Indication Treatment of pediatric subjects with newly diagnosed advanced myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) prior to hematopoietic stem cell transplantation (HSCT).

Objectives Primary Objective The primary objective is to assess the treatment effect on response rate (MDS: either complete remission [CR], partial remission [PR], or marrow CR; JMML: either clinical complete remission [cCR] or clinical partial remission [cPR]); at Cycle 3 Day 28 (each cycle is 28 days) and to compare against standard therapy using a matched-pairs analysis of historical data.

Secondary Objective The secondary objective is to further evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of azacitidine in this subject population.

Study Design This is a prospective, open-label, Phase 2 study consisting of 2 parallel experimental arms, one for each disease group: MDS and JMML. Each arm is designed based on Simon's Optimal 2 stage study design. The sample size has been calculated to allow evaluation of the response rate at 28 day-Cycle 3 Day 28 in each of the 2 disease groups. Each of the experimental arms will also individually be compared against a historical control arm using data retrospectively collected from the European Working Group of MDS in childhood (EWOG-MDS) registry by means of a matched-pairs analysis; matched for predefined subject baseline characteristics defined before any results from this study are known post Stage 1. If matched pair is not viable then other methodologies will be explored to evaluate and compare response rates reported in literature and also in registry database Twenty subjects with MDS and 35 JMML subjects evaluable for the primary endpoint (ie, subjects that receive at least 1 dose of investigational product [IP]) will be enrolled at approximately 45 centers in Europe. Each experimental arm has 1 interim analysis planned (at the end of Stage 1). If, during Stage 1 evaluation, less than 2 subjects are observed with a CR, PR, or marrow CR after 3 months of azacitidine in the first 9 subjects with MDS, then enrollment will be stopped. Similarly, if less than 3 subjects are observed with a cPR or cCR after 3 months of azacitidine in the first 18 subjects with JMML, then enrollment will be stopped.

Study Population Pediatric subjects aged 1 month to less than 18 years of age with newly diagnosed conditions of advanced myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML).

Length of Study The enrollment period will last for up to 22 months with subjects being treated for a minimum of 3 months and a maximum of 6 months, until transplantation or disease progression (based on an independent central review of responses). Once investigational product (IP) has been discontinued, subjects will then be followed for 1 year after the last dose of investigational product (IP). The follow-up may not be terminated because of new anticancer treatment or hematopoietic stem cell transplantation (HSCT).

The End of Trial is defined as either the date of the last visit of the last subject to complete the study, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical Analysis Plan (SAP), whichever is the later date.

Inclusion Criteria:

Myelodysplastic Syndromes (MDS) :

1. Understand and voluntarily provide permission (subjects and/or when applicable, parental/legal representative) to the informed consent form/informed assent form (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 Myelodysplastic Syndromes (MDS), with latest peripheral blood (PB) and bone marrow (BM) biopsy confirming diagnosis within the 14 days prior to informed consent signature, with one of the following:

   1. RAEB (Refractory anemia with excess blasts): 2% to 19% blasts in PB or 5% to 19% blasts in BM.
   2. RAEB-t (Refractory anemia with excess blasts in transformation): 20% to 29% of blasts in PB or BM.
   3. Secondary Myelodysplastic Syndromes presenting as chronic myelomonocytic leukemia (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 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [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 Investigational Product (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):

    1. 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
    2. Female subjects must, as appropriate to age and the discretion of the study physician, either commit to true abstinence1 from heterosexual contact (which must be reviewed on a monthly basis) and/or agree to the use of approved contraceptive method (eg. oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; 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:

    1. Agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential (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 (JMML):

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 Juvenile Myelomonocytic Leukemia (JMML), with PB and BM confirming diagnosis prior to informed consent signature, with one of the following

   1. somatic mutation in PTPN11
   2. somatic mutation in KRAS
   3. somatic mutation in NRAS and HbF % > 5x normal value for age
   4. 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.

    1. 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
    2. Female subjects must, as appropriate to age and the discretion of the study physician, either commit to true abstinence2 from heterosexual contact (which must be reviewed on a monthly basis) and/or agree to the use of approved contraceptive method (eg. oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; 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 female of childbearing potential (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.

Exclusion Criteria:

Myelodysplastic Syndromes (MDS):

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 central nervous system (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.