Treatment of Acute Lymphoblastic Leukemia in Children

Study Overview
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Brief Summary
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The purpose of this study is to reduce the side-effects from anti-leukemia therapy. The therapy in this study is based upon treatment information learned from prior clinical research programs as well as from laboratory research.

Detailed Description
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Children with acute lymphoblastic leukemia are treated somewhat differently depending on the relative risk of the leukemia recurring. Patients will be separated into Standard Risk and High Risk. The treatment program for both groups is separated into 4 phases. The phases of treatment are induction, central nervous system (CNS) therapy, intensification and continuation. The induction phase of therapy lasts for about one month and its purpose is to kill all detectable leukemia cells. Patients in both groups will receive the following medication: prednisone, vincristine, doxorubicin, methotrexate, leucovorin, asparaginase, cytarabine (ARA-C), and hydrocortisone. Patients in the Hight Risk group will also receive dexrazoxane. Patients whose leukemia is found to have a specific genetic abnormality involving a gene on chromosome 11 (known as MLL gene) will have a MLL intensification phase which begins after complete remission and lasts about 1 month. The drugs involved in MLL intensification are: vincristine, methotrexate, leucovorin, hydrocortisone, cytarabine and L-asparaginase. CNS therapy begins immediately after the end of induction therapy, after remission is documented. This phase of treatment should last 3 weeks and includes a series of spinal taps with the instillation of anti-leukemia drugs. Four spinal taps will be performed over a two-week period. Both groups will receive vincristine, 6-mercaptopurine and methotrexate/cytarabine/hydrocortisone. Patients in the High Risk group will also receive doxorubicin with dexrazoxane. Radiation therapy will also be delivered to patients in the High Risk group during the CNS therapy phase. Radiation will be given in 8 daily treatments. The total dose of radiation used during this study is lower than what has been used in the past to help reduce side effects without increasing the risk of relapse. The intensification phase begins after the CNS therapy ends and lasts for 30 weeks. This phase is intended to further reduce the number of leukemia cells in the body and consists of cycles of chemotherapy repeated every three weeks with weekly shots of asparaginase. The drugs administered to both groups during this phase are: prednisone or dexamethasone, vincristine,6-mercaptopurine, methotrexate, E. coli asparaginase and cytarabine. Patients in the High Risk group will also receive doxorubicin and dexrazoxane. The continuation phase begins after the completion of the intensification phase and the goal is to eradicate all leukemia from the body. It consists of cycles of chemotherapy repeated every 3 weeks and is continued until the patient has been in remission for 2 years. The drugs administered during this phase are vincristine, prednisone or dexamethasone, 6-mercaptopurine, methotrexate and cytarabine. During this trial there are two randomizations, each is between the standard treatment and the investigational treatment. One randomization involves the drug E. coli L-asparaginase and two ways of dosing this drug. One way is to give the same standard dose of the drug that has been administered for years. The other way is to start with a lower dose and measure the amount of the drug in the blood every 3 weeks adjusting the dose as necessary. The goal of doing this is to maintain adequate drug levels with lower doses in the hope the it may reduce some side effects of the drug. The second randomization involves the drugs prednisone and dexamethasone. Both drugs have been used in the past to help treat ALL but it is not known if there is a difference between the two drugs, especially in terms of side effects. Patients will be randomized to either receive dexamethasone or prednisone. Throughout the study blood tests, urine tests, spinal taps, and bone marrow tests will be performed to monitor the disease status, side effects from medications and other complications from therapy. Quality of life questionnaires will also be performed by the patient (if older than 8), parent and patient's clinician.

Official Title
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Treatment of Acute Lymphoblastic Leukemia in Children

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: prednisone
* Drug: dexamethasone
* Drug: doxorubicin
* Drug: E. coli asparaginase
* Drug: vincristine
* Drug: methotrexate
* Drug: Leucovorin
* Drug: Asparaginase
* Drug: cytarabine
* Drug: Methotrexate/Hydrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute lymphoblastic leukemia excluding known mature B-cell ALL by the presence of any of the following: surface immunoglobulin, L3 morphology, t(8;14) (q24;q32), t(8;22) or t(2;8) Age > 12 months but less than 18 years Exclusion Criteria: Prior therapy except, 1 week of steroids, or emergent radiation therapy to the mediastinum Known HIV positive

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individualized ASP dose<br> | Drug: doxorubicin<br>* Induction Phase: Intravenously on Days 0,1 Intensification Phase: Intravenously on Day 1 of each cycle<br>* Other names: dexrazoxane;Drug: E. coli asparaginase<br>* Intensification Phase: In the muscle weekly. Dose will vary<br>Drug: vincristine<br>* Induction: Intravenously on days 0, 7, 14, 21 MLL Intensification Phase: Intravenously on Days 1, 8, 15, 22 CNS Therapy: Intravenously on Day 1 Intensification Phase: Intravenously on day 1 of each cycle Continuation Phase: Intravenously on Day 1 of each cycle<br>Drug: methotrexate<br>* Induction: Intravenously on Day 2 MLL Intensification: Intravenously on Days 1, 8 Intensification: (when doxorubicin completed) Intravenously or into the muscle weekly Continuation: Intravenously or into the muscle weekly<br>Drug: Leucovorin<br>* Induction Phase: Intravenously or orally begins 36 hours after methotrexate MLL Intensification: Intravenously or orally begins 36 hours after methotrexate<br>Drug: cytarabine<br>* Induction: Intrathecal on Days 0, 14, 28 MLL Intensification: Intravenously on Days 15, 16, 22, 23<br>* Other names: ARA-C;Drug: Methotrexate/Hydrocortisone<br>* Induction: Intrathecal on Days 14, 28 MLL Intensification: Intrathecal on Days 2,9<br>|
| Active Comparator: Fixed dose ASP<br> | Drug: doxorubicin<br>* Induction Phase: Intravenously on Days 0,1 Intensification Phase: Intravenously on Day 1 of each cycle<br>* Other names: dexrazoxane;Drug: E. coli asparaginase<br>* Intensification Phase: In the muscle weekly. Dose will vary<br>Drug: vincristine<br>* Induction: Intravenously on days 0, 7, 14, 21 MLL Intensification Phase: Intravenously on Days 1, 8, 15, 22 CNS Therapy: Intravenously on Day 1 Intensification Phase: Intravenously on day 1 of each cycle Continuation Phase: Intravenously on Day 1 of each cycle<br>Drug: methotrexate<br>* Induction: Intravenously on Day 2 MLL Intensification: Intravenously on Days 1, 8 Intensification: (when doxorubicin completed) Intravenously or into the muscle weekly Continuation: Intravenously or into the muscle weekly<br>Drug: Leucovorin<br>* Induction Phase: Intravenously or orally begins 36 hours after methotrexate MLL Intensification: Intravenously or orally begins 36 hours after methotrexate<br>Drug: cytarabine<br>* Induction: Intrathecal on Days 0, 14, 28 MLL Intensification: Intravenously on Days 15, 16, 22, 23<br>* Other names: ARA-C;Drug: Methotrexate/Hydrocortisone<br>* Induction: Intrathecal on Days 14, 28 MLL Intensification: Intrathecal on Days 2,9<br>|
| Experimental: Dexamethasone<br> | Drug: dexamethasone<br>* Intensification Phase: Given orally days 1-5 of each cycle Continuation Phase: Given orally days 1-5 pf each cycle<br>Drug: doxorubicin<br>* Induction Phase: Intravenously on Days 0,1 Intensification Phase: Intravenously on Day 1 of each cycle<br>* Other names: dexrazoxane;Drug: vincristine<br>* Induction: Intravenously on days 0, 7, 14, 21 MLL Intensification Phase: Intravenously on Days 1, 8, 15, 22 CNS Therapy: Intravenously on Day 1 Intensification Phase: Intravenously on day 1 of each cycle Continuation Phase: Intravenously on Day 1 of each cycle<br>Drug: methotrexate<br>* Induction: Intravenously on Day 2 MLL Intensification: Intravenously on Days 1, 8 Intensification: (when doxorubicin completed) Intravenously or into the muscle weekly Continuation: Intravenously or into the muscle weekly<br>Drug: Leucovorin<br>* Induction Phase: Intravenously or orally begins 36 hours after methotrexate MLL Intensification: Intravenously or orally begins 36 hours after methotrexate<br>Drug: Asparaginase<br>* Induction: Into the muscle on Day 4 MLL Intensification: Into the muscle on Days 16, 23<br>Drug: cytarabine<br>* Induction: Intrathecal on Days 0, 14, 28 MLL Intensification: Intravenously on Days 15, 16, 22, 23<br>* Other names: ARA-C;Drug: Methotrexate/Hydrocortisone<br>* Induction: Intrathecal on Days 14, 28 MLL Intensification: Intrathecal on Days 2,9<br>|
| Active Comparator: Prednisone<br> | Drug: prednisone<br>* Induction Phase: Given orally or intravenously Days 0-28 Intensification Phase: Given orally Days 1-5 of each cycle Continuation Phase: Given orally Days 1-5 of each cycle<br>Drug: doxorubicin<br>* Induction Phase: Intravenously on Days 0,1 Intensification Phase: Intravenously on Day 1 of each cycle<br>* Other names: dexrazoxane;Drug: vincristine<br>* Induction: Intravenously on days 0, 7, 14, 21 MLL Intensification Phase: Intravenously on Days 1, 8, 15, 22 CNS Therapy: Intravenously on Day 1 Intensification Phase: Intravenously on day 1 of each cycle Continuation Phase: Intravenously on Day 1 of each cycle<br>Drug: methotrexate<br>* Induction: Intravenously on Day 2 MLL Intensification: Intravenously on Days 1, 8 Intensification: (when doxorubicin completed) Intravenously or into the muscle weekly Continuation: Intravenously or into the muscle weekly<br>Drug: Leucovorin<br>* Induction Phase: Intravenously or orally begins 36 hours after methotrexate MLL Intensification: Intravenously or orally begins 36 hours after methotrexate<br>Drug: Asparaginase<br>* Induction: Into the muscle on Day 4 MLL Intensification: Into the muscle on Days 16, 23<br>Drug: cytarabine<br>* Induction: Intrathecal on Days 0, 14, 28 MLL Intensification: Intravenously on Days 15, 16, 22, 23<br>* Other names: ARA-C;Drug: Methotrexate/Hydrocortisone<br>* Induction: Intrathecal on Days 14, 28 MLL Intensification: Intrathecal on Days 2,9<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To optimize dosing of E. coli L-asparaginase during the intensification period |  | 5 years | 
| To determine the side effects of prednisone versus dexamethasone. |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare randomized treatment groups using health-related, quality-of-life analysis |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute lymphoblastic leukemia in children, High Risk ALL, Standard Risk ALL, E. coli asparaginase