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

Randomized Phase-II Trial Evaluating Induction Therapy With Idarubicin and Etoposide Plus Sequential or Concurrent Azacitidine and Maintenance Therapy With Azacitidine

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

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: Cytarabine; Drug: Idarubicin; Drug: Etoposide; Drug: Lenograstim; Drug: Azacitidine

• Study Type: Interventional
• Enrollment (Actual): 277
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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: Lenograstim; Consolidation therapy: subcutaneously daily beginning on day 10 until neutrophil count > 0.5 x 109/l.; 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)
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: Lenograstim; Consolidation therapy: subcutaneously daily beginning on day 10 until neutrophil count > 0.5 x 109/l.; 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)
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: Lenograstim; Consolidation therapy: subcutaneously daily beginning on day 10 until neutrophil count > 0.5 x 109/l.; 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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		6 months
quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30)	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].	at the end of therapy (in average 6 months) and once a year in the follow-up
duration of leukopenia after each consolidation cycle		42 days
duration of neutropenia after each consolidation cycle		42 days
duration of thrombocytopenia after each consolidation cycle		42 days
duration of leukopenia after each induction cycle		28 days
duration of neutropenia after each induction cycle		28 days
duration of thrombocytopenia after each induction cycle		28 days

Collaborators and Investigators

• Sponsor: University of Ulm
• Investigators: Principal Investigator: Richard F Schlenk, MD, University Hospital of Ulm

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): October 2, 2016

Study Registration Dates

• First Submitted: August 2, 2010
• First Submitted That Met QC Criteria: August 11, 2010
• First Posted (Estimate): August 12, 2010

Study Record Updates

• Last Update Posted (Actual): December 31, 2020
• Last Update Submitted That Met QC Criteria: December 29, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: azacitidine; Acute myeloid Leukemia (AML)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Etoposide; Lenograstim; Azacitidine; Cytarabine; Idarubicin
• Other Study ID Numbers: AMLSG 12-09