Combination Chemotherapy With or Without Gemtuzumab in Treating Young Patients With Newly Diagnosed Acute Myeloid Leukemia
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| ClinicalTrials.gov Identifier: NCT00372593 |
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Recruitment Status :
Completed
First Posted : September 7, 2006
Results First Posted : January 13, 2015
Last Update Posted : April 28, 2017
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Leukemia | Drug: asparaginase Drug: cytarabine Drug: daunorubicin hydrochloride Drug: etoposide Drug: gemtuzumab ozogamicin Drug: mitoxantrone hydrochloride | Phase 3 |
Show Detailed Description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 1070 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official 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 |
| Study Start Date : | August 2006 |
| Actual Primary Completion Date : | August 2013 |
| Actual Study Completion Date : | August 2013 |
| Arm | Intervention/treatment |
|---|---|
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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. |
Drug: asparaginase
Given intramuscularly
Other Names:
Drug: cytarabine Given IV
Other Names:
Drug: daunorubicin hydrochloride Given IV over 6 hours
Other Names:
Drug: etoposide Given IV over 1-4 hours
Other Names:
Drug: mitoxantrone hydrochloride Given IV over 1 hour
Other Names:
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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.
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Drug: asparaginase
Given intramuscularly
Other Names:
Drug: cytarabine Given IV
Other Names:
Drug: daunorubicin hydrochloride Given IV over 6 hours
Other Names:
Drug: etoposide Given IV over 1-4 hours
Other Names:
Drug: gemtuzumab ozogamicin Given IV over 2 hours
Other Names:
Drug: mitoxantrone hydrochloride Given IV over 1 hour
Other Names:
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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. |
Drug: asparaginase
Given intramuscularly
Other Names:
Drug: cytarabine Given IV
Other Names:
Drug: daunorubicin hydrochloride Given IV over 6 hours
Other Names:
Drug: etoposide Given IV over 1-4 hours
Other Names:
Drug: mitoxantrone hydrochloride Given IV over 1 hour
Other Names:
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- Event-free Survival at 3 Years [ Time Frame: Time from study entry to time of induction failure, relapse, or death, assessed 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 α-spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error.
- Overall Survival at 3 Years [ Time Frame: Time from study entry, assessed 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 α-spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error.
- Remission Induction Rate After 2 Courses of Induction Therapy [ Time Frame: After 2 courses of induction (I and II) therapy, assessed for up to 10 years ]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.
- Disease-free Survival (DFS) [ Time Frame: At 3 years from end of Intensification I ]Time from end of Intensification I to relapse, death or last contact
- Mortality [ Time Frame: During the first three courses of therapy ]Number of participants who died during the first three courses of therapy.
- Time to Marrow Recovery [ Time Frame: At 25 days after treatment with Induction I, Induction II, and Intensification I ]Mean time to ANC recovery - defined as ANC greater than 500/MicroLiter for 3 consecutive days.
- Toxicities, Including Infectious Complications [ Time Frame: From the time therapy is initiated, assessed up to 10 years ]Number of participants with at least one grade 3 or higher adverse event during therapy.
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| Ages Eligible for Study: | up to 29 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
DISEASE CHARACTERISTICS:
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Newly diagnosed acute myeloid leukemia (AML)
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Meets customary criteria for AML with ≥ 20% bone marrow blasts (by WHO classification)
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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)
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- Isolated myeloid sarcoma (i.e., myeloblastoma or chloroma) allowed regardless of bone marrow results
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- 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
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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
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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:
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00372593
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| Study Chair: | Alan S. Gamis, MD, MPH | Children's Mercy Hospital | |
| Study Chair: | Richard Aplenc, MD, MSCE | Children's Hospital of Philadelphia |
Publications of Results:
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Children's Oncology Group |
| ClinicalTrials.gov Identifier: | NCT00372593 History of Changes |
| Other Study ID Numbers: |
AAML0531 COG-AAML0531 ( Other Identifier: Children's Oncology Group ) CDR0000487497 ( Other Identifier: Clinical Trials.gov ) |
| First Posted: | September 7, 2006 Key Record Dates |
| Results First Posted: | January 13, 2015 |
| Last Update Posted: | April 28, 2017 |
| Last Verified: | February 2017 |
Keywords provided by Children's Oncology Group:
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adult acute myeloid leukemia with 11q23 (MLL) abnormalities adult acute myeloid leukemia with inv(16)(p13;q22) adult acute myeloid leukemia with t(16;16)(p13;q22) adult acute myeloid leukemia with t(8;21)(q22;q22) untreated adult acute myeloid leukemia untreated childhood acute myeloid leukemia and other myeloid malignancies adult acute basophilic leukemia adult acute eosinophilic leukemia adult acute minimally differentiated myeloid leukemia (M0) adult acute myeloblastic leukemia without maturation (M1) adult acute myeloblastic leukemia with maturation (M2) adult acute myelomonocytic leukemia (M4) adult acute monoblastic leukemia (M5a) adult acute monocytic leukemia (M5b) |
adult erythroleukemia (M6a) adult pure erythroid leukemia (M6b) adult acute megakaryoblastic leukemia (M7) childhood acute basophilic leukemia childhood acute eosinophilic leukemia childhood acute minimally differentiated myeloid leukemia (M0) childhood acute myeloblastic leukemia without maturation (M1) childhood acute myeloblastic leukemia with maturation (M2) childhood acute myelomonocytic leukemia (M4) childhood acute monocytic leukemia (M5b) childhood acute monoblastic leukemia (M5a) childhood acute erythroleukemia (M6) childhood acute megakaryocytic leukemia (M7) |
Additional relevant MeSH terms:
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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms by Histologic Type Neoplasms Etoposide Mitoxantrone Daunorubicin Etoposide phosphate Gemtuzumab Cytarabine Asparaginase Antineoplastic Agents, Phytogenic Antineoplastic Agents Topoisomerase II Inhibitors |
Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antimetabolites, Antineoplastic Antimetabolites Antiviral Agents Anti-Infective Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Analgesics Sensory System Agents Peripheral Nervous System Agents Antibiotics, Antineoplastic |