A Study of Venetoclax in Combination With Conventional Chemotherapy in Pediatric Patients With Acute Myeloid Leukemia

Purpose

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

Condition

  • Acute Myeloid Leukemia

Eligibility

Eligible Ages
Between 29 Days and 21 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • 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/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.

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Low Risk 		All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Cytabrine, Danunorubicin Hydrochloride, Gemtuzumab Ozogamicin, Etoposide, Mitoxantrone Hydrochloride, Gilteritinib
  • Drug: Venetoclax
    Venetoclax 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.
    Other names:
    • Venclextra
    • ABT-99
  • Drug: Cytarabine
    Given IV over 30 minutes q12 hours on days 1-8 (16 doses)
    Other names:
    • Ara-C
    • Cytosar-U®
  • Drug: Gemtuzumab Ozogamicin
    Given IV
    Other names:
    • Mylotarg
  • Drug: Daunorubicin Hydrochloride
    IV over 1 hour on days 1, 3, and 5
    Other names:
    • FI-6339
    • L-lyxo-Hexopyranoside
  • Drug: Idarubicin Hydrochloride
    Given IV over 15 minutes on days 3-5
    Other names:
    • IMI-30
    • Zavedos
  • Drug: Mitoxantrone Hydrochloride
    IV over 1 hour on days 2-4
    Other names:
    • Neotalem
    • Pralifan
    • Novantrone
  • Drug: Etoposide
    Given IV over 1 hour on days 1-5
    Other names:
    • VP-16
    • Vepesid®
  • Drug: Gilteritinib
    PO on days 8-28 (21 doses)
    Other names:
    • Xospata
Experimental
Intermediate Risk 		All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Cytabrine, Danunorubicin Hydrochloride, Fludarabine Phosphate, Gemtuzumab Ozogamicin, Etoposide, Idarubin Hydrochloride, Mitoxantrone Hydrochloride, Gilteritinib
  • Drug: Venetoclax
    Venetoclax 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.
    Other names:
    • Venclextra
    • ABT-99
  • Drug: Cytarabine
    Given IV over 30 minutes q12 hours on days 1-8 (16 doses)
    Other names:
    • Ara-C
    • Cytosar-U®
  • Drug: Gemtuzumab Ozogamicin
    Given IV
    Other names:
    • Mylotarg
  • Drug: Daunorubicin Hydrochloride
    IV over 1 hour on days 1, 3, and 5
    Other names:
    • FI-6339
    • L-lyxo-Hexopyranoside
  • Drug: Fludarabine Phosphate
    Given IV over 30 minutes on days 1-5
    Other names:
    • SH T 586
  • Drug: Idarubicin Hydrochloride
    Given IV over 15 minutes on days 3-5
    Other names:
    • IMI-30
    • Zavedos
  • Drug: Mitoxantrone Hydrochloride
    IV over 1 hour on days 2-4
    Other names:
    • Neotalem
    • Pralifan
    • Novantrone
  • Drug: Etoposide
    Given IV over 1 hour on days 1-5
    Other names:
    • VP-16
    • Vepesid®
  • Drug: Gilteritinib
    PO on days 8-28 (21 doses)
    Other names:
    • Xospata
Experimental
High Risk 		All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Azacitidine, Cytabrine, Danunorubicin Hydrochloride, Fludarabine Phosphate, Gemtuzumab Ozogamicin, Etoposide, Idarubin Hydrochloride, Gilteritinib
  • Drug: Venetoclax
    Venetoclax 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.
    Other names:
    • Venclextra
    • ABT-99
  • Drug: Azacitidine
    Given IV over 30 minutes on days 1-5
    Other names:
    • Mylosar
    • Vidaza
  • Drug: Cytarabine
    Given IV over 30 minutes q12 hours on days 1-8 (16 doses)
    Other names:
    • Ara-C
    • Cytosar-U®
  • Drug: Gemtuzumab Ozogamicin
    Given IV
    Other names:
    • Mylotarg
  • Drug: Daunorubicin Hydrochloride
    IV over 1 hour on days 1, 3, and 5
    Other names:
    • FI-6339
    • L-lyxo-Hexopyranoside
  • Drug: Fludarabine Phosphate
    Given IV over 30 minutes on days 1-5
    Other names:
    • SH T 586
  • Drug: Idarubicin Hydrochloride
    Given IV over 15 minutes on days 3-5
    Other names:
    • IMI-30
    • Zavedos
  • Drug: Etoposide
    Given IV over 1 hour on days 1-5
    Other names:
    • VP-16
    • Vepesid®
  • Drug: Gilteritinib
    PO on days 8-28 (21 doses)
    Other names:
    • Xospata

Recruiting Locations

Children's National and nearby locations

Children's National Medical Center
Washington, District of Columbia 20020
Contact:
Reuven Schore, MD
202-476-2800
rschore@childrensnational.org

More Details

NCT ID
NCT05955261
Status
Recruiting
Sponsor
St. Jude Children's Research Hospital

Study Contact

Hiroto Inaba, MD, PhD
866-278-5833
referralinfo@stjude.org

Detailed Description

Treatment will be based on genetic characteristics and response to therapy. Venetoclax will be given with each course of therapy. Low-risk patients will receive four courses of chemotherapy and intermediate-risk patients will receive five courses. High-risk patients who do not have a suitable stem cell donor or who decline HCT will receive five courses of chemotherapy. The definition of suitable stem cell donor and the conditioning regimens used for HCT will be determined by local institutional protocols or guidelines. Intervention: Low Risk Induction 1: 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. Induction 2: 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. Intensification: 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 receive gilteritinib PO QD on days 8-28 during intensification 1 and 2. Intermediate Risk Induction 1: 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. Induction 2: 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 receive gilteritinib PO QD on days 8-28. Intensification: 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 receive gilteritinib PO QD on days 8-28 during intensification 1-3. High Risk Induction 1: 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. Induction 2: 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 receive gilteritinib PO QD on days 8-28. Intensification: 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 ventoclax 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 ventoclax 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 receive gilteritinib PO QD on days 8-28.

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