Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia

Study Overview
=================
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. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating young patients with acute lymphoblastic leukemia. PURPOSE: Thisphase III trial is studying several different combination chemotherapy regimens to compare how well they work in treating young patients with acute lymphoblastic leukemia.

Detailed Description
-----------------
OBJECTIVES: Compare the relative efficacy of induction therapy comprising dexamethasone or prednisone, in terms of a higher rate of event-free survival (EFS) and overall survival and a reduced rate of relapse, in pediatric patients with intermediate-risk or high-risk acute lymphoblastic leukemia (ALL). Compare the relative safety of a reduced-intensity reintensification regimen comprising dexamethasone, vincristine, cyclophosphamide, and anthracyclines vs a standard treatment regimen in pediatric patients with standard-risk ALL identified by fast clearance of leukemic cells. Compare the efficacy of a second delayed reintensification regimen vs standard reintensification therapy, in terms of improved EFS, in pediatric patients with intermediate-risk ALL. Compare the efficacy of extended reintensification therapy (triple reinduction) vs standard reintensification therapy (intensive pulses and one reintensification) in pediatric patients with high-risk ALL. OUTLINE: This is a randomized, multicenter study. Prednisone prephase therapy: Patients receive oral prednisone on days 1-7 and one dose of methotrexate (MTX) intrathecally (IT) on day 1. Induction/consolidation therapy, protocol I: Patients are randomized to 1 of 2 treatment arms. Arm I (closed to accrual as of 6/30/2006): Patients receive prednisone (PRED) on days 8-28. Arm II (closed to accrual as of 6/30/2006): Patients receive dexamethasone (DEXA) on days 8-28. Patients in both arms also receive vincristine (VCR) and daunorubicin hydrochloride (DNR) once weekly in weeks 2-5; asparaginase (ASP) on days 12-33; cyclophosphamide (CPM) on days 36 and 64; cytarabine (ARA-C) in weeks 6-9; mercaptopurine (MP) on days 36-63; and MTX IT on days 1, 15, 29,38 and 52.* NOTE: *Patients with CNS disease also receive MTX IT on days 8 and 22. After completion of induction/consolidation therapy, patients are stratified according to risk group based on disease response (standard-risk [SR] group [negative minimal residual disease (MRD) on day 33 and before protocol M, day 78] vs high-risk [HR] group [MRD ≥ 10^-³ on day 78] vs intermediate-risk [IR] group [all nonSR/nonHR]).* Patients with SR and IR disease proceed to consolidation therapy-protocol M. Patients with HR disease proceed to HR block therapy. NOTE: *Patients meeting any of the following criteria are placed in the HR group regardless of MRD response: Philadelphia chromosome-positive disease (BCR/ABL or t[9;22]; translocations [t4;11][q11;q23] or MLL/AF4); prednisone-poor-response (≥ 1,000 blasts/mm³ in the peripheral blood on day 8 after prednisone prephase therapy); or no response to study induction therapy (M2/3 at day 33). • Consolidation, protocol M: Patients receive MP on days 1-56 and MTX on days 8, 22, 36, and 50. After completion of extracompartment therapy, SR and IR patients proceed to reintensification therapy. SR patients are randomized to arms I or II. IR patients are randomized to arms I or III. HR patients who have completed induction/consolidation therapy are randomized to arms IV or V. Reinduction therapy: o Arm I (standard reinduction therapy, protocol II [closed to accrual as of 6/30/2006]): SR and IR patients receive DEXA on days 1-22; VCR and doxorubicin hydrochloride (DOX) in weeks 2-5; ASP on days 8, 11, 15, and 18; CPM on day 36; ARA-C and thioguanine (TG) on days 36-49; and MTX IT on days 38 and 45. Patients then proceed to maintenance therapy. Arm II (reduced-intensity reinduction therapy, protocol III [closed to accrual as of 6/30/2006]): SR patients receive DEXA on days 1-15; VCR and DOX on days 1 and 8; ASP on days 1, 4, 8, and 11; CPM on day 15; ARA-C and TG on days 15-28; and MTX IT on days 16 and 23. Patients then proceed to maintenance therapy. Arm III (reduced-intensity reinduction/second delayed reinduction therapy [double reintensification therapy] [closed to accrual as of 6/30/2006]): IR patients receive reduced-intensity reintensification therapy as in arm II. After a 10-week interim maintenance phase, treatment repeats once for a second delayed course of reintensification therapy. Patients then proceed to maintenance therapy. Arm IV (standard reintensification therapy [closed to accrual as of 6/30/2006]): HR patients receive one sequence of the following HR therapy elements, in this order: 1, 2, 3, following standard reinduction therapy protocol II repeated twice after a four weeks Interim Maintenance phase. Patients then proceed to maintenance therapy. Element HR-1: Patients receive DEXA on days 1-5; VCR on days 1 and 6; ARA-C twice on day 5; MTX and CPM every 12 hours on days 2-4 (5 doses); ASP on day 6 ; and MTX/ARA-C/PRED IT on day 1. Element HR-2: Patients receive DEXA on days 1-5; vindesine on days 1 and 6; DNR on day 5; MTX and ifosfamide every 12 hours on days 2-4 (5 doses); ASP on day 6; and MTX/ARA-C/PRED IT on day 1. Element HR-3: Patients receive DEXA on days 1-5; ARA-C every 12 hours on days 1-2 (4 doses); etoposide five times daily on days 3-5; ASP on day 5; and MTX/ARA-C/PRED IT on day 1. Arm V (extended reintensification therapy [triple protocol III] [closed to accrual as of 6/30/2006]): HR patients receive HR therapy elements 3, 2, and 1 following reintensification therapy repeated the therapy element three times with 4-week interim maintenance phases in between. Patients then proceed to maintenance therapy. Interim maintenance/maintenance therapy: Patients receive MTX once weekly and MP daily until week 104 plus IT MTX every eight weeks. Radiotherapy: HR patients or patients with T-cell acute lymphoblastic leukemia or CNS disease undergo CNS radiotherapy. PROJECTED ACCRUAL: A total of 2,039 patients has been accrued for this study.

Official Title
-----------------
AIEOP LLA 2000 Multicenter Study for the Diagnosis and Treatment of Childhood Acute Lymphoblastic Leukemia

Conditions
-----------------
Leukemia

Intervention / Treatment
-----------------
* Drug: dexamethasone
* Drug: asparaginase
* Drug: Asparaginase
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: daunorubicin
* Drug: doxorubicin
* Drug: Etoposide
* Drug: Ifosfamide
* Drug: mercaptopurine
* Drug: Methotrexate
* Drug: prednisone
* Drug: thioguanine
* Drug: Vincristine
* Drug: Vindesine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed acute lymphoblastic leukemia (ALL) No secondary ALL More than 4 weeks since prior chemotherapy More than 4 weeks since prior steroids Exclusion Criteria: Prior disease that would preclude treatment with chemotherapy

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I<br>o Arm I (closed to accrual as of 6/30/2006): Patients receive prednisone (PRED) on days 8-28. | Drug: asparaginase<br>* native E-coli Asparaginase 5,000 IU/sqm x 8 doses<br>Drug: cyclophosphamide<br>* 1,000 mg/sqm i.v. 2 doses in Induction phase 1000 mg/sqm i.v. 1 dose in Protocoll II 500 mg/sqm i.v. 1 dose in protocol III<br>Drug: cytarabine<br>* 75 mg/sqm i.v.or s.c. 4 doses/week for 4 weeks in Induction phase 75 mg/sqm i.v.or s.c. 4 doses/week for 2 weeks in Protocol II and III<br>Drug: daunorubicin<br>* 30 mg/sqm i.v. 4 doses in Induction phase<br>Drug: mercaptopurine<br>* 60 mg/sqm p.o. c 28 days in Induction phase 60 mg/sqm p.o. x 56 days in Protocol M 50 mg/sqm daily in Maintenance phase<br>Drug: Methotrexate<br>* by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance<br>Drug: prednisone<br>* 60 mg/sqm daily p.o. for 28 days then tapered in Induction phase<br>Drug: Vincristine<br>* 1.5 mg/sqm i.v. x 4 doses in Induction phase and Protocol II 1.5 mg/sqm i.v. x 2 doses in Protocol III and HR block 1<br>|
| Experimental: II<br>o Arm II (closed to accrual as of 6/30/2006): Patients receive dexamethasone (DEXA) on days 8-28. | Drug: dexamethasone<br>* 10 mg/sqm/day from for 21 days<br>Drug: asparaginase<br>* native E-coli Asparaginase 5,000 IU/sqm x 8 doses<br>Drug: cyclophosphamide<br>* 1,000 mg/sqm i.v. 2 doses in Induction phase 1000 mg/sqm i.v. 1 dose in Protocoll II 500 mg/sqm i.v. 1 dose in protocol III<br>Drug: cytarabine<br>* 75 mg/sqm i.v.or s.c. 4 doses/week for 4 weeks in Induction phase 75 mg/sqm i.v.or s.c. 4 doses/week for 2 weeks in Protocol II and III<br>Drug: daunorubicin<br>* 30 mg/sqm i.v. 4 doses in Induction phase<br>Drug: mercaptopurine<br>* 60 mg/sqm p.o. c 28 days in Induction phase 60 mg/sqm p.o. x 56 days in Protocol M 50 mg/sqm daily in Maintenance phase<br>Drug: Methotrexate<br>* by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance<br>Drug: Vincristine<br>* 1.5 mg/sqm i.v. x 4 doses in Induction phase and Protocol II 1.5 mg/sqm i.v. x 2 doses in Protocol III and HR block 1<br>|
| Experimental: Reintensification Arm I<br>o Arm I (standard reinduction therapy, protocol II [closed to accrual as of 6/30/2006]): SR and IR patients receive DEXA on days 1-22; VCR and doxorubicin hydrochloride (DOX) in weeks 2-5; ASP on days 8, 11, 15, and 18; CPM on day 36; ARA-C and thioguanine (TG) on days 36-49; and MTX IT on days 38 and 45. Patients then proceed to maintenance therapy. | Drug: Asparaginase<br>* native E-Coli Asparaginase 10,000 IU/sqm x 4 doses<br>Drug: cyclophosphamide<br>* 1,000 mg/sqm i.v. 2 doses in Induction phase 1000 mg/sqm i.v. 1 dose in Protocoll II 500 mg/sqm i.v. 1 dose in protocol III<br>Drug: cytarabine<br>* 75 mg/sqm i.v.or s.c. 4 doses/week for 4 weeks in Induction phase 75 mg/sqm i.v.or s.c. 4 doses/week for 2 weeks in Protocol II and III<br>Drug: doxorubicin<br>* 30 mg/sqm i.v. x 4 doses in Protocol II and III<br>Drug: mercaptopurine<br>* 60 mg/sqm p.o. c 28 days in Induction phase 60 mg/sqm p.o. x 56 days in Protocol M 50 mg/sqm daily in Maintenance phase<br>Drug: Methotrexate<br>* by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance<br>Drug: thioguanine<br>* 60 mg/sqm p.o. x 14 days in Protocol II and Protocol III<br>Drug: Vincristine<br>* 1.5 mg/sqm i.v. x 4 doses in Induction phase and Protocol II 1.5 mg/sqm i.v. x 2 doses in Protocol III and HR block 1<br>|
| Experimental: Reintensification Arm II<br>• Arm II (reduced-intensity reinduction therapy, protocol III [closed to accrual as of 6/30/2006]): SR patients receive DEXA on days 1-15; VCR and DOX on days 1 and 8; ASP on days 1, 4, 8, and 11; CPM on day 15; ARA-C and TG on days 15-28; and MTX IT on days 16 and 23. Patients then proceed to maintenance therapy. | Drug: Asparaginase<br>* native E-Coli Asparaginase 10,000 IU/sqm x 4 doses<br>Drug: cyclophosphamide<br>* 1,000 mg/sqm i.v. 2 doses in Induction phase 1000 mg/sqm i.v. 1 dose in Protocoll II 500 mg/sqm i.v. 1 dose in protocol III<br>Drug: cytarabine<br>* 75 mg/sqm i.v.or s.c. 4 doses/week for 4 weeks in Induction phase 75 mg/sqm i.v.or s.c. 4 doses/week for 2 weeks in Protocol II and III<br>Drug: doxorubicin<br>* 30 mg/sqm i.v. x 4 doses in Protocol II and III<br>Drug: mercaptopurine<br>* 60 mg/sqm p.o. c 28 days in Induction phase 60 mg/sqm p.o. x 56 days in Protocol M 50 mg/sqm daily in Maintenance phase<br>Drug: Methotrexate<br>* by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance<br>Drug: thioguanine<br>* 60 mg/sqm p.o. x 14 days in Protocol II and Protocol III<br>Drug: Vincristine<br>* 1.5 mg/sqm i.v. x 4 doses in Induction phase and Protocol II 1.5 mg/sqm i.v. x 2 doses in Protocol III and HR block 1<br>|
| Experimental: Reintensification Arm III<br>• Arm III (reduced-intensity reinduction/second delayed reinduction therapy [double reintensification therapy] [closed to accrual as of 6/30/2006]): IR patients receive reduced-intensity reintensification therapy as in arm II. After a 10-week interim maintenance phase, treatment repeats once for a second delayed course of reintensification therapy. Patients then proceed to maintenance therapy. | Drug: Asparaginase<br>* native E-Coli Asparaginase 10,000 IU/sqm x 4 doses<br>Drug: cytarabine<br>* 75 mg/sqm i.v.or s.c. 4 doses/week for 4 weeks in Induction phase 75 mg/sqm i.v.or s.c. 4 doses/week for 2 weeks in Protocol II and III<br>Drug: doxorubicin<br>* 30 mg/sqm i.v. x 4 doses in Protocol II and III<br>Drug: mercaptopurine<br>* 60 mg/sqm p.o. c 28 days in Induction phase 60 mg/sqm p.o. x 56 days in Protocol M 50 mg/sqm daily in Maintenance phase<br>Drug: Methotrexate<br>* by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance<br>Drug: Vincristine<br>* 1.5 mg/sqm i.v. x 4 doses in Induction phase and Protocol II 1.5 mg/sqm i.v. x 2 doses in Protocol III and HR block 1<br>|
| Experimental: Reintensification Arm IV<br>• Arm IV (standard reintensification therapy [closed to accrual as of 6/30/2006]): HR patients receive one sequence of the following HR therapy elements, in this order: 1, 2, 3, following standard reinduction therapy protocol II repeated twice after a four weeks Interim Maintenance phase. Patients then proceed to maintenance therapy. Element HR-1: Patients receive DEXA on days 1-5; VCR on days 1 and 6; ARA-C twice on day 5; MTX and CPM every 12 hours on days 2-4 (5 doses); ASP on day 6 ; and MTX/ARA-C/PRED IT on day 1. Element HR-2: Patients receive DEXA on days 1-5; vindesine on days 1 and 6; DNR on day 5; MTX and ifosfamide every 12 hours on days 2-4 (5 doses); ASP on day 6; and MTX/ARA-C/PRED IT on day 1. Element HR-3: Patients receive DEXA on days 1-5; ARA-C every 12 hours on days 1-2 (4 doses); etoposide five times daily on days 3-5; ASP on day 5; and MTX/ARA-C/PRED IT on day 1. | Drug: Etoposide<br>* 100 mg/sqm i.v. for 3 doses in HR block 3<br>Drug: Ifosfamide<br>* 800 mg/sqm i.v.q12h x 5 in HR block 2<br>Drug: Methotrexate<br>* by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance<br>Drug: Vincristine<br>* 1.5 mg/sqm i.v. x 4 doses in Induction phase and Protocol II 1.5 mg/sqm i.v. x 2 doses in Protocol III and HR block 1<br>Drug: Vindesine<br>* 3 mg/sqm i.v. x 2 doses in HR block 2<br>|
| Experimental: Reintensification Arm V<br>• Arm V (extended reintensification therapy [triple protocol III] [closed to accrual as of 6/30/2006]): HR patients receive HR therapy elements 3, 2, and 1 following reintensification therapy repeated the therapy element three times with 4-week interim maintenance phases in between. Patients then proceed to maintenance therapy. Interim maintenance/maintenance therapy: Patients receive MTX once weekly and MP daily until week 104 plus IT MTX every eight weeks. Radiotherapy: HR patients or patients with T-cell acute lymphoblastic leukemia or CNS disease undergo CNS radiotherapy. | Drug: Etoposide<br>* 100 mg/sqm i.v. for 3 doses in HR block 3<br>Drug: Ifosfamide<br>* 800 mg/sqm i.v.q12h x 5 in HR block 2<br>Drug: Methotrexate<br>* by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance<br>Drug: Vincristine<br>* 1.5 mg/sqm i.v. x 4 doses in Induction phase and Protocol II 1.5 mg/sqm i.v. x 2 doses in Protocol III and HR block 1<br>Drug: Vindesine<br>* 3 mg/sqm i.v. x 2 doses in HR block 2<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of dexamethasone vs prednisone during the induction phase |  | 5 years | 
| Event-free survival (EFS) and overall survival after initial remission in intermediate-risk and high-risk patients |  | 5 years | 
| Safety and efficacy of treatment reduction during reintensification in standard-risk patients |  | 5 years | 
| EFS after second delayed reintensification in intermediate-risk patients |  | 5 years | 
| Outcome after extended reintensification therapy in high-risk patients |  | 5 years |