Venetoclax and Cytarabine with or without Idarubicin Hydrochloride in Treating Pediatric Patients with Refractory or Relapsed Acute Myeloid Leukemia

This phase I trial studies the side effects and best dose of venetoclax and cytarabine when given with or without idarubicin hydrochloride in treating pediatric patients with acute myeloid leukemia that does not respond to treatment (refractory) or has returned after a period of improvement (relapsed). Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cell growth. Drugs used in chemotherapy, such as cytarabine, idarubicin hydrochloride, and azacitidine, 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 venetoclax, cytarabine, and idarubicin hydrochloride may work better in treating pediatric patients with acute myeloid leukemia.

Inclusion Criteria

• Participants must have a diagnosis of AML or acute leukemia of ambiguous lineage (acute undifferentiated leukemia or mixed phenotype acute leukemia) and have refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy; or relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission; patients in all categories above must have >= 5% blasts in the bone marrow as assessed by morphology or >= 1% blasts in the bone marrow as assessed by 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 stem cell transplantation (SCT)
• Direct bilirubin =< 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 4 x ULN
• Normal creatinine for age or a calculated creatinine clearance >= 60 mL/min/1.73 m^2
• 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 gastrointestinal (GI) function or GI disease that may significantly alter the absorption of venetoclax

PRIMARY OBJECTIVE:

I. To determine a tolerable combination of venetoclax plus chemotherapy in pediatric patients with relapsed or refractory acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage.

SECONDARY OBJECTIVE:

I. To estimate the overall response rate to the combination of venetoclax and chemotherapy in pediatric patients with relapsed or refractory AML or acute leukemia of ambiguous lineage.

EXPLORATORY OBJECTIVES:

I. To explore associations between biomarkers (leukemia cell genomics, BH3 profiling, BCL2 family protein expression, and changes in BCL2 family protein) and response.

II. To assess the quality of life of pediatric patients with relapsed or refractory AML or acute leukemia of ambiguous lineage undergoing treatment with venetoclax and chemotherapy, and to explore relationships between clinical factors and patient-reported quality of life outcomes.

III. To characterize the pharmacokinetics of venetoclax after the first dose and at steady-state.

IV. To explore the safety and activity of venetoclax plus azacytidine and cytarabine.

OUTLINE: This is a dose-escalation study of venetoclax and cytarabine. Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive cytarabine intrathecally (IT), methotrexate IT, or methotrexate IT, therapeutic hydrocortisone IT, and cytarabine IT (ITMHA) at least 24 hours before day 1. Patients without evidence of central nervous system (CNS) leukemia receive no further IT therapy. Patients with CNS disease receive weekly ITMHA, beginning on day 8, until the cerebrospinal fluid (CSF) becomes free of leukemia. Patients also receive venetoclax orally (PO) once daily (QD) on days 1-28 and cytarabine intravenously (IV) every 12 hours (Q12H) on days 8-11 or 8-17 in the absence of disease progression or unacceptable toxicity. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive IT therapy, venetoclax, and cytarabine as in Cohort A. Patients also receive idarubicin hydrochloride IV on day 8 in the absence of disease progression or unacceptable toxicity. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

COHORT C: Patients receive IT therapy as in Cohort A. Patients also receive venetoclax PO QD on days 1-21, azacitidine IV on days 1-7, and cytarabine Q12H on days 8-11. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at 30 days.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Saint Jude Children's Research Hospital

Principal Investigator
Jeffrey E. Rubnitz

• Primary ID VENAML
• Secondary IDs NCI-2017-01129
• Clinicaltrials.gov ID NCT03194932