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

• ClinicalTrials.gov Identifier: NCT01180322
• Recruitment Status: Unknown
• First Posted: August 12, 2010
• Last Update Posted: September 2, 2013
• Sponsor: University of Ulm
• Information provided by (Responsible Party): Dr. Richard Schlenk, University of Ulm

Study Description

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

Study Design

• 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

Arms and Interventions

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.

Outcome Measures

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 ]

Eligibility Criteria

• 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.

Contacts and Locations

Locations

Austria

Universitätsklinikum Innsbruck

Innsbruck, Austria, 6020

Krankenhaus der Barmherzigen Schwestern

Linz, Austria, 4010

Elisabethinen Krankenhaus Linz

Linz, Austria, 4020

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

Klinikum Stuttgart

Stuttgart, Germany, 70174

Diakonie-Klinikum Stuttgart

Stuttgart, Germany, 70176

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

• 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
• 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:

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