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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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A | Active Comparator | Standard Therapy |
|
| Arm B | Experimental | Investigational Therapy "Azacitidine Prior" |
|
| Arm C | Experimental | Investigational Therapy "Azacitidine Concurrent" |
|
| Arm D | Experimental | Investigational Therapy "Azacitidine After" |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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). |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Event-free survival | after two years of follow-up | |
| Relapse-free survival | after two years of follow-up | |
| overall survival |
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Inclusion Criteria:
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)
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| Name | Affiliation | Role |
|---|---|---|
| Richard F Schlenk, MD | University Hospital of Ulm | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Universitätsklinikum Innsbruck | Innsbruck | 6020 | Austria | |||
| Krankenhaus der Barmherzigen Schwestern |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37885041 | Derived | 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. |
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|
| 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). |
|
| 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. |
|
| 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) |
|
| Lenograstim | Drug | Consolidation therapy: subcutaneously daily beginning on day 10 until neutrophil count > 0.5 x 109/l. |
|
| 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 |
| Linz |
| 4010 |
| Austria |
| Elisabethinen Krankenhaus Linz | Linz | 4020 | Austria |
| Landeskliniken Salzburg | Salzburg | 5020 | Austria |
| Hanuschkrankenhaus | Vienna | 1140 | Austria |
| Universitätsklinikum Charité Berlin | Berlin | 13353 | Germany |
| Knappschaftskrankenhaus Bochum-Langendreer | Bochum | 44892 | Germany |
| Universitätsklinikum Bonn | Bonn | 53111 | Germany |
| Städtisches Klinikum Braunschweig | Braunschweig | 38114 | Germany |
| Klinikum Bremen-Mitte | Bremen | 28177 | Germany |
| Klinikum Darmstadt | Darmstadt | 64283 | Germany |
| Universitätsklinikum Düsseldorf | Düsseldorf | 40225 | Germany |
| Kliniken Essen Süd, Evangelischs Krankenhaus | Essen | 45239 | Germany |
| Klinikum Esslingen | Esslingen am Neckar | 73730 | Germany |
| Klinikum Frankfurt-Höchst | Frankfurt | 65929 | Germany |
| Medizinisches Versorgungszentrum Fulda | Fulda | 36043 | Germany |
| Universitätsklinikum Gießen | Giessen | 35392 | Germany |
| Wilhelm-Anton-Hospital Goch | Goch | 47574 | Germany |
| Universitätsklinikum Göttingen | Göttingen | 37075 | Germany |
| Sklepios Klinik Hamburg-Altona | Hamburg | 22763 | Germany |
| Evangelisches Krankenhaus Hamm | Hamm | 59063 | Germany |
| Klinikum Hanau | Hanau | 63450 | Germany |
| KRH Klinikum Hannover-Siloah | Hanover | 30449 | Germany |
| Medizinische Hochschule Hannover | Hanover | 30625 | Germany |
| SLK-Kliniken Heilbronn | Heilbronn | 74078 | Germany |
| Städtisches Klinikum Karlsruhe | Karlsruhe | 76133 | Germany |
| Universitätsklinikum Schleswig-Holstein | Kiel | 24116 | Germany |
| Caritas-Krankenhaus Lebach | Lebach | 66822 | Germany |
| Klinikum Lippe | Lemgo | 32657 | Germany |
| Klinikum Lüdenscheid | Lüdenscheid | 58515 | Germany |
| Klinikum der Johannes-Guttenberg-Universität | Mainz | 55131 | Germany |
| Johannes Wesling Klinikum Minden | Minden | 32429 | Germany |
| Stauferklinikum Schwäbisch-Gmünd | Mutlangen | 73557 | Germany |
| Klinikum rechts der Isar | München | 81675 | Germany |
| Klinikum Passau | Passau | 94032 | Germany |
| Krankenhaus der Barmherzigen Brüder | Regensburg | 93049 | Germany |
| Caritas-Klinik St. Theresia | Saarbrücken | 66113 | Germany |
| Klinikum Stuttgart | Stuttgart | 70174 | Germany |
| Diakonie-Klinikum Stuttgart | Stuttgart | 70176 | Germany |
| Krankenhaus der Barmherzigen Brüder | Trier | 54292 | Germany |
| Universitätsklinikum Tübingen | Tübingen | 72076 | Germany |
| Universitätsklinikum Ulm | Ulm | 89081 | Germany |
| Schwarzwald-Baar-Klinikum | Villingen-Schwenningen | 78050 | Germany |
| Helios Klinikum | Wuppertal | 42283 | Germany |
| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| D003561 | Cytarabine |
| D015255 | Idarubicin |
| D005047 | Etoposide |
| D001374 | Azacitidine |
| D000078224 | Lenograstim |
| ID | Term |
|---|---|
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001087 | Arabinonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D003630 | Daunorubicin |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D011034 | Podophyllotoxin |
| D013764 | Tetrahydronaphthalenes |
| D009281 | Naphthalenes |
| D005960 | Glucosides |
| D001372 | Aza Compounds |
| D012263 | Ribonucleosides |
| D016179 | Granulocyte Colony-Stimulating Factor |
| D003115 | Colony-Stimulating Factors |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D016298 | Hematopoietic Cell Growth Factors |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
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