Fludarabine, Idarubicin and Venetoclax with Standard Chemotherapy for the Treatment of Childhood Acute Myeloid Leukemia and Myeloid Sarcoma, UPDATE AML Trial

Status: active

This early phase I trial tests the effect of modifying standard of care treatment to include fludarabine, idarubicin and venetoclax in treating children with acute myeloid leukemia (AML) and myeloid sarcoma. Standard of care treatment usually includes combinations of chemotherapy drugs and may often include a stem cell transplant. Chemotherapy drugs, such as cytarabine, methotrexate, etoposide, and asparaginase Erwinia chrysanthemi, 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. Anti-inflammatory drugs, such as hydrocortisone, lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. Fludarabine blocks cells from making deoxyribonucleic acid and may kill cancer cells. It is a type of purine antagonist and a type of ribonucleotide reductase inhibitor. Idarubicin is in a class of medications called anthracyclines. It works by slowing or stopping the growth of cancer cells in the body. 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 combination of chemotherapy drugs, the total number of rounds (cycles) of treatment needed and the intensity of treatment depends on the aggressiveness of the AML. Aggressiveness is based on certain characteristics of the AML and is referred to as the risk for relapse. Modifying treatment based on risk category and response may be safe, tolerable, and/or effective and may reduce the likelihood of long-term complications with less intensive chemotherapy in children with AML and myeloid sarcoma.

Inclusion Criteria

Patients ≥ 1 months old to ≤ 30 years old are eligible
Patients must be diagnosed with AML or myeloid sarcoma according to the 2022 World Health Organization (WHO) classification with or without extramedullary disease. Patients with AML must have 1 of the following at initial diagnosis: * ≥ 20% bone marrow blasts ** In cases where extensive fibrosis may result in a dry tap, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy * < 20% bone marrow blasts with one or more of the bolded+underlined genetic abnormalities ** t(8;21)(q22;q22.1): RUNX1::RUNX1T1 ** inv(16)(p13.1q22) or t(16;16)(p13.1;q22): CBFB::MYH11 ** Translocation involving 11q23.3: KMT2A rearrangement ** t(6;9)(p23;q34.1): DEK::NUP214 ** inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2): MECOM rearrangement ** Megakaryoblastic with t(1;22)(p13.3;q13.3): RBM15::MRTFA ** Mutated NPM1 ** CEBPA bZip mutation ** t(1;22)(p13.3;q13.1): RBM15(OTT) fusion ** t(7;12)(q36.3;p13.2): MNX1::ETV6 ** t(8;16)(p11.2;p13.3): KAT6A::CREBBP ** t(5;11)(q35.3;p15.5): NUP98::NSD1 ** inv(16)(p13.3q24.3): CBFA2T3::GLIS2 ** t(11;12)(p15.5;p13.5): NUP98::KDM5A ** 11q23.3 partial tandem duplication (PTD): KMT2A PTD * A complete blood count (CBC) documenting the presence of at least 1,000/µL circulating leukemic cells (blasts) if a bone marrow aspirate or biopsy cannot be performed (i.e., a white blood cell [WBC] count ≥ 10,000/μL with ≥ 10% blasts or a WBC count of ≥ 5,000/μL with ≥ 20% blasts) * Biopsy-proven myeloid sarcoma with or without bone marrow involvement ** Note: patients with newly diagnosed AML, myelodysplasia-related ARE eligible while patients with therapy-related AML are excluded
Patients must receive DA10+GO (cytarabine days 1-10 + daunorubicin days 1,3,5 [DA10] + gemtuzumab ozogamcin [GO]) as prescribed in AAML1831 or the Texas Children’s Cancer and Hematology Center (TXCH) practice standard for Induction 1. Patients may have received any number of intrathecal treatments and have any central nervous system (CNS) status at the time of enrollment
Patients must have a performance status corresponding to Karnofsky/Lansky score ≥ 40. (Use Karnofsky for patients ≥ 16 years of age and Lanksy for patients ≤ 16 years of age.)
A creatinine clearance or glomerular filtration rate (GFR) ≥ 60 ml/min/1.73m^2 (within 7 days prior to enrollment) * If post-enrollment lab value is outside the limits of eligibility, or laboratory values are > 7 days old then must be re-checked within 48 hours prior to initiating therapy
A direct bilirubin < 2 mg/dL (within 7 days prior to enrollment) * If post-enrollment lab value is outside the limits of eligibility, or laboratory values are > 7 days old then must be re-checked within 48 hours prior to initiating therapy
Alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN) or 225 U/L (within 7 days prior to enrollment), with the ULN being 45 U/L for the purpose of this study * If post-enrollment lab value is outside the limits of eligibility, or laboratory values are > 7 days old then must be re-checked within 48 hours prior to initiating therapy
International normalized ratio (INR) ≤ 1.5 (within 7 days prior to enrollment)
Ejection fraction (EF) ≥ 50% (within 7 days prior to enrollment) (preferred method Biplane Simpson’s EF) or if EF unavailable, shortening fraction (SF) ≥ 24%, within 14 days prior to planned start of Induction 2 therapy
For patients with cardiac dysfunction (EF < 50% or SF < 24% if EF is unavailable) prior to enrollment, (within 7 days prior to enrollment) if clinically safe and feasible, repeat echocardiogram is strongly advised in order to confirm cardiac dysfunction following clinical stabilization, particularly if occurring in the setting of sepsis or other transient physiologic stressor. If the repeat echocardiogram demonstrates an EF ≥ 50%, the patient is eligible to enroll
All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria

Patients with the following constitutional conditions are not eligible: * Fanconi anemia * Schwachman Diamond syndrome * Telomere disorders * Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21 * Germline predispositions known, or suspected by the treating physician to increase risk of toxicity with AML therapy * Therapy-related AML
Patients with any of the following oncologic diagnoses are not eligible: * Any concurrent malignancy * Juvenile myelomonocytic leukemia * Philadelphia chromosome positive AML * Mixed phenotype acute leukemia * Acute promyelocytic leukemia * AML with FLT3 internal tandem duplication (FLT3-ITD)
Female patients who are pregnant may not participate. A pregnancy test is required for female patients of childbearing potential
Lactating females who plan to breastfeed their infants are not eligible
Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation are not eligible

PRIMARY OBJECTIVES:

I. To determine the tolerability of idarubicin (IDA), fludarabine (FLU), and cytarabine (ARAC) (Ida-FLA) when given to intermediate-risk (IR) and high-risk (HR) patients for Induction 2.

II. To determine the tolerability of venetoclax (VEN)-Ida-AraC (VIA) when given to IR patients for Intensification 2.

III. To determine the tolerability of VEN-Ida-AraC (VIA) when given to HR patients for Intensification 1.

SECONDARY OBJECTIVES:

I. To determine the pediatric morphological complete remission (ped-morph CR) rates at the End-Induction 2 for IR and HR patients.

II. To determine the proportion of IR/HR patients who were measurable residual disease (MRD)+ by flow cytometry at End-Induction 1 who become MRD- at End-Induction 2.

III. To estimate the 3-year event-free survival (EFS) and overall survival (OS) of IR patients.

IV. To estimate the 3-year EFS and OS of HR patients.

V. To determine the rate of count recovery (absolute neutrophil count [ANC] > 500/ul and platelets > 20,000/ul without transfusion in the previous 7 days) by day 42 of the Intensification 1 cytarabine + etoposide (AE) cycle for IR patients.

VI. To determine the tolerability of each intensified regimen as a whole for IR patients receiving Ida-FLA for Induction 2 and VIA for Intensification 2.

VII. To determine the tolerability of each intensified regimen as a whole for HR patients receiving Ida-FLA for Induction 2 and VIA for Intensification 1.

EXPLORATORY OBJECTIVES:

I. To evaluate the feasibility of developing patient-specific digital polymerase chain reaction (PCR) (dPCR) MRD assays for bone marrow and cell-free blood nucleic acid, describe longitudinal MRD trajectories and evaluate the concordance of dPCR MRD with clinical flow cytometry-based MRD.

II. To determine rates of left ventricular systolic dysfunction for IR and HR patients treated with idarubicin, and describe changes in cardiac biomarker levels during therapy.

III. To assess patient and/or caregiver reports of treatment toxicities and the impact of AML therapy on quality of life, using validated pediatric-specific patient-reported outcome (PRO) tools.

IV. To generate patient-derived xenografts using leukemia samples of patients consenting to biobanking.

V. To identify potential epigenetic, genetic, signaling and metabolomic markers of treatment response or resistance. Planned investigations include, but are not limited to, quantifying selenium pathway markers and BCL2-family protein expression.

OUTLINE: Patients receive standard of care induction treatment with cytarabine and daunorubicin and gemtuzumab ozogamicin for 1 cycle and are then assigned to 1 of 3 treatment plans based on risk group.

TREATMENT PLAN I (LOW-RISK PATIENTS): Patients receive chemotherapy for 3 cycles per standard of care.

TREATMENT PLAN II (IR PATIENTS):

INDUCTION 2: Patients receive fludarabine intravenously (IV) over 30 minutes on days 1-5, cytarabine IV over 3 hours on days 1-5, and idarubicin IV over 15 minutes on days 3-5 of each cycle. Patients also receive methotrexate, hydrocortisone and cytarabine intrathecally (IT) on day 1 of each cycle. Cycles repeat every 28-36 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity.

INTENSIFICATION 1: Patients with CR/CR with incomplete blood count recovery (CRi)/CR with partial recovery of platelet count (CRp) after Induction 2 receive cytarabine IV over 1 hour and etoposide IV over 90 minutes on days 1-5 of each cycle. Patients also receive methotrexate, hydrocortisone and cytarabine IT on day 1 of each cycle. Cycles repeat every 28-36 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity.

INTENSIFICATION 2: Patients receive venetoclax orally (PO) once daily (QD) on days 1-14, cytarabine IV over 1 hour on days 1-4, and idarubicin IV over 15 minutes on day 1 of each cycle. Patients also receive methotrexate, hydrocortisone, and cytarabine IT on day 1 of each cycle. Cycles repeat every 28-36 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity.

INTENSIFICATION 3: Patients receive cytarabine IV over 3 hours every 12 hours on days 1-2 and 8-9 and asparaginase Erwinia chrysanthemi intramuscularly (IM) on days 2 and 9 of each cycle. Cycles repeat every 28-36 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity.

TREATMENT PLAN III (HR PATIENTS):

INDUCTION 2: Patients receive fludarabine IV over 30 minutes and cytarabine IV over 3 hours on days 1-5, and idarubicin IV over 15 minutes on days 3-5 of each cycle. Patients also receive methotrexate, hydrocortisone and cytarabine IT on day 1 of each cycle. Cycles repeat every 28-36 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity.

INTENSIFICATION 1: Patients with CR/CRi/CRp after Induction 2 receive venetoclax PO QD on days 1-14, cytarabine IV over 1 hour on days 1-4 and idarubicin IV over 15 minutes on day 1 of each cycle. Patients also receive methotrexate, hydrocortisone, and cytarabine IT on day 1 of each cycle. Cycles repeat every 28-36 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients with a suitable donor for allogeneic stem cell transplant proceed to standard of care hematopoietic stem cell transplantation. Patients without a suitable donor receive 5 total cycles of chemotherapy, following the treatment plan for IR patients.

Additionally, patients undergo blood sample collection, lumbar puncture (LP), bone marrow aspiration and biopsy, echocardiography (ECHO) or multigated acquisition scan (MUGA), biopsy and/or computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study.

After completion of study treatment, patients are followed monthly for the first 6 months, then every 3-6 months for the first 3 years.

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Fludarabine, Idarubicin and Venetoclax with Standard Chemotherapy for the Treatment of Childhood Acute Myeloid Leukemia and Myeloid Sarcoma, UPDATE AML Trial

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Fludarabine, Idarubicin and Venetoclax with Standard Chemotherapy for the Treatment of Childhood Acute Myeloid Leukemia and Myeloid Sarcoma, UPDATE AML Trial

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