C93.1
Conditions
Interventions
Group 1: 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 cyc
Sponsors
Universitätsklinikum Freiburg, Kinder- und Jugendklinik, Klinik IV, Pädiatrische Hämatologie/Onkologie
Eligibility
Sex/Gender
All
Age
1 Months to 18 Years
Inclusion criteria
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 laborato
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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? | — |
Secondary
| Measure | Time frame |
|---|---|
| 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? | — |
Countries
France, Germany, Ireland, Italy, Netherlands, Spain, Sweden, Switzerland
Contacts
Public ContactChristian Flotho
Universitätsklinikum Freiburg, KJK, Pädiatrische Hämatologie/Onkologie, Klinik IV
Outcome results
None listed