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

NCT00613457 | Completed Phase 3 DMC

• 1 other identifier: AIEOP LLA 2000
• Study Type: interventional
• Target: 2,039
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Leukemia

Outcome Measures

Primary Outcomes (5)

• 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

Study Arms (7)

I

EXPERIMENTAL

o Arm I (closed to accrual as of 6/30/2006): Patients receive prednisone (PRED) on days 8-28.

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.

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.

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.

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.

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.

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.

Drug: Etoposide; Drug: Ifosfamide; Drug: Methotrexate; Drug: Vincristine; Drug: Vindesine

Interventions

dexamethasone DRUG

10 mg/sqm/day from for 21 days

II

Asparaginase DRUG

native E-coli Asparaginase 5,000 IU/sqm x 8 doses

I; II

cyclophosphamide DRUG

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

I; II; Reintensification Arm I; Reintensification Arm II

cytarabine DRUG

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

I; II; Reintensification Arm I; Reintensification Arm II; Reintensification Arm III

daunorubicin DRUG

30 mg/sqm i.v. 4 doses in Induction phase

I; II

doxorubicin DRUG

30 mg/sqm i.v. x 4 doses in Protocol II and III

Reintensification Arm I; Reintensification Arm II; Reintensification Arm III

Etoposide DRUG

100 mg/sqm i.v. for 3 doses in HR block 3

Reintensification Arm IV; Reintensification Arm V

Ifosfamide DRUG

800 mg/sqm i.v.q12h x 5 in HR block 2

Reintensification Arm IV; Reintensification Arm V

mercaptopurine DRUG

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

I; II; Reintensification Arm I; Reintensification Arm II; Reintensification Arm III

Methotrexate DRUG

by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance

I; II; Reintensification Arm I; Reintensification Arm II; Reintensification Arm III; Reintensification Arm IV; Reintensification Arm V

prednisone DRUG

60 mg/sqm daily p.o. for 28 days then tapered in Induction phase

I

thioguanine DRUG

60 mg/sqm p.o. x 14 days in Protocol II and Protocol III

Reintensification Arm I; Reintensification Arm II

Vincristine DRUG

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

I; II; Reintensification Arm I; Reintensification Arm II; Reintensification Arm III; Reintensification Arm IV; Reintensification Arm V

Vindesine DRUG

3 mg/sqm i.v. x 2 doses in HR block 2

Reintensification Arm IV; Reintensification Arm V

Eligibility Criteria

• Age: 1 Year - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Histologically confirmed acute lymphoblastic leukemia (ALL)
• No secondary ALL
• More than 4 weeks since prior chemotherapy
• More than 4 weeks since prior steroids

You may not qualify if:

• Prior disease that would preclude treatment with chemotherapy

Sponsors & Collaborators

• Associazione Italiana Ematologia Oncologia Pediatrica: lead

Related Publications (8)

• 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.

  PMID: 37021527 DERIVED

• Cario 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.

  PMID: 31601692 DERIVED

• Schrappe 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.

  PMID: 29148893 DERIVED

• Moricke 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.

  PMID: 26888258 DERIVED

• Conter 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.

  PMID: 26853647 DERIVED

• Conter 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.

  PMID: 24415536 DERIVED

• Schrappe 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.

  PMID: 21719599 DERIVED

• Conter 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.

  PMID: 20154213 DERIVED

MeSH Terms

Conditions

Leukemia

Interventions

Dexamethasone; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Etoposide; Ifosfamide; Mercaptopurine; Methotrexate; Prednisone; Thioguanine; Vincristine; Vindesine

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Amidohydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Aminoglycosides; Glycosides; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Oxazines; Sulfhydryl Compounds; Sulfur Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Aminopterin; Pterins; Pteridines; Pregnadienediols; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines

Study Officials

• Giuseppe Masera, MD

  Clinica Pediatrica Università di milano Bicocca

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: January 21, 2008
• First Posted: February 13, 2008
• Study Start: September 1, 2000
• Primary Completion: July 1, 2006
• Study Completion: July 1, 2006
• Last Updated: January 14, 2015

Record last verified: 2015-01