Study of Venetoclax in Combination With Chemotherapy in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Leukemia of Ambiguous Lineage

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 every 12 hours on days 8-11 (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.

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.

Inclusion Criteria:

- Participants must have a diagnosis of AML or acute leukemia of ambiguous lineage
(acute undifferentiated leukemia or mixed phenotype a cute leukemia) and meet the
criteria below:

- Refractory leukemia, defined as persistent leukemia after at least two courses of
induction chemotherapy, OR

- Early relapsed leukemia, defined as the re-appearance of leukemia after the
achievement of remission and within one year of diagnosis, OR

- Relapsed leukemia that is refractory to at least one course of salvage therapy
(i.e., therapy given after the relapse has occurred), OR

- Second or greater relapse

- Patients with late relapses, defined as the re-appearance of leukemia after the
achievement of remission and greater than one year from diagnosis, may be
enrolled in the dose expansion portion of the study only.

- Patients in all categories above must have ≥ 5% blasts in the bone marrow as
assessed by morphology or flow cytometry. However, if an adequate bone marrow
sample cannot be obtained, patients may be enrolled if there is unequivocal
evidence of leukemia with ≥ 5% blasts in the peripheral blood. In addition,
patients in all categories must not be eligible to undergo curative therapy, such
as immediate SCT, because of disease burden, time needed to identify a stem cell
donor, or other reasons.

- Adequate organ function defined as the following:

- Direct bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

- AST (SGOT) and ALT (SGPT) ≤ 4 x ULN

- Normal creatinine for age or a calculated creatinine clearance ≥ 60 mL/min/1.73
m2

- Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%

- St. Jude patients must be between 2 years and ≤ 21 years of age, on therapy (active
patient), or within 3 years of completion of therapy. Patients treated at
collaborating sites must be ≤ 24 years old.

- Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥
50% for patients who are > 16 years old.

- Patients must have fully recovered from the acute effects of all prior therapy and
cannot have evidence of graft-versus-host disease (GVHD)

Exclusion Criteria:

- Must not be pregnant or breastfeeding. Male or female of reproductive potential must
agree to use effective contraception for the duration of study participation.

- Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic
leukemia, or bone marrow failure syndromes are not eligible.

- Uncontrolled infection. Infections controlled on concurrent anti-microbial agents are
acceptable, and anti-microbial prophylaxis per institutional guidelines are
acceptable.

- Impairment of GI function or GI disease that may significantly alter the absorption of
venetoclax.