Trial document





This trial has been registered retrospectively.
drksid header

  DRKS00007185

Trial Description

start of 1:1-Block title

Title

DNA methylation signatures and response to azacitidine therapy in juvenile myelomonocytic leukemia or pediatric advanced myelodysplastic
syndrome

end of 1:1-Block title
start of 1:1-Block acronym

Trial Acronym

JMML/MDS-Mesrat

end of 1:1-Block acronym
start of 1:1-Block url

URL of the Trial

[---]*

end of 1:1-Block url
start of 1:1-Block public summary

Brief Summary in Lay Language

The investigator-initiated research project described here is designed to expand on the scientific benefit gained from AZA-JMML-001 by reutilizing biological material and clinical data collected from children with JMML or MDS under therapy with azacitidine, and performing more in-depth studies to elucidate the relation between aberrant DNA methylation in JMML and MDS, response to hypomethylating treatment, and prognosis after HSCT.

end of 1:1-Block public summary
start of 1:1-Block scientific synopsis

Brief Summary in Scientific Language

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative disorder, accounting for approximately 3% of hematologic malignancies in children (Locatelli, 2005; Niemeyer, 2008). JMML predominates in young children, with the median age at diagnosis being 2 years. Leukemic cells in 65% of children with JMML have a normal karyotype, while monosomy 7 is seen in 25% and 10% have other chromosomal abnormalities (Niemeyer, 1997).
Myelodysplastic syndromes (MDS) are clonal proliferative stem cell diseases leading to
hematopoietic insufficiency, peripheral cytopenia and cell dysplasia. Accounting for 4% of pediatric hematopoietic neoplasia, MDS is far less common in children than in adults. Pediatric MDS differs from adult MDS in presentation, clinical course and prognosis, but also with respect to underlying molecular genetic lesions. MDS also occurs as a consequence of prior chemotherapy or radiation therapy and is then called secondary
The treatment of children with advanced MDS (>5% blasts in bone marrow or >2% blasts in peripheral blood) remains a major challenge even though these patients tend to have a relatively stable course for weeks or months. Therapy of pediatric advanced MDS entails significant toxicity and a high risk of relapse. Conventional chemotherapy without HSCT results in survival rates below 30%. Approximately 60% of children with primary MDS can be cured with allogeneic HSCT (Strahm, 2011).
Azacitidine is an analogue of cytidine that was developed in the 1960s. It is believed to exert its antineoplastic effects by multiple mechanisms including, at higher doses, direct cytotoxicity on hematopoietic cells and, at lower doses not resulting in rapid induction of cell death or cell cycle arrest, inhibition of DNA cytosine methylation (Leone, 2002). The therapeutic potential of azacitidine in hematological neoplasias relates to the mechanism of gene re-expression by DNA demethylation and evidence that hypermethylation of promoter regions of tumor suppressor genes is frequently associated with cancer (Jones, 1986).
The analysis of azacitidine pharmacodynamics in AZA-JMML-001 involves bone marrow samples on days 1 and 15 of cycle 1, day 28 of cycle 3, at the time of relapse/disease progression and pre-HSCT. These samples will be used to extract DNA for assessment of the DNA-hypomethylating activity of azacitidine. To control for varying leukemic cell content in patients with good response to azacitidine, changes in DNA methylation will be normalized to the proportion of leukemic cells in the sample as assessed by targeted deep sequencing of a known point mutation in PTPN11, NRAS or KRAS.
Changes made on 2016/05/05 because of Amendment from 2016/03/03

end of 1:1-Block scientific synopsis
start of 1:1-Block organizational data

Organizational Data

  •   DRKS00007185
  •   2016/02/18
  •   [---]*
  •   yes
  •   Approved
  •   578/14, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
end of 1:1-Block organizational data
start of 1:n-Block secondary IDs

Secondary IDs

  • [---]*
end of 1:n-Block secondary IDs
start of 1:N-Block indications

Health Condition or Problem studied

  •   C93.1 -  Chronic myelomonocytic leukaemia
end of 1:N-Block indications
start of 1:N-Block interventions

Interventions/Observational Groups

  •   In the framework of AZA-JMML-001, bone marrow samples will be obtained for the assessment of the pharmacodynamic activity of azacitidine (DNA-hypomethylating activity) on days 1 and 15 of cycle 1, day 28 of cycle 3, at the time of relapse/disease progression and pre-HSCT.
    At time of enrollment into AZA-JMML-001, consent from parents or legal guardians will be sought to re-use these samples for non-commerical research including the investigator-initiated research project described here. In addition to the biomaterial available from the AZA-JMML-001 study, a sample of 5 ml peripheral blood will be collected from study subjects at each time point of bone marrow collection for the purpose of the non-commercial research described here. Since close to all study subjects will have a central venous line in place, the collection of peripheral blood at time of bone marrow puncture will not cause additional anxiety or pain to the study subjects. With this research project epigenetic changes are examined in leukaemia cells. Besides, it concerns specific analyses for the judgement of reactivation of genes by Azacitidin (regulation of methylation).
end of 1:N-Block interventions
start of 1:1-Block design

Characteristics

  •   Non-interventional
  •   Other
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Pharmacogenetics
  •   Single (group)
  •   N/A
  •   N/A
end of 1:1-Block design
start of 1:1-Block primary endpoint

Primary Outcome

1) Is aberrant DNA methylation at defined genetic loci in JMML bone marrow cells at the time of diagnosis predictive of response to hypomethylating treatment with azacitidine, or predictive of the risk of relapse after allogeneic HSCT, or both?

end of 1:1-Block primary endpoint
start of 1:1-Block secondary endpoint

Secondary Outcome

2) Are the dynamics of change in aberrant DNA methylation under hypomethylating treatment with azacitidine (rather than the initial methylation status itself) at defined genetic loci in JMML/MDS bone marrow cells predictive of outcome, specifically the risk of relapse after allogeneic HSCT?
3) If investigation of aberrant DNA methylation in JMML/MDS bone marrow cells, either at diagnosis or dynamically under hypomethylating treatment with azacitidine, allows for prognostic risk assessment in JMML/MDS, can the same information be derived from the investigation of aberrant DNA methylation in peripheral blood cells from patients with JMML/MDS?

end of 1:1-Block secondary endpoint
start of 1:n-Block recruitment countries

Countries of Recruitment

  •   Germany
  •   France
  •   Ireland
  •   Italy
  •   Netherlands
  •   Spain
  •   Sweden
  •   Switzerland
end of 1:n-Block recruitment countries
start of 1:n-Block recruitment locations

Locations of Recruitment

  • University Medical Center 
end of 1:n-Block recruitment locations
start of 1:1-Block recruitment

Recruitment

  •   Actual
  •   2015/08/18
  •   35
  •   Multicenter trial
  •   International
end of 1:1-Block recruitment
start of 1:1-Block inclusion criteria

Inclusion Criteria

  •   Both, male and female
  •   1   Months
  •   18   Years
end of 1:1-Block inclusion criteria
start of 1:1-Block inclusion criteria add

Additional Inclusion Criteria

Myelodysplastic Syndrome Subjects:
1. Understand and voluntarily provide permission (subjects and/or when applicable,
parental/legal representative) to the ICF/IAF prior to conducting any study-related
assessments/procedures.
2. Able to adhere to the study visit schedule and other protocol requirements.
3. Male or female age 1 month to less than 18 years old at the time of informed
consent/informed assent.
4. Newly diagnosed advanced primary or secondary MDS, with latest PB and BM biopsy
confirming diagnosis within the 14 days prior to informed consent signature, with one of
the following (confirmed by Regional Reference laboratory reports from diagnosis prior to entering the study):
a) RAEB: 2% to 19% blasts in PB or 5% to 19% blasts in BM.
b) RAEB-t: 20% to 29% of blasts in PB or BM.
c) Secondary MDS presenting as CMML without increase in blasts but with
chromosomal abnormality.
5. Lansky play score at least equal to 60; or Karnofsky performance status at least equal to
60.
6. Life expectancy of at least 3 months.
7. Normal renal function defined as less than or equal to NCI CTCAE v 4.0 Grade 1
(maximum 1.5 x Upper Limit of Normal [ULN]).
8. Normal liver function defined as less than or equal to NCI CTCAE v 4.0 Grade 1
(maximum 2.5 x ULN for transaminases and bilirubin).
9. Females of childbearing potential and male subjects that have reached puberty and are
younger than 18 years of age must agree to undergo physician-approved reproductive
education and discuss the side effects of the IP on reproduction with parent(s) and/or
guardian(s).
10. Females of childbearing potential, defined as females who have achieved menarche
and/or 8 years or older and have not undergone a hysterectomy or bilateral
oophorectomy, must meet the following conditions below. (Note: Amenorrhea
following cancer therapy does not rule out childbearing potential):
a) Have a negative serum pregnancy test within 72 hours prior to starting IP as verified
by the Investigator. Agree to ongoing pregnancy testing during the course of the
study (see Table 4 and Table 5).
b) Female subjects must, as appropriate to age and the discretion of the study physician,
either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis) and/or agree to the use of approved contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on azacitidine;
and for 3 months following the last dose.
11. Male subjects must, as appropriate to age and the discretion of the study physician:
a. Agree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 3 months
following azacitidine discontinuation, even if he has undergone a successful
vasectomy.
Juvenile Myelomonocytic Leukemia Subjects:
1. Understand and voluntarily provide permission (subjects and/or when applicable,
parental/legal representative) to the ICF/IAF prior to conducting any study-related
assessments/procedures.
2. Able to adhere to the study visit schedule and other protocol requirements.
3. Male or female age 1 month to less than 18 years old at the time of informed
consent/informed assent.
4. Newly diagnosed JMML, with PB and BM confirming diagnosis prior to informed
consent signature, with one of the following (confirmed by laboratory reports from initial
diagnosis by Regional Reference Laboratories):
a) somatic mutation in PTPN11
b) somatic mutation in KRAS
c) somatic mutation in NRAS and HbF % > 5x normal value for age
d) clinical diagnosis of neurofibromatosis Type 1.
5. Lansky play score at least equal to 60; or Karnofsky performance status at least equal to
60.
6. Life expectancy of at least 3 months.
7. Normal renal function defined as less than or equal to NCI CTCAE v 4.0 Grade 1
(maximum 1.5 x ULN).
8. Normal liver function defined as less than or equal to NCI CTCAE v 4.0 Grade 1
(maximum 2.5 x ULN for transaminases and bilirubin).
9. Females of childbearing potential and male subjects that have reached puberty and are
younger than 18 years of age must agree to undergo physician-approved reproductive
education and discuss the side effects of the IP on reproduction with parent(s) and/or
guardian(s).
10. Females of childbearing potential, defined as females who have achieved menarche
and/or 8 years or older and have not undergone a hysterectomy or bilateral
oophorectomy, must meet the following conditions below. (Note: Amenorrhea
following cancer therapy does not rule out childbearing potential):
a) Have a negative serum pregnancy test within 72 hours prior to starting IP as verified
by the Investigator. Agree to ongoing pregnancy testing during the course of the
study.
b) Female subjects must, as appropriate to age and the discretion of the study physician,
either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis) and/or agree to the use of approved contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on azacitidine;
and for 3 months following the last dose.
11. Male subjects must, as appropriate to age and the discretion of the study physician:
a. Agree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 3 months
following azacitidine discontinuation, even if he has undergone a successful vasectomy.
12. SO2 greater than 92% (without additional supply of O2).
13. Peripheral blood monocyte count of at least 1.0 x 109/L.
14. Blast percentage in PB and BM less than 20%.
15. Splenomegaly.

end of 1:1-Block inclusion criteria add
start of 1:1-Block exclusion criteria

Exclusion Criteria

Myelodysplastic Syndrome Subjects:
1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Any condition including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study.
3. Any condition that confounds the ability to interpret data from the study.
4. Treated by any investigational agent in a clinical study within 4 weeks prior to signing of
informed consent / informed assent.
5. Any CNS involvement.
6. Isolated extramedullary disease.
7. Current uncontrolled infection.
8. Cardiac toxicity (shortening fraction below 28%).
9. Concurrent treatment with another anticancer therapy.
10. Pregnancy or lactation.
11. Prior treatment with a demethylating agent.
12. Allergy to azacitidine or mannitol.
13. Any other organ dysfunction (NCI-CTCAE v 4.0 Grade 4) that will interfere with the
administration of the therapy according to this protocol.
14. Genetic abnormalities indicative of Core Binding factor AML; t(8;21), inv16, t(16;16),
and t(15;17).
15. Subjects with inherited BM failure syndromes (ie, Fanconi’s anemia, congenital severe neutropenia, Shwachman-Diamond syndrome).
Juvenile Myelomonocytic Leukemia Subjects:
1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Any condition including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study.
3. Any condition that confounds the ability to interpret data from the study.
4. Treated by any investigational agent in a clinical study within 4 weeks prior to signing of
informed consent / informed assent.
5. Any CNS involvement.
6. Isolated extramedullary disease.
7. Current uncontrolled infection.
8. Cardiac toxicity (shortening fraction below 28%).
9. Concurrent treatment with another anticancer therapy.
10. Pregnancy or lactation.
11. Prior treatment with a demethylating agent.
12. Allergy to azacitidine or mannitol.
13. Any other organ dysfunction (NCI-CTCAE v 4.0 Grade 4) that will interfere with the
administration of the therapy according to this protocol.
14. Germline molecular aberrations in CBL, PTPN11, NRAS, or KRAS.

end of 1:1-Block exclusion criteria
start of 1:n-Block addresses

Addresses

  • start of 1:1-Block address primary-sponsor
    • Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin, Klinik IV, Pädiatrische Hämatologie/Onkologie
    • Mathildenstr. 1
    • 79106  Freiburg
    • Germany
    end of 1:1-Block address primary-sponsor
    start of 1:1-Block address contact primary-sponsor
    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
    end of 1:1-Block address contact primary-sponsor
  • start of 1:1-Block address scientific-contact
    • Universitätsklinikum Freiburg, ZKJ, Pädiatrische Hämatologie/Onkologie, Klinik IV
    • Mr.  Prof. Dr. med  Christian  Flotho 
    • Mathildenstr. 1
    • 79106  Freiburg
    • Germany
    end of 1:1-Block address scientific-contact
    start of 1:1-Block address contact scientific-contact
    end of 1:1-Block address contact scientific-contact
  • start of 1:1-Block address public-contact
    • Universitätsklinikum Freiburg, ZKJ, Pädiatrische Hämatologie/Onkologie, Klinik IV
    • Mr.  Prof. Dr. med  Christian  Flotho 
    • Mathildenstr. 1
    • 79106  Freiburg
    • Germany
    end of 1:1-Block address public-contact
    start of 1:1-Block address contact public-contact
    end of 1:1-Block address contact public-contact
end of 1:n-Block addresses
start of 1:n-Block material support

Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin, Klinik IV, Pädiatrische Hämatologie/Onkologie
    • Mathildenstr. 1
    • 79106  Freiburg
    • Germany
    end of 1:1-Block address materialSupport
    start of 1:1-Block address contact materialSupport
    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
    end of 1:1-Block address contact materialSupport
end of 1:n-Block material support
start of 1:1-Block state

Status

  •   Recruiting complete, follow-up complete
  •   2018/08/24
end of 1:1-Block state
start of 1:n-Block publications

Trial Publications, Results and other Documents

  • [---]*
end of 1:n-Block publications
* This entry means the parameter is not applicable or has not been set.