| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| acute myeloid leukeamia |
| akute myeloische Leukämie |
|
| E.1.1.1 | Medical condition in easily understood language |
| acute myeloid leukeamia |
| akute myeloische Leukämie |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000880 |
| E.1.2 | Term | Acute myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
The objective of the trial is to assess efficacy and safety of induction therapy with response-adapted sequential azacitidine and conventional AML induction chemotherapy in patients > 60 years with newly diagnosed AML (at the dose level resulting from the dose evaluation phase of the trial).
Primary objective
To assess efficacy in terms of the overall response rate (ORR) till day 90 including:
- Complete remissions (CR)
- Complete Remission with incomplete blood count recovery (CRi)
- Partial remissions (PR) |
|
| E.2.2 | Secondary objectives of the trial |
- Safety of response-adapted sequential azacitidine and chemotherapy
- Overall survival one year after start of trial therapy
- Overall survival two years after start of trial therapy
- Event-free survival one and two years after start of trial therapy
- Days alive and out of hospital
- Rate of treatment failure according to IWG response criteria
- Number of patients undergoing HCT
- Correlate study endpoints with the points achieved at the time of diagnosis according to the following questionnaire: instrumental activities of daily living (iADLs, “Instrumentelle Aktivitäten des täglichen Lebens”)
- Correlate study endpoints with the Eastern Cooperative Oncology Group (ECOG) Performance Status at the time of diagnosis
- Compare response and survival in patients treated with response-adapted sequential azacitidine and chemotherapy with historical patient populations treated with the same conventional chemotherapy |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The concomitant scientific project will only include patients who have signed the informed consent form for translational studies. It aims at the determination of the following:
- Determination of mutation status of Flt-3 and Npm1 genes (method: PCR / capillary electrophoresis)
Mutations in the Flt-3 and Npm1 genes are frequent in AML, and have been shown to correlate with outcome. Together with the cytogenetics, they currently provide the most informative molecular markers of disease status.
- Determination of the expression level of the NM23 and Myc genes (method: real-time RT-PCR and western blotting)
The expression level of NM23 mRNA and protein reportedly correlates with clinical outcome in AML. Furthermore, there is evidence of coordinate transcriptional and translational regulation of NM23 and Myc. The expression of both genes will be determined as a potentially valuable additional prognostic indicator.
- Determination of the global methylation status (method: Bisulfite PCR analysis of repetitive DNA elements).To further define association between LINE Methylation and azacitidine response: Analysis of methylation in selected cell subpopulations (CD34+ cells).
AML is characterized by a global hypomethylation of the genome accompanied by the specific hypermethylation of CpG islands associated with specific genes. It is therefore important to monitor the effects of therapeutic demethylating agents on both parameters. Bisulfite PCR of highly repetitive LINE or Alu sequences provides a measure of the mean methylation status across approximately 15000 genomic loci.
To compare between LINE methylation levels in bone marrow cells of patients and that in non-leukemic cells, a buccal mucosa swab is required at the time of AML diagnosis. This allows to define further association between LINE Methylation in leukemic cells and azacitidine response.
- Determination of the specific methylation status of CpG islands associated with the estrogen receptor (ER) and p15INK4B genes. (method: gene specific PCR bisulfite sequencing).
The ER and P15 loci are among those most frequently inactivated by methylation in AML. Since methylation status correlates both with gene expression and survival, these two loci are most likely to be informative in studies of specific gene methylation.
- Determination of the expression levels of cancer testis antigens (method: real-time RT-PCR)
The mechanisms by which demethylating agents reduce tumour cell load are unclear. However, in addition to the re-activation of tumour suppressor genes, there is evidence that the activation of tumor antigens (including the CTAs MAGE-1, SSX and NY-ESO-1) may trigger a beneficial immune response.
- To define a possible association between LINE methylation, and azacitidine response with plasma nutrient profile (the amino acid methionine), serum of patients at diagnosis (at screening) will be used for measurement of methionine levels and response.
- Determination of the activity of DNMT2 under azacitidine therapy in both in both unsorted and CD34-sorted bone marrow cells
NOTE: the processing and banking of DNA, RNA and protein samples from each patient will enable the future extension of both the methylation and expression studies to additional loci.
For the scientific project, the following samples will be collected:
- 2x10 ml of bone marrow aspirate in an anticoagulated tube (EDTA) for methylation and molecular analysis (all patients)
- 5 ml serum (only for patients from Leipzig)
- Buccal mucosa cell swab (only for patients from Leipzig)
Time point of collection:
Are described in detail in section 6.3 and outlined again in the table where all study related assessments and schedules are shown. |
|
| E.3 | Principal inclusion criteria |
Subjects must meet ALL of the following criteria to be enrolled in the study:
1. Newly diagnosed (within the last 28 days) and untreated AML (> 20% blasts in the bone marrow based on the WHO classification) including:
- de novo AML
- AML secondary to prior myelodysplastic disease
- AML secondary to exposure to potentially leukemogenic therapies or agents (eg, radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 2 years
2. Age > 60 years
3. Eligible for intensive chemotherapy and allogeneic hematopoietic cell transplantation
4. Serum bilirubin levels ≤ 1.5 x the upper limit of normal (ULN). Higher levels are acceptable if these can be attributed to
- active hemolysis (as indicated by positive direct Coombs’ testing, decreased haptoglobin level, elevated indirect bilirubin and/or lactate dehydrogenase [LDH]),
- or ineffective erythropoiesis (as indicated by bone marrow findings)
5. Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) level ≤ 2 x ULN
6. Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) level ≤ 2 x ULN
7. serum creatinine levels ≤ 1.5 x ULN
8. Left ventricular ejection fraction by echocardiography > 50%
9. Women of childbearing potential may participate, providing they meet the following conditions:
• must agree to use effective contraceptive methods throughout the study and for 6 months following the date of the last dose of study medication
• must have a negative serum pregnancy test obtained within 72 hours prior to day 1.
10. Males with female partner of childbearing potential must agree to use effective contraceptive methods throughout the study and should avoid fathering a child for 6 months following the date of the last dose of study medication.
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (Appendix A)
12. Capable of giving informed consent
13. Written informed consent |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will not be included in the study
1. Acute promyelocytic leukaemia (AML M3)
2. Previous cytotoxic or any other hypomethylating or biological treatment for AML, exception: hydroxyurea
3. Any diagnosis of malignant disease within the previous 12 months (excluding basal cell carcinoma with no complications)
4. Hepatic tumors in the medical history
5. Known or suspected hypersensitivity to azacitidine (incl. additives), Mitoxantrone (incl. additives), Ara-C (incl. additives)
6. Patients with serious concomitant medical illness:
- severe congestive heart failure [grade ≥ 3 according to CTCAE] or
- clinically unstable ischemia or
- acute myocardial infarction in the previous six months or
- pulmonary hypertension [grade > 3 according to CTCAE] or
- severe cardiac arrythmias [grade > 3 according to CTCAE] or
- chronic pulmonary diseases [grade > 3 according to CTCAE] or
- uncontrolled hypertension or
- uncontrolled diabetes or
- uncontrolled severe infections [grade > 3 according to CTCAE] or
- any other severe or uncontrolled medical illness
7. Psychiatric illness that would prevent granting of informed consent
8. Active viral infection with known human immunodeficiency virus (HIV) or viral hepatitis type B or C
9. Treatment with any of the following concomitant medications:
- Corticosteroids, unless otherwise indicated, e.g. blood product transfusion reaction or prevention
- Retinoids
- Cytokines (except as outlined in Section 3.2.1)
- Interleukin-11
- EPO
10. Participation in other clinical trials in the last 30 days |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of the phase II part of the trial is the overall response rate on day 90. Overall response rate (ORR) includes:
- Complete remissions (CR)
- Complete Remission with Incomplete Blood Count recovery (CRi)
- Partial remissions (PR)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Screening/Baseline
- During Azacitidine application and induction chemotherapies
- Adaption/Response assessment (days 15, 69, 90)
- once weekly during the first azacitidine cycle, on days 1 and 15 of each following azacitidine cycle, once weekly during induction chemotherapy
- follow-up
|
|
| E.5.2 | Secondary end point(s) |
Safety of response-adapted sequential azacitidine and chemotherapy. Safety will be assessed in terms of adverse events and laboratory values.
Overall survival one and two years after start of trial therapy
Survival data will be collected throughout the study for each subject. The secondary efficacy variable, time to death from any cause, is defined as the time between enrolment and death from any cause. All subjects will be followed until drop-out, death, or study termination. This includes patients with premature study termination.
Event-free survival is defined as time from enrolment to one of the following events:
- disease progression (according to IWG criteria),
- relapse after CR or CRi,
- death of any cause.
Subjects who drop out or are alive at study termination will have their overall survival times censored at the time of last contact, as appropriate.
Rate of treatment failure on day 90 according to IWG response criteria.
Treatment failure includes cases of aplasia and intermediate causes according to the definition of treatment failure by the IWG response criteria for AML.
Description of efficacy in terms of overall response, survival and event-free survival by subgroups:
- patients with azacitidine alone
- patients with azacitidine and conventional induction chemotherapy
Days alive and out of hospital
This endpoint will encompass the whole individual study period of two years. Information on each hospitalization will be collected. This includes information on start and end of hospital stay, reason for hospitalization (e.g., disease progression, AML-related illness, treatment-related adverse event), as well as information on the actual treatment setting (azacitidine resp. conventional induction chemotherapy).
Every day a patient is alive and completely outside a hospital is counted. In case a patient is lost to follow-up before end of the two years study period, days after drop-out will not be counted.
Number of patients undergoing HCT; data on patients undergoing HCT will be collected.
Correlate study endpoints with the results achieved at the time of baseline according to the following questionnaire:
- instrumental activities of daily living (iADLs) and
- the Eastern Cooperative Oncology Group (ECOG) Performance Status at the time of diagnosis
Compare response and survival in patients treated with response-adapted sequential azacitidine and chemotherapy with historical patient populations treated with the same conventional chemotherapy (data of patients >60 years treated in the AML 2004 #069 OSHO)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Screening/Baseline
- During Azacitidine application and induction chemotherapies
- Adaption/Response assessment (days 15, 69, 90)
- once weekly during the first azacitidine cycle, on days 1 and 15 of each following azacitidine cycle, once weekly during induction chemotherapy
- follow-up
|
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
|
| The trial formally starts with the first signature of a patient informed consent form. After the last visit of the last patient there are three months of data capture and data cleaning before the database will be closed. The following biometrical analysis will take six months after that the trial formally ends. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
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