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AflacLL1901 (CHOA-AML)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04326439
Recruitment Status : Terminated (Due to unforeseen circumstances, the study team was limited in enrolling patients on this trial; thus, it was terminated.)
First Posted : March 30, 2020
Results First Posted : June 15, 2022
Last Update Posted : June 15, 2022
Sponsor:
Information provided by (Responsible Party):
Himalee Sabnis, Emory University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia AML, Childhood Drug: Cytarabine Drug: Daunorubicin Drug: Erwinase Drug: Etoposide Drug: Gemtuzumab ozogamicin Procedure: Stem cell transplantation (SCT) Drug: Sorafenib Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CHOA-AML: A Pilot Study for Newly Diagnosed Pediatric Patients With Acute Myeloid Leukemia (AML)
Actual Study Start Date : January 24, 2020
Actual Primary Completion Date : March 15, 2022
Actual Study Completion Date : March 15, 2022


Arm Intervention/treatment
Experimental: Aflac-AML Regimen for Low Risk AML Patients

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
100 mg/m²/dose every 12 hours IV Days 1-10
Other Name: cytosine arabinoside, ARA-C

Drug: Daunorubicin
50 mg/m²/dose IV Days 1, 3, 5
Other Name: Rubidomycin

Drug: Erwinase
25,000 International Units/m²/dose IM Days 2, 9
Other Name: Erwinaze, Erwinia L-Asparaginase, Erwinia Chrysanthemi L-asparaginase, Crisantaspase

Drug: Etoposide
150 mg/m²/dose IV Days 1-5
Other Name: VePesid, VP-16

Drug: Gemtuzumab ozogamicin
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.
Other Name: Mylotarg®, CDP-771, CMA-676, hP67.6-calicheamicin

Experimental: Aflac-AML Regimen for High Risk AML Patients

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
100 mg/m²/dose every 12 hours IV Days 1-10
Other Name: cytosine arabinoside, ARA-C

Drug: Daunorubicin
50 mg/m²/dose IV Days 1, 3, 5
Other Name: Rubidomycin

Drug: Erwinase
25,000 International Units/m²/dose IM Days 2, 9
Other Name: Erwinaze, Erwinia L-Asparaginase, Erwinia Chrysanthemi L-asparaginase, Crisantaspase

Drug: Etoposide
150 mg/m²/dose IV Days 1-5
Other Name: VePesid, VP-16

Drug: Gemtuzumab ozogamicin
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.
Other Name: Mylotarg®, CDP-771, CMA-676, hP67.6-calicheamicin

Procedure: Stem cell transplantation (SCT)
Transplantation of multipotent hematopoietic stem cells from bone marrow
Other Name: Hematopoietic stem cell transplantation (HSCT), Bone Marrow Transplant (BMT)

Drug: Sorafenib
200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 400 mg. Days 7 through 34.
Other Name: BAY 43-9006 Tosylate, BAY 54-9085 Nexavar




Primary Outcome Measures :
  1. Event-free Survival (EFS) in Low Risk Patients and High Risk Patients [ Time Frame: Up to 2 years post-intervention ]
    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


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Up to 2 years post-intervention ]
    Time from study entry and from end of first course of therapy for newly diagnosed patients with pediatric acute myeloid leukemia

  2. Minimal Residual Disease (MRD) Negative Status [ Time Frame: Post-induction I, an average of 28 days ]
    Number of patients that are in remission (MRD negative) after course 1 in participants receiving GO and those that did not receive GO.

  3. Disease-free Survival (DFS) for Patients Who Are MRD Negative [ Time Frame: Up to 2 years post-intervention ]
    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

  4. Cardiotoxicity in Patients With de Novo AML That Receive the Four-cycle Aflac-AML Regimen With the Inclusion of Dexrazoxane [ Time Frame: At completion of Cycle 4 (each cycle average is 28 days) ]
    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)

  5. Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course [ Time Frame: At the end of each cycle (each cycle average is 28 days) ]
    Number of participants that developed infection and/or febrile neutropenia at the end of each treatment cycle.

  6. Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle [ Time Frame: 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04326439


Locations
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United States, Georgia
Egleston Hospital
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
Investigators
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Principal Investigator: Himalee Sabnis, MD Emory University
  Study Documents (Full-Text)

Documents provided by Himalee Sabnis, Emory University:
Informed Consent Form  [PDF] July 27, 2021

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Himalee Sabnis, Assistant Professor, Emory University
ClinicalTrials.gov Identifier: NCT04326439    
Other Study ID Numbers: IRB00111627
First Posted: March 30, 2020    Key Record Dates
Results First Posted: June 15, 2022
Last Update Posted: June 15, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Himalee Sabnis, Emory University:
acute myeloid leukemia
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Etoposide
Daunorubicin
Sorafenib
Asparaginase
Gemtuzumab
Calicheamicins
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Antibiotics, Antineoplastic
Antineoplastic Agents, Immunological