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Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)

PHASE3RECRUITING

A study to evaluate if the randomized addition of venetoclax to a chemotherapy backbone (fludarabine/cytarabine/gemtuzumab ozogamicin \[GO\]) improves survival of children/adolescents/young adults with acute myeloid leukemia (AML) in 1st relapse who are unable to receive additional anthracyclines, or in 2nd relapse.

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Study details:

Relapse of AML is driven by chemotherapy resistant stem cells. One mechanism of chemotherapeutic resistance in AML is the overexpression of the protein B-cell lymphoma 2 (BCL-2), an anti-apoptotic protein which sequesters intracellular activators of apoptosis. Venetoclax is a selective, potent, orally bioavailable, small molecule inhibitor of B-cell lymphoma (BCL)-2 that restores programmed cell death in cancer cells.

This is a trial for children, adolescents and young adults with 2nd relapsed AML or 1st relapsed AML unable to receive additional anthracycline. This is randomized trial of venetoclax in combination with intensive chemotherapy (fludarabine/cytarabine/gemtuzumab ozogamicin) for the first two cycles that would inform and evaluate if this agent is an effective option for this population to improve its poor prognosis. Participants can receive up to two cycles of induction chemotherapy before hematopoietic stem cell transplantation (HSCT).

Participants benefiting from treatment and who are not able to proceed to HSCT have the possibility to continue to receive azacitidine in monotherapy (Arm A, control arm) or in combination with venetoclax (Arm B, experimental arm).

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  • Participants must have enrolled on APAL2020SC, NCT Number: NCT04726241 prior to enrollment on ITCC-101/APAL2020D. (This is only applicable for participants in USA/Canada/Australia/New Zealand sites/LLS territory).
  • Participants must be ≥ 29 days of age and ≤ 21 years of age at enrollment.
  • Participants must have one of the following: Children, adolescents, and young adults with acute myeloid leukemia without FLT3/internal tandem duplication (ITD) mutation in: 1. Second relapse, who are sufficiently fit to undergo another round of intensive chemotherapy 2. First relapse who per investigator discretion cannot tolerate additional anthracycline containing chemotherapy.
  • Participants must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (≥ 50% Lansky or Karnofsky score)
  • Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to start of protocol treatment: 1. Cytotoxic chemotherapy: Must not have received cytotoxic chemotherapy within 14 days prior to start of protocol treatment, except for corticosteroids, low dose cytarabine or hydroxyurea that can be given up to 24 hours prior to start of protocol treatment. 2. Intrathecal cytotoxic therapy: No wash-out time is required for participants having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone. 3. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate before start of protocol treatment. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before start of protocol treatment. Any toxicity related to prior antibody therapy must be recovered to Grade ≤ 1. 4. Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors) before start of protocol treatment. 5. Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or ≥7 days for short-acting growth factor before start of protocol treatment. 6. Radiation therapy (RT) (before start of protocol treatment): * ≥ 14 days have elapsed for local palliative RT (small port); * ≥ 84 days must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis; * ≥ 42 days must have elapsed if other substantial bone marrow (BM) radiation. 7. Stem Cell Infusions (before start of protocol treatment): * ≥ 84 days since allogeneic (non-autologous) bone marrow or stem cell transplant (with or without total body irradiation [TBI]) or boost infusion (any stem cell product; not including donor lymphocyte infusion [DLI]) * No evidence of active graft versus host disease (GVHD). 8. Participants who are receiving cyclosporine, tacrolimus or other agents to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial. Participants must be off medications to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant for at least 14 days prior to enrollment. 9. Cellular Therapy: ≥ 42 days after the completion of donor lymphocyte infusion (DLI) or any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.) before start of protocol treatment. 10. Participants with prior exposure to venetoclax are eligible in this trial
  • Adequate organ function: 1. Adequate Renal Function defined as: * Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60ml/min/1.73 m^2, or * Normal serum creatinine based on age/sex 2. Adequate Liver Function defined as: * Direct bilirubin < 1.5 x upper limit of normal (ULN), and * Alkaline phosphatase ≤ 2.5 x ULN, and * Serum glutamic pyruvic transaminase (SGPT) alanine aminotransferase (ALT) ≤ 2.5 x ULN. If liver abnormality is due to radiographically identifiable leukemia infiltrate, the participant will remain eligible. 3. Cardiac performance: Minimum cardiac function defined as: * No history of congestive heart failure in need of medical treatment * No pre-treatment diminished left ventricular function on echocardiography (shortening fraction [SF] < 25% or ejection fraction [EF] < 40%) * No signs of congestive heart failure at presentation of relapse.
  • Participant, parent or guardian must sign and date informed consent and pediatric assent (when required), prior to the initiation of screening or study specific procedures, according to local law and legislation.

    • Exclusion criteria

  • Participants who in the opinion of the investigator may not be able to comply with the study requirements of the study, are not eligible.
  • Participants with Down syndrome.
  • Participants with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic leukemia (JMML).
  • Participants with isolated CNS3 disease or symptomatic CNS3 disease.
  • Participants with malabsorption syndrome or any other condition that precludes enteral administration of venetoclax.
  • Participants who are currently receiving another investigational drug (GO is not considered investigational in this study).
  • Participants with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known congenital bone marrow failure syndrome.
  • Participants with known prior allergy to any of the medications used in protocol therapy.
  • Participants with documented active, uncontrolled infection at the time of study entry.
  • No known human immunodeficiency virus (HIV) infection.
  • Post menarchal female participants with positive pregnancy test.
  • Concomitant Medications: Participants who have received strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort within 7 days of the start of study treatment. Participants who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days of the start of study treatment. Participants who have hypersensitivity to the active substance or to any of the excipients listed in summary of product characteristics (SPC).
  • Pregnancy or Breast-Feeding: Participants who are pregnant or breast-feeding. Participants of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method per clinical trials facilitation group (CTFG) guidelines for the duration of study therapy and for 6 months after the completion of all study therapy. Male participants must use a condom during intercourse and agree not to father a child or donate sperm during therapy and for the duration of study therapy and for 4 months after the completion of all study therapy.
  • Gemtuzumab ozogamicin should not be given: to participants with history of veno-occlusive disease (VOD)/Sinusoidal obstruction syndrome (SOS) grade 4 to participants with history of VOD/SOS grade 3 to participants with CD33 negative leukemic blasts (determined at local lab). Note that these participants are eligible for the study but will not be treated with gemtuzumab ozogamicin.
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    Eligibility

    Age eligible for study : 29 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2022-10-01

    Primary completion: 2027-02-01

    Study completion finish: 2032-02-01

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE3

    trial

    Trial ID

    NCT05183035

    Intervention or treatment

    DRUG: Fludarabine

    DRUG: Cytarabine

    DRUG: Gemtuzumab Ozogamicin

    DRUG: Azacitidine

    DRUG: Venetoclax

    Conditions

    • • Acute Myeloid Leukemia
    Image related to Acute Myeloid Leukemia

    • Condition: Acute Myeloid Leukemia

    • DRUG: Fludarabine and other drugs

    • Nedlands, Western Australia, Australia and more

    • Sponsor: LLS PedAL Initiative, LLC

    You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

    Are you running this trial? If you're a clinic or sponsor, you can claim this study. Claim or learn more.

    Find a site

    Closest Location:

    Perth Children's Hospital

    Research sites nearby

    Select from list below to view details:

    • Perth Children's Hospital

      Nedlands, Western Australia, Australia

    • Children's Health Queensland Hospital and Health Service

      South Brisbane, Queensland, Australia

    • The Royal Children's Hospital - Children's Cancer Centre

      Parkville, Victoria, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    ACTIVE_COMPARATOR: Arm A: Control Arm without Venetoclax
    • During cycle 1 (each cycle is 42 days), participants will receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 1-5. Gemtuzumab 3 mg/m\^2 will be given on Day 6 (only for participants with CD33 expression on leukemia blasts).
    • During cycle 2 participants will receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 1-5.
    • After cycle 2 participants are assessed for hematopoietic stem cell transplantation (HSCT) or azacitidine maintenance therapy.
    DRUG: Fludarabine
    • Intravenous (IV) infusion
    EXPERIMENTAL: Arm B: Experimental Arm with Venetoclax
    • During cycle 1 (each cycle is 42 days), participants will receive 300 mg adult dose equivalent of venetoclax once on Day 1 followed by 600 mg adult dose equivalent of venetoclax on Days 2-21. Participants will also receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 8-12. Gemtuzumab 3 mg/m\^2 will be given on Day 13 (only for participants with CD33 expression on leukemia blasts).
    • During cycle 2, participants will receive 600 mg adult dose equivalent of venetoclax on Days 1-21. Participants will receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 1-5.
    • After cycle 2 participants are assessed for HSCT or azacitidine maintenance therapy in combination with venetoclax.
    DRUG: Fludarabine
    • Intravenous (IV) infusion

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Overall Survival (OS)Not SpecifiedUp to 5 years

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Morphology Event Free Survival (EFS)Not SpecifiedUp to 5 years
    Flow-based Event Free Survival (EFS)Not SpecifiedUp to 5 years
    Morphological Overall Response Rate (ORR)Not SpecifiedUp to Day 84
    Flow-based Overall Response Rate (ORR)Not SpecifiedUp to Day 84
    Duration of Response (DOR)Not SpecifiedUp to 5 years
    Cumulative Incidence of Relapse (CIR)Not SpecifiedUp to 5 years
    Number of Participants with Non-relapse Mortality (NRM)Not SpecifiedUp to 5 years
    Hematopoietic Stem Cell Transplantation (HSCT) RateNot SpecifiedUp to 5 years
    Number of Participants with Adverse Events (AEs)Not SpecifiedUp to 5 years
    Maximum Observed Plasma Concentration (Cmax) of VenetoclaxNot SpecifiedPre-dose, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 8 and Day 13 (cycle is 42 days); once on follow-up visits of Cycle 2 between Day 5 and Day 21
    Time to Maximum Observed Plasma Concentration (Tmax) of VenetoclaxNot SpecifiedPre-dose, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 8 and Day 13 (cycle is 42 days); once on follow-up visits of Cycle 2 between Day 5 and Day 21
    Area Under the Plasma Concentration-time Curve Over a 24-hour Dose Interval (AUC0-24)Not SpecifiedPre-dose, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 8 and Day 13 (cycle is 42 days); once on follow-up visits of Cycle 2 between Day 5 and Day 21
    Participants That Are Minimal Residual Disease (MRD) Negative with Complete Remission (CR), Partial Complete Remission (CRp), or Complete Remission with Incomplete Hematologic Recovery (CRi)Not SpecifiedUp to 5 years

    Frequently Asked Questions

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    You may be eligible to participate in this trial based on your search.Apply for study
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    References

    Clinical Trials Gov: Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)

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