Azacitidine and Combination Chemotherapy in Treating Infants With Acute Lymphoblastic Leukemia and KMT2A Gene Rearrangement

PRIMARY OBJECTIVES:

I. To evaluate the tolerability of azacitidine in addition to Interfant-06 standard
chemotherapy in infants with newly diagnosed acute lymphoblastic leukemia (ALL) with KMT2A
gene rearrangement (KMT2A-R).

SECONDARY OBJECTIVES:

I. To evaluate the biologic activity of azacitidine by pharmacodynamic assessment of global
deoxyribonucleic acid (DNA) methylation in peripheral blood mononuclear cells (PBMCs) of
infants treated with azacitidine.

TERTIARY OBJECTIVES:

I. To determine the 5 year event-free survival (EFS) of infants with KMT2A-R treated with
azacitidine in addition to Interfant-06 standard chemotherapy.

II. To correlate minimal residual disease (MRD) with outcome in the context of the protocol
therapy.

III. To perform pharmacokinetic (PK) testing of azacitidine in infants. IV. To test the
expansion of infant T lymphocytes by stimulation with artificial antigen presenting cells
identical to those used in chimeric antigen receptor T-cell (CART)-19 production.

V. To collect pharmacodynamic (PD) data for asparaginase activity following pegaspargase
administration in infants.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive methotrexate intrathecally (IT) on days 1 and 29,
prednisolone orally (PO) or nasogastrically (NG) three times daily (TID) on days 1-7,
daunorubicin hydrochloride intravenously (IV) over 1-15 minutes on days 8-9, cytarabine IV
over 30 minutes on days 8-21 and IT on day 15, dexamethasone PO, NG, or IV TID on days 8-28,
vincristine sulfate IV over 1 minute on days 8, 15, 22, and 29, pegaspargase IV over 1-2
hours or intramuscularly (IM) on day 12, and hydrocortisone sodium succinate IT on days 15
and 29 in the absence of disease progression or unacceptable toxicity. Only patients with
KMT2A-R continue to post-induction chemotherapy.

POST-INDUCTION CHEMOTHERAPY:

AZACITIDINE BLOCK I: Prior to CONSOLIDATION, patients receive azacitidine IV over 10-40
minutes daily for 5 days in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Following completion of AZACITIDINE BLOCK I, patients receive cyclophosphamide
IV over 30-60 minutes on days 1 and 29, mercaptopurine PO or NG daily on days 1-28,
cytarabine IV or subcutaneously (SC) daily on days 3-6, 10-13, 17-20, and 24-27 and IT on day
10, methotrexate IT on day 24, and hydrocortisone sodium succinate IT on days 10 and 24 in
the absence of disease progression or unacceptable toxicity.

AZACITIDINE BLOCK II: Prior to INTERIM MAINTENANCE, patients receive azacitidine as in
AZACITIDINE BLOCK I

INTERIM MAINTENANCE: Following completion of AZACITIDINE BLOCK II, patients receive
mercaptopurine PO or NG daily on days 1-14, methotrexate IV over 24 hours on days 1 and 8 and
IT on days 2 and 9, leucovorin calcium PO or IV on days 3-4 and 10-11, hydrocortisone sodium
succinate IT on days 2 and 9, cytarabine IV over 3 hours every 12 hours on days 15-16 and
22-23 for a total of 8 doses, and pegaspargase IV over 1-2 hours or IM on day 23 in the
absence of disease progression or unacceptable toxicity.

AZACITIDINE BLOCK III: Prior to DELAYED INTENSIFICATION PART I, patients receive azacitidine
as in AZACITIDINE BLOCK I.

DELAYED INTENSIFICATION PART I: Following completion of AZACITIDINE BLOCK III, patients
receive pegaspargase IV over 1-2 hours or IM on day 1, dexamethasone PO, NG, or IV TID on
days 1-14 and 15-21 with a taper on days 15-21, thioguanine PO or NG daily on days 1-28,
vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22, daunorubicin hydrochloride IV
over 1-15 minutes on days 1, 8, 15, and 22, cytarabine IV or SC on days 2-5, 9-12, 16-19, and
23-26 and IT on days 1 and 15, and hydrocortisone sodium succinate IT on days 1 and 15 in the
absence of disease progression or unacceptable toxicity.

AZACITIDINE BLOCK IV: Prior to DELAYED INTENSIFICATION PART II, patients receive azacitidine
as in AZACITIDINE BLOCK I.

DELAYED INTENSIFICATION PART II: Following completion of AZACITIDINE BLOCK IV, patients
receive thioguanine PO or NG daily on days 1-14, cyclophosphamide IV over 15-30 minutes on
days 1 and 15, cytarabine IV or SC on days 2-5 and 9-12 in the absence of disease progression
or unacceptable toxicity.

MAINTENANCE: Following DELAYED INTENSIFICATION PART II, patients receive mercaptopurine PO or
NG on days 1-168, methotrexate IT on day 1 and 92 and PO once weekly on days 8-91 and 98-168,
hydrocortisone sodium succinate IT on day 1, 57, and 99, and cytarabine IT on day 57.
Starting on day 169, patients receive mercaptopurine PO or NG on days 1-84 and methotrexate
PO once weekly. Courses repeat every 84 days for 2 years from the start of INDUCTION
CHEMOTHERAPY in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Infants must be > 36 weeks gestational age at the time of enrollment

- Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health
Organization [WHO] classification) (also termed B-precursor acute lymphoblastic
leukemia) or acute leukemia of ambiguous lineage (ALUL), which includes mixed
phenotype acute leukemia (MPAL); for patients with ALUL, the morphology and
immunophenotype must be at least 50% B lymphoblastic

- Central nervous system (CNS) status must be determined based on a sample obtained
prior to the administration of any systemic or intrathecal chemotherapy, with the
exception of steroid pretreatment

Exclusion Criteria:

- Patients with known absence of KMT2A-rearrangement leukemia prior to enrollment

- Patients with Down syndrome

- Patients with secondary B acute lymphoblastic leukemia (B-ALL) that developed after
treatment of a prior malignancy with cytotoxic chemotherapy

- With the exception of steroid pretreatment or the administration of intrathecal
methotrexate or intrathecal cytarabine, receipt of any other prior cytotoxic
chemotherapy for either the current diagnosis of B-ALL or any cancer diagnosed prior
to the initiation of protocol therapy on AALL15P1