A Study of Safety, Efficacy and Pharmacodynamics of Azacitidine in Children and Young Adults With Acute Myeloid Leukemia.

Inclusion Criteria:

Safety Run-in Part:

1. Understand and voluntarily provide permission (subjects and when applicable, parental/legal representative(s)) to the informed consent/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 subjects aged 3 months to less than 18 years old at the time of informed consent/assent.

4. Documented diagnosis of Acute myeloid leukemia (AML) according to World Health Organization (WHO) classification with at least one of the following molecular aberrations below:

   1. t(8;21), RUNX1-RUNX1T1
   2. inv(16), CBFb/MYH11
   3. t(9;11), MLL-AF9
   4. NPM1 mutation
   5. FLT3-ITD mutation.
5. Documentation of molecular remission (MRD less than 5 x 10-4) confirmed at the start of last consolidation course or within 1 month after completion of consolidation treatment.
6. Detection of molecular relapse in the Peripheral Blood (PB) by real-time quantitative polymerase chain reaction (RQ-PCR) within the 7 days prior to signing informed consent/assent form and confirmation of relapse during the screening period. Molecular relapse is defined as an increase in molecular remission (MRD) level of a subject-specific fusion gene or aberration by at least 1 log (10-fold) to a level of at least 5 x 10-4. For subjects who are MRD negative, the rise should be at least 1 log (10-fold) greater than previous sensitivity to a level of 5 x 10-4 or above. An increase in PB must be confirmed in PB and bone marrow (BM) aspirate by RQ-PCR. Confirmation of a molecular relapse is given if the MRD positivity is at the same level or higher in the PB and BM sample compared to the PB MRD levels at the detection of the relapse and in the absence of clinical relapse (defined as at least 5% blasts in PB and/or BM and/or proven histological extramedullary relapse).
7. Lansky play score at least equal to 50; or Karnofsky performance status at least equal to 50, whichever is applicable.
8. 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 study therapy on reproduction with parent/parents and/or guardian/guardians.

9. 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 study therapy as verified by the study doctor. Agree to ongoing pregnancy testing during the course of the study and after end of study therapy at the 28-day follow-up visit. This applies even if the subject practices true abstinence* from heterosexual contact.
   2. 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 (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.

10. 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 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.

Randomized Part (at the time of signing ICF/IAF):

1. Understand and voluntarily provide permission (subjects and when applicable,parental/legal representative(s)) 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 subjects aged 3 months to less than 21 years old at the time of informed consent/assent. Note: Minimum of 60 subjects less than 18 years of age must be included. The remainder of the randomized subjects may be greater than or equal to 18 but less than 21 years of age.

4. Documented diagnosis of AML, according to WHO classification with at least one of the following molecular aberrations below that is determined by the central laboratory to be present using BM aspirate from initial diagnosis,:

   1. t(8;21), RUNX1-RUNX1T1
   2. inv(16), CBFb/MYH11
   3. t(9;11), MLL-AF9
   4. NPM1 mutation
   5. FLT3-ITD mutation.
5. Documentation of molecular remission (MRD less than 5 x 10-4) confirmed at the start of last consolidation course or within 1 month after completion of consolidation treatment.

Randomized Part (criteria must be checked at Predrug Verification Visit and re-checked at randomization):

1. Predrug verification visit should occur within 7 days of detection of molecular relapse in the PB by RQ-PCR during the screening period. Molecular relapse is defined as an increase in MRD level of a subject-specific fusion gene or aberration by at least 1 log (10-fold) to a level of at least 5 x 10-4. For subjects who are MRD negative, the rise should be at least 1 log (10-fold) greater than previous sensitivity to a level of 5 x 10-4 or above. An increase in PB must be confirmed in PB and BM aspirate by RQ-PCR. Confirmation of a molecular relapse is given if the MRD positivity is at the same level or higher in the PB and BM sample compared to the PB MRD levels at the detection of the relapse and in the absence of clinical relapse (defined as at least 5% blasts in PB and/or BM and/or proven histological extramedullary relapse).
2. Lansky play score at least equal to 50; or Karnofsky performance status at least equal to 50, whichever is applicable.

3. Females of Childbearing Potential and male subjects that have reached puberty and are:

   1. Younger than 18 years of age must agree to undergo physician-approved reproductive education and discuss the side effects of the study therapy on reproduction with parent/parents and/or guardian/guardians.
   2. Between 18 and 21 years of age must agree to undergo physician-approved reproductive education and discuss the side effects of the study therapy on reproduction with the study physician.

4. 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 randomization as verified by the study doctor. Agree to ongoing pregnancy testing during the course of the study and after end of study therapy at the 28-day follow-up visit. This applies even if the subject practices true abstinence* from heterosexual contact.
   2. 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 (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.

5. 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 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.

      • True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception].

Exclusion Criteria:

Safety Run-in Part (criteria must be checked at Screening and re-checked on Cycle 1 Day

The presence of any of the following will exclude a subject from enrollment:

Concomitant Treatment

1. Concomitant treatment with any other anticancer therapy except those specified in protocol.

2. Received maintenance therapy after end of consolidation therapy and CR1.

   Prior Treatment

3. HSCT (hematopoietic stem cell transplantation) within previous 3 months.

4. Treated by any investigational agent in a clinical study within previous 4 weeks.

   Medical Condition/Laboratory

5. Pregnant or lactating.
6. Symptomatic central nervous system (CNS)-involvement or isolated extramedullary disease at initial diagnosis.
7. FAB (French-American-British) type M3 leukemia (acute promyelocytic leukemia)
8. Therapy-related AML
9. AML of Down syndrome or other congenital syndromes giving rise to leukemia or treatment complications.
10. Symptomatic cardiac disorders (CTCAE (Common Terminology Criteris for Adverse Events) Grade 3 or 4).
11. 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.
12. Any other organ dysfunction (NCI CTCAE v4 (National Cancer Institute Common Terminology Criteria for Adverse Events Grade 4) that will interfere with the administration of the therapy according to this protocol.
13. Acute effects of prior chemotherapy/stem cell transplantation.
14. Hypersensitivity to azacitidine.
15. Serum Bilirubin above 1.5 x ULN.
16. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) above 3 x ULN.
17. Any significant medical condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or that would prevent the subject from participating in the study.

Randomized Part (at the time of signing ICF/IAF):

The presence of any of the following will exclude a subject from enrollment:

Concomitant Treatment

1. Concomitant treatment with any other anti-cancer therapy except those specified in protocol.

2. Received maintenance therapy after end of consolidation therapy and CR1.

   Prior Treatment

3. HSCT within previous 3 months.

4. Treated by any investigational agent in a clinical study within previous 4 weeks.

   Medical Condition/Laboratory

5. Symptomatic CNS-involvement or isolated extramedullary disease at initial diagnosis.
6. FAB type M3 leukemia (acute promyelocytic leukemia)
7. Therapy-related AML
8. AML of Down syndrome or other congenital syndromes giving rise to leukemia or treatment complications.
9. Acute effects of prior chemotherapy/stem cell transplantation.
10. Hypersensitivity to azacitidine.

Randomized Part (criteria must be checked at Predrug Verification Visit and re-checked at randomization):

The presence of any of the following will exclude a subject from randomization:

Prior Treatment

1. Treated by any investigational agent in a clinical study within previous 4 weeks.

   Medical Condition/Laboratory

2. Pregnant or lactating.
3. Symptomatic cardiac disorders (CTCAE Grade 3 or 4).
4. 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.
5. Any other organ dysfunction (NCI CTCAE v4.0 Grade 4) that will interfere with the administration of the therapy according to this protocol.
6. Serum bilirubin above 1.5 x ULN.
7. AST/ALT above 3 x ULN.
8. Any significant medical condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or that would prevent the subject from participating in the study.