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.
Additional locations may be listed on ClinicalTrials.gov for NCT03194932.
See trial information on ClinicalTrials.gov for a list of participating sites.
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.
Lead OrganizationSaint Jude Children's Research Hospital
Principal InvestigatorJeffrey E. Rubnitz
