
Passau, Germany, 94032
Krankenhaus der Barmherzigen Brüder
Regensburg, Germany, 93049
Caritas-Klinik St. Theresia
Saarbrücken, Germany, 66113
Diakonie-Klinikum Stuttgart
Stuttgart, Germany, 70176
Klinikum Stuttgart
Stuttgart, Germany, 70174
Krankenhaus der Barmherzigen Brüder
Trier, Germany, 54292
Universitätsklinikum Tübingen
Tübingen, Germany, 72076
Universitätsklinikum Ulm
Ulm, Germany, 89081
Schwarzwald-Baar-Klinikum
Villingen-Schwenningen, Germany, 78050
Helios Klinikum
Wuppertal, Germany, 42283
Sponsors and Collaborators
University of Ulm
Investigators
Principal Investigator: Richard F Schlenk, MD University Hospital of Ulm
  More Information

No publications provided

Responsible Party: Dr. Richard Schlenk, PD Dr., University of Ulm
ClinicalTrials.gov Identifier: NCT01180322     History of Changes
Other Study ID Numbers: AMLSG 12-09
Study First Received: August 2, 2010
Last Updated: August 30, 2013
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University of Ulm:
azacitidine
Acute myeloid Leukemia (AML)

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type
Azacitidine
Etoposide
Etoposide phosphate
Idarubicin
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on November 24, 2014