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

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Brief Title

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

Official Title

A Groupwide Pilot Study to Test the Tolerability and Biologic Activity of the Addition of Azacitidine (NSC# 102816) to Chemotherapy in Infants With Acute Lymphoblastic Leukemia (ALL) and KMT2A (MLL) Gene Rearrangement

Brief Summary

      This pilot phase II trial studies the side effects of azacitidine and combination
      chemotherapy in infants with acute lymphoblastic leukemia and KMT2A gene rearrangement. Drugs
      used in chemotherapy, such as methotrexate, prednisolone, daunorubicin hydrochloride,
      cytarabine, dexamethasone, vincristine sulfate, pegaspargase, hydrocortisone sodium
      succinate, azacitidine, cyclophosphamide, mercaptopurine, leucovorin calcium, and thioguanine
      work in different ways to stop the growth of cancer cells, either by killing the cells, by
      stopping them from dividing, or by stopping them from spreading. Giving more than one drug
      may kill more cancer cells.
    

Detailed Description

      PRIMARY OBJECTIVE:

      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 OBJECTIVE:

      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.

      EXPLORATORY 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. Cycles 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Tolerability of azacitidine in combination with Interfant-06 standard chemotherapy in 30 evaluable infant patients with newly diagnosed ALL with KMT2A gene rearrangement (KMT2A-R)

Secondary Outcome

 Biologic activity, defined as global deoxyribonucleic acid (DNA) methylation change in peripheral blood mononuclear cells (PBMC)s

Condition

Acute Leukemia of Ambiguous Lineage

Intervention

Azacitidine

Study Arms / Comparison Groups

 Treatment (azacitidine, combination chemotherapy)
Description:  See Detailed Description

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

78

Start Date

March 27, 2017

Completion Date

September 30, 2022

Primary Completion Date

September 30, 2020

Eligibility Criteria

        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
      

Gender

All

Ages

N/A - 364 Days

Accepts Healthy Volunteers

No

Contacts

Erin M Guest, , 

Location Countries

Australia

Location Countries

Australia

Administrative Informations


NCT ID

NCT02828358

Organization ID

NCI-2016-00973

Secondary IDs

NCI-2016-00973

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Erin M Guest, Principal Investigator, Children's Oncology Group


Verification Date

July 2021