AzTrials
AzTrials

LeukemiaPhase 3NCT01117441

International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia

A Phase 3 study testing PEG-L-asparaginase, cyclophosphamide and cytarabine in people with Leukemia, run by University Hospital Schleswig-Holstein at 139 sites in 7 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Rationale/Purpose: 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. Read more about this study

Who is it for?
Ages 1 year to 18 years
Conditions the study is for
Leukemia
What is being tested?
PEG-L-asparaginase, cyclophosphamide and cytarabine
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6,136 participants
Where
139 sitesin 7 countries
Study dates
Jun 2010to 31 Dec 2021
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • newly diagnosed acute lymphoblastic leukemia
  • age ≥ 1 year (> 365 days) and < 18 years old (up to 17 years old and 365 days)
  • no Ph+ (BCR/ABL or t(9;22)-positive) ALL
  • no evidence of pregnancy or lactation period
  • no participation in another clinical study
  • patient enrolled in a participating center
  • written informed consent

Who cannot join

  • pre-treatment with cytostatic drugs
  • pre-treatment with cytostatic drugs
  • steroid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis
  • treatment started according to another protocol
  • underlying diseases that prohibit treatment according to the protocol
  • ALL diagnosed as second malignancy steroid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis

Trial locations and contacts

139 sites in 7 countries.

139 sites in 7 countries

Italy55 sites

  • Centro Regionale Oncoematologia Pediatrica Ospedale dei Bambini "G. Salesi" Clinica Pediatrica

    Ancona, 60123

  • Dipartimento Biomedicina Età Evolutiva U.O Pediatrica I Policlinico

    Bari, 70124

  • U.O.C. Pediatria e Patologia Neonatale Ospedale San Martino

    Belluno, 32100

  • U.O. Pediatrica - OO.RR Bergamo

    Bergamo, 24100

  • Istituto Ortopedico Rizzoli Sez. di chemioterapia dei tumori dell'apparato locomotore

    Bologna, 40136

  • Oncologia ed Ematologia "Lalla Seràgnoli" Clinica Pediatrica Policlinico Sant'Orsola Malpighi

    Bologna, 40138

  • Pediatria Ospedale Regionale

    Bolzano, 39100

  • Clinica Pediatrica Oncoematologia pediatrica e TMO Ospedale dei Bambini

    Brescia, 25123

  • Istituto di Clinica Pediatrica Ospedale Regionale per le Microcitemie

    Cagliari, 09121

  • Divisione Ematologia - Oncologia Pediatrica Clinica Pediatrica

    Catania, 95123

  • Unità Operativa di Ematologia ed Oncologia Pediatrica Az. Osp. "Pugliese-Ciaccio"

    Catanzaro, 88100

  • Unità Operativa Pediatria Azienda Ospedaliera Annuziata

    Cosenza, 87100

  • Dipartimento di Medicina Clinica e Sperimentale Sezione di Pediatria Università di Ferrara

    Ferrara, 41100

  • Dipartimento A.I. Oncoematologia Pediatrica e Cure Domiciliari U.O. Oncoematologia Pediatrica Azienda Ospedaliero-Universitaria Meyer

    Florence, 50139

  • Dipartimento di Ematologia e Oncologia Pediatrica Instituto " G. Gaslini"

    Genova, 16148

  • Ospedale "Vito Fazzi" U.O. di Pediatria

    Lecce, 73100

  • Clinica Pediatrica II De Marchi

    Milan, 20122

  • Unità di Ricerca Clinica Pediatrica HSR TIGET - Istituto Scientifico San Raffaele

    Milan, 20132

  • Divisione di Oncologia Pediatrica Ist. Nazionale Studio e Cura Tumori

    Milan, 20133

  • Divisione Pediatria "Mariani" Ospedale "Niguarda Ca' Granda"

    Milan, 20162

  • U.O. di Ematologia, oncologia e trapianto Azienda Policlinico di Modena

    Modena, 41100

  • Clinica Pediatrica dell'Università Milano - Bicocca A.O. San Gerardo - Fondazione MBBM

    Monza, 20052

  • Dipartimento di Oncologia A.O. Santobono - Pausilipon

    Naples, 80123

  • A.O. "A. Cardarelli", U.O.S. Talassemia pediatrica ed emoglobinopatie pediatriche

    Naples, 80131

  • Servizio di Oncologia Pediatrica Dipartimento di Pediatria Seconda Università degli Studi di Napoli

    Naples, 80138

  • U.O.C. Pediatria - TIN, Ospedale "Umberto Primo" ASL SA - 1

    Nocera Inferiore, 84014

  • S.C.D.U. Azienda Ospedaliera "Maggiore della carità"

    Novara, 28100

  • Dipartimento di Pediatria Università di Padova Cattedra Di Oncoematologia Pediatrica

    Padova, 35128

  • Oncoematologia Pediatrica Ospedale dei Bambini G. di Cristina

    Palermo, 90134

  • U.O. di Pediatria e Oncoematologia Pediatrica Az. Osp. Di Parma Ospedali Riuniti

    Parma, 43100

  • Oncoematologia Pediatrica IRCCS, Policlinico San Matteo

    Pavia, 27100

  • S.C. di Oncoematologia Pediatrica con Trapianto di CSE, Ospedale "S.M. della Misericordia" A.O. Perugia

    Perugia, 06156

  • Ematologia, Ospedale di Muraglia

    Pesaro, 61100

  • U.O. Pediatrica Azienda Ospedaliera San Salvatore

    Pesaro, 61100

  • Dipartimento di Ematologia Ospedale Civile

    Pescara, 65123

  • Centro di Oncoematologia Pediatrica e Trapianto Midollo Osseo Azienda Ospedaliero Universitaria Pisana Ospedale S. Chiara

    Pisa, 56126

  • Centro Integrato di Emato-oncologia e dell'adolescenza A.O. S. Maria degli Angeli - Pordenone e IRCCS Centro di Riferimento Oncologico - Aviano

    Pordenone, 33170

  • Divisione Ematologia Ospedali Riuniti

    Reggio Calabria, 89100

  • U.O Pediatria Ospedale Infermi Azienda USL Rimini

    Rimini, 47900

  • Ospedale Sant'Eugenio clinica pediatrica Univ. Tor Vergata

    Roma, 00144

  • Oncoematologia pediatrica Università "La Sapienza" Roma

    Roma, 00161

  • Sezione Ematologia Dipart. di biotecnologie Cellulari ed Ematologia Università "La Sapienza"

    Roma, 00161

  • Divisione di Ematologia Pediatrica Ospedale "Bambin Gesù"Istituto di Ricerca Scientifica

    Roma, 00165

  • Divisione Oncologia Pediatrica Ospedale "Bambin Gesù"

    Roma, 00165

  • Divisione Oncologia Pediatrica Università Cattolica di Roma

    Roma, 00168

  • U.O. Oncoematologia Pediatrica Ospedale "Casa Sollievo della Sofferenza"

    San Giovanni Rotondo, 71013

  • Clinica Pediatrica Università

    Sassari, 07100

  • Dipartimento di Pediatria Ostetricia e Medicina della Riproduzione Università degli Studi di Siena

    Siena, 53100

  • Ospedale Infantile Regina Margherita

    Torino, 10126

  • Unità Operativa di Pediatria - U.T.I.N. Az.Osp. "Card. G. Panico"

    Tricase, 73039

  • U.O. Emato-Oncologia Pediatrica Università degli studi di Trieste Ospedale Infantile Burlo Garofolo

    Trieste, 34137

  • SOS Oncologia Pediatrica Policlinico Universitario

    Udine, 33100

  • Clinica Pediatrica Università degli Studi dell'Insubria di Varese Ospedale "Filippo del Ponte"

    Varese, 21100

  • U.O.C Oncoematologia Pediatrica Policlinico "G.B: Rossi"

    Verona, 37134

  • Ospedale San Bortolo, U.O. di Pediatria e patologia Neonatale

    Vicenza, 36100

Other trials in Italy

Germany52 sites

  • Kinderklinik der med. Fakultät der RWTH, Bereich Hämatologie/Onkologie

    Aachen, 52074

  • I. Klinik für Kinder u. Jugendliche, Klinikum Augsburg, Hämatologie/ Onkologie

    Augsburg, 86156

  • Klinikum Bayreuth, Kinderklinik

    Bayreuth, 95445

  • Klinikum Berlin-Buch II. Kinderklinik, Bereich Onkologie/Allg. Pädiatrie

    Berlin, 13125

  • Kinderklinik der Charité, Campus Virchow Klinikum (CVK), Abt.: Kinderhämatologie

    Berlin, 13353

  • Städtisches Krankenhaus, Kinderklinik

    Braunschweig, 38118

  • Klinikum Chemnitz gGmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie / Onkologie

    Chemnitz, 09009

  • Kliniken der Stadt Köln GmbH, Kinderkrankenhaus Riehl

    Cologne, 50735

  • Med. Einrichtungen der Universität zu Köln, Klinik für Allg. Kinderheilkunde, Onkologisch-hämatologische Station

    Cologne, 50937

  • Carl-Thiem-Klinikum, Kinderklinik, Abt. Hämatologie/Onkologie

    Cottbus, 03048

  • Vestische Kinder- u. Jugendklinik, Universitätsklinik Witten/Herdecke

    Datteln, 45711

  • Klinikum Lippe-Detmold, Kinder- und Jugendmedizin

    Detmold, 32756

  • Klinikum Dortmund, Klinik f. Kinder- und Jugendmedizin

    Dortmund, 44137

  • Uni.Klinik Carl Gustav Carus, Klinik f. Kinderheilkunde

    Dresden, 01307

  • Universitätskinderklinik

    Düsseldorf, 40225

  • Helios Klinikum Erfurt GmbH, Klinik für Kinderheilkunde

    Erfurt, 99089

  • Universitätsklinikum Erlangen, Kinder- und Jugendmedizin, Abt. für Onkologie/ Hämatologie/Immunologie

    Erlangen, 91054

  • Universitätsklinikum Essen, Kinderklinik, Hämatologie/Onkologie

    Essen, 45122

  • Universitäts-Kinderklinik, Klinik für Kinderheilkunde III, Pädiatrische Hämatologie/Onkologie

    Frankfurt, 60590

  • Universitäts-Kinderklinik, Haematologie/ Onkologie

    Freiburg im Breisgau, 79106

  • Klinikum der Justus-Liebig-Universität, Zentrum für Kinderheilkunde, Abt. Hämatologie/Onkologie

    Giessen, 35385

  • Universitäts-Kinderklinik Päd. I, Hämatologie/Onkologie

    Göttingen, 37099

  • Klinik und Poliklinik für Kinder und Jugendmedizin, Allgemeine Pädiatrie mit Poliklinik/Pädiatrische Onkologie und Hämatologie

    Greifswald, 17475

  • Uniklinikum d. Martin Luther Universität, Halle Wittenberg, Univ.-und Poliklinik für Kinder- und Jugendmedizin

    Halle, 06120

  • Medizinische Hochschule Hannover, Zentrum Kinderheilkunde u. Jugendmedizin

    Hanover, 30625

  • Universitäts-Kinderklinik, Päd. Onkologie, Hämatologie, und Immunologie

    Heidelberg, 69120

  • Klinikum Heilbronn GmbH, Klinik für Kinderheilkunde und Jugendmedizin/Perinatalzentrum

    Heilbronn, 74078

  • Gemeinschaftskrankenhaus Herdecke, Kinderabteilung

    Herdecke, 58313

  • Universitätsklinik für, Kinder- und Jugendmedizin, Päd. Hämatologie/ Onkologie

    Homburg / Saar, 66421

  • Klinikum, der Friedrich-Schiller-Universität, Klinik für Kinder- und Jugendmedizin

    Jena, 7740

  • Städtisches Klinikum Karlsruhe, Kinderklinik

    Karlsruhe, 76133

  • Klinikum Kassel, Kinderklinik

    Kassel, 34125

  • Klinik für Allgemeine Paediatrie, Univ.-Klinikum Schleswig-Holstein, Campus Kiel

    Kiel, 24105

  • Städtisches Krankenhaus Kemperhof, Kinderklinik

    Koblenz, 56073

  • Department für Frauen- und Kindermedizin, Abteilung für Pädiatrische Onkologie, Hämatologie und Hämostaseologie

    Leipzig, 04103

  • Universität zu Lübeck, Klinik für Kinder- u. Jugendmedizin, Abt. Hämatologie/ Onkologie/Immunologie

    Lübeck, 23538

  • Universitätsklinikum Magdeburg, Klinik für Päd. Hämatologie/Onkologie

    Magdeburg, 39120

  • Klinikum Mannheim gGmbH, Kinderklinik, Abt. Hämatologie/Onkologie

    Mannheim, 68167

  • Johannes Wesling Klinikum Minden

    Minden, 32429

  • Städt. Krankenhaus München GmbH, Krankenhaus München-Schwabingen, Kinderklinik d. TU

    München, 80804

  • Universitäts-Kinderklinik, Päd. Hämatologie und Onkologie

    Münster, 48149

  • Cnopf'sche Kinderklinik, Onkologie

    Nuremberg, 90419

  • Klinikum Oldenburg gGmbH, Zentrum für Kinder- u. Jugendmedizin, (Elisabeth Kinderkrankenhaus)

    Oldenburg, 26133

  • Universitäts-Kinderklinik

    Rostock, 18055

  • Asklepios-Klinik, Sankt Augustin GmbH

    Sankt Augustin, 53757

  • HELIOS Kliniken Schwerin, Klinik f. Kinder-u. Jugendmedizin

    Schwerin, 19049

  • Olga-Hospital, Kinderklinik, Pädiatrisches Zentrum, Abt. Hämatologie/Onkologie

    Stuttgart, 70176

  • Krankenanstalt Trier, Mutterhaus der Borromaeerinnen, Pädiatrische Abteilung

    Trier, 54290

  • Universitäts-Kinderklinik, Abt. Kinderheilkunde II, Hämatologie/Onkologie

    Tübingen, 72076

  • Universitäts-Kinderklinik

    Ulm, 89075

  • Stadtkrankenhaus, Kinderklinik

    Wolfsburg, 38440

  • Universitäts-Kinderklinik

    Würzburg, 97080

Other trials in Germany

Austria8 sites

  • Krankenhaus Dornbirn, Abt. für Kinder- und Jugendheilkunde

    Dornbirn, 6850

  • Univ.-Kinderklinik Graz, Abt. Pädiatrische Hämato-Onkologie

    Graz, 8036

  • Department f. Kinder- u. Jugendheilkunde, Universitätsklinik f. Pädiatrie II

    Innsbruck, 6020

  • A.oe. Landeskrankenhaus Klagenfurt, Abt. für Kinder- und Jugendheilkunde

    Klagenfurt, 9026

  • A.oe. Landeskrankenhaus Leoben, Abt. für Kinder und Jugendliche

    Leoben, 8700

  • Landes-Kinderklinik Linz, Haematologie/Onkologie

    Linz, 4020

  • St. Johanns Spital / Landeskrankenhaus, Salzburg, Kinderspital Abt. Kinder u. Jugendheilkunde

    Salzburg, 5020

  • St. Anna Kinderspital, Zentrum für Kinder- und Jugendheilkunde

    Vienna, 1090

Other trials in Austria

Czechia8 sites

  • University Hospital Brno, Department of Pediatric Oncology

    Brno, 662 63

  • Regional Hospital České Budějovice, Department of Pediatrics

    České Budějovice, 370 01

  • University Hospital Hradec Králové, Department of Pediatrics

    Hradec Králové, 500 12

  • University Hospital Olomouc, Department of Pediatrics

    Olomouc, 770 00

  • Teaching Hospital Ostrava-Poruba, Department of Pediatrics

    Ostrava-Poruba, 708 52

  • University Hospital Plzeň, Department of Pediatrics

    Pilsen, 304 60

  • University Hospital Motol, Department of Pediatric Hematology and Oncology

    Prague, 150 06

  • Masaryk´s Hospital Ústí nad Labem, Department of Pediatrics

    Ústí nad Labem, 401 13

Other trials in Czechia

Israel8 sites

  • HaEmek Medical Center

    Afula, 18101

  • Soroka Medical Center

    Beersheba, 84101

  • Rambam Medical Center

    Haifa, 31096

  • Bnai-Zion Medical Center

    Haifa, 33394

  • Hadassah University Medical Center

    Jerusalem, 91120

  • Schneider Children Medical Center of Israel

    Petah Tikva, 49202

  • Dana children hospital

    Tel Aviv, 64239

  • Sheba Medical Center

    Tel HaShomer

Other trials in Israel

Switzerland6 sites

  • Kinderklinik, Hämatologie/Onkologie

    Aarau, 5000

  • Baseler Kinderspital, Hämatologische Poliklinik

    Basel, 4005

  • Repartio di Pediatria

    Bellinzona, 6500

  • Pädiatrische Klinik, Kinderspital Luzern, Kinderonkologie

    Lucerne, 6000

  • Hämatologie/Onkologie, Ostschweizer Kinderspital, FMH Pädiatrie, Hämatologie

    Sankt Gallen, 9006

  • Kinderspital Zürich, Universitäts-Kinderklinik

    Zurich, 8032

Other trials in Switzerland

Australia2 sites

  • The Sydney Children's Hospital, Centre for Children's Cancer and Blood Disorders

    Randwick, NSW 2031

  • The Children's Hospital at Westmead, Department of Oncology

    Westmead, NSW 2145

Other trials in Australia

About this study

Rationale/Purpose: 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 (ALL).

This trial is studying several different combination chemotherapy regimens to compare how well they work in treating young patients with ALL.

Read more

Study objectives

Primary study questions:

  • Non high-risk (non-HR) precursor-B ALL (pB-ALL) patients with TEL/AML1-negative ALL or unknown TEL/AML1 status and flow cytometry minimal residual disease (MRD) in bone marrow on day 15 <0.1% or with TEL/AML1-positive ALL (randomized study question R1): Can the daunorubicin dose in Protocol IA be safely reduced by 50 % with a non-inferior EFS and a reduction of toxicity (treatment-related mortality and AE/SAE in Protocol I)?
  • Patients with pB-ALL and risk group medium risk (MR) (randomized study question R2): Can the clinical outcome be improved by protracted asparagine depletion achieved through application of intensified PEG-L-asparaginase during reintensification and early maintenance?
  • High-risk (HR) patients (as identified by day 33 - randomized study question RHR): Can the clinical outcome be improved by protracted exposure to PEG-L-asparaginase during Protocol IB?

Secondary study questions:

  • Standard risk (SR) patients identified by at least one sensitive marker: Is the clinical outcome comparable to that obtained in SR patients (identified with two sensitive markers) in AIEOP-BFM ALL 2000, or can the outcome even be improved with the use of PEG-L-asparaginase instead of native E. coli L-ASP?
  • T-ALL non-HR patients: Can the high level of outcome which was obtained for these patients in study AIEOP-BFM ALL 2000 be preserved or even improved with the use of PEG-L-ASP instead of native E. coli L-ASP?
  • HR patients with persisting high MRD levels despite the use of the HR blocks in the intensified consolidation phase "MRD Non-Responders": Is it possible to improve the outcome and to achieve a further reduction of leukemic cell burden by administration of an innovative treatment schedule (DNX-FLA)?
  • Patients participating in the randomized asparaginase studies (pB-ALL/MR, HR): Are asparaginase activity and asparaginase antibodies associated with development of allergic reactions, and do they have an effect on the outcome of the patients?
  • What is the relative value of different methods of MRD monitoring in the definition of alternative stratification systems within a BFM-oriented protocol?
Read the detailed description

Risk Stratification

  • T/non-HR: T-ALL in absence of any HR criteria (see below)
  • pB/non-HR: pB-ALL in absence of any HR criteria (see below).
  • SR (polymerase chain reaction(PCR)-MRD-SR (MRD-negative on day 33 and 78) or, if no PCR-MRD result available, FCM d15 < 0.1%)
  • MR (no SR)
  • HR: Prednisone poor-response (≥1000 blast cells/µl in peripheral blood on day 8), blast cells ≥10% in bone marrow on day 15 as measured by FCM, non-remission on day 33, positivity for MLL/AF4 or t(4;11), hypodiploidy (< 45 chromosomes), PCR-MRD-HR (MRD ≥10E-3 on day 78) or PCR-MRD-MR SER (only in pB-ALL, MRD ≥ 10-3 on day 33 and MRD positive at a level of < 10E-3 on day 78)

Chemotherapy

According to the risk group, patients receive the following chemotherapy elements:

T/non-HR: Protocol I, Protocol M, Protocol II and Maintenance pB/non-HR: Protocol I, Protocol M, Protocol II and Maintenance HR: Protocol I, HR-1', HR-2', HR-3', 3x Protocol III, Maintenance Patients of the HR group with PCR-MRD ≥10E-3 after element HR-3' are eligible for treatment with element DNX-FLA.

Protocol I Cytoreductive prephase: Prednisone (PDN) on days 1-7 and one dose of methotrexate (MTX) intrathecal (IT) on day 1 Protocol IA: Prednisone (PDN) on days 8 to 28 (21 days); vincristine (VCR) on days 8, 15, 22, 29 (4 doses); daunorubicin (DNR) on days 8, 15, 22 and 29 (4 doses); pegylated L-asparaginase (PEG-L-ASP) on days 12 and 26; MTX IT on days 12 and 33 and in case of blast cells in cerebrospinal fluid at diagnosis additional IT MTX is given on days 19 and 26.

Protocol IA': Only two doses of DNR on days 8 and 15 given to patients eligible for randomization R1 and randomized into the experimental arm Protocol IA-CPM: additional cyclophosphamide (CPM) on day 10 only in T-ALL patients with prednisone poor-response Protocol IA-Dexa (IAD): Dexamethasone (DXM) instead of PDN is given to all patients with T-ALL without any high-risk criteria as identified by day 8.

Protocol IB: CPM on days 36 and 64; cytarabine (ARA-C) on days 38-41, 45-48, 52-55 and 59-62; 6-mercaptopurine (6-MP) on days 36 to 63 (28 days); MTX IT on day 45 and 59 Protocol IB-ASP+: additional PEG-L-ASP on days 40, 47, 54, and 61 (4 doses) are given to the patients eligible for randomization RHR and randomized into the experimental arm.

Protocol M 6-MP on days 1- 56, high-dose MTX (HD-MTX) on days 8, 22, 36, 50 and MTX IT on days 8, 22, 36 and 50 Protocol II Protocol IIA: DXM on days 1 to 21 (21 days); VCR on days 8, 15, 22, 29 (4 doses); doxorubicine (DOX) on days 8, 15, 22 and 29 (4 doses); PEG-L-ASP on day 8 (1 dose); MTX IT on days 1 and 18 only in patients with initial CNS involvement.

Protocol IIA-ASP+: additional PEG-L-ASP on day 22 for patients eligible for randomization R2 and randomized into the experimental arm.

Protocol IIB: CPM on day 36; ARA-C on days 38-41 and 45-48; thioguanine (TG) on days 36 to 49 (14 days) and MTX IT on days 38 and 45.

Protocol IIB-ASP+: additional PEG-L-ASP on days 36 and 50 for eligible for randomization R2 and randomized into the experimental arm.

Protocol III DXM on days 1-15; VCR on days 1 and 8; DOX on days 1 and 8; PEG-L-ASP on day 1; CPM on day 15; ARA-C on days 17-20 and 24-27; TG on days 15 - 28 and MTX IT on days 17 and 24, also on day 1 in patients with initial CNS involvement HR-1' DXM on days 1-5; VCR on days 1 and 6; HD-MTX on day 1; CPM every 12 hours on days 2-4 (5 doses); HD-ARA-C every 12 hours on day 5 (2 doses); PEG-L-ASP on day 6, MTX IT on day 1 HR-2' DXM on days 1 to 5; VDS on days 1 and 6; HD-MTX on day 1; IFO every 12 hours on days 2-4 (5 doses); DNR on day 5; PEG-L-ASP on day 6; MTX IT on day 1 and 1 in patients with initial CNS involvement also day 5 HR-3' DXM on days 1-5; ARA-C 4 x on days 1-2 in 12 h intervals; etoposide (VP-16) every 12 hours on days 3-5 (5 doses); PEG-L-ASP on day 6; MTX IT on day 1 DNX-FLA Flucytosine (FLU) on days 1-5 (5 doses); HD-ARA-C on days 1 to 5 (5 doses); liposomal daunorubicin (DNX) on days 1, 3 and 5 (3 doses); MTX IT on day 1

Interim/Maintenance (until week 104):

6-MP p.o. daily; MTX p.o. once a week, doses adjusted to white blood cell count; PEG-L-ASP: every second week (6 doses), only for patients eligible for randomization R2 and randomized into the experimental arm; MTX IT every 6 weeks up to a total of 6 doses for the following subgroups (all CNS-negative):

  • T-ALL (HR or non-HR) with < 2 years of age at start of maintenance,
  • T-ALL, non-HR and initial WBC < 100 000/μl
  • pB-ALL with PPR and/or FCM-MRD day 15 ≥ 10 % and/or PCR-MRDMR SER as only HR criteria

Radiotherapy Patients without CNS involvement and

  • T-ALL/non-HR, WBC ≥ 100 000/μl, and age ≥ 2 years at start of pCRT or
  • with risk group HR and age ≥ 2 years at start of pCRT except pB-ALL with PPR and/or FCM-MRD day 15 ≥ 10 % and/or PCR-MRD-MR SER as only HR criteria receive preventive cranial radiotherapy with 12 Gy

Patients with CNS involvement receive therapeutic cranial radiotherapy with 18 Gy (age 1 to <2 years 12 Gy).

Conditions
Leukemia
Being tested
PEG-L-asparaginase, cyclophosphamide, cytarabine, daunorubicin hydrochloride, dexamethasone
Medical subject headings
Leukemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PEG-L-asparaginaseDrug

    Also called Oncaspar medac

    see detailed protocol description

  • cyclophosphamideDrug

    see detailed protocol description

  • cytarabineDrug

    see detailed protocol description

  • daunorubicin hydrochlorideDrug

    see detailed protocol description

  • dexamethasoneDrug

    see detailed protocol description

  • doxorubicin hydrochlorideDrug

    see detailed protocol description

  • etoposideDrug

    see detailed protocol description

  • ifosfamideDrug

    see detailed protocol description

  • mercaptopurineDrug

    see detailed protocol description

  • methotrexateDrug

    see detailed protocol description

  • prednisoneDrug

    see detailed protocol description

  • thioguanineDrug

    see detailed protocol description

  • vincristine sulfateDrug

    see detailed protocol description

  • vindesineDrug

    see detailed protocol description

  • daunoxomeDrug

    see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment

  • fludarabineDrug

    see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment

  • Radiation TherapyRadiation

    for eligibility for radiotherapy see detailed protocol description

Study groups in NCT01117441
Study groupRoleWhat they receive
R1 control armActive comparatorsee detailed protocol description
Receives: Drug: PEG-L-asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: mercaptopurine; Drug: methotrexate; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Radiation: Radiation Therapy
R1 experimental armExperimentalsee detailed protocol description
Receives: Drug: PEG-L-asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: mercaptopurine; Drug: methotrexate; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Radiation: Radiation Therapy
R2 control armActive comparatorsee detailed protocol description
Receives: Drug: PEG-L-asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: mercaptopurine; Drug: methotrexate; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Radiation: Radiation Therapy
R2 experimental armExperimentalsee detailed protocol description
Receives: Drug: PEG-L-asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: mercaptopurine; Drug: methotrexate; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Radiation: Radiation Therapy
R-HR control armActive comparatorsee detailed protocol description
Receives: Drug: PEG-L-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: daunoxome; Drug: fludarabine; Radiation: Radiation Therapy
R-HR experimental armExperimentalsee detailed protocol description
Receives: Drug: PEG-L-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: daunoxome; Drug: fludarabine; Radiation: Radiation Therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Event-free survival

    • Randomization R1: Event-free survival from time of randomization
    • Historical comparison non-HR T-ALL: Event-free survival from diagnosis
    • Historical comparison "MRD Non-Responders": Event-free survival from start of DNX-FLA (morphological non-response after HR-3' is no event for this study question)

    Measured: 10 years from the start of recruitment

  2. Disease-free survival

    • Randomization R2: Disease-free survival from time of randomization
    • Historical comparison SR: Disease-free survival from start of Protocol M

    Measured: 10 years from the start of recruitment

  3. minimal residual disease (MRD)

    Randomization RHR: rate of MRD highly positive patients (MRD ≥ 10-3) at TP2 (week 12)

    Measured: week 12 of treatment

Secondary outcomes (5)

  1. survival

    All randomized and historical comparisons: Survival

    Measured: 10 years from the start of recruitment

  2. treatment-related mortality

    All randomized and historical comparisons: treatment-related mortality in induction or CCR (overall and by chemotherapy/SCT)

    Measured: up to 25 months from the diagnosis

  3. adverse events

    All randomized and historical comparisons: incidence and frequency of adverse events of interest and serious adverse events

    Measured: up to 25 months from the diagnosis

  4. event-free survival

    Randomization R-HR: Event-free survival from time of randomization

    Measured: 10 years from the start of recruitment

  5. minimal residual disease

    "MRD Non-Responders": MRD levels after DNX-FLA

    Measured: after 24 weeks of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 May 2010 (estimated)
  2. Study startJun 2010
  3. Primary completion31 Dec 2021
  4. Study completion31 Dec 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Factorial
Masking
None (open label)
Enrolment
6,136 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01117441
Sponsor's protocol ID
AIEOP-BFM ALL 2009
Status last verified
May 2022
First submitted
3 May 2010
Last updated
24 May 2022
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 20154213

  • Flohr T, Schrauder A, Cazzaniga G, Panzer-Grumayer R, van der Velden V, Fischer S, Stanulla M, Basso G, Niggli FK, Schafer BW, Sutton R, Koehler R, Zimmermann M, Valsecchi MG, Gadner H, Masera G, Schrappe M, van Dongen JJ, Biondi A, Bartram CR; International BFM Study Group (I-BFM-SG). Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia. 2008 Apr;22(4):771-82. doi: 10.1038/leu.2008.5. Epub 2008 Jan 31.

    PubMed 18239620

  • Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, Ludwig WD, Ritter J, Harbott J, Mann G, Klingebiel T, Zintl F, Niemeyer C, Kremens B, Niggli F, Niethammer D, Welte K, Stanulla M, Odenwald E, Riehm H, Schrappe M. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010 Feb;24(2):265-84. doi: 10.1038/leu.2009.257. Epub 2009 Dec 10.

    PubMed 20010625

  • Gottschalk H, Moricke A, Conter V, Schrappe M, Stary J, Cario G, Dworzak M, Attarbaschi A, Barbaric D, Locatelli F, Bodmer N, Elitzur S, Silvestri D, Dalla-Pozza L, Bergmann AK, Flotho C, Buldini B, Stanulla M, Izraeli S, Rizzari C, Bourquin JP, Biondi A, Valsecchi MG, Zimmermann M. Reducing Daunorubicin in Induction Therapy in Children With B-Lineage ALL With Favorable Prognosis: Results of Phase III Trial AIEOP-BFM ALL 2009. J Clin Oncol. 2025 Dec 10;43(35):3739-3749. doi: 10.1200/JCO-25-01357. Epub 2025 Nov 10.

    PubMed 41213101

  • Conter V, Valsecchi MG, Cario G, Zimmermann M, Attarbaschi A, Stary J, Niggli F, Dalla Pozza L, Elitzur S, Silvestri D, Locatelli F, Moricke A, Engstler G, Smisek P, Bodmer N, Barbaric D, Izraeli S, Rizzari C, Boos J, Buldini B, Zucchetti M, von Stackelberg A, Matteo C, Lehrnbecher T, Lanvers-Kaminsky C, Cazzaniga G, Gruhn B, Biondi A, Schrappe M. Four Additional Doses of PEG-L-Asparaginase During the Consolidation Phase in the AIEOP-BFM ALL 2009 Protocol Do Not Improve Outcome and Increase Toxicity in High-Risk ALL: Results of a Randomized Study. J Clin Oncol. 2024 Mar 10;42(8):915-926. doi: 10.1200/JCO.23.01388. Epub 2023 Dec 14.

    PubMed 38096462

  • 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.

    PubMed 37021527

  • Wurthwein G, Lanvers-Kaminsky C, Siebel C, Gerss J, Moricke A, Zimmermann M, Stary J, Smisek P, Schrappe M, Rizzari C, Zucchetti M, Hempel G, Wicha SG, Boos J; AIEOP-BFM ALL 2009 Asparaginase Working Party. Population Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia: Treatment Phase Dependency and Predictivity in Case of Missing Data. Eur J Drug Metab Pharmacokinet. 2021 Mar;46(2):289-300. doi: 10.1007/s13318-021-00670-8. Epub 2021 Feb 17.

    PubMed 33595793

  • Tasian SK, Peters C. Targeted therapy or transplantation for paediatric ABL-class Ph-like acute lymphocytic leukaemia? Lancet Haematol. 2020 Dec;7(12):e858-e859. doi: 10.1016/S2352-3026(20)30369-0. No abstract available.

    PubMed 33242441

  • 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.

    PubMed 31601692

  • Kroll M, Kaupat-Bleckmann K, Morickel A, Altenl J, Schewel DM, Stanullal M, Zimmermann M, Schrappe M, Cario G. Methotrexate-associated toxicity in children with Down syndrome and acute lymphoblastic leukemia during consolidation therapy with high dose methotrexate according to ALL-BFM treatment regimen. Haematologica. 2020 Apr;105(4):1013-1020. doi: 10.3324/haematol.2019.224774. Epub 2019 Aug 1.

    PubMed 31371414

  • Wurthwein G, Lanvers-Kaminsky C, Hempel G, Gastine S, Moricke A, Schrappe M, Karlsson MO, Boos J. Population Pharmacokinetics to Model the Time-Varying Clearance of the PEGylated Asparaginase Oncaspar(R) in Children with Acute Lymphoblastic Leukemia. Eur J Drug Metab Pharmacokinet. 2017 Dec;42(6):955-963. doi: 10.1007/s13318-017-0410-5.

    PubMed 28349335

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing PEG-L-asparaginase, cyclophosphamide and cytarabine in people with Leukemia, run by University Hospital Schleswig-Holstein at 139 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 139 sites in Italy, Germany, Austria, Czechia, Israel and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Event-free survival (time frame: 10 years from the start of recruitment). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01117441, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 May 2022.

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