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

Leukemia Clinical Trial

Official title:

ALL-BFM 2000 Multi-Center Study for the Treatment of Children and Adolescents With Acute Lymphoblastic Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00430118
• Other study ID #: CDR0000528029
• Secondary ID: ALL-BFM-2000EU-2
• Status: Completed
• Phase: Phase 3
• First received: January 30, 2007
• Last updated: May 28, 2013
• Start date: July 2000
• Est. completion date: January 2012

Study information

• Verified date: May 2013
• Source: University of Schleswig-Holstein
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical 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. 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.

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, 12, 33, 45, and 59.*

NOTE: *Patients with CNS disease also receive MTX IT on days 18 and 27.

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 extracompartment therapy. Patients with HR disease proceed to reintensification 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).

• Extracompartment therapy, 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.

• Reintensification 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.

NOTE: *Patients with CNS disease also receive MTX IT on days 1 and 18.

• 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 17 and 24.* Patients then proceed to maintenance therapy.

NOTE: *Patients with CNS disease also receive MTX on day 1.

• 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 two sequences of the following HR therapy elements (i.e., in this order: 1, 2, 3, 1, 2, 3) following reintensification therapy as in arm I. 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 days 6 and 11; 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 days 6 and 11; and MTX/ARA-C/PRED IT on day 1.* NOTE: *HR patients with CNS disease also receive IT therapy on day 5.

• 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 days 6 and 11; 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 as in arm IV following reintensification therapy as in arm II repeated the therapy element twice 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.

• Radiotherapy: HR patients or patients with T-cell acute lymphoblastic leukemia or CNS disease undergo CNS radiotherapy.

PROJECTED ACCRUAL: A total of 2,000 patients will be accrued for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4559
• Est. completion date: January 2012
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 18 Years

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed acute lymphoblastic leukemia (ALL)

• No secondary ALL

PATIENT CHARACTERISTICS:

• No prior disease that would preclude treatment with chemotherapy

PRIOR CONCURRENT THERAPY:

• More than 4 weeks since prior chemotherapy

• More than 4 weeks since prior steroids

Study Design

Allocation: Randomized, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• asparaginase

• cyclophosphamide

• cytarabine

• daunorubicin hydrochloride

• dexamethasone

• doxorubicin hydrochloride

• etoposide

• ifosfamide

• mercaptopurine

• methotrexate

• prednisone

• thioguanine

• vincristine sulfate

• vindesine

Radiation:
• radiation therapy

Locations

Country	Name	City	State
Austria	Krankenhaus Dornbirn	Dornbirn
Austria	Landeskrankenhaus Feldkirch	Feldkirch-Tisis
Austria	Universitaet Kinderklinik	Graz
Austria	Innsbruck Universitaetsklinik	Innsbruck
Austria	Landeskrankenhaus Klagenfurt	Klagenfurt
Austria	LKH Leoben	Leoben
Austria	A. oe. Krankenhaus der Barmherzigen Schwestern Kinderabteilung	Linz
Austria	Landes-Kinderkrankenhaus	Linz
Austria	St. Johanns-Spital	Salzburg
Austria	St. Anna Children's Hospital	Vienna
Germany	Kinderklinik - Universitaetsklinikum Aachen	Aachen
Germany	Klinikum Augsburg	Augsburg
Germany	Caritas-Krankenhaus Bad Mergentheim	Bad Mergentheim
Germany	Klinikum Bayreuth	Bayreuth
Germany	Charite University Hospital - Campus Virchow Klinikum	Berlin
Germany	Helios Klinikum Berlin	Berlin
Germany	Kinderklinik der Universitaet Bonn	Bonn
Germany	Staedtisches Klinikum - Howedestrase	Braunschweig
Germany	Klinikum Chemnitz gGmbH	Chemnitz
Germany	Klinikum Coburg	Coburg
Germany	Children's Hospital	Cologne
Germany	Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl	Cologne
Germany	Carl - Thiem - Klinkum Cottbus	Cottbus
Germany	Vestische Kinderklinik Universitaetsklinik Witten/Herdecke	Datteln
Germany	Klinikum Lippe - Detmold	Detmold
Germany	Klinikum Dortmund	Dortmund
Germany	Universitatsklinikum Carl Gustav Carus	Dresden
Germany	Klinikum Duisburg	Duisburg
Germany	Helios Klinikum Erfurt	Erfurt
Germany	Universitaets - Kinderklinik	Erlangen
Germany	Universitaetsklinikum Essen	Essen
Germany	Klinikum der J.W. Goethe Universitaet	Frankfurt
Germany	Universitaetskinderklinik - Universitaetsklinikum Freiburg	Freiburg
Germany	Kinderklinik	Giessen
Germany	Universitaetsklinikum Goettingen	Goettingen
Germany	Universitaetsklinikum Halle	Halle
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitaets-Kinderklinik Heidelberg	Heidelberg
Germany	SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen	Heilbronn
Germany	Gemeinschaftskrankenhaus	Herdecke
Germany	Universitaetsklinikum des Saarlandes	Homburg
Germany	Universitaets - Kinderklinik	Jena
Germany	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe
Germany	Klinikum Kassel	Kassel
Germany	University Hospital Schleswig-Holstein - Kiel Campus	Kiel
Germany	Klinikum Kemperhof Koblenz	Koblenz
Germany	St. Annastift Krankenhaus	Ludwigshafen
Germany	Universitaets - Kinderklinik - Luebeck	Luebeck
Germany	Universitatsklinikum der MA	Magdeburg
Germany	Staedtisches Klinik - Kinderklinik	Mannheim
Germany	Universitaetsklinikum Giessen und Marburg GmbH - Marburg	Marburg
Germany	Klinikum Minden	Minden
Germany	Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster	Muenster
Germany	Krankenhaus Muenchen Schwabing	Munich
Germany	Kinderklinik Kohlhof	Neunkirchen
Germany	Cnopf'sche Kinderklinik	Nuremberg
Germany	Klinikum Oldenburg	Oldenburg
Germany	Kinderklinik - Universitaetsklinikum Rostock	Rostock
Germany	Saarbrucker Winterbergkliniken	Saarbrucken
Germany	Klinikum Schwerin	Schwerin
Germany	Kinderklink Siegen Deutsches Rotes Kreuz	Siegen
Germany	Johanniter-Kinderklinik	St. Augustin
Germany	Olgahospital	Stuttgart
Germany	Krankenanstalt Mutterhaus der Borromaerinnen	Trier
Germany	Universitaetsklinikum Tuebingen	Tuebingen
Germany	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm
Germany	St. Marienhospital - Vechta	Vechta
Germany	Reinhard-Nieter-Krankenhaus	Wilhelmshaven
Germany	Klinikum der Stadt Wolfsburg	Wolfsburg
Germany	Universitaets - Kinderklinik Wuerzburg	Wuerzburg
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Universitaets-Kinderspital beider Basel	Basel
Switzerland	Ospedale "la Carita", Locarno	Locarno
Switzerland	Kinderspital Luzern	Lucerne 16
Switzerland	Ostschweizer Kinderspital	St. Gallen
Switzerland	University Children's Hospital	Zurich

Sponsors (1)

Lead Sponsor	Collaborator
University of Schleswig-Holstein

Countries where clinical trial is conducted

Austria,  Germany,  Switzerland, 

References & Publications (7)

Attarbaschi A, Mann G, Panzer-Grümayer R, Röttgers S, Steiner M, König M, Csinady E, Dworzak MN, Seidel M, Janousek D, Möricke A, Reichelt C, Harbott J, Schrappe M, Gadner H, Haas OA. Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol. 2008 Jun 20;26(18):3046-50. doi: 10.1200/JCO.2008.16.1117. — View Citation

Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grümayer R, Möricke A, Aricò 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, — View Citation

Dworzak MN, Schumich A, Printz D, Pötschger U, Husak Z, Attarbaschi A, Basso G, Gaipa G, Ratei R, Mann G, Gadner H. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 d — View Citation

Flohr T, Schrauder A, Cazzaniga G, Panzer-Grümayer R, van der Velden V, Fischer S, Stanulla M, Basso G, Niggli FK, Schäfer BW, Sutton R, Koehler R, Zimmermann M, Valsecchi MG, Gadner H, Masera G, Schrappe M, van Dongen JJ, Biondi A, Bartram CR; Internatio — View Citation

Kox C, Zimmermann M, Stanulla M, Leible S, Schrappe M, Ludwig WD, Koehler R, Tolle G, Bandapalli OR, Breit S, Muckenthaler MU, Kulozik AE. The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the A — View Citation

Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grümayer R, Möricke 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, Schäfer BW, Aricò M, Welte K, van Do — View Citation

Schrey D, Borghorst S, Lanvers-Kaminsky C, Hempel G, Gerss J, Möricke A, Schrappe M, Boos J. Therapeutic drug monitoring of asparaginase in the ALL-BFM 2000 protocol between 2000 and 2007. Pediatr Blood Cancer. 2010 Jul 1;54(7):952-8. doi: 10.1002/pbc.224 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy of dexamethasone vs prednisone during the induction phase		End of Trial	No
Primary	Event-free survival (EFS) and overall survival after initial remission in intermediate-risk and high-risk patients		End of Trial	No
Primary	Safety and efficacy of treatment reduction during reintensification in standard-risk patients		End of Trial	Yes
Primary	EFS after second delayed reintensification in intermediate-risk patients		End of Trial	No
Primary	Outcome after extended reintensification therapy in high-risk patients		End of Trial	No