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

Information source: University of Schleswig-Holstein
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Leukemia

Intervention: asparaginase (Drug); cyclophosphamide (Drug); cytarabine (Drug); daunorubicin hydrochloride (Drug); dexamethasone (Drug); doxorubicin hydrochloride (Drug); etoposide (Drug); ifosfamide (Drug); mercaptopurine (Drug); methotrexate (Drug); prednisone (Drug); thioguanine (Drug); vincristine sulfate (Drug); vindesine (Drug); radiation therapy (Radiation)

Phase: Phase 3

Status: Completed

Sponsored by: University of Schleswig-Holstein

Official(s) and/or principal investigator(s):
Martin Schrappe, MD, PhD, Study Chair, Affiliation: University of Schleswig-Holstein

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.

Clinical Details

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

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

Primary outcome:

Efficacy of dexamethasone vs prednisone during the induction phase

Event-free survival (EFS) and overall survival after initial remission in intermediate-risk and high-risk patients

Safety and efficacy of treatment reduction during reintensification in standard-risk patients

EFS after second delayed reintensification in intermediate-risk patients

Outcome after extended reintensification therapy in high-risk patients

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, 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.

Eligibility

Minimum age: 1 Year. Maximum age: 18 Years. Gender(s): Both.

Criteria:

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

Locations and Contacts

Krankenhaus Dornbirn, Dornbirn A-6850, Austria

Landeskrankenhaus Feldkirch, Feldkirch-Tisis A-6807, Austria

Universitaet Kinderklinik, Graz 8036, Austria

Innsbruck Universitaetsklinik, Innsbruck A-6020, Austria

Landeskrankenhaus Klagenfurt, Klagenfurt 9026, Austria

LKH Leoben, Leoben A-8700, Austria

A. oe. Krankenhaus der Barmherzigen Schwestern Kinderabteilung, Linz 4010, Austria

Landes-Kinderkrankenhaus, Linz A-4020, Austria

St. Johanns-Spital, Salzburg A-5020, Austria

St. Anna Children's Hospital, Vienna A-1090, Austria

Kinderklinik - Universitaetsklinikum Aachen, Aachen D-52074, Germany

Klinikum Augsburg, Augsburg DOH-86156, Germany

Caritas-Krankenhaus Bad Mergentheim, Bad Mergentheim D-97980, Germany

Klinikum Bayreuth, Bayreuth D-95445, Germany

Charite University Hospital - Campus Virchow Klinikum, Berlin D-13353, Germany

Helios Klinikum Berlin, Berlin 13125, Germany

Kinderklinik der Universitaet Bonn, Bonn D-53113, Germany

Staedtisches Klinikum - Howedestrase, Braunschweig 38118, Germany

Klinikum Chemnitz gGmbH, Chemnitz D-09116, Germany

Klinikum Coburg, Coburg 96450, Germany

Children's Hospital, Cologne D-50924, Germany

Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl, Cologne D-50735, Germany

Carl - Thiem - Klinkum Cottbus, Cottbus D-03048, Germany

Vestische Kinderklinik Universitaetsklinik Witten/Herdecke, Datteln 45711, Germany

Klinikum Lippe - Detmold, Detmold D-32756, Germany

Klinikum Dortmund, Dortmund D-44137, Germany

Universitatsklinikum Carl Gustav Carus, Dresden D-01307, Germany

Klinikum Duisburg, Duisburg D-47055, Germany

Helios Klinikum Erfurt, Erfurt 99089, Germany

Universitaets - Kinderklinik, Erlangen 91054, Germany

Universitaetsklinikum Essen, Essen D-45147, Germany

Klinikum der J.W. Goethe Universitaet, Frankfurt D-60590, Germany

Universitaetskinderklinik - Universitaetsklinikum Freiburg, Freiburg D-79106, Germany

Kinderklinik, Giessen D-35385, Germany

Universitaetsklinikum Goettingen, Goettingen D-37075, Germany

Universitaetsklinikum Halle, Halle D-06097, Germany

Medizinische Hochschule Hannover, Hannover D-30625, Germany

Universitaets-Kinderklinik Heidelberg, Heidelberg D-69120, Germany

SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen, Heilbronn D-74064, Germany

Gemeinschaftskrankenhaus, Herdecke 58313, Germany

Universitaetsklinikum des Saarlandes, Homburg 66421, Germany

Universitaets - Kinderklinik, Jena D-07745, Germany

Staedtisches Klinikum Karlsruhe gGmbH, Karlsruhe 76133, Germany

Klinikum Kassel, Kassel D-34125, Germany

University Hospital Schleswig-Holstein - Kiel Campus, Kiel D-24105, Germany

Klinikum Kemperhof Koblenz, Koblenz D-56065, Germany

St. Annastift Krankenhaus, Ludwigshafen 67065, Germany

Universitaets - Kinderklinik - Luebeck, Luebeck D-23538, Germany

Universitatsklinikum der MA, Magdeburg 39120, Germany

Staedtisches Klinik - Kinderklinik, Mannheim D-68167, Germany

Universitaetsklinikum Giessen und Marburg GmbH - Marburg, Marburg D-35043, Germany

Klinikum Minden, Minden D-32423, Germany

Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster, Muenster D-48149, Germany

Krankenhaus Muenchen Schwabing, Munich 80804, Germany

Kinderklinik Kohlhof, Neunkirchen D-66539, Germany

Cnopf'sche Kinderklinik, Nuremberg 90419, Germany

Klinikum Oldenburg, Oldenburg 26133, Germany

Kinderklinik - Universitaetsklinikum Rostock, Rostock D-18057, Germany

Saarbrucker Winterbergkliniken, Saarbrucken 66119, Germany

Klinikum Schwerin, Schwerin D-19049, Germany

Kinderklink Siegen Deutsches Rotes Kreuz, Siegen D-57072, Germany

Johanniter-Kinderklinik, St. Augustin 53757, Germany

Olgahospital, Stuttgart D-70176, Germany

Krankenanstalt Mutterhaus der Borromaerinnen, Trier D-54290, Germany

Universitaetsklinikum Tuebingen, Tuebingen D-72076, Germany

Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm, Ulm D-89075, Germany

St. Marienhospital - Vechta, Vechta D-49377, Germany

Reinhard-Nieter-Krankenhaus, Wilhelmshaven D-26389, Germany

Klinikum der Stadt Wolfsburg, Wolfsburg D-38440, Germany

Universitaets - Kinderklinik Wuerzburg, Wuerzburg D-97080, Germany

Kantonsspital Aarau, Aarau CH-5001, Switzerland

Universitaets-Kinderspital beider Basel, Basel CH-4005, Switzerland

Ospedale "la Carita", Locarno, Locarno 6600, Switzerland

Kinderspital Luzern, Lucerne 16 CH-6000, Switzerland

Ostschweizer Kinderspital, St. Gallen CH-9006, Switzerland

University Children's Hospital, Zurich CH-8032, Switzerland

Additional Information

Clinical trial summary from the National Cancer Institute's PDQ® database

Related publications:

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.

Starting date: July 2000
Last updated: May 28, 2013

Page last updated: August 23, 2015

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