Trial document

This trial has been registered retrospectively.
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Trial Description

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Trial Acronym


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URL of the Trial


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Brief Summary in Lay Language

AML is a rare cancer in children and adolescents, also known as blood cancer. In the bone marrow certain white blood cells are formed uncontrollably, which then displace the normal blood formation and lead to the symptoms of AML either due to the lack of normal cells (red blood cells, platelets) or the greatly increased number of leukemia cells in the blood. Initial signs of AML relapsed were noted in potential patients. So far, a relapsed has only been diagnosed when leukemia cells are already visible in the bone marrow or blood (so-called open relapsed).
If the leukemia cells have certain genetic characteristics (mutations, translocations), molecular genetics methods can determine much lower levels of leukemia cells than with the microscope (microscope: 5 leukemia cells in 100 normal cells, molecular genetics1 leukemia cell in 1000 or 10,000 normal cells).
For this reason, potential patients were regularly checked whether it was possible to detect a relapse of AML earlier than with microscopic examination (so-called molecular relapsed) using these molecular genetic methods.
In potential patients a molecular relapsed was diagnozed.
Currently, the most promising treatment for a relapse of AML with the potential to cure the disease is a stem cell transplantation. The search for a donor and the preparation of a stem cell transplantation usually take several months.
One way to bridge the waiting period is to participate in this study and to be treated with azacitidine (= Vidaza®). For all children and adolescents participating in this study, there is the advantage that the search for a suitable stem cell donor can be initiated at an early stage.

Azacitidine is not yet approved for the treatment of AML in children and adolescents and its use in this study is experimental. A total of 20 patients in Europe will participate in this study.
Azacitidine is a cancer drug that belongs to a group of agents called demethylating drugs. Demethylation means reactivating certain genes that are turned off in the leukemia cells. Demethylation is intended to reduce the growth of diseased cells in the blood and bone marrow. The efficacy of azacitidine in children suffering from AML has not been studied in larger clinical trials. However, there is evidence from publications in professional journals that azacitidine may be effective in children with AML. For this reason, this study is being conducted to investigate whether azacitidine is effective in children with AML prior to stem cell transplantation.
Since an increase in leukemia cells could be detected, the purpose of this study is to find out whether if an immediate treatment of the molecular relapsed is possible and better than the subsequent treatment of the open relapsed.
It is not yet known if this early treatment of molecular relapse is actually better than the previous treatment of open recurrence. That's the aim of this study.

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Brief Summary in Scientific Language

The majority of patients with newly diagnosed AML achieve a CR after induction chemotherapy. However, relapse occurs in about one-third of children and far fewer achieve CR after reinduction chemotherapy. The probability of survival at 4 years is 38% in the most recent study of relapsed AML patients (Kaspers, 2013), which is consistent with earlier studies showing survival rates around 30%. Failure to achieve CR after reinduction is associated with failure of subsequent attempts at curative therapy such as HSCT. Further improvements of current treatment, including improvements in remission induction for relapsed patients are thus required.
Recent data suggest that in AML, residual leukemic cells below the 5% limit required for a morphologic CR can have an adverse impact on outcome. In 1 retrospective study, persistence of cytogenetic abnormalities in patients who were otherwise in morphologic CR was associated with significantly worse relapse-free survival and OS (Chen, 2011). Using more sensitive flow cytometry methods, presence of minimal residual disease (MRD) by flow cytometry in AML patients in first complete remission (CR1) was shown to be associated with significantly inferior survival after HSCT as compared with MRD-negative patients (Walter, 2011).
Simple qualitative polymerase chain reaction (PCR) positivity is not a reliable measurement for relapse as it has been reported in several patients who did not later relapse. However, molecular relapse identified by real-time polymerase chain reaction (RT-PCR) with increasing levels of MRD is almost always followed by hematological relapse (Ommen, 2010), which supports the use of RQ-PCR in this clinical study.
Early detection of MRD may provide an opportunity to implement pre-emptive therapies to clinical/hematological relapse. Minimal residual disease is a significant predictor of clinical relapse regardless of morphologic result which confirms the prognostic importance of MRD measurements:
Event- free survival (EFS) rates were significantly worse in patients with MRD greater than 1% after the first induction and/or 0.1% after the second induction. A majority of events were leukemia relapses. These data provide the evidence that molecular relapses are followed by hematological relapses. For this reason, patients will be followed regularly with MRD monitoring in order to detect molecular relapses and responses as part of the regular patient care (MRD-Monitoring).
Other supportive data (Lane, 2008) indicate that a greater than 1 log rise in MRD levels defines molecular relapse in AML and predicts subsequent morphologic relapse. Based on these data, patients will be considered molecular relapsed patients when a greater than or equal to 1 log rise in MRD level is observed.
A second setting where MRD level appears to predict the clinical outcome is prior to BM transplantation. A recent retrospective investigator-initiated study was conducted to measure MRD levels in AML pediatric patients at the time of transplant (Hansen, 2013). This study had its limitation but examined the impact of MRD levels just prior to HSCT and found that there seemed to be some influence on the outcome when a certain MRD level is present at the time of HSCT.
Deoxyribonucleic acid methylation is observed in a majority of genes examined in pediatric myelodysplastic syndrome (MDS), Juvenile Myelomonocytic Leukemia (JMML), and AML, similar to the adulthood conditions. Aberrant methylation in these genes provides rationale for the use of hypomethylating agents as therapies in the childhood conditions.
The use of azacitidine at a hypomethylating dose has been reported in a few case studies. A 1.5-year-old JMML patient with monosomy 7 was treated with azacitidine 100 mg/m2 in 1-hour intravenous (IV) transfusions for 5 consecutive days of each 28-day cycle for 8 cycles (Furlan, 2009). This dose and regimen of azacitidine resulted in a complete cytogenetic response at the initiation of Cycle 6 and a reduction in methylation of the CALCA gene promoter.
Azacitidine has been authorized for treatment in adult patients since 2008 and has been used widely off-label in pediatric trials according to pediatric reports. A number of studies specifically designed to evaluate the use of azacitidine to treat AML or acute lymphatic leukemia (ALL) in pediatrics have been published. These included approximately 2200 pediatric patients with AML or ALL who were treated with azacitidine primarily in combination with a variety of anti-neoplastic agents. The daily dose of azacitidine used in these pediatric AML and ALL studies usually ranged from 50 to 300 mg/m2/day, which most likely exceeded the dose range for optimal hypomethylating activity. Most of the pediatric patients in these publications had relapsed or refractory AML or ALL at the time of study enrollment. The adverse event (AE) profile of azacitidine in pediatric patients with AML or ALL appears to be similar to that of adults with MDS. In the AML studies, response rates were variable (CR: 6% to 85%) with combination azacitidine therapy.
Unlike intensive chemotherapy, azacitidine is relatively safe and is associated with a moderate incidence of severe drug-related toxicities and with much improved outcome and quality of life in adult patients with MDS and AML (less than 30% blasts).
In conclusion, there is a clear unmet medical need in relapsed AML and azacitidine as a hypomethylating agent is expected to be of significant benefit to children in this setting.
In conclusion children and adolescents with AML in remission, who are diagnosed with a molecular relapse, should be offered an epigenetically effective treatment with azacitidine. The therapy should decrease the MRD level, ideally it becomes negative again. Patients who achieved or maintained a very low or negative MRD level, toxicities should be reduced by omitting one or two reinduction elements prior to alloSCT.

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Do you plan to share individual participant data with other researchers?


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Description IPD sharing plan:


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Organizational Data

  •   DRKS00015449
  •   2018/09/13
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  •   yes
  •   Approved
  •   18-7940-AF, Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen
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Secondary IDs

  •   2017-003422-32 
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Health Condition or Problem studied

  •   C92.0 -  Acute myeloblastic leukaemia [AML]
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Interventions/Observational Groups

  •   Azacitidine 75mg/qm BSF/d 7 following days (cycle) max. 6 cycles
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  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   II
  •   Yes
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Primary Outcome

To evaluate the effect of azacitidine treatment in AML subjects at molecular relapse after CR1 with regard to molecular response prior to further treatment (reinduction / HSCT)

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Secondary Outcome

To assess the safety of azacitidine treatment in children and adolescents with a molecular relapse of AML. Disease free and overall survival post molecular relapse at 12 and 24 months, and post study completion; quality of life (PedsQL questionnaire, AE reports).

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Countries of Recruitment

  •   Germany
  •   Netherlands
  •   Denmark
  •   Austria
  •   Switzerland
  •   Czech Republic
  •   Sweden
  •   Belgium
  •   Italy
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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  •   Actual
  •   2018/06/06
  •   20
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   3   Months
  •   21   Years
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Additional Inclusion Criteria

1.Aged 3 months to <21 years with documented diagnosis of AML according to WHO classification with at least one quantitative genetic maker, e.g. one of the following aberrations:
•t(8;21); RUNX1-RUNX1T1
•inv(16); CBFb-MYH11
•t(9;11); MLL-AF9
•t(10;11); MLL-AF10
•WT1; etc.
2.First complete remission (MRD in PB less than 5 x 10-4) confirmed at the start of last consolidation course or within 1 month after completion of consolidation treatment
3.Detection of a confirmed molecular relapse of an AML
4.Understand and voluntarily provide permission (subjects and when applicable, parental/legal representative(s)) to the ICF prior to conducting any study related assessments/procedures
5.Able to adhere to the study visit schedule and other protocol requirements
6.Lansky performance score at least equal to 50; or Karnofsky performance status at least equal to 50, whichever is applicable
7.Negative serum pregnancy tests for females of child bearing potential within 10 days prior to treatment

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Exclusion Criteria

1.Concomitant treatment with any other anticancer therapy except those specified in protocol
2.HSCT within previous 3 months
3.Treated by any investigational agent in a clinical study within previous 4 weeks
4.Pregnancy or lactating
5.FAB type M3 leukemia (acute promyelocytic leukemia)
6.Therapy-related AML
7.AML of Down syndrome or other congenital syndromes giving rise to leukemia or treatment complications
8.Symptomatic cardiac disorders (CTCAE 4.0 Grade 3 or 4)
9.Evidence of invasive fungal infection or other severe systemic infection requiring treatment doses of systemic/parenteral therapy including known active viral infection with human immunodeficiency virus (HIV) or Hepatitis Type B and C
10.Any other organ dysfunction (CTCAE 4.0 Grade 3 or 4) that will interfere with the administration of the therapy according to this protocol
11.Ongoing severe toxicities (CTCAE 4.0 Grade 3 or 4) of prior chemotherapy/stem cell transplantation
12.Hypersensitivity to the active substance or other excipients contained in the investigational medical product listed in the summary of product characteristics (SmPC) or Investigators Brochure (IB).
13.Abnormal liver function
14. Symptomatic CNS-involvement or isolated extramedullary disease at initial diagnosis
15. Female and male subjects with child bearing potential who avoid using highly effective anticonceptive measure(ment)s

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  • start of 1:1-Block address primary-sponsor
    • GPOH gemeinnützige GmbHAML-BFM Studienzentrale
    • Ms.  Katharina  Waack-Buchholz 
    • Holsterhauser Platz 2
    • 45147  Essen
    • Germany
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    • Pädiatrisches Forschungsnetzwerk gGmbH
    • Ms.  Dr.  Katharina  Jansen 
    • Holsterhauser Platz 2
    • 45147  Essen
    • Germany
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    • AML-BFM studiengruppeUniversitätskinderklinik III
    • Mr.  Prof.  Reinhardt  Dirk 
    • Hufelandstr. 55
    • 47122  Essen
    • Germany
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    • GPOH gemeinnützige GmbHAML-BFM Studienzentrale
    • Ms.  Katharina  Waack-Buchholz 
    • Holsterhauser Platz 2
    • 45147  Essen
    • Germany
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Sources of Monetary or Material Support

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    • Celgene International II Sàrl
    • Rue des Moulins 4
    • 2108  Couvet
    • Switzerland
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    • Pädiatrisches Forschungsnetzwerk gGmbH
    • Ms.  Dr.  Katharina  Jansen 
    • Holsterhauser Platz 2
    • 45147  Essen
    • Germany
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  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.