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

Sponsor

University Hospital Schleswig-Holstein (Other)

Overall Status

Completed

CT.gov ID

NCT00430118

Collaborator

(none)

4,559

Enrollment

Locations

Arms

138

Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: 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 Radiation: radiation therapy	Phase 3

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

4559 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 2000

Actual Primary Completion Date :

Jan 1, 2012

Actual Study Completion Date :

Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Induction Prot I/Dexa - reinduction Prot III	Drug: asparaginase Drug: cyclophosphamide Drug: cytarabine Drug: daunorubicin hydrochloride Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: ifosfamide Drug: mercaptopurine Drug: methotrexate Drug: prednisone Drug: thioguanine Drug: vincristine sulfate Drug: vindesine Radiation: radiation therapy
Experimental: Induction Prot I/Pred - reinduction Prot III	Drug: asparaginase Drug: cyclophosphamide Drug: cytarabine Drug: daunorubicin hydrochloride Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: ifosfamide Drug: mercaptopurine Drug: methotrexate Drug: prednisone Drug: thioguanine Drug: vincristine sulfate Drug: vindesine Radiation: radiation therapy
Experimental: Induction Prot I/Dexa - reinduction Prot II	Drug: asparaginase Drug: cyclophosphamide Drug: cytarabine Drug: daunorubicin hydrochloride Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: ifosfamide Drug: mercaptopurine Drug: methotrexate Drug: prednisone Drug: thioguanine Drug: vincristine sulfate Drug: vindesine Radiation: radiation therapy
Active Comparator: Induction Prot I/Pred - reinduction Prot II	Drug: asparaginase Drug: cyclophosphamide Drug: cytarabine Drug: daunorubicin hydrochloride Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: ifosfamide Drug: mercaptopurine Drug: methotrexate Drug: prednisone Drug: thioguanine Drug: vincristine sulfate Drug: vindesine Radiation: radiation therapy
Experimental: Induction Prot I/Dexa - reinduction 2x Prot III	Drug: asparaginase Drug: cyclophosphamide Drug: cytarabine Drug: daunorubicin hydrochloride Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: ifosfamide Drug: mercaptopurine Drug: methotrexate Drug: prednisone Drug: thioguanine Drug: vincristine sulfate Drug: vindesine Radiation: radiation therapy
Experimental: Induction Prot I/Pred - reinduction 2x Prot III	Drug: asparaginase Drug: cyclophosphamide Drug: cytarabine Drug: daunorubicin hydrochloride Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: ifosfamide Drug: mercaptopurine Drug: methotrexate Drug: prednisone Drug: thioguanine Drug: vincristine sulfate Drug: vindesine Radiation: radiation therapy
Experimental: Induction Prot I/Dexa - reinduction 3 HR courses + 3x Prot III	Drug: 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 Radiation: radiation therapy
Experimental: Induction Prot I/Pred - reinduction 3 HR courses + 3x Prot III	Drug: 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 Radiation: radiation therapy
Experimental: Induction Prot I/Dexa - reinduction 6 HR courses + Prot II	Drug: 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 Radiation: radiation therapy
Active Comparator: Induction Prot I/Pred - reinduction 6 HR courses + Prot II	Drug: 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 Radiation: radiation therapy

Outcome Measures

Primary Outcome Measures

Efficacy of dexamethasone vs prednisone during the induction phase [End of Trial]
Event-free survival (EFS) and overall survival after initial remission in intermediate-risk and high-risk patients [End of Trial]
Safety and efficacy of treatment reduction during reintensification in standard-risk patients [End of Trial]
EFS after second delayed reintensification in intermediate-risk patients [End of Trial]
Outcome after extended reintensification therapy in high-risk patients [End of Trial]

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Krankenhaus Dornbirn	Dornbirn	Austria	A-6850
2	Landeskrankenhaus Feldkirch	Feldkirch-Tisis	Austria	A-6807
3	Universitaet Kinderklinik	Graz	Austria	8036
4	Innsbruck Universitaetsklinik	Innsbruck	Austria	A-6020
5	Landeskrankenhaus Klagenfurt	Klagenfurt	Austria	9026
6	LKH Leoben	Leoben	Austria	A-8700
7	A. oe. Krankenhaus der Barmherzigen Schwestern Kinderabteilung	Linz	Austria	4010
8	Landes-Kinderkrankenhaus	Linz	Austria	A-4020
9	St. Johanns-Spital	Salzburg	Austria	A-5020
10	St. Anna Children's Hospital	Vienna	Austria	A-1090
11	Kinderklinik - Universitaetsklinikum Aachen	Aachen	Germany	D-52074
12	Klinikum Augsburg	Augsburg	Germany	DOH-86156
13	Caritas-Krankenhaus Bad Mergentheim	Bad Mergentheim	Germany	D-97980
14	Klinikum Bayreuth	Bayreuth	Germany	D-95445
15	Helios Klinikum Berlin	Berlin	Germany	13125
16	Charite University Hospital - Campus Virchow Klinikum	Berlin	Germany	D-13353
17	Kinderklinik der Universitaet Bonn	Bonn	Germany	D-53113
18	Staedtisches Klinikum - Howedestrase	Braunschweig	Germany	38118
19	Klinikum Chemnitz gGmbH	Chemnitz	Germany	D-09116
20	Klinikum Coburg	Coburg	Germany	96450
21	Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl	Cologne	Germany	D-50735
22	Children's Hospital	Cologne	Germany	D-50924
23	Carl - Thiem - Klinkum Cottbus	Cottbus	Germany	D-03048
24	Vestische Kinderklinik Universitaetsklinik Witten/Herdecke	Datteln	Germany	45711
25	Klinikum Lippe - Detmold	Detmold	Germany	D-32756
26	Klinikum Dortmund	Dortmund	Germany	D-44137
27	Universitatsklinikum Carl Gustav Carus	Dresden	Germany	D-01307
28	Klinikum Duisburg	Duisburg	Germany	D-47055
29	Helios Klinikum Erfurt	Erfurt	Germany	99089
30	Universitaets - Kinderklinik	Erlangen	Germany	91054
31	Universitaetsklinikum Essen	Essen	Germany	D-45147
32	Klinikum der J.W. Goethe Universitaet	Frankfurt	Germany	D-60590
33	Universitaetskinderklinik - Universitaetsklinikum Freiburg	Freiburg	Germany	D-79106
34	Kinderklinik	Giessen	Germany	D-35385
35	Universitaetsklinikum Goettingen	Goettingen	Germany	D-37075
36	Universitaetsklinikum Halle	Halle	Germany	D-06097
37	Medizinische Hochschule Hannover	Hannover	Germany	D-30625
38	Universitaets-Kinderklinik Heidelberg	Heidelberg	Germany	D-69120
39	SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen	Heilbronn	Germany	D-74064
40	Gemeinschaftskrankenhaus	Herdecke	Germany	58313
41	Universitaetsklinikum des Saarlandes	Homburg	Germany	66421
42	Universitaets - Kinderklinik	Jena	Germany	D-07745
43	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe	Germany	76133
44	Klinikum Kassel	Kassel	Germany	D-34125
45	University Hospital Schleswig-Holstein - Kiel Campus	Kiel	Germany	D-24105
46	Klinikum Kemperhof Koblenz	Koblenz	Germany	D-56065
47	St. Annastift Krankenhaus	Ludwigshafen	Germany	67065
48	Universitaets - Kinderklinik - Luebeck	Luebeck	Germany	D-23538
49	Universitatsklinikum der MA	Magdeburg	Germany	39120
50	Staedtisches Klinik - Kinderklinik	Mannheim	Germany	D-68167
51	Universitaetsklinikum Giessen und Marburg GmbH - Marburg	Marburg	Germany	D-35043
52	Klinikum Minden	Minden	Germany	D-32423
53	Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster	Muenster	Germany	D-48149
54	Krankenhaus Muenchen Schwabing	Munich	Germany	80804
55	Kinderklinik Kohlhof	Neunkirchen	Germany	D-66539
56	Cnopf'sche Kinderklinik	Nuremberg	Germany	90419
57	Klinikum Oldenburg	Oldenburg	Germany	26133
58	Kinderklinik - Universitaetsklinikum Rostock	Rostock	Germany	D-18057
59	Saarbrucker Winterbergkliniken	Saarbrucken	Germany	66119
60	Klinikum Schwerin	Schwerin	Germany	D-19049
61	Kinderklink Siegen Deutsches Rotes Kreuz	Siegen	Germany	D-57072
62	Johanniter-Kinderklinik	St. Augustin	Germany	53757
63	Olgahospital	Stuttgart	Germany	D-70176
64	Krankenanstalt Mutterhaus der Borromaerinnen	Trier	Germany	D-54290
65	Universitaetsklinikum Tuebingen	Tuebingen	Germany	D-72076
66	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm	Germany	D-89075
67	St. Marienhospital - Vechta	Vechta	Germany	D-49377
68	Reinhard-Nieter-Krankenhaus	Wilhelmshaven	Germany	D-26389
69	Klinikum der Stadt Wolfsburg	Wolfsburg	Germany	D-38440
70	Universitaets - Kinderklinik Wuerzburg	Wuerzburg	Germany	D-97080
71	Kantonsspital Aarau	Aarau	Switzerland	CH-5001
72	Universitaets-Kinderspital beider Basel	Basel	Switzerland	CH-4005
73	Ospedale "la Carita", Locarno	Locarno	Switzerland	6600
74	Kinderspital Luzern	Lucerne 16	Switzerland	CH-6000
75	Ostschweizer Kinderspital	St. Gallen	Switzerland	CH-9006
76	University Children's Hospital	Zurich	Switzerland	CH-8032