Study of Venetoclax in Combination With Chemotherapy in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Leukemia of Ambiguous Lineage
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to test the safety and determine the best dose of venetoclax and
      cytarabine when given with or without idarubicin in treating pediatric patients with acute
      myeloid leukemia (AML) that did not respond to treatment (refractory) or has come back after
      treatment (relapsed).

      PRIMARY OBJECTIVE: Determine a tolerable combination of venetoclax plus chemotherapy in
      pediatric patients with relapsed or refractory AML or acute leukemia of ambiguous lineage.
      The primary endpoints are the recommended phase 2 doses (RP2D) of venetoclax plus cytarabine
      and venetoclax plus cytarabine and idarubicin.

      SECONDARY OBJECTIVE: Estimate the overall response rate to the combination of venetoclax and
      chemotherapy in pediatric patients with relapsed or refractor AML or acute leukemia of
      ambiguous lineage. The secondary endpoints are the rates of complete remission (CR) and
      complete remission with incomplete count recovery (CRi) for patients treated at the RP2D.
    

Detailed description: 
      This study will be done in two parts:

        -  Part 1 - Dose Escalation: The goal of Part 1 of the study is to find the highest
           tolerable combination and recommended phase 2 doses (RP2D) of venetoclax plus cytarabine
           and venetoclax plus cytarabine and idarubicin that can be given to patients with
           leukemia.

        -  Part 2 - Dose Expansion: After determination of doses in Part 1, patients will be
           enrolled on Part 2 to look at the effects of venetoclax plus cytarabine and venetoclax
           plus cytarabine and idarubicin.

      Depending on when participants enroll on the study, Part 1 participants will receive one of
      the following courses of therapy:

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours on days 8-17; OR

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours on days 8-11; OR

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours on days 8-11; idarubicin once
           on day 8; OR

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours on days 8-17; idarubicin once
           on day 8.

      Part 2 participants will receive one of the following courses of therapy:

        -  Venetoclax daily on days 1-28; cytarabine - to be determined from Part 1 of the study;
           OR

        -  Venetoclax daily on days 1-28; cytarabine - to be determined from Part 1 of the study;
           idarubicin once on day 8.

      The cytarabine dosage will be that found in Part 1 to be the highest safest dose.

      Those participants receiving idarubicin will also receive dexrazoxane.

      Note: Part 1 has been completed. Part 2 participants receive the following determined from
      Part 1 of the study:

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours days 8-11 OR

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours days 8-11; idarubicin once on
           day 8.

      All participants on both Part 1 and Part 2 receive one intrathecal (IT) chemotherapy before
      starting the first cycle. Patients with CNS disease will receive weekly IT therapy until the
      cerebrospinal fluid becomes free of leukemia (minimum of 4 doses). Bone marrow aspiration and
      biopsy to assess response will be performed between days 28 and 42 of cycle 1. Patients who
      achieve complete remission/complete remission with incomplete count recovery/partial
      remission (CR/CRi/PR) and who do not experience unacceptable toxicity during cycle 1 may
      receive up to four cycles of chemotherapy.

      Cohort C (Amendment 5.0): Treatment of participants enrolled in cohort C will include:
      Venetoclax daily on days 1-21; cytarabine every 12 hours days 8-11; azacytidine days 1-7.
      Participants will receive one intrathecal (IT) chemotherapy before starting the first cycle.
      Participants with CNS disease will receive weekly ITMHA until the cerebrospinal fluid becomes
      free of leukemia.

      The rolling-6 design will be used to determine the safety of cohort C. After cohort C is
      deemed to be safe, additional patients will be enrolled, if necessary, so that at least 6
      patients are treated in cohort C to confirm tolerability. After tolerability is confirmed, 6
      additional patients will be treated to explore activity.
    

Intervention name(s): Venetoclax; Cytarabine; Idarubicin; Intrathecal Triple Therapy; Azacitidine
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Venetoclax will be given as oral tablets, which are intended to be swallowed intact and may not to be crushed or otherwise altered for administration, or as an oral suspension for patients who cannot swallow tablets.; Given intravenously (IV) or intrathecally (IT).; Given IV.; Given IT.; Given IV.
Other intervention name(s): Venclextra®; ABT-199; Cytosine arabinoside; Ara-C; Cytosar®; Idamycin PFS; ITMHA; methotrexate/hydrocortisone/cytarabine; VIDAZA®
Intervention MeSH terms: Cytarabine; Hydrocortisone; Methotrexate; Azacitidine; Venetoclax; Idarubicin
Intervention model: Single Group Assignment
Intervention model description: Participants receive venetoclax plus cytarabine alone or combination chemotherapy of cytarabine plus idarubicin.
Masking: None (Open Label)
Primary purpose: Treatment