| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with suspected diagnosis of acute myeloid leukemia or related
precursor neoplasm, or acute leukemia of ambiguous lineage (classified
according to the WHO classification) (>=18years)
Exclusion Criteria:
AML with other recurrent genetic abnormalities AML with t(8;21)(q22;q22); RUNX1-RUNX1T1, with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11, with t(15;17)(q22;q12); PML-RARA (or variant translocations with other RARA gene fusions), NPM1 mutation, FL T3 mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| diagnosis of acute myeloid leukemia and not eligible for other genotype specific trials of the AMLSG |
| Neu diagnostizierte akute myeloische Leukämie nicht geeignet für Genotyp-spezifische Therapiekonzepte der AMLSG |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
primary efficacy objective:
To evaluate the impact of sequential or concurrent addition of 5-
azacytidine to intensive induction chemotherapy with idarubicin and
etoposide on the CR rate |
|
| E.2.2 | Secondary objectives of the trial |
secondary efficacy objectives:
• To evaluate the impact of sequential or concurrent addition of 5-azacytidine to intensive induction chemotherapy with idarubicin and etoposide/etoposidphosphate on RFS, EFS and OS
• To evaluate the impact of 5-azacytidine maintenance therapy in patients achieving a CR on RFS and OS
• To evaluate the efficacy of lenograstim based on duration of neutro- and leukopenia as well as incidence of infection and duration of hospitalization after consolidation therapy
• Assessment of quality of live
Safety Objectives:
- Evaluation of safety based on toxicity induced by 5-azacytidine
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Both female and male patients meeting the mentioned inclusion and exclusion criteria will be included in this clinical trial, because the risk to get AML does not depend on a patient’s gender. Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study
• 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.
|
|
| E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a patient from study enrollment:
• 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 MUGA or 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 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
• Rates of CR after induction therapy
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the end of the study the prim. endpoint CR rate will be evaluated according to the optimal two stage design. |
|
| E.5.2 | Secondary end point(s) |
secondary efficacy endpoints:
• Event-free survival
• Relapse-free Survival (RFS), cumulative incidence of relapse (CIR) or death in CR (CID)
• Overall survival
• Days in hospital during each cycle and during the whole intervention
• Duration of leuko-, neutro- and thrombocytopenia after consolidation therapy
Safety Endpoints
• Rate of early deaths and hypoplastic deaths (ED/HD)
• 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
• Duration of leuko-, neutro- and thrombocytopenia after induction therapy
QoL Endpoint
• 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Continuous assessment for safety is performed for i) rates of ED/HD with a maximally tolerated rate (MTR) of 10%, ii) single non-hematological toxicity grade 4 related to azacitidine with MTR of 10%, iii) neutropenia grade 3 or 4 after each cycle of induction therapy of longer than day 35 after start of treatment cycle with a MTR of 5% and iv) thrombocytopenia grade 3 or 4 after each induction therapy of longer than day 35 after start of treatment cycle with a MTR of 5%. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 43 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| this Information is provided in the protocol: 13.2, 11 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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