Combination Chemotherapy in Treating Children With Newly Diagnosed Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known which regimen of chemotherapy is more effective for acute lymphoblastic leukemia. PURPOSE: This randomized phase III trial is comparing four regimens of combination chemotherapy to see how well they work in treating children with newly diagnosed acute lymphoblastic leukemia.

Detailed Description
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OBJECTIVES: Determine if multidrug delayed-intensification therapy improves outcome in children with newly diagnosed standard-risk acute lymphocytic leukemia. Compare the efficacy and toxicity of methotrexate administered over 4 hours vs methotrexate administered over 24 hours in this patient population. Determine the correlation between event-free survival, minimal residual disease, and early response in this patient population treated with this multiple drug regimen. OUTLINE: This is a randomized, multicenter study. Induction (weeks 1-4): Patients receive induction therapy on POG 9900. Consolidation (weeks 5-32): Patients are randomized to one of four treatment arms. Patients with t(1;19) are randomized to either arm III or arm IV. Arm I (weeks 5-24): Patients receive IT methotrexate (MTX) on day 1 followed by MTX IV over 20 minutes followed by MTX continuously over 23.6 hours on weeks 7, 10, 13, 16,19, and 22. At 42 hours after the beginning of the MTX infusion, patients receive oral leucovorin calcium every 6 hours for a total of 3 doses. Patients also receive oral mercaptopurine daily beginning on week 5 and continuing until the completion of consolidation therapy; oral dexamethasone twice daily on days 1-7 of weeks 8 and 17; and vincristine IV on day 1 of weeks 8, 9, 17, and 18. Arm II (weeks 5-24): Patients receive MTX IV over 4 hours on weeks 7, 10, 13, 16, 19, and 22. At 42 hours after the beginning of the MTX infusion, patients receive oral leucovorin calcium as in arm I. Patients also receive mercaptopurine, dexamethasone, vincristine, and IT MTX as in arm I. Arm III (weeks 5-32): Patients receive MTX IV as in arm I on weeks 7, 10, 13, 24, 27, and 30; leucovorin calcium as in arm I; pegaspargase IM on day 2, 3, OR 4 of week 16; and oral mercaptopurine daily on weeks 5-13, and from week 24 until the completion of consolidation therapy. Patients also receive IT MTX as in arm I on weeks 7, 10, 13, 16, 20, 21, and 30; oral dexamethasone twice daily on weeks 8, 16-18, and 28 for a total of 35 days; vincristine IV on day 1 of weeks 8, 9, 16, 17, 18, 28, and 29; daunorubicin IV on day 1 of weeks 16-18; cyclophosphamide IV over 30 minutes on day 1 of week 20; cytarabine IV or subcutaneously daily on days 2-5 of weeks 20 and 21; and oral thioguanine daily on weeks 20-21. Arm IV (weeks 5-32): Patients receive MTX IV as in arm II on weeks 7, 10, 13, 24, 27, and 30; leucovorin calcium as in arm I; and pegaspargase, mercaptopurine, IT MTX, dexamethasone, vincristine, daunorubicin, cyclophosphamide, cytarabine, and thioguanine as in arm III. Intensive continuation (weeks 25-80): At weeks 25-72 for arms I and II, and at weeks 33-80 for arms III and IV, patients receive oral MTX every 6 hours for 4 doses on weeks 1, 3, 5, 7, 9, and 11; oral mercaptopurine daily; oral leucovorin calcium every 12 hours for 2 doses beginning 48 hours after the start of MTX; IT MTX and vincristine IV on day 1 of week 12; and oral dexamethasone twice daily on days 1-7, beginning with the administration of vincristine. Treatment repeats every 12 weeks for 4 courses. Additional continuation (weeks 73-130): At weeks 73-130 for arms I and II, and at weeks 81-130 for arms III and IV, patients receive oral MTX weekly; oral mercaptopurine daily; vincristine IV on day 1 every 12 weeks; oral dexamethasone as during intensive continuation therapy; and IT MTX on day 1 every 12 weeks, beginning with the last week of the first course (in place of oral MTX). Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then every 6-12 months for 1 year. PROJECTED ACCRUAL: A total of 1,014 patients will be accrued for this study within 3.22 years.

Official Title
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ALinC 17: Protocol for Patients With Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL): A Phase III Study

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: dexamethasone
* Drug: leucovorin calcium
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: pegaspargase
* Drug: thioguanine
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Confirmed diagnosis of newly diagnosed B-precursor acute lymphocytic leukemia Standard risk (not low, high, or very high risk) Prior registration and treatment on POG 9900 Classification Study PATIENT CHARACTERISTICS: Age: 1 to 21 at diagnosis Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Not specified Renal: Not specified Other: Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy Not specified Endocrine therapy Not specified Radiotherapy Not specified Surgery Not specified

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 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: Arm I<br>Patients receive IT methotrexate on day 1 followed by methotrexate IV over 20 minutes followed by methotrexate continuously over 23.6 hrs on wks 7, 10, 13, 16,19, and 22. At 42 hrs after the beginning of the methotrexate infusion, patients receive oral leucovorin calcium every 6 hrs for a total of 3 doses. Patients also receive oral mercaptopurine daily beginning on wk 5 and continuing until the completion of consolidation therapy; oral dexamethasone twice daily on days 1-7 of wks 8 and 17; and vincristine sulfate IV on day 1 of wks 8, 9, 17, and 18. | Drug: dexamethasone<br>* 6 mg/m2/day divided BID for 7 days during weeks 8 and 17.<br>* Other names: DEX;Drug: leucovorin calcium<br>* 5 mg/m2/dose of leucovorin will be given PO q12h x 2 doses beginning 48 hours after the start of the MTX.<br>Drug: mercaptopurine<br>* 50 mg/m2 dose po qhs Weeks 5 through 13 (total 9 wks) and from Week 24 until the end of consolidation. Only hold for uncomplicated myelosuppression, only if IV MTX course is delayed, until ANC > 500/μL and platelets > 75,000/uL<br>* Other names: 6-MP;Drug: methotrexate<br>* IV: 1 gm/m2 given as a 200 mg/m2 bolus over 20 min followed by 800 mg/m2 over 23.6 hours given during Weeks 7, 10, 13, 16, 19, and 22. IT: Doses by age, Weeks 7, 10, 13, 16, 19 and 22.<br>* Other names: MTX;Drug: vincristine sulfate<br>* 1.5 mg/m2 IV on Day 1 of Weeks 8, 9, 17 and 18 (max 2 mg)<br>* Other names: VCR;|
| Experimental: Arm II<br>Patients receive methotrexate IV over 4 hours on weeks 7, 10, 13, 16, 19, and 22. At 42 hours after the beginning of the methotrexate infusion, patients receive oral leucovorin calcium as in arm I. Patients also receive mercaptopurine, dexamethasone, vincristine sulfate, and IT methotrexate as in arm I. | Drug: dexamethasone<br>* 6 mg/m2/day divided BID for 7 days during weeks 8 and 17.<br>* Other names: DEX;Drug: leucovorin calcium<br>* 5 mg/m2/dose of leucovorin will be given PO q12h x 2 doses beginning 48 hours after the start of the MTX.<br>Drug: mercaptopurine<br>* 50 mg/m2 dose po qhs Weeks 5 through 13 (total 9 wks) and from Week 24 until the end of consolidation. Only hold for uncomplicated myelosuppression, only if IV MTX course is delayed, until ANC > 500/μL and platelets > 75,000/uL<br>* Other names: 6-MP;Drug: methotrexate<br>* IV: 1 gm/m2 given as a 200 mg/m2 bolus over 20 min followed by 800 mg/m2 over 23.6 hours given during Weeks 7, 10, 13, 16, 19, and 22. IT: Doses by age, Weeks 7, 10, 13, 16, 19 and 22.<br>* Other names: MTX;Drug: vincristine sulfate<br>* 1.5 mg/m2 IV on Day 1 of Weeks 8, 9, 17 and 18 (max 2 mg)<br>* Other names: VCR;|
| Experimental: Arm III<br>Patients receive methotrexate IV as in arm I on weeks 7, 10, 13, 24, 27, and 30; leucovorin calcium as in arm I; pegaspargase IM on day 2, 3, OR 4 of wk 16; oral mercaptopurine daily on wks 5-13, and from wk 24 until the completion of consolidation therapy. Patients also receive IT methotrexate as in arm I on wks 7, 10, 13, 16, 20, 21, and 30; oral dexamethasone 2x daily on weeks 8, 16-18, and 28 for a total of 35 days; vincristine sulfate IV on day 1 of wks 8, 9, 16, 17, 18, 28, and 29; daunorubicin hydrochloride IV on day 1 of wks 16-18; cyclophosphamide IV over 30 minutes on day 1 of week 20; cytarabine IV or subcutaneously daily on days 2-5 of wks 20 and 21; and oral thioguanine daily on wks 20-21. | Drug: cyclophosphamide<br> <br> Drug: cytarabine<br> <br> Drug: daunorubicin hydrochloride<br>* 30 mg/m2 IV Day 1 of weeks 16, 17, and 18. Give Week 16 dose if ANC ≥ 500/μL and platelets ≥ 75,000/μL. Continue to give during Weeks 17 and 18, even in the face of uncomplicated myelosuppression<br>* Other names: daunomycin;Drug: dexamethasone<br>* 6 mg/m2/day divided BID for 7 days during weeks 8 and 17.<br>* Other names: DEX;Drug: leucovorin calcium<br>* 5 mg/m2/dose of leucovorin will be given PO q12h x 2 doses beginning 48 hours after the start of the MTX.<br>Drug: mercaptopurine<br>* 50 mg/m2 dose po qhs Weeks 5 through 13 (total 9 wks) and from Week 24 until the end of consolidation. Only hold for uncomplicated myelosuppression, only if IV MTX course is delayed, until ANC > 500/μL and platelets > 75,000/uL<br>* Other names: 6-MP;Drug: methotrexate<br>* IV: 1 gm/m2 given as a 200 mg/m2 bolus over 20 min followed by 800 mg/m2 over 23.6 hours given during Weeks 7, 10, 13, 16, 19, and 22. IT: Doses by age, Weeks 7, 10, 13, 16, 19 and 22.<br>* Other names: MTX;Drug: pegaspargase<br>* 2,500 IU/m2 will be given IM x 1 on Days 2,3,or 4 of Week 16; > or = 1 day after the IT MTX<br>* Other names: PEG;Drug: thioguanine<br>* 60 mg/m2 po qhs during Weeks 20 and 21 (total 14 days). Start week 20 when ANC > or = 500/ul and platelets > or = 75,000/uL. Continue to give all 14 doses despite uncomplicated myelosuppression.<br>* Other names: 6-TG;Drug: vincristine sulfate<br>* 1.5 mg/m2 IV on Day 1 of Weeks 8, 9, 17 and 18 (max 2 mg)<br>* Other names: VCR;|
| Experimental: Arm IV<br>Patients receive methotrexate IV as in arm II on weeks 7, 10, 13, 24, 27, and 30; leucovorin calcium as in arm I; and pegaspargase, mercaptopurine, IT methotrexate, dexamethasone, vincristine sulfate, daunorubicin hydrochloride, cyclophosphamide, cytarabine, and thioguanine as in arm III. | Drug: cyclophosphamide<br> <br> Drug: cytarabine<br> <br> Drug: daunorubicin hydrochloride<br>* 30 mg/m2 IV Day 1 of weeks 16, 17, and 18. Give Week 16 dose if ANC ≥ 500/μL and platelets ≥ 75,000/μL. Continue to give during Weeks 17 and 18, even in the face of uncomplicated myelosuppression<br>* Other names: daunomycin;Drug: dexamethasone<br>* 6 mg/m2/day divided BID for 7 days during weeks 8 and 17.<br>* Other names: DEX;Drug: leucovorin calcium<br>* 5 mg/m2/dose of leucovorin will be given PO q12h x 2 doses beginning 48 hours after the start of the MTX.<br>Drug: mercaptopurine<br>* 50 mg/m2 dose po qhs Weeks 5 through 13 (total 9 wks) and from Week 24 until the end of consolidation. Only hold for uncomplicated myelosuppression, only if IV MTX course is delayed, until ANC > 500/μL and platelets > 75,000/uL<br>* Other names: 6-MP;Drug: methotrexate<br>* IV: 1 gm/m2 given as a 200 mg/m2 bolus over 20 min followed by 800 mg/m2 over 23.6 hours given during Weeks 7, 10, 13, 16, 19, and 22. IT: Doses by age, Weeks 7, 10, 13, 16, 19 and 22.<br>* Other names: MTX;Drug: pegaspargase<br>* 2,500 IU/m2 will be given IM x 1 on Days 2,3,or 4 of Week 16; > or = 1 day after the IT MTX<br>* Other names: PEG;Drug: thioguanine<br>* 60 mg/m2 po qhs during Weeks 20 and 21 (total 14 days). Start week 20 when ANC > or = 500/ul and platelets > or = 75,000/uL. Continue to give all 14 doses despite uncomplicated myelosuppression.<br>* Other names: 6-TG;Drug: vincristine sulfate<br>* 1.5 mg/m2 IV on Day 1 of Weeks 8, 9, 17 and 18 (max 2 mg)<br>* Other names: VCR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in outcome in children receiving multidrug delayed-intensification therapy | The overall plan is to accrue for 3.1 years or until all accrual goals have been met, whichever occurs first. Since power is determined by event-rates, lower or higher than expected event rates could lead to an amendment to alter the accrual goal. This consideration will be made independent of arm-specific outcome, in order to eliminate bias | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival, minimal residual disease, and early response | The test statistic will compare Kaplan-Meier curves. Cox multiple regression will be utilized. | 5 years | 
| Occurrence of anticipated failures | An O'Brien-Fleming analysis will be conducted. | Up to 5 years | 
| Total grade 3+ central nervous system (CNS) toxicity rates based on the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 |  | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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untreated childhood acute lymphoblastic leukemia