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Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syndrome

Information source: Children's Oncology Group
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Childhood Acute Myeloid Leukemia; Childhood Myelodysplastic Syndrome; de Novo Myelodysplastic Syndrome; Down Syndrome; Myeloid Leukemia Associated With Down Syndrome

Intervention: Asparaginase (Drug); Asparaginase Erwinia chrysanthemi (Drug); Cytarabine (Drug); Daunorubicin Hydrochloride (Drug); Etoposide (Drug); Laboratory Biomarker Analysis (Other); Mitoxantrone Hydrochloride (Drug); Thioguanine (Drug)

Phase: Phase 3

Status: Not yet recruiting

Sponsored by: Children's Oncology Group

Official(s) and/or principal investigator(s):
Jason Berman, Principal Investigator, Affiliation: Children's Oncology Group

Summary

This phase III trial studies response-based chemotherapy in treating newly diagnosed acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome. Drugs used in chemotherapy 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. Response-based chemotherapy separates patients into different risk groups and treats them according to how they respond to the first course of treatment (Induction I). Response-based treatment may be effective in treating acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome while reducing the side effects.

Clinical Details

Official title: Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome

Study design: Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: EFS

Secondary outcome:

Average total number of days per patient spent on protocol therapy

Duration of hospitalization

Early death rates

Infection rates

Overall survival

Percentage of patients experiencing grade 3 or higher toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Relapse risk

Time to count recovery

Treatment related mortality

Detailed description: PRIMARY OBJECTIVES: I. To determine the 2-year event-free-survival (EFS) for children with standard risk Down syndrome (DS) acute myeloid leukemia (AML) (minimal residual disease [MRD]-negative after one cycle of induction therapy) after elimination of high dose (HD) Ara-C (cytarabine) from the treatment regimen. II. To determine the 2-year EFS for children with high risk DS AML (MRD-positive after one cycle of induction therapy) after intensification of treatment equivalent to that used for high risk AML in children without DS. SECONDARY OBJECTIVES: I. To determine the extent to which elimination of HD Ara-C from the treatment of standard risk DS AML decreases adverse events and resource utilization. II. To determine if elimination of HD Ara-C from treatment of standard risk DS AML results in a significant decrease in the number of days per patient spent on protocol therapy compared to predecessor study AAML0431. III. To determine if elimination of HD Ara-C from treatment of standard risk DS AML results in a significant decrease in the average number of days of hospitalization per patient compared to predecessor studies AAML0431 and A2971. IV. To determine if elimination of HD Ara-C from treatment of standard risk DS AML results in a significant decrease in the number (per patient) and rate (per duration of treatment) of sterile site infections compared to the predecessor study AAML0431. V. To determine if elimination of HD Ara-C from treatment of standard risk DS AML results in a significant decrease of resource utilization by AML treatment compared to the predecessor study AAML0431. VI. To compare the feasibility and analytical characteristics of flow cytometry, polymerase chain reaction (PCR) and targeted error-corrected sequencing of GATA binding protein 1 (globin transcription factor 1) (GATA1) mutations as methods to detect MRD in DS AML. VII. To test in a large cohort of patients with DS AML whether known somatic mutations, in cohesin complex, RAS pathway and epigenetic regulator genes in blasts of DS-AML are prognostic and can be used for future risk-adapted stratification of treatment in future trials. VIII. To establish a DS AML cell bank of viably frozen bone marrow samples collected at the end of induction and corresponding non-tumor deoxyribonucleic acid (DNA) samples collected at end of Induction 1. OUTLINE: INDUCTION I: Patients receive cytarabine intrathecally (IT) on day 1 and intravenously (IV) continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine orally (PO) twice daily (BID) on days 1-4. Induction I continues for a minimum of 28 days. Patients are assigned to 1 of 2 treatment arms based on their MRD status after completion of Induction I. ARM A (STANDARD RISK): INDUCTION II: Patients receive cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine PO BID on days 1-4. Induction II continues for a minimum of 28 days. INDUCTION III: Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days. INTENSIFICATION I: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 60-120 minutes on days 1-3. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive cytarabine and etoposide as in Intensification I. Intensification II continues for a minimum of 28 days. ARM B (HIGH RISK): INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours BID on days 1-4 and mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6. Induction II continues for a minimum of 28 days. INTENSIFICATION I: Patients receive high dose cytarabine IV over 1-3 hours BID and etoposide IV over 60-120 minutes on days 1-5. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive high dose cytarabine IV over 1-3 hours BID on days 1, 2, 8, and 9. Patients also receive asparaginase or asparaginase Erwinia chrysanthemi (E. carotovora) intramuscularly (IM) on days 2 and 9. Intensification II continues for a minimum of 28 days. After completion of study treatment, patients are followed up at 1 month, monthly for 12 months, every 3 months for 12 months, every 6 months for 3 years, annually for 5 years, and then at relapse.

Eligibility

Minimum age: 91 Days. Maximum age: 3 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients must have constitutional trisomy 21 (Down syndrome) or trisomy 21 mosaicism

(by karyotype or fluorescence in situ hybridization [FISH])

- Patients with previously untreated de novo AML who meet the criteria for AML with >=

20% bone marrow blasts as set out in the World Health Organization (WHO) Myeloid Neoplasm classification

- Patients with cytopenias and/or bone marrow blasts who do not meet the criteria for

the diagnosis of AML (WHO Myeloid Neoplasm classification) because of < 20% marrow blasts are eligible if they meet the criteria for a diagnosis of myelodysplastic syndrome (MDS)

- Patients with a history of transient myeloproliferative disorder (which may or may

not have required chemotherapy intervention), who:

- Are > 90 days old at diagnosis of AML/MDS

- > 30 days from the last dose of cytarabine

- Have >= 20% blasts in the bone marrow, regardless of the interval of time since

TMD resolution, or

- Are > 8 weeks since TMD resolution with >= 5% bone marrow (BM) blasts, and,

- Who have an increasing blast count in serial BM aspirates performed at least 4

weeks apart

- With the exception of TMD as outlined and corticosteroids, children who have

previously received chemotherapy, radiation therapy or any anti-leukemic therapy are not eligible for this protocol

- There are no minimal organ function requirements for enrollment on this study

- Note: Previous cardiac repair with sufficient cardiac function is not an

exclusion criteria

- Each patient's parents or legal guardians must sign a written informed consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute

(NCI) requirements for human subjects research must be met Exclusion Criteria:

- Patients with promyelocytic leukemia (French-American-British [FAB] M3) are not

eligible

Locations and Contacts

Children's Oncology Group, Philadelphia, Pennsylvania 19104, United States; Not yet recruiting
Jason N. Berman, Phone: 902-470-8048, Email: jason.berman@iwk.nshealth.ca
Jason N. Berman, Principal Investigator
Additional Information

Starting date: August 2015
Last updated: August 12, 2015

Page last updated: August 23, 2015

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