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

Acute Myeloid Leukemia (AML) Clinical Trial

— azacitidine  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01180322
• Other study ID #: AMLSG 12-09
• Status: Completed
• Phase: Phase 2
• Start date: November 2010
• Est. completion date: October 2, 2016

Study information

• Verified date: December 2020
• Source: University of Ulm
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 277
• Est. completion date: October 2, 2016
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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

Locations

Country	Name	City	State
Austria	Universitätsklinikum Innsbruck	Innsbruck
Austria	Elisabethinen Krankenhaus Linz	Linz
Austria	Krankenhaus der Barmherzigen Schwestern	Linz
Austria	Landeskliniken Salzburg	Salzburg
Austria	Hanuschkrankenhaus	Wien
Germany	Universitätsklinikum Charité Berlin	Berlin
Germany	Knappschaftskrankenhaus Bochum-Langendreer	Bochum
Germany	Universitätsklinikum Bonn	Bonn
Germany	Städtisches Klinikum Braunschweig	Braunschweig
Germany	Klinikum Bremen-Mitte	Bremen
Germany	Klinikum Darmstadt	Darmstadt
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Kliniken Essen Süd, Evangelischs Krankenhaus	Essen
Germany	Klinikum Esslingen	Esslingen
Germany	Klinikum Frankfurt-Höchst	Frankfurt
Germany	Medizinisches Versorgungszentrum Fulda	Fulda
Germany	Universitätsklinikum Gießen	Gießen
Germany	Wilhelm-Anton-Hospital Goch	Goch
Germany	Universitätsklinikum Göttingen	Göttingen
Germany	Sklepios Klinik Hamburg-Altona	Hamburg
Germany	Evangelisches Krankenhaus Hamm	Hamm
Germany	Klinikum Hanau	Hanau
Germany	KRH Klinikum Hannover-Siloah	Hannover
Germany	Medizinische Hochschule Hannover	Hannover
Germany	SLK-Kliniken Heilbronn	Heilbronn
Germany	Städtisches Klinikum Karlsruhe	Karlsruhe
Germany	Universitätsklinikum Schleswig-Holstein	Kiel
Germany	Caritas-Krankenhaus Lebach	Lebach
Germany	Klinikum Lippe	Lemgo
Germany	Klinikum Lüdenscheid	Lüdenscheid
Germany	Klinikum der Johannes-Guttenberg-Universität	Mainz
Germany	Johannes Wesling Klinikum Minden	Minden
Germany	Klinikum rechts der Isar	München
Germany	Stauferklinikum Schwäbisch-Gmünd	Mutlangen
Germany	Klinikum Passau	Passau
Germany	Krankenhaus der Barmherzigen Brüder	Regensburg
Germany	Caritas-Klinik St. Theresia	Saarbrücken
Germany	Diakonie-Klinikum Stuttgart	Stuttgart
Germany	Klinikum Stuttgart	Stuttgart
Germany	Krankenhaus der Barmherzigen Brüder	Trier
Germany	Universitätsklinikum Tübingen	Tübingen
Germany	Universitätsklinikum Ulm	Ulm
Germany	Schwarzwald-Baar-Klinikum	Villingen-Schwenningen
Germany	Helios Klinikum	Wuppertal

Sponsors (1)

Lead Sponsor	Collaborator
University of Ulm

Countries where clinical trial is conducted

Austria,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Event-free survival		after two years of follow-up
Secondary	Relapse-free survival		after two years of follow-up
Secondary	overall survival		after two years of follow-up
Secondary	days in hospital during each cycle and during the whole intervention		6 months
Secondary	Rate of early deaths or hypoplastic deaths (ED/HD)		56 days
Secondary	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
Secondary	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
Secondary	duration of leukopenia after each consolidation cycle		42 days
Secondary	duration of neutropenia after each consolidation cycle		42 days
Secondary	duration of thrombocytopenia after each consolidation cycle		42 days
Secondary	duration of leukopenia after each induction cycle		28 days
Secondary	duration of neutropenia after each induction cycle		28 days
Secondary	duration of thrombocytopenia after each induction cycle		28 days