Treatment of Acute Lymphoblastic Leukemia in Children

NCT ID: NCT00165178

Last Updated: 2013-04-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 498 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-09-30
• Study Completion Date: 2011-05-31

Brief Summary

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

• 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.

Conditions

Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Individualized ASP dose

Group Type: EXPERIMENTAL

doxorubicin

Intervention Type: DRUG

Induction Phase: Intravenously on Days 0,1 Intensification Phase: Intravenously on Day 1 of each cycle

E. coli asparaginase

Intervention Type: DRUG

Intensification Phase: In the muscle weekly. Dose will vary

vincristine

Intervention Type: DRUG

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

methotrexate

Intervention Type: DRUG

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

Leucovorin

Intervention Type: DRUG

Induction Phase: Intravenously or orally begins 36 hours after methotrexate MLL Intensification: Intravenously or orally begins 36 hours after methotrexate

cytarabine

Intervention Type: DRUG

Induction: Intrathecal on Days 0, 14, 28 MLL Intensification: Intravenously on Days 15, 16, 22, 23

Methotrexate/Hydrocortisone

Intervention Type: DRUG

Induction: Intrathecal on Days 14, 28 MLL Intensification: Intrathecal on Days 2,9

Fixed dose ASP

Group Type: ACTIVE_COMPARATOR

doxorubicin

Intervention Type: DRUG

Induction Phase: Intravenously on Days 0,1 Intensification Phase: Intravenously on Day 1 of each cycle

E. coli asparaginase

Intervention Type: DRUG

Intensification Phase: In the muscle weekly. Dose will vary

vincristine

Intervention Type: DRUG

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

methotrexate

Intervention Type: DRUG

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

Leucovorin

Intervention Type: DRUG

Induction Phase: Intravenously or orally begins 36 hours after methotrexate MLL Intensification: Intravenously or orally begins 36 hours after methotrexate

cytarabine

Intervention Type: DRUG

Induction: Intrathecal on Days 0, 14, 28 MLL Intensification: Intravenously on Days 15, 16, 22, 23

Methotrexate/Hydrocortisone

Intervention Type: DRUG

Induction: Intrathecal on Days 14, 28 MLL Intensification: Intrathecal on Days 2,9

Dexamethasone

Group Type: EXPERIMENTAL

dexamethasone

Intervention Type: DRUG

Intensification Phase: Given orally days 1-5 of each cycle Continuation Phase: Given orally days 1-5 pf each cycle

doxorubicin

Intervention Type: DRUG

Induction Phase: Intravenously on Days 0,1 Intensification Phase: Intravenously on Day 1 of each cycle

vincristine

Intervention Type: DRUG

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

methotrexate

Intervention Type: DRUG

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

Leucovorin

Intervention Type: DRUG

Induction Phase: Intravenously or orally begins 36 hours after methotrexate MLL Intensification: Intravenously or orally begins 36 hours after methotrexate

Asparaginase

Intervention Type: DRUG

Induction: Into the muscle on Day 4 MLL Intensification: Into the muscle on Days 16, 23

cytarabine

Intervention Type: DRUG

Induction: Intrathecal on Days 0, 14, 28 MLL Intensification: Intravenously on Days 15, 16, 22, 23

Methotrexate/Hydrocortisone

Intervention Type: DRUG

Induction: Intrathecal on Days 14, 28 MLL Intensification: Intrathecal on Days 2,9

Prednisone

Group Type: ACTIVE_COMPARATOR

prednisone

Intervention Type: DRUG

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

doxorubicin

Intervention Type: DRUG

Induction Phase: Intravenously on Days 0,1 Intensification Phase: Intravenously on Day 1 of each cycle

vincristine

Intervention Type: DRUG

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

methotrexate

Intervention Type: DRUG

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

Leucovorin

Intervention Type: DRUG

Induction Phase: Intravenously or orally begins 36 hours after methotrexate MLL Intensification: Intravenously or orally begins 36 hours after methotrexate

Asparaginase

Intervention Type: DRUG

Induction: Into the muscle on Day 4 MLL Intensification: Into the muscle on Days 16, 23

cytarabine

Intervention Type: DRUG

Induction: Intrathecal on Days 0, 14, 28 MLL Intensification: Intravenously on Days 15, 16, 22, 23

Methotrexate/Hydrocortisone

Intervention Type: DRUG

Induction: Intrathecal on Days 14, 28 MLL Intensification: Intrathecal on Days 2,9

Interventions

prednisone

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

Intervention Type: DRUG

dexamethasone

Intensification Phase: Given orally days 1-5 of each cycle Continuation Phase: Given orally days 1-5 pf each cycle

Intervention Type: DRUG

doxorubicin

Induction Phase: Intravenously on Days 0,1 Intensification Phase: Intravenously on Day 1 of each cycle

Intervention Type: DRUG

E. coli asparaginase

Intensification Phase: In the muscle weekly. Dose will vary

Intervention Type: DRUG

vincristine

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

Intervention Type: DRUG

methotrexate

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

Intervention Type: DRUG

Leucovorin

Induction Phase: Intravenously or orally begins 36 hours after methotrexate MLL Intensification: Intravenously or orally begins 36 hours after methotrexate

Intervention Type: DRUG

Asparaginase

Induction: Into the muscle on Day 4 MLL Intensification: Into the muscle on Days 16, 23

Intervention Type: DRUG

cytarabine

Induction: Intrathecal on Days 0, 14, 28 MLL Intensification: Intravenously on Days 15, 16, 22, 23

Intervention Type: DRUG

Methotrexate/Hydrocortisone

Induction: Intrathecal on Days 14, 28 MLL Intensification: Intrathecal on Days 2,9

Intervention Type: DRUG

Other Intervention Names

dexrazoxane; ARA-C

Eligibility Criteria

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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boston Children's Hospital

OTHER

Sponsor Role: collaborator

University of Rochester

OTHER

Sponsor Role: collaborator

McMaster University

OTHER

Sponsor Role: collaborator

San Jorge Children's Hospital (Puerto Rico)

UNKNOWN

Sponsor Role: collaborator

St. Justine's Hospital

OTHER

Sponsor Role: collaborator

Maine Children's Cancer Program

OTHER

Sponsor Role: collaborator

Ochsner Health System

OTHER

Sponsor Role: collaborator

Tulane University School of Medicine

OTHER

Sponsor Role: collaborator

Laval University

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: collaborator

Dana-Farber Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Lewis B. Silverman, M.D.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lewis Silverman, MD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Countries

United States

References

Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin MA, Arkin S, Declerck L, Cohen HJ, Sallan SE. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood. 2001 Mar 1;97(5):1211-8. doi: 10.1182/blood.v97.5.1211.

Reference Type: BACKGROUND

PMID: 11222362 (View on PubMed)

Silverman LB, Declerck L, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin MA, Lipton JM, Cohen HJ, Sallan SE. Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia. 2000 Dec;14(12):2247-56. doi: 10.1038/sj.leu.2401980.

Reference Type: BACKGROUND

PMID: 11187916 (View on PubMed)

Goldberg JM, Silverman LB, Levy DE, Dalton VK, Gelber RD, Lehmann L, Cohen HJ, Sallan SE, Asselin BL. Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol. 2003 Oct 1;21(19):3616-22. doi: 10.1200/JCO.2003.10.116.

Reference Type: BACKGROUND

PMID: 14512392 (View on PubMed)

Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB, Lipsitz SR, Colan SD, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin MA, Gelber RD, Sallan SE. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med. 2004 Jul 8;351(2):145-53. doi: 10.1056/NEJMoa035153.

Reference Type: BACKGROUND

PMID: 15247354 (View on PubMed)

Vrooman LM, Stevenson KE, Supko JG, O'Brien J, Dahlberg SE, Asselin BL, Athale UH, Clavell LA, Kelly KM, Kutok JL, Laverdiere C, Lipshultz SE, Michon B, Schorin M, Relling MV, Cohen HJ, Neuberg DS, Sallan SE, Silverman LB. Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol. 2013 Mar 20;31(9):1202-10. doi: 10.1200/JCO.2012.43.2070. Epub 2013 Jan 28.

Reference Type: DERIVED

PMID: 23358966 (View on PubMed)

Other Identifiers

00-001

Identifier Type: -

Identifier Source: org_study_id