Venetoclax in Combination with Conventional Chemotherapy for the Treatment of Pediatric Patients with Acute Myeloid Leukemia
This phase II trial tests how well venetoclax works in combination with standard chemotherapy in treating pediatric patients with acute myeloid leukemia (AML). Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. The usual treatment for AML is a group of cancer-fighting drugs called chemotherapy. Chemotherapy drugs, like cytarabine, daunorubicin hydrochloride, fludarabine phosphate, idarubicin hydrochloride, mitoxantrone 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. Etoposide is also a chemotherapy drug in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid repair and may kill cancer cells. Adding venetoclax to conventional chemotherapy may kill more cancer cells than chemotherapy alone in pediatric patients with AML.
Inclusion Criteria
- Diagnosis of AML fulfilling the criteria of the World Health Organization (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 white blood cell (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/m^2 per day for =< 7 days)
- Female patients of childbearing potential must have a negative pregnancy test within 2 weeks prior to enrollment
- Male and female participants of reproductive potential must agree to use an effective contraceptive method during the study and for 6 months after study treatment
- Written informed consent from the patient and/or parent/legal guardian
- Direct bilirubin =< 1.5 x institutional upper limit of normal
Exclusion Criteria
- 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
- Patients may not receive moderate or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) within 3 days of enrollment
Additional locations may be listed on ClinicalTrials.gov for NCT05955261.
Locations matching your search criteria
United States
California
Madera
Orange
San Diego
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Washington
Massachusetts
Boston
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Charlotte
Ohio
Cincinnati
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Memphis
Texas
Fort Worth
PRIMARY OBJECTIVES:
I. Estimate the proportion of patients who become minimal residual disease (MRD) negative by flow cytometry after one course of venetoclax-based induction therapy.
II. Establish the tolerability adding venetoclax to standard chemotherapy in pediatric patients with AML.
SECONDARY OBJECTIVE:
I. Estimate the rates of complete remission (CR), event-free survival (EFS), and overall survival (OS) in pediatric patients who receive venetoclax-based chemotherapy.
EXPLORATORY OBJECTIVES:
I. Explore associations between leukemia cell genomics, BCL2 family member protein levels, BH3 profiling, pharmacogenomics, and response to therapy as assessed by MRD and variant clearance using cell-free deoxyribonucleic acid (DNA) (cfDNA).
II. Explore the association of the ACS10 polygenic cytarabine pharmacogenomics score, transcriptomics-based leukemic stem cell score (pLSC6), and CD33 polymorphisms with outcome.
III. Explore associations between genetic variants in genes relevant to venetoclax (BCL2, BCL-XL, BIM, and MCL1) and genes involved in venetoclax metabolism and transport (CYP3A4, PgP1/ABCB1, and ABCG2) and outcome.
IV. Explore differences in T cell phenotype, function, and methylation status in patients receiving venetoclax for the treatment of AML.
V. Explore the gene expression profiles of residual leukemia cells in patients with MRD levels > 1% after one course of induction therapy by single-cell ribonucleic acid (RNA)-sequencing (seq).
VI. Describe functional and quality of life outcomes in patients using ratings and performance-based neurocognitive assessment, and explore associations of clinical factors with these outcomes.
OUTLINE:
INDUCTION 1: Patients receive venetoclax orally (PO) once daily (QD) on days -2 to 11, cytarabine intravenously (IV) over 30 minutes every 12 hours on days 1-8, daunorubicin hydrochloride IV over 1 hour QD on days 1, 3, and 5, etoposide IV over one hour QD on days 1-5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspirate and biopsy, lumbar puncture, and skin biopsy on day 29. Patients also undergo blood sample collection on days 1, 15, 22, and 29. Patients also undergo echocardiography (ECHO) at pre-treatment.
INDUCTION 2: Patients are assigned to 1 of 2 arms based on risk evaluation.
INDUCTION 2, LOW-RISK (LR) AML: Patients receive venetoclax PO QD on days 1-14, cytarabine IV over 30 minutes every 12 hours on days 1-8, daunorubicin hydrochloride IV over 1 hour QD on days 1, 3, and 5, and etoposide IV over 1 hour QD on days 1-5. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate, lumbar puncture, and bone marrow biopsy at the time of hematopoietic recovery after induction 2. Patients also undergo blood sample collection on day 1 and then at the time of bone marrow aspiration, if indicated. Patients also undergo ECHO prior to each course of therapy that contains daunorubicin hydrochloride, idarubicin hydrochloride, or mitoxantrone.
INDUCTION 2, INTERMEDIATE RISK (IR) AML/HIGH RISK (HR) AML: Patients receive venetoclax PO QD on days 1-14, fludarabine phosphate IV over 30 minutes QD on days 1-5, cytarabine IV over 3 hours QD starting 4 hours after each dose of fludarabine on days 1-5, idarubicin hydrochloride IV over 15 minutes QD on days 3-5. Patients with FLT3 activation also receive gilteritinib PO QD on days 8-28. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate, lumbar puncture, and bone marrow biopsy at the time of hematopoietic recovery after induction 2. Patients also undergo blood sample collection on day 1 and then at the time of bone marrow aspiration, if indicated. Patients also undergo ECHO prior to each course of therapy that contains daunorubicin hydrochloride, idarubicin hydrochloride, or mitoxantrone.
INTENSIFICATION: Patients are assigned to 1 of 3 arms based on risk evaluation and intention to undergo hematopoietic cell transplant (HCT).
INTENSIFICATION, LR AML: Patients receive venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-4, and mitoxantrone hydrochloride IV over 1 hour QD on days 2-4 during intensification 1 and then venetoclax PO QD on days 1-7 and high-dose cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5 during intensification 2. Patients with FLT3 activation also receive gilteritinib PO QD on days 8-28 during intensification 1 and 2. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients may undergo bone marrow aspiration, bone marrow biopsy, and lumbar puncture as clinically indicated and undergo blood sample collection on day 1 of each cycle. Patients also undergo ECHO prior to each course of therapy that contains daunorubicin hydrochloride, idarubicin hydrochloride, or mitoxantrone, and at the end of therapy.
INTENSIFICATION, IR AML/HR AML NOT UNDERGOING HCT: Patients receive venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-4, and mitoxantrone hydrochloride IV over 1 hour QD on days 2-4 during intensification 1, venetoclax PO QD on days 1-7 and high-dose cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5 during intensification 2, and then venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-5, and etoposide IV over 1 hour QD on days 1-5 during intensification 3. Patients with FLT3 activation also receive gilteritinib PO QD on days 8-28 during intensification 1, 2, and 3. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients may undergo bone marrow aspiration, bone marrow biopsy, and lumbar puncture as clinically indicated and undergo blood sample collection on day 1 of each cycle. Patients also undergo ECHO prior to each course of therapy that contains daunorubicin hydrochloride, idarubicin hydrochloride, or mitoxantrone, and at the end of therapy.
INTENSIFICATION, HR AML UNDERGOING HCT: Patients with MRD < 0.1% proceed directly to HCT if donor is available. If a donor is not yet available, patients with MRD < 0.1% may receive venetoclax PO QD on days 1-21 and azacitidine IV over 30 minutes QD on days 1-5 or venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-5, and etoposide IV over 1 hour QD on days 1-5. Patients with MRD 0.1% to < 1% may receive venetoclax PO QD on days 1-21 and azacitidine IV over 30 minutes QD on days 1-5 or venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-5, and etoposide IV over 1 hour QD on days 1-5. Patients with MRD >= 1% may receive venetoclax PO QD on days 1-10, azacitidine IV over 30 minutes QD on days 1-5, and high-dose cytarabine IV over 3 hours every 12 hours on days 6, 8, and 10. Patients with FLT3 activation also receive gilteritinib PO QD on days 8-28. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients proceed to HCT once donor is available. Patients may undergo bone marrow aspiration, bone marrow biopsy, and lumbar puncture as clinically indicated and undergo blood sample collection on day 1 of each cycle. Patients also undergo ECHO prior to each course of therapy that contains daunorubicin hydrochloride, idarubicin hydrochloride, or mitoxantrone, and at the end of therapy.
After completion of study treatment, patients follow up until 10 years from enrollment or death, whichever occurs first.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSaint Jude Children's Research Hospital
Principal InvestigatorHiroto Inaba
- Primary IDAML23
- Secondary IDsNCI-2023-04138
- ClinicalTrials.gov IDNCT05955261