Clinical trial NCT00430118: Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia
Official title: ALL-BFM 2000 Multi-Center Study for the Treatment of Children and Adolescents With Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia
Keywords: T-cell childhood acute lymphoblastic leukemia
recurrent childhood acute lymphoblastic leukemia
untreated childhood acute lymphoblastic leukemia
B-cell childhood acute lymphoblastic leukemia
Lead sponsor: University Hospital Schleswig-Holstein
Sponsor class: OTHER
First posted: 2007-02-01
Enrollment: 4559
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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, 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 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

Primary outcomes:
measure: Efficacy of dexamethasone vs prednisone during the induction phase
timeFrame: End of Trial
measure: Event-free survival (EFS) and overall survival after initial remission in intermediate-risk and high-risk patients
timeFrame: End of Trial
measure: Safety and efficacy of treatment reduction during reintensification in standard-risk patients
timeFrame: End of Trial
measure: EFS after second delayed reintensification in intermediate-risk patients
timeFrame: End of Trial
measure: Outcome after extended reintensification therapy in high-risk patients
timeFrame: End of Trial
Secondary outcomes:
Other outcomes:
Locations:
city: Dornbirn
country: Austria
facility: Krankenhaus Dornbirn
city: Feldkirch-Tisis
country: Austria
facility: Landeskrankenhaus Feldkirch
city: Graz
country: Austria
facility: Universitaet Kinderklinik
city: Innsbruck
country: Austria
facility: Innsbruck Universitaetsklinik
city: Klagenfurt
country: Austria
facility: Landeskrankenhaus Klagenfurt
city: Leoben
country: Austria
facility: LKH Leoben
city: Linz
country: Austria
facility: A. oe. Krankenhaus der Barmherzigen Schwestern Kinderabteilung
city: Linz
country: Austria
facility: Landes-Kinderkrankenhaus
city: Salzburg
country: Austria
facility: St. Johanns-Spital
city: Vienna
country: Austria
facility: St. Anna Children's Hospital
city: Aachen
country: Germany
facility: Kinderklinik - Universitaetsklinikum Aachen
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bad Mergentheim
country: Germany
facility: Caritas-Krankenhaus Bad Mergentheim
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: Helios Klinikum Berlin
city: Berlin
country: Germany
facility: Charite University Hospital - Campus Virchow Klinikum
city: Bonn
country: Germany
facility: Kinderklinik der Universitaet Bonn
city: Braunschweig
country: Germany
facility: Staedtisches Klinikum - Howedestrase
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Coburg
country: Germany
facility: Klinikum Coburg
city: Cologne
country: Germany
facility: Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl
city: Cologne
country: Germany
facility: Children's Hospital
city: Cottbus
country: Germany
facility: Carl - Thiem - Klinkum Cottbus
city: Datteln
country: Germany
facility: Vestische Kinderklinik Universitaetsklinik Witten/Herdecke
city: Detmold
country: Germany
facility: Klinikum Lippe - Detmold
city: Dortmund
country: Germany
facility: Klinikum Dortmund
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus
city: Duisburg
country: Germany
facility: Klinikum Duisburg
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
city: Erlangen
country: Germany
facility: Universitaets - Kinderklinik
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Universitaetskinderklinik - Universitaetsklinikum Freiburg
city: Giessen
country: Germany
facility: Kinderklinik
city: Goettingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Halle
country: Germany
facility: Universitaetsklinikum Halle
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitaets-Kinderklinik Heidelberg
city: Heilbronn
country: Germany
facility: SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen
city: Herdecke
country: Germany
facility: Gemeinschaftskrankenhaus
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Jena
country: Germany
facility: Universitaets - Kinderklinik
city: Karlsruhe
country: Germany
facility: Staedtisches Klinikum Karlsruhe gGmbH
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Koblenz
country: Germany
facility: Klinikum Kemperhof Koblenz
city: Ludwigshafen
country: Germany
facility: St. Annastift Krankenhaus
city: Luebeck
country: Germany
facility: Universitaets - Kinderklinik - Luebeck
city: Magdeburg
country: Germany
facility: Universitatsklinikum der MA
city: Mannheim
country: Germany
facility: Staedtisches Klinik - Kinderklinik
city: Marburg
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH - Marburg
city: Minden
country: Germany
facility: Klinikum Minden
city: Muenster
country: Germany
facility: Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster
city: Munich
country: Germany
facility: Krankenhaus Muenchen Schwabing
city: Neunkirchen
country: Germany
facility: Kinderklinik Kohlhof
city: Nuremberg
country: Germany
facility: Cnopf'sche Kinderklinik
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Rostock
country: Germany
facility: Kinderklinik - Universitaetsklinikum Rostock
city: Saarbrucken
country: Germany
facility: Saarbrucker Winterbergkliniken
city: Schwerin
country: Germany
facility: Klinikum Schwerin
city: Siegen
country: Germany
facility: Kinderklink Siegen Deutsches Rotes Kreuz
city: St. Augustin
country: Germany
facility: Johanniter-Kinderklinik
city: Stuttgart
country: Germany
facility: Olgahospital
city: Trier
country: Germany
facility: Krankenanstalt Mutterhaus der Borromaerinnen
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Ulm
country: Germany
facility: Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
city: Vechta
country: Germany
facility: St. Marienhospital - Vechta
city: Wilhelmshaven
country: Germany
facility: Reinhard-Nieter-Krankenhaus
city: Wolfsburg
country: Germany
facility: Klinikum der Stadt Wolfsburg
city: Wuerzburg
country: Germany
facility: Universitaets - Kinderklinik Wuerzburg
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Universitaets-Kinderspital beider Basel
city: Locarno
country: Switzerland
facility: Ospedale "la Carita", Locarno
city: Lucerne 16
country: Switzerland
facility: Kinderspital Luzern
city: St. Gallen
country: Switzerland
facility: Ostschweizer Kinderspital
city: Zurich
country: Switzerland
facility: University Children's Hospital
Study officials:
affiliation: University Hospital Schleswig-Holstein
name: Martin Schrappe, MD, PhD
role: STUDY_CHAIR
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