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 therapyDuration 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
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