Description:
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.
Title
- Brief Title: AflacLL1901 (CHOA-AML)
- Official Title: CHOA-AML: A Pilot Study for Newly Diagnosed Pediatric Patients With Acute Myeloid Leukemia (AML)
Clinical Trial IDs
- ORG STUDY ID:
IRB00111627
- NCT ID:
NCT04326439
Conditions
- Acute Myeloid Leukemia
- AML, Childhood
Interventions
| Drug | Synonyms | Arms |
|---|
| Cytarabine | cytosine arabinoside, ARA-C | Aflac-AML Regimen for High Risk AML Patients |
| Daunorubicin | Rubidomycin | Aflac-AML Regimen for High Risk AML Patients |
| Erwinase | Erwinaze, Erwinia L-Asparaginase, Erwinia Chrysanthemi L-asparaginase, Crisantaspase | Aflac-AML Regimen for High Risk AML Patients |
| Etoposide | VePesid, VP-16 | Aflac-AML Regimen for High Risk AML Patients |
| Gemtuzumab ozogamicin | Mylotarg®, CDP-771, CMA-676, hP67.6-calicheamicin | Aflac-AML Regimen for High Risk AML Patients |
| Sorafenib | BAY 43-9006 Tosylate, BAY 54-9085 Nexavar | Aflac-AML Regimen for High Risk AML Patients |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Aflac-AML Regimen for Low Risk AML Patients | Experimental | 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. | - Cytarabine
- Daunorubicin
- Erwinase
- Etoposide
- Gemtuzumab ozogamicin
|
| Aflac-AML Regimen for High Risk AML Patients | Experimental | 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. | - Cytarabine
- Daunorubicin
- Erwinase
- Etoposide
- Gemtuzumab ozogamicin
- Sorafenib
|
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 |
| Minimum Eligible Age: | N/A |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Event-free survival (EFS) in Low risk patients |
| Time Frame: | Up to 2 years post-intervention |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Overall survival (OS) |
| Time Frame: | Up to 2 years post-intervention |
| Safety Issue: | |
| Description: | Time from study entry and from end of first course of therapy for newly diagnosed patients with pediatric acute myeloid leukemia |
| Measure: | Minimal residual disease (MRD) negative status |
| Time Frame: | Post-induction I, an average of 28 days |
| Safety Issue: | |
| Description: | Proportion of patients that are in remission (MRD negative) after course 1 in participants receiving GO and those that did not receive GO. |
| Measure: | Disease-free survival (DFS) for patients who are MRD negative |
| Time Frame: | Up to 2 years post-intervention |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Incidence of 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) |
| Safety Issue: | |
| Description: | Proportion 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) |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Terminated |
| Lead Sponsor: | Emory University |
Trial Keywords
Last Updated
July 21, 2021
