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

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ClinicalTrials.gov Identifier: NCT01180322
Recruitment Status : Unknown
Verified August 2013 by Dr. Richard Schlenk, University of Ulm.
Recruitment status was:  Active, not recruiting
First Posted : August 12, 2010
Last Update Posted : September 2, 2013
Sponsor:
Information provided by (Responsible Party):
Dr. Richard Schlenk, University of Ulm

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


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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 336 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : November 2010
Actual Primary Completion Date : June 2012
Estimated Study Completion Date : October 2016


Arm Intervention/treatment
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.





Primary Outcome Measures :
  1. Rates of complete remission (CR) after induction therapy [ Time Frame: 56 days ]
    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 :
  1. Event-free survival [ Time Frame: after two years of follow-up ]
  2. Relapse-free survival [ Time Frame: after two years of follow-up ]
  3. overall survival [ Time Frame: after two years of follow-up ]
  4. days in hospital during each cycle and during the whole intervention [ Time Frame: 6 months ]
  5. Rate of early deaths or hypoplastic deaths (ED/HD) [ Time Frame: 56 days ]
  6. 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 ]
  7. quality of life [ Time Frame: at the end of therapy (in average 6 months) and once a year in the follow-up ]
    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].

  8. duration of leukopenia after each consolidation cycle [ Time Frame: 42 days ]
  9. duration of neutropenia after each consolidation cycle [ Time Frame: 42 days ]
  10. duration of thrombocytopenia after each consolidation cycle [ Time Frame: 42 days ]
  11. duration of leukopenia after each induction cycle [ Time Frame: 28 days ]
  12. duration of neutropenia after each induction cycle [ Time Frame: 28 days ]
  13. duration of thrombocytopenia after each induction cycle [ Time Frame: 28 days ]


Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01180322


Locations
Show Show 44 study locations
Sponsors and Collaborators
University of Ulm
Investigators
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Principal Investigator: Richard F Schlenk, MD University Hospital of Ulm
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Responsible Party: Dr. Richard Schlenk, PD Dr., University of Ulm
ClinicalTrials.gov Identifier: NCT01180322    
Other Study ID Numbers: AMLSG 12-09
First Posted: August 12, 2010    Key Record Dates
Last Update Posted: September 2, 2013
Last Verified: August 2013
Keywords provided by Dr. Richard Schlenk, University of Ulm:
azacitidine
Acute myeloid Leukemia (AML)
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Etoposide
Idarubicin
Azacitidine
Lenograstim
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Adjuvants, Immunologic