LeukemiaPhase 3AIEOP LLA 2000NCT00613457
Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia
A Phase 3 study testing dexamethasone, asparaginase and cyclophosphamide in people with Leukemia, run by Associazione Italiana Ematologia Oncologia Pediatrica.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 year to 17 years
- Conditions the study is for
- Leukemia
- What is being tested?
- dexamethasone, asparaginase and cyclophosphamide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2,039 participants
- Where
- No sites listed yet
- Study dates
- Sep 2000to Jul 2006
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Histologically confirmed acute lymphoblastic leukemia (ALL)
- No secondary ALL
- More than 4 weeks since prior chemotherapy
- More than 4 weeks since prior steroids
Who cannot join
- Prior disease that would preclude treatment with chemotherapy
About this study
Official title: AIEOP LLA 2000 Multicenter Study for the Diagnosis and Treatment of Childhood Acute Lymphoblastic Leukemia
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.
Read the 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:
- 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.
- Conditions
- Leukemia
- Being tested
- dexamethasone, asparaginase, cyclophosphamide, cytarabine, daunorubicin
- Medical subject headings
- Leukemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
dexamethasoneDrug
10 mg/sqm/day from for 21 days
asparaginaseDrug
native E-coli Asparaginase 5,000 IU/sqm x 8 doses
AsparaginaseDrug
native E-Coli Asparaginase 10,000 IU/sqm x 4 doses
cyclophosphamideDrug
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
cytarabineDrug
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
daunorubicinDrug
30 mg/sqm i.v. 4 doses in Induction phase
doxorubicinDrug
30 mg/sqm i.v. x 4 doses in Protocol II and III
EtoposideDrug
100 mg/sqm i.v. for 3 doses in HR block 3
IfosfamideDrug
800 mg/sqm i.v.q12h x 5 in HR block 2
mercaptopurineDrug
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
MethotrexateDrug
by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance
prednisoneDrug
60 mg/sqm daily p.o. for 28 days then tapered in Induction phase
thioguanineDrug
60 mg/sqm p.o. x 14 days in Protocol II and Protocol III
VincristineDrug
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
VindesineDrug
3 mg/sqm i.v. x 2 doses in HR block 2
| Study group | Role | What they receive |
|---|---|---|
| I | Experimental | o Arm I (closed to accrual as of 6/30/2006): Patients receive prednisone (PRED) on days 8-28. Receives: Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin; Drug: mercaptopurine; Drug: Methotrexate; Drug: prednisone; Drug: Vincristine |
| II | Experimental | o Arm II (closed to accrual as of 6/30/2006): Patients receive dexamethasone (DEXA) on days 8-28. Receives: Drug: dexamethasone; Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin; Drug: mercaptopurine; Drug: Methotrexate; Drug: Vincristine |
| Reintensification Arm I | Experimental | 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. Receives: Drug: Asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: doxorubicin; Drug: mercaptopurine; Drug: Methotrexate; Drug: thioguanine; Drug: Vincristine |
| Reintensification Arm II | Experimental | • 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. Receives: Drug: Asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: doxorubicin; Drug: mercaptopurine; Drug: Methotrexate; Drug: thioguanine; Drug: Vincristine |
| Reintensification Arm III | Experimental | • 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. Receives: Drug: Asparaginase; Drug: cytarabine; Drug: doxorubicin; Drug: mercaptopurine; Drug: Methotrexate; Drug: Vincristine |
| Reintensification Arm IV | Experimental | • 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. Receives: Drug: Etoposide; Drug: Ifosfamide; Drug: Methotrexate; Drug: Vincristine; Drug: Vindesine |
| Reintensification Arm V | Experimental | • 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. Receives: Drug: Etoposide; Drug: Ifosfamide; Drug: Methotrexate; Drug: Vincristine; Drug: Vindesine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Efficacy of dexamethasone vs prednisone during the induction phase
Measured: 5 years
Event-free survival (EFS) and overall survival after initial remission in intermediate-risk and high-risk patients
Measured: 5 years
Safety and efficacy of treatment reduction during reintensification in standard-risk patients
Measured: 5 years
EFS after second delayed reintensification in intermediate-risk patients
Measured: 5 years
Outcome after extended reintensification therapy in high-risk patients
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2008 (estimated)
- Study startSep 2000
- Primary completionJul 2006
- Study completionJul 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 2,039 participants (actual)
Sponsor and investigators
- Lead sponsor
- Associazione Italiana Ematologia Oncologia Pediatrica
- Sponsor type
- University, hospital or other
- Investigators
- Giuseppe Masera, MD, Study chair, Clinica Pediatrica Università di milano Bicocca
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00613457
- Sponsor's protocol ID
- AIEOP LLA 2000
- Other IDs
- AIEOP LLA 2000
- Acronym
- AIEOP LLA 2000
- Status last verified
- Jan 2015
- First submitted
- 21 Jan 2008
- Last updated
- 14 Jan 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Heilmann J, Vieth S, Moricke A, Attarbaschi A, Barbaric D, Bodmer N, Colombini A, Dalla-Pozza L, Elitzur S, Izraeli S, Mann G, Niggli F, Silvestri D, Stary J, Rizzari C, Valsecchi MG, Zapotocka E, Zimmermann M, Cario G, Schrappe M, Conter V. Effect of two additional doses of intrathecal methotrexate during induction therapy on serious infectious toxicity in pediatric patients with acute lymphoblastic leukemia. Haematologica. 2023 Dec 1;108(12):3278-3286. doi: 10.3324/haematol.2022.281788.
PubMed 37021527Cario G, Leoni V, Conter V, Attarbaschi A, Zaliova M, Sramkova L, Cazzaniga G, Fazio G, Sutton R, Elitzur S, Izraeli S, Lauten M, Locatelli F, Basso G, Buldini B, Bergmann AK, Lentes J, Steinemann D, Gohring G, Schlegelberger B, Haas OA, Schewe D, Buchmann S, Moericke A, White D, Revesz T, Stanulla M, Mann G, Bodmer N, Arad-Cohen N, Zuna J, Valsecchi MG, Zimmermann M, Schrappe M, Biondi A. Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols. Haematologica. 2020 Jul;105(7):1887-1894. doi: 10.3324/haematol.2019.231720. Epub 2019 Oct 10.
PubMed 31601692Schrappe M, Bleckmann K, Zimmermann M, Biondi A, Moricke A, Locatelli F, Cario G, Rizzari C, Attarbaschi A, Valsecchi MG, Bartram CR, Barisone E, Niggli F, Niemeyer C, Testi AM, Mann G, Ziino O, Schafer B, Panzer-Grumayer R, Beier R, Parasole R, Gohring G, Ludwig WD, Casale F, Schlegel PG, Basso G, Conter V. Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000). J Clin Oncol. 2018 Jan 20;36(3):244-253. doi: 10.1200/JCO.2017.74.4946. Epub 2017 Nov 17.
PubMed 29148893Moricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Arico M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rossig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. doi: 10.1182/blood-2015-09-670729. Epub 2016 Feb 17.
PubMed 26888258Conter V, Valsecchi MG, Buldini B, Parasole R, Locatelli F, Colombini A, Rizzari C, Putti MC, Barisone E, Lo Nigro L, Santoro N, Ziino O, Pession A, Testi AM, Micalizzi C, Casale F, Pierani P, Cesaro S, Cellini M, Silvestri D, Cazzaniga G, Biondi A, Basso G. Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis. Lancet Haematol. 2016 Feb;3(2):e80-6. doi: 10.1016/S2352-3026(15)00254-9. Epub 2016 Jan 26.
PubMed 26853647Conter V, Valsecchi MG, Parasole R, Putti MC, Locatelli F, Barisone E, Lo Nigro L, Santoro N, Arico M, Ziino O, Pession A, Testi AM, Micalizzi C, Casale F, Zecca M, Casazza G, Tamaro P, La Barba G, Notarangelo LD, Silvestri D, Colombini A, Rizzari C, Biondi A, Masera G, Basso G. Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study. Blood. 2014 Mar 6;123(10):1470-8. doi: 10.1182/blood-2013-10-532598. Epub 2014 Jan 10.
PubMed 24415536Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grumayer R, Moricke A, Parasole R, Zimmermann M, Dworzak M, Buldini B, Reiter A, Basso G, Klingebiel T, Messina C, Ratei R, Cazzaniga G, Koehler R, Locatelli F, Schafer BW, Arico M, Welte K, van Dongen JJ, Gadner H, Biondi A, Conter V. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011 Aug 25;118(8):2077-84. doi: 10.1182/blood-2011-03-338707. Epub 2011 Jun 30.
PubMed 21719599Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A, Arico M, Zimmermann M, Mann G, De Rossi G, Stanulla M, Locatelli F, Basso G, Niggli F, Barisone E, Henze G, Ludwig WD, Haas OA, Cazzaniga G, Koehler R, Silvestri D, Bradtke J, Parasole R, Beier R, van Dongen JJ, Biondi A, Schrappe M. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010 Apr 22;115(16):3206-14. doi: 10.1182/blood-2009-10-248146. Epub 2010 Feb 12.
PubMed 20154213
Study at a glance
From the registry record, last updated by the sponsor on 14 Jan 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- AIEOP LLA 2000 Multicenter Study for the Diagnosis and Treatment of Childhood Acute Lymphoblastic Leukemia
- ClinicalTrials.gov ID
- NCT00613457
- Acronym / sponsor ID
- AIEOP LLA 2000 / AIEOP LLA 2000
- Conditions
- Leukemia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 2,039 participants (actual)
- Lead sponsor
- Associazione Italiana Ematologia Oncologia PediatricaUniversity, hospital or other
- Study start
- Sep 2000
- Primary completion
- Jul 2006 (actual)
- Study completion
- Jul 2006 (actual)
- First posted
- 13 Feb 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| I | Experimental | Drug: asparaginase, Drug: cyclophosphamide, Drug: cytarabine, Drug: daunorubicin, Drug: mercaptopurine, Drug: Methotrexate, Drug: prednisone, Drug: Vincristineo Arm I (closed to accrual as of 6/30/2006): Patients receive prednisone (PRED) on days 8-28. |
| II | Experimental | Drug: dexamethasone, Drug: asparaginase, Drug: cyclophosphamide, Drug: cytarabine, Drug: daunorubicin, Drug: mercaptopurine, Drug: Methotrexate, Drug: Vincristineo Arm II (closed to accrual as of 6/30/2006): Patients receive dexamethasone (DEXA) on days 8-28. |
| Reintensification Arm I | Experimental | Drug: Asparaginase, Drug: cyclophosphamide, Drug: cytarabine, Drug: doxorubicin, Drug: mercaptopurine, Drug: Methotrexate, Drug: thioguanine, Drug: Vincristineo 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. |
| Reintensification Arm II | Experimental | Drug: Asparaginase, Drug: cyclophosphamide, Drug: cytarabine, Drug: doxorubicin, Drug: mercaptopurine, Drug: Methotrexate, Drug: thioguanine, Drug: Vincristine• 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. |
| Reintensification Arm III | Experimental | Drug: Asparaginase, Drug: cytarabine, Drug: doxorubicin, Drug: mercaptopurine, Drug: Methotrexate, Drug: Vincristine• 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. |
| Reintensification Arm IV | Experimental | Drug: Etoposide, Drug: Ifosfamide, Drug: Methotrexate, Drug: Vincristine, Drug: Vindesine• 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. |
| Reintensification Arm V | Experimental | Drug: Etoposide, Drug: Ifosfamide, Drug: Methotrexate, Drug: Vincristine, Drug: Vindesine• 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. |
Who may qualify
- Ages
- 1 year to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- Histologically confirmed acute lymphoblastic leukemia (ALL)
- No secondary ALL
- More than 4 weeks since prior chemotherapy
- More than 4 weeks since prior steroids
Key exclusion criteria (1 listed)
- Prior disease that would preclude treatment with chemotherapy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| dexamethasone10 mg/sqm/day from for 21 days | Drug | II |
| asparaginasenative E-coli Asparaginase 5,000 IU/sqm x 8 doses | Drug | I, II |
| Asparaginasenative E-Coli Asparaginase 10,000 IU/sqm x 4 doses | Drug | Reintensification Arm I, Reintensification Arm II, Reintensification Arm III |
| cyclophosphamide1,000 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 | Drug | I, II, Reintensification Arm I, Reintensification Arm II |
| cytarabine75 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 | Drug | I, II, Reintensification Arm I, Reintensification Arm II, Reintensification Arm III |
| daunorubicin30 mg/sqm i.v. 4 doses in Induction phase | Drug | I, II |
| doxorubicin30 mg/sqm i.v. x 4 doses in Protocol II and III | Drug | Reintensification Arm I, Reintensification Arm II, Reintensification Arm III |
| Etoposide100 mg/sqm i.v. for 3 doses in HR block 3 | Drug | Reintensification Arm IV, Reintensification Arm V |
| Ifosfamide800 mg/sqm i.v.q12h x 5 in HR block 2 | Drug | Reintensification Arm IV, Reintensification Arm V |
| mercaptopurine60 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 | Drug | I, II, Reintensification Arm I, Reintensification Arm II, Reintensification Arm III |
| Methotrexateby age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance | Drug | I, II, Reintensification Arm I, Reintensification Arm II, Reintensification Arm III, Reintensification Arm IV, Reintensification Arm V |
| prednisone60 mg/sqm daily p.o. for 28 days then tapered in Induction phase | Drug | I |
| thioguanine60 mg/sqm p.o. x 14 days in Protocol II and Protocol III | Drug | Reintensification Arm I, Reintensification Arm II |
| Vincristine1.5 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 | Drug | I, II, Reintensification Arm I, Reintensification Arm II, Reintensification Arm III, Reintensification Arm IV, Reintensification Arm V |
| Vindesine3 mg/sqm i.v. x 2 doses in HR block 2 | Drug | Reintensification Arm IV, Reintensification Arm V |
Primary outcome
Efficacy of dexamethasone vs prednisone during the induction phase
Time frame: 5 years
Event-free survival (EFS) and overall survival after initial remission in intermediate-risk and high-risk patients
Time frame: 5 years
Safety and efficacy of treatment reduction during reintensification in standard-risk patients
Time frame: 5 years
EFS after second delayed reintensification in intermediate-risk patients
Time frame: 5 years
Outcome after extended reintensification therapy in high-risk patients
Time frame: 5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jan 2015.
- Derived from this study: PubMed 37021527Heilmann J, Vieth S, Moricke A, Attarbaschi A, Barbaric D, Bodmer N, Colombini A, Dalla-Pozza L, Elitzur S, Izraeli S, Mann G, Niggli F, Silvestri D, Stary J, Rizzari C, Valsecchi MG, Zapotocka E, Zimmermann M, Cario G, Schrappe M, Conter V. Effect of two additional doses of intrathecal methotrexate during induction therapy on serious infectious toxicity in pediatric patients with acute lymphoblastic leukemia. Haematologica. 2023 Dec 1;108(12):3278-3286. doi: 10.3324/haematol.2022.281788.
- Derived from this study: PubMed 31601692Cario G, Leoni V, Conter V, Attarbaschi A, Zaliova M, Sramkova L, Cazzaniga G, Fazio G, Sutton R, Elitzur S, Izraeli S, Lauten M, Locatelli F, Basso G, Buldini B, Bergmann AK, Lentes J, Steinemann D, Gohring G, Schlegelberger B, Haas OA, Schewe D, Buchmann S, Moericke A, White D, Revesz T, Stanulla M, Mann G, Bodmer N, Arad-Cohen N, Zuna J, Valsecchi MG, Zimmermann M, Schrappe M, Biondi A. Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols. Haematologica. 2020 Jul;105(7):1887-1894. doi: 10.3324/haematol.2019.231720. Epub 2019 Oct 10.
- Derived from this study: PubMed 29148893Schrappe M, Bleckmann K, Zimmermann M, Biondi A, Moricke A, Locatelli F, Cario G, Rizzari C, Attarbaschi A, Valsecchi MG, Bartram CR, Barisone E, Niggli F, Niemeyer C, Testi AM, Mann G, Ziino O, Schafer B, Panzer-Grumayer R, Beier R, Parasole R, Gohring G, Ludwig WD, Casale F, Schlegel PG, Basso G, Conter V. Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000). J Clin Oncol. 2018 Jan 20;36(3):244-253. doi: 10.1200/JCO.2017.74.4946. Epub 2017 Nov 17.
- Derived from this study: PubMed 26888258Moricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Arico M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rossig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. doi: 10.1182/blood-2015-09-670729. Epub 2016 Feb 17.
- Derived from this study: PubMed 26853647Conter V, Valsecchi MG, Buldini B, Parasole R, Locatelli F, Colombini A, Rizzari C, Putti MC, Barisone E, Lo Nigro L, Santoro N, Ziino O, Pession A, Testi AM, Micalizzi C, Casale F, Pierani P, Cesaro S, Cellini M, Silvestri D, Cazzaniga G, Biondi A, Basso G. Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis. Lancet Haematol. 2016 Feb;3(2):e80-6. doi: 10.1016/S2352-3026(15)00254-9. Epub 2016 Jan 26.
- Derived from this study: PubMed 24415536Conter V, Valsecchi MG, Parasole R, Putti MC, Locatelli F, Barisone E, Lo Nigro L, Santoro N, Arico M, Ziino O, Pession A, Testi AM, Micalizzi C, Casale F, Zecca M, Casazza G, Tamaro P, La Barba G, Notarangelo LD, Silvestri D, Colombini A, Rizzari C, Biondi A, Masera G, Basso G. Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study. Blood. 2014 Mar 6;123(10):1470-8. doi: 10.1182/blood-2013-10-532598. Epub 2014 Jan 10.
- Derived from this study: PubMed 21719599Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grumayer R, Moricke A, Parasole R, Zimmermann M, Dworzak M, Buldini B, Reiter A, Basso G, Klingebiel T, Messina C, Ratei R, Cazzaniga G, Koehler R, Locatelli F, Schafer BW, Arico M, Welte K, van Dongen JJ, Gadner H, Biondi A, Conter V. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011 Aug 25;118(8):2077-84. doi: 10.1182/blood-2011-03-338707. Epub 2011 Jun 30.
- Derived from this study: PubMed 20154213Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A, Arico M, Zimmermann M, Mann G, De Rossi G, Stanulla M, Locatelli F, Basso G, Niggli F, Barisone E, Henze G, Ludwig WD, Haas OA, Cazzaniga G, Koehler R, Silvestri D, Bradtke J, Parasole R, Beier R, van Dongen JJ, Biondi A, Schrappe M. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010 Apr 22;115(16):3206-14. doi: 10.1182/blood-2009-10-248146. Epub 2010 Feb 12.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Giuseppe Masera, MD study chair
Clinica Pediatrica Università di milano Bicocca
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing dexamethasone, asparaginase and cyclophosphamide in people with Leukemia, run by Associazione Italiana Ematologia Oncologia Pediatrica.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Jan 2015. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Efficacy of dexamethasone vs prednisone during the induction phase (time frame: 5 years). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00613457, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jan 2015.