AflacLL1901 (CHOA-AML)

Study Overview
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Brief Summary
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The investigators propose to study an Aflac-AML chemotherapy backbone prospectively to validate its use in all pediatric AML and to further evaluate the cardiotoxicity with this approach for low risk AML.

Detailed Description
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Advances in risk stratification and therapy, have improved the event-free survival (EFS) and overall survival (OS) for pediatric acute myeloid leukemia (AML) to approximately 50% and 65% respectively, with current treatment strategies. Patients with good response to induction and/or those who lack high-risk cytogenetic and molecular features [classified as low-risk AML (LR-AML)] have even better outcomes with EFS and OS approaching 70% and 85% respectively; however, treatment-related toxicities remain a major concern. Anthracycline-based therapeutic regimens expose patients to the risk of anthracycline-induced cardiotoxicity. Therefore, strategies that reduce cardiac toxicities using tailored approaches while maintaining and/or improving outcomes are needed for all patients with AML. The Children's Oncology Group (COG) regimens AAML1031 and AAML0531 utilized an anthracycline-intensive backbone for LR-AML with cumulative anthracycline doxorubicin-equivalent doses of up to 492mg/m2. However, high-risk patients treated with chemotherapy alone received an intensified induction chemotherapy (using mitoxantrone-cytarabine) but with overall reduced doses of anthracycline-equivalent (342mg/m2). The investigators piloted an institutional practice to treat all LR-AML patients with four cycle regimen (Aflac-AML) with the goal of reducing cumulative anthracycline exposure, thereby reducing the risk of cardiotoxicity, while providing three high-dose cytarabine courses. In this pilot institutional experience with this approach, they were able to maintain excellent outcomes for this low-risk group with 3-year event-free survival (EFS) and OS of 70.0% ± 0.1% and 85.5% ± 0.08% respectively, from end of course 1. Recent evolution in cytogenetic classification has further delineated risk groups in AML. Gemtuzumab ozogamicin (GO), an antibody-drug conjugate was shown to reduce relapse risk in patients with CC genotype with de-novo AML on COG study AAML0531. The investigators propose to study an Aflac-AML chemotherapy backbone prospectively to validate its use in all pediatric AML and to further evaluate the cardiotoxicity with this approach for low risk AML.

Official Title
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CHOA-AML: A Pilot Study for Newly Diagnosed Pediatric Patients With Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia, AML, Childhood

Intervention / Treatment
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* Drug: Cytarabine
* Drug: Daunorubicin
* Drug: Erwinase
* Drug: Etoposide
* Drug: Gemtuzumab ozogamicin
* Procedure: Stem cell transplantation (SCT)
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: Patients must be less than 21 years of age at the time of study enrollment Diagnosis: Patients must be newly diagnosed with AML Patients with previously untreated primary AML who meet the customary criteria for AML with ≥ 20% bone marrow blasts as set out in the 2016 WHO Myeloid Neoplasm Classification are eligible. Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive. In cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/FISH testing is feasible can be substituted for the marrow exam at diagnosis. Patients with <20% bone marrow blasts are eligible if they have: A karyotypic abnormality characteristic of de novo AML (t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities, the unequivocal presence of megakaryoblasts, or Biopsy proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis) Performance Level: Patients with acceptable organ function and any performance status are eligible for enrollment Exclusion Criteria: Patients with any of the following constitutional conditions are not eligible: Fanconi anemia Shwachman syndrome Any other known bone marrow failure syndrome Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21 Note: Enrollment may occur, pending results of clinically indicated studies to exclude these conditions. Other Excluded Conditions: Any concurrent malignancy Juvenile myelomonocytic leukemia (JMML) Philadelphia chromosome positive AML Biphenotypic or bilineal acute leukemia Acute promyelocytic leukemia (APL) Acute myeloid leukemia arising from myelodysplasia Therapy-related myeloid neoplasms

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aflac-AML Regimen for Low Risk AML Patients<br>Participants in this arm will receive the standard Aflac-AML Regimen with the following chemotherapy: Induction-1: patients on Induction-I will receive gemtuzumab + ADE therapy based on genotyping. Lasts a total of 28 days. Induction II - MA Intensification I - AE Intensification II - HD ARAC/LASP Patients with low risk status who had low risk markers and were MRD positive at the end of Induction I and continue to be MRD positive after Induction II will come off protocol. | Drug: Cytarabine<br>* 100 mg/m²/dose every 12 hours IV Days 1-10<br>* Other names: cytosine arabinoside, ARA-C;Drug: Daunorubicin<br>* 50 mg/m²/dose IV Days 1, 3, 5<br>* Other names: Rubidomycin;Drug: Erwinase<br>* 25,000 International Units/m²/dose IM Days 2, 9<br>* Other names: Erwinaze, Erwinia L-Asparaginase, Erwinia Chrysanthemi L-asparaginase, Crisantaspase;Drug: Etoposide<br>* 150 mg/m²/dose IV Days 1-5<br>* Other names: VePesid, VP-16;Drug: Gemtuzumab ozogamicin<br>* Administered as a single 3 mg/m2 dose of GO to be given between days 6-10 during Induction I for patients with CC genotype, in addition to ADE therapy.<br>* Other names: Mylotarg®, CDP-771, CMA-676, hP67.6-calicheamicin;|
| Experimental: Aflac-AML Regimen for High Risk AML Patients<br>Participants in this arm will receive standard Aflac-AML Regimen with the following chemotherapy: Induction-1: patients will receive gemtuzumab in addition to ADE therapy based on genotyping. Induction I lasts a total of 28 days. Induction 1 for FLT3-ITD patients - ADE (10+3+5) with GO with Sorafenib Induction II - MA Induction II for FLT3-ITD patients - MA with Sorafenib Intensification I - AE Intensification I for FLT3-ITD patients - AE with sorafenib Intensification II - HD ARAC/LASP Intensification II for FLT3-ITD patients - HD ARAC/LASP with sorafenib Hematopoietic stem cell transplantation (HSCT) If a patient is classified as High risk after Induction I, they may proceed to best allogenic donor SCT following Induction II. These patients may receive a third course of chemotherapy prior to HSCT. In cases where HSCT is not an option, patients can receive 4 cycles of chemotherapy. Only patients with FLT3-ITD mutation will receive sorafenib. | Drug: Cytarabine<br>* 100 mg/m²/dose every 12 hours IV Days 1-10<br>* Other names: cytosine arabinoside, ARA-C;Drug: Daunorubicin<br>* 50 mg/m²/dose IV Days 1, 3, 5<br>* Other names: Rubidomycin;Drug: Erwinase<br>* 25,000 International Units/m²/dose IM Days 2, 9<br>* Other names: Erwinaze, Erwinia L-Asparaginase, Erwinia Chrysanthemi L-asparaginase, Crisantaspase;Drug: Etoposide<br>* 150 mg/m²/dose IV Days 1-5<br>* Other names: VePesid, VP-16;Drug: Gemtuzumab ozogamicin<br>* Administered as a single 3 mg/m2 dose of GO to be given between days 6-10 during Induction I for patients with CC genotype, in addition to ADE therapy.<br>* Other names: Mylotarg®, CDP-771, CMA-676, hP67.6-calicheamicin;Procedure: Stem cell transplantation (SCT)<br>* Transplantation of multipotent hematopoietic stem cells from bone marrow<br>* Other names: Hematopoietic stem cell transplantation (HSCT), Bone Marrow Transplant (BMT);Drug: Sorafenib<br>* 200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 400 mg. Days 7 through 34.<br>* Other names: BAY 43-9006 Tosylate, BAY 54-9085 Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) in Low Risk Patients and High Risk Patients | Event-free survival defined as the time from on study to death, failure to achieve remission or relapse in newly diagnosed patients with pediatric acute myeloid leukemia in the Low risk stratification group and High risk stratification group | Up to 2 years post-intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from study entry and from end of first course of therapy for newly diagnosed patients with pediatric acute myeloid leukemia | Up to 2 years post-intervention | 
| Minimal Residual Disease (MRD) Negative Status | Number of patients that are in remission (MRD negative) after course 1 in participants receiving GO and those that did not receive GO. | Post-induction I, an average of 28 days | 
| Disease-free Survival (DFS) for Patients Who Are MRD Negative | Disease-free survival for patients who are MRD negative but lack high or low risk molecular and cytogenetic features, defined as time from end of first course of therapy to death or relapse | Up to 2 years post-intervention | 
| Cardiotoxicity in Patients With de Novo AML That Receive the Four-cycle Aflac-AML Regimen With the Inclusion of Dexrazoxane | Number of patients that develop cardiac ejection fraction <50% (CTCAE V5.0 grade 2 or greater dysfunction) either during therapy (early cardiotoxicity) or after completion of therapy (late cardiotoxicity) | At completion of Cycle 4 (each cycle average is 28 days) | 
| Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | Number of participants that developed infection and/or febrile neutropenia at the end of each treatment cycle. | At the end of each cycle (each cycle average is 28 days) | 
| Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle | Duration of hospital admission in patients that developed infection and febrile neutropenia at the end of each treatment cycle | At the end of each cycle (each cycle average is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia