AflacLL1901 (CHOA-AML)

NCT ID: NCT04326439

Last Updated: 2022-06-15

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-24
• Study Completion Date: 2022-03-15

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.

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.

Conditions

Acute Myeloid Leukemia; AML, Childhood

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Cytarabine

Intervention Type: DRUG

100 mg/m²/dose every 12 hours IV Days 1-10

Daunorubicin

Intervention Type: DRUG

50 mg/m²/dose IV Days 1, 3, 5

Erwinase

Intervention Type: DRUG

25,000 International Units/m²/dose IM Days 2, 9

Etoposide

Intervention Type: DRUG

150 mg/m²/dose IV Days 1-5

Gemtuzumab ozogamicin

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Cytarabine

Intervention Type: DRUG

100 mg/m²/dose every 12 hours IV Days 1-10

Daunorubicin

Intervention Type: DRUG

50 mg/m²/dose IV Days 1, 3, 5

Erwinase

Intervention Type: DRUG

25,000 International Units/m²/dose IM Days 2, 9

Etoposide

Intervention Type: DRUG

150 mg/m²/dose IV Days 1-5

Gemtuzumab ozogamicin

Intervention Type: DRUG

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.

Stem cell transplantation (SCT)

Intervention Type: PROCEDURE

Transplantation of multipotent hematopoietic stem cells from bone marrow

Sorafenib

Intervention Type: DRUG

200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 400 mg. Days 7 through 34.

Interventions

Cytarabine

100 mg/m²/dose every 12 hours IV Days 1-10

Intervention Type: DRUG

Daunorubicin

50 mg/m²/dose IV Days 1, 3, 5

Intervention Type: DRUG

Erwinase

25,000 International Units/m²/dose IM Days 2, 9

Intervention Type: DRUG

Etoposide

150 mg/m²/dose IV Days 1-5

Intervention Type: 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.

Intervention Type: DRUG

Stem cell transplantation (SCT)

Transplantation of multipotent hematopoietic stem cells from bone marrow

Intervention Type: PROCEDURE

Sorafenib

200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 400 mg. Days 7 through 34.

Intervention Type: DRUG

Other Intervention Names

cytosine arabinoside, ARA-C; Rubidomycin; Erwinaze, Erwinia L-Asparaginase, Erwinia Chrysanthemi L-asparaginase, Crisantaspase; VePesid, VP-16; Mylotarg®, CDP-771, CMA-676, hP67.6-calicheamicin; Hematopoietic stem cell transplantation (HSCT), Bone Marrow Transplant (BMT); BAY 43-9006 Tosylate, BAY 54-9085 Nexavar

Eligibility 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

• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Emory University

OTHER

Sponsor Role: lead

Responsible Party

Himalee Sabnis

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Himalee Sabnis, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Locations

Egleston Hospital

Atlanta, Georgia, United States

Countries

United States

References

Sabnis HS, Minson KA, Monroe C, Allen K, Metts JL, Cooper TM, Woods WG, Castellino SM, Keller FG. A strategy to reduce cumulative anthracycline exposure in low-risk pediatric acute myeloid leukemia while maintaining favorable outcomes. Leuk Res. 2020 Sep;96:106421. doi: 10.1016/j.leukres.2020.106421. Epub 2020 Jul 12.

Reference Type: DERIVED

PMID: 32683126 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

IRB00111627

Identifier Type: -

Identifier Source: org_study_id