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

Sponsor

University of Ulm (Other)

Overall Status

Completed

CT.gov ID

NCT01180322

Collaborator

(none)

277

Enrollment

Locations

Arms

Duration (Months)

6.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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

Actual Enrollment :

277 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 :

Nov 1, 2010

Actual Primary Completion Date :

Jun 1, 2012

Actual Study Completion Date :

Oct 2, 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

Rates of complete remission (CR) after induction therapy [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

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) [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].
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	Country	Postal Code
1	Universitätsklinikum Innsbruck	Innsbruck	Austria	6020
2	Krankenhaus der Barmherzigen Schwestern	Linz	Austria	4010
3	Elisabethinen Krankenhaus Linz	Linz	Austria	4020
4	Landeskliniken Salzburg	Salzburg	Austria	5020
5	Hanuschkrankenhaus	Wien	Austria	1140
6	Universitätsklinikum Charité Berlin	Berlin	Germany	13353
7	Knappschaftskrankenhaus Bochum-Langendreer	Bochum	Germany	44892
8	Universitätsklinikum Bonn	Bonn	Germany	53111
9	Städtisches Klinikum Braunschweig	Braunschweig	Germany	38114
10	Klinikum Bremen-Mitte	Bremen	Germany	28177
11	Klinikum Darmstadt	Darmstadt	Germany	64283
12	Universitätsklinikum Düsseldorf	Düsseldorf	Germany	40225
13	Kliniken Essen Süd, Evangelischs Krankenhaus	Essen	Germany	45239
14	Klinikum Esslingen	Esslingen	Germany	73730
15	Klinikum Frankfurt-Höchst	Frankfurt	Germany	65929
16	Medizinisches Versorgungszentrum Fulda	Fulda	Germany	36043
17	Universitätsklinikum Gießen	Gießen	Germany	35392
18	Wilhelm-Anton-Hospital Goch	Goch	Germany	47574
19	Universitätsklinikum Göttingen	Göttingen	Germany	37075
20	Sklepios Klinik Hamburg-Altona	Hamburg	Germany	22763
21	Evangelisches Krankenhaus Hamm	Hamm	Germany	59063
22	Klinikum Hanau	Hanau	Germany	63450
23	KRH Klinikum Hannover-Siloah	Hannover	Germany	30449
24	Medizinische Hochschule Hannover	Hannover	Germany	30625
25	SLK-Kliniken Heilbronn	Heilbronn	Germany	74078
26	Städtisches Klinikum Karlsruhe	Karlsruhe	Germany	76133
27	Universitätsklinikum Schleswig-Holstein	Kiel	Germany	24116
28	Caritas-Krankenhaus Lebach	Lebach	Germany	66822
29	Klinikum Lippe	Lemgo	Germany	32657
30	Klinikum Lüdenscheid	Lüdenscheid	Germany	58515
31	Klinikum der Johannes-Guttenberg-Universität	Mainz	Germany	55131
32	Johannes Wesling Klinikum Minden	Minden	Germany	32429
33	Stauferklinikum Schwäbisch-Gmünd	Mutlangen	Germany	73557
34	Klinikum rechts der Isar	München	Germany	81675
35	Klinikum Passau	Passau	Germany	94032
36	Krankenhaus der Barmherzigen Brüder	Regensburg	Germany	93049
37	Caritas-Klinik St. Theresia	Saarbrücken	Germany	66113
38	Klinikum Stuttgart	Stuttgart	Germany	70174
39	Diakonie-Klinikum Stuttgart	Stuttgart	Germany	70176
40	Krankenhaus der Barmherzigen Brüder	Trier	Germany	54292
41	Universitätsklinikum Tübingen	Tübingen	Germany	72076
42	Universitätsklinikum Ulm	Ulm	Germany	89081
43	Schwarzwald-Baar-Klinikum	Villingen-Schwenningen	Germany	78050
44	Helios Klinikum	Wuppertal	Germany	42283