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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00372593




Registration number
NCT00372593
Ethics application status
Date submitted
6/09/2006
Date registered
7/09/2006
Date last updated
28/04/2017

Titles & IDs
Public title
Combination Chemotherapy With or Without Gemtuzumab in Treating Young Patients With Newly Diagnosed Acute Myeloid Leukemia
Scientific title
A Phase III Randomized Trial of Gemtuzumab Ozogamicin (Mylotarg) Combined With Conventional Chemotherapy for De Novo Acute Myeloid Leukemia (AML) in Children, Adolescents, and Young Adults
Secondary ID [1] 0 0
COG-AAML0531
Secondary ID [2] 0 0
AAML0531
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - asparaginase
Treatment: Drugs - cytarabine
Treatment: Drugs - daunorubicin hydrochloride
Treatment: Drugs - etoposide
Treatment: Drugs - gemtuzumab ozogamicin
Treatment: Drugs - mitoxantrone hydrochloride

Active Comparator: Arm A: Standard Arm - No GMTZ, AML Pts w/out Down Syndrome - Patients receive intrathecal (IT) cytarabine (ARA-C) at diagnosis or on day 1 of treatment or twice a week for up to 6 doses. They also receive an infusion of ARA-C on days 1-10; a 6-hour infusion of daunorubicin hydrochloride on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5.
After 3 weeks of rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5.
After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5.
After 3 weeks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4; and a 1-hour infusion of mitoxantrone on days 3-6. After 3 weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days 2 and 9.

Experimental: Arm B: Experimental - with GMTZ, AML Pts w/out Down Syndrome - Pts receive IT ARA-C at diagnosis or on day 1 of treatment or twice a week for up to six doses. They also receive an infusion of ARA-C on days 1-10; a 6-hr infusion of daunorubicin on days 1, 3, & 5; a 4-hr infusion of etoposide on days 1-5; and a 2-hr infusion of GMTZ - gemtuzumab ozogamicin (Mylotarg) on day 6. After 3 wks of rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5. After 3 wks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4; and a 1-hr infusion of mitoxantrone hydrochloride on days 3-6. They also receive a 2-hr infusion of gemtuzumab on day 7. After 3 weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days 2 and 9.

Active Comparator: Arm A: Standard Arm - No GMTZ, AML Patients with Down Syndrome - Patients receive intrathecal (IT) cytarabine (ARA-C) at diagnosis or on day 1 of treatment or twice a week for up to 6 doses. They also receive an infusion of ARA-C on days 1-10; a 6-hour infusion of daunorubicin hydrochloride on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5.
After 3 weeks of rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5.
After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5.
After 3 weeks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4; and a 1-hour infusion of mitoxantrone on days 3-6. After 3 weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days 2 and 9.


Treatment: Drugs: asparaginase
Given intramuscularly

Treatment: Drugs: cytarabine
Given IV

Treatment: Drugs: daunorubicin hydrochloride
Given IV over 6 hours

Treatment: Drugs: etoposide
Given IV over 1-4 hours

Treatment: Drugs: gemtuzumab ozogamicin
Given IV over 2 hours

Treatment: Drugs: mitoxantrone hydrochloride
Given IV over 1 hour

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-free Survival at 3 Years - The Kaplan-Meier method will be used to calculate estimates of Event Free Survival (EFS). The log-rank test will be used to compare survival between treatment groups. Analysis of EFS of Down syndrome patients will be performed separately. Monitoring for efficacy of GMTZ with respect to Overall Survival (OS) and EFS will utilize monitoring based on the Lan-DeMets criterion with a-spending function at^2 (truncated at 3 standard deviations) and 2.5% type I error.
Timepoint [1] 0 0
Time from study entry to time of induction failure, relapse, or death, assessed at 3 years
Primary outcome [2] 0 0
Overall Survival at 3 Years - The Kaplan-Meier method will be used to calculate estimates of OS. Analysis of OS of Down syndrome patients will be performed separately. Monitoring for efficacy of GMTZ with respect to OS and EFS will utilize monitoring based on the Lan-DeMets criterion with a-spending function at^2 (truncated at 3 standard deviations) and 2.5% type I error.
Timepoint [2] 0 0
Time from study entry, assessed at 3 years
Secondary outcome [1] 0 0
Remission Induction Rate After 2 Courses of Induction Therapy - Patients without an evaluable bone marrow at the end of Induction I will be excluded from the calculation of remission rate after 2 courses of therapy because their responses are not evaluable. The following patients will be considered to not be in complete remission (CR) after 2 courses of therapy: (1) patients who die during Induction I and II; (2) patients with = 5% blasts or extramedullary disease at the end of Induction II.
Timepoint [1] 0 0
After 2 courses of induction (I and II) therapy, assessed for up to 10 years
Secondary outcome [2] 0 0
Disease-free Survival (DFS) - Time from end of Intensification I to relapse, death or last contact
Timepoint [2] 0 0
At 3 years from end of Intensification I
Secondary outcome [3] 0 0
Mortality - Number of participants who died during the first three courses of therapy.
Timepoint [3] 0 0
During the first three courses of therapy
Secondary outcome [4] 0 0
Time to Marrow Recovery - Mean time to ANC recovery - defined as ANC greater than 500/MicroLiter for 3 consecutive days.
Timepoint [4] 0 0
At 25 days after treatment with Induction I, Induction II, and Intensification I
Secondary outcome [5] 0 0
Toxicities, Including Infectious Complications - Number of participants with at least one grade 3 or higher adverse event during therapy.
Timepoint [5] 0 0
From the time therapy is initiated, assessed up to 10 years

Eligibility
Key inclusion criteria
DISEASE CHARACTERISTICS:

- Newly diagnosed acute myeloid leukemia (AML)

- Meets customary criteria for AML with = 20% bone marrow blasts (by WHO
classification)

- Patients with < 20% bone marrow blasts and cytopenia or myelodysplastic
syndromes (e.g., chronic myelomonocytic leukemia, refractory anemia (RA), RA
with excess blasts, RA with ringed sideroblasts) are eligible provided 1 of
the following criteria is met:

- Karyotypic abnormality characteristic of de novo AML (t[8;21][q22;q22],
inv[16][p13q22], t[16;16][p13;q22], or 11q23 abnormalities)

- Unequivocal presence of megakaryoblasts (by WHO classification)

- Isolated myeloid sarcoma (i.e., myeloblastoma or chloroma) allowed regardless of
bone marrow results

- Infants < 1 month of age with progressive disease* are eligible NOTE: *Infants < 1
month of age with AML may be given supportive care until it is clear that the leukemia
is not regressing (i.e., the disappearance of peripheral blasts and the normalization
of peripheral blood counts)

- Patients with Down syndrome = 4 years of age are eligible

- No juvenile myelomonocytic leukemia

- No Fanconi's anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone
marrow failure syndrome

- No promyelocytic leukemia (M3)

- No secondary or treatment-related AML

- Matched family donor criteria (for patients with intermediate-risk or high-risk
disease):

- HLA-A, -B, -C, and beta chain (-DRB1), identical or 1 antigen or allele
mismatched by molecular high resolution technique

- All available first-degree family members (parents and siblings) must be HLA
typed

- No syngeneic donors

- Matched alternative donor criteria (for patients with high-risk disease):

- HLA-A, -B, -C, and -DRB1, identical or 1 antigen or allele mismatched donor

- HLA-A, -B, and -DRB1 4 of 6 antigen matched unrelated cord blood donor

- Mismatched family member donor with = 1 haplotype match or 5 of 6 antigen
phenotypic match

PATIENT CHARACTERISTICS:

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

- No prior chemotherapy, radiation therapy, or any antileukemic therapy

- Topical or inhalation steroids for other conditions allowed

- Intrathecal cytarabine given at diagnosis allowed

- No other prior treatment for AML

- No concurrent peripheral blood stem cell transplantation in patients with matched
family donor
Minimum age
No limit
Maximum age
29 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA
Recruitment hospital [1] 0 0
Westmead Institute for Cancer Research at Westmead Hospital - Westmead
Recruitment hospital [2] 0 0
Royal Children's Hospital - Herston
Recruitment hospital [3] 0 0
Women's and Children's Hospital - North Adelaide
Recruitment hospital [4] 0 0
Princess Margaret Hospital for Children - Perth
Recruitment postcode(s) [1] 0 0
2145 - Westmead
Recruitment postcode(s) [2] 0 0
4029 - Herston
Recruitment postcode(s) [3] 0 0
5006 - North Adelaide
Recruitment postcode(s) [4] 0 0
6001 - Perth
Recruitment outside Australia
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United States of America
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Alabama
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Arizona
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Geneva

Funding & Sponsors
Primary sponsor type
Other
Name
Children's Oncology Group
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Cancer Institute (NCI)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer
cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies,
such as gemtuzumab, can block cancer growth in different ways. Some block the ability of
cancer cells to grow and spread. Others find cancer cells and help kill them or carry
cancer-killing substances to them. Giving combination chemotherapy together with gemtuzumab
may kill more cancer cells. It is not yet known whether combination chemotherapy is more
effective with or without gemtuzumab in treating patients with newly diagnosed acute myeloid
leukemia.

PURPOSE: This randomized phase III trial is studying combination chemotherapy and gemtuzumab
to see how well they work compared with combination chemotherapy alone in treating young
patients with newly diagnosed acute myeloid leukemia.
Trial website
https://clinicaltrials.gov/show/NCT00372593
Trial related presentations / publications
Pollard JA, Alonzo TA, Loken M, Gerbing RB, Ho PA, Bernstein ID, Raimondi SC, Hirsch B, Franklin J, Walter RB, Gamis A, Meshinchi S. Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML. Blood. 2012 Apr 19;119(16):3705-11. doi: 10.1182/blood-2011-12-398370. Epub 2012 Feb 29.
Public notes

Contacts
Principal investigator
Name 0 0
Alan S. Gamis, MD, MPH
Address 0 0
Children's Mercy Hospital Kansas City
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications