This is a phase 2 study to test the hypothesis that venetoclax in combination with standard chemotherapy will be tolerable and active in pediatric patients with newly diagnosed acute myeloid leukemia (AML).
Primary Objectives:
* Establish the tolerability adding venetoclax to standard chemotherapy in pediatric patients with AML * Estimate the proportion of patients who become minimal residual disease (MRD) negative by flow cytometry after one course of venetoclax-based induction therapy
Secondary Objectives:
\- Estimate the rates of complete remission (CR), event-free survival (EFS), and overall survival (OS) in pediatric patients who receive venetoclax-based chemotherapy
Diagnosis of AML fulfilling the criteria of the WHO classification of myeloid neoplasms or < 20% marrow myeloblasts and evidence of a clonal de novo AML genetic abnormality or myeloid sarcoma or primary myelodysplastic syndrome (MDS) with ≥ 10% blasts or a complete blood count with the presence of at least 1,000 blasts/μL (e.g., a WBC count ≥ 10,000/μL with ≥ 10% blasts or a WBC count ≥ 5,000/μL with ≥ 20% blasts
Age > 28 days and < 22 years
No prior therapy for this malignancy except for one dose of intrathecal therapy and hydroxyurea or low-dose cytarabine (≤ 200 mg/m² per day for ≤ 7 days)
Female patients of childbearing potential must have a negative pregnancy test within 2 weeks prior to enrollment
Patients with treatment-related AML, Down syndrome, acute promyelocytic leukemia, chronic myeloid leukemia in blast crisis, juvenile myelomonocytic leukemia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other bone marrow failure syndromes are not eligible
Uncontrolled systemic fungal, bacterial, or viral infection or significant concurrent disease that would compromise patient safety or compliance, study participation, follow up, or interpretation of study results
Prior exposure to any dose of anthracycline or anthracenedione
Patients may not receive strong or moderate CYP3A inducers, such as rifampin, within 3 days of enrollment
Parallel
Venetoclax
DrugVenetoclax will be given with each course of therapy. Patients with low-risk AML will receive four courses of therapy, intermediate-risk patients will receive five courses of therapy, and high-risk patients will receive two or three courses of therapy followed by hematopoietic stem cell transplantation.
Azacitidine
DrugGiven IV over 30 minutes on days 1-5
Cytarabine
DrugGiven IV over 30 minutes q12 hours on days 1-8 (16 doses)
Gemtuzumab Ozogamicin
DrugGiven IV
Daunorubicin Hydrochloride
DrugIV over 1 hour on days 1, 3, and 5
Fludarabine Phosphate
DrugGiven IV over 30 minutes on days 1-5
Idarubicin Hydrochloride
DrugGiven IV over 15 minutes on days 3-5
Mitoxantrone Hydrochloride
DrugIV over 1 hour on days 2-4
Etoposide
DrugGiven IV over 1 hour on days 1-5
Gilteritinib
DrugPO on days 8-28 (21 doses)
Minimal residual disease (MRD)-negativity rate
Will compute a binomial confidence interval for the proportion of MRD-evaluable patients who become MRD-negative (defined as MRD \< 0.1%) after induction 1.
Incidence of death or unacceptable adverse event
A patient is deemed to have tolerated a course of therapy if they complete that course without death or an unacceptable adverse event. Will monitor the tolerability or each course using multi-stage binomial stopping rules. Will use the method of Jung and Kim to compute 95% confidence intervals that adjust for the multi-stage monitoring.
Event-free survival
The Kaplan-Meier method will be used and 95% confidence intervals will be computed for event-free survival at 3 years.
Overall survival
The Kaplan-Meier method will be used and 95% confidence intervals will be computed for overall survival at 3 years.
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St. Jude Children's Research Hospital
Lead sponsor
AbbVie
Collaborator
