LeukemiaPhase 3NCT00003728
Combination Chemotherapy Plus Steroid Therapy in Treating Children With Acute Lymphoblastic Leukemia or Lymphoblastic Non-Hodgkin's Lymphoma
A Phase 3 study testing asparaginase, cyclophosphamide and cytarabine in people with Leukemia and Lymphoma, run by European Organisation for Research and Treatment of Cancer - EORTC at 23 sites in 3 countries.
Trial summary
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which regimen of combination chemotherapy plus steroid therapy is more effective for acute lymphoblastic leukemia or… Read more about this study
- Who is it for?
- Ages Up to 17 years
- What is being tested?
- asparaginase, cyclophosphamide and cytarabine
- Type of treatment
- Surgery or procedure
- How many people
- 1,500 participants
- Where
- 23 sitesin 3 countries
- Study dates
- Dec 1998to May 2008
- 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 Up to 17 years
- All sexes
- No healthy volunteers
- Child
DISEASE CHARACTERISTICS:
- Histologically confirmed acute lymphoblastic leukemia (ALL) of FAB L1 or L2 morphology
- Positive SIg allowed OR
- Histologically confirmed precursor B or precursor T lymphoblastic non-Hodgkin's lymphoma (NHL)
- No diffuse large cell B-cell lymphoma, Burkitt's lymphoma, or high-grade B-cell lymphoma (Burkitt-like)
- Very low-risk (VLR) patients meeting 1 of the following criteria:
- ALL of B-cell lineage
- WBC less than 10,000/mm^3
- Must meet 1 of the following conditions:
- DNA index greater than 1.16 and less than 1.50 and chromosome number 51-66 or unknown
- DNA index not assessed and chromosome number 51-66
- DNA index greater than 1.16 and less than 1.50 and chromosome number is unknown
- Good response to prephase therapy
- Absence of t(9;22) or BCR/ABL, t(4;11)/MLL-AF4, or 11q23/MLL rearrangement
- No acute undifferentiated leukemia (AUL)
- No CNS or gonadal involvement
- Precursor B-lymphoblastic NHL stage I or II OR
- Average risk (AR) patients:
- Must meet 1 of the following criteria:
- ALL with good response to prephase therapy who are neither VLR or very high risk (VHR)
- VLR ALL with CNS involvement (CSF positive or negative)
- Precursor B-lymphoblastic NHL stage III or IV without any VHR feature
- Precursor T-lymphoblastic NHL
- AR patients substratified in:
- AR1: B-cell lineage ALL with WBC less than 100,000/mm^3
- Surreptitious or hemorrhagic CSF becoming negative at D4 of prephase therapy
- Precursor B-lymphoblastic NHL stage III or IV
- Precursor T-lymphoblastic NHL stage I or II
- AR2: B-cell lineage ALL with WBC at least 100,000/mm^3
- T-cell lineage ALL regardless of the WBC
- Overt or non-equivocal CNS involvement at D0 or any CSF involvement at D4
- Gonadal involvement
- Precursor T-lymphoblastic NHL stage III or IV
- Newborn Down syndrome patients with AR2 features are assigned to the AR1 group OR
- VHR patients:
- Must meet 1 of the following criteria:
- ALL patients meeting 1 of the following conditions:
- Poor response to prephase therapy (at least 1,000/mm^3 blasts in peripheral blood after completion of prephase therapy)
- t(9;22) or BCR/ABL
- t(4;11)/MLL-AF4 = 11q23/MLL rearrangement
- Near haploidy (no more than 34 chromosomes or DNA index less than 0.7)
- Hypodiploid (35-40 chromosomes or DNA index 0.7 to 0.8)
- AUL
- For B lineage ALL: failure to achieve complete response (CR) after completion of protocol IA
- For T lineage ALL: failure to achieve CR or good partial response (GPR) after completion of protocol IA
- Minimal-residual disease (greater than 1,000 blasts/100,000 mononuclear bone marrow cells) at evaluation of IA (day 35)
- NHL patients who failed to achieve CR or GPR after completion of protocol IA
- All VHR patients are eligible for stem cell transplantation except those whose sole VHR criterion is a poor response to prephase therapy and who have none of the following features:
- T-cell immunophenotype
- Early B ALL (CD10 negative)
- WBC at least 100,000/mm^3
- Newborn Down syndrome patients with VHR features are assigned to AR1 group NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.
PATIENT CHARACTERISTICS:
Age:
- Under 18
Performance status:
- Not specified
Life expectancy:
- Not specified
Hematopoietic:
- See Disease Characteristics
Hepatic:
- Not specified
Renal:
- Not specified
PRIOR CONCURRENT THERAPY:
Biologic therapy:
- See Disease Characteristics
Chemotherapy:
- Not specified
Endocrine therapy:
- Not specified
Radiotherapy:
- Not specified
Surgery:
- Not specified
Other:
- No prior therapy
Trial locations and contacts
23 sites in 3 countries.
23 sites in 3 countries
France13 sites
Centre Hospitalier Regional et Universitaire d'Angers
Angers, 49033
CHR de Besancon - Hopital Saint-Jacques
Besançon, 25030
CHU de Caen
Caen, 14033
CHU de Grenoble - Hopital de la Tronche
Grenoble, 38043
Hopital Debrousse
Lyon, 69322
Hopital Arnaud de Villeneuve
Montpellier, 34059
CHR Hotel Dieu
Nantes, 44035
Hopital de l'Archet CHU de Nice
Nice, F-06202
CHU - Hopital Robert Debre
Paris, 75019
Hopital Jean Bernard
Poitiers, 86021
Hopital Americain
Reims, 51092
Hopital Universitaire Hautepierre
Strasbourg, 67098
Hopital des Enfants
Toulouse, 31026
Belgium8 sites
Ziekenhuis Netwerk Antwerpen Middelheim
Antwerp, 2020
Hopital Universitaire Des Enfants Reine Fabiola
Brussels, 1020
Academisch Ziekenhuis der Vrije Universiteit Brussel
Brussels, 1090
Ghent University
Ghent, B-9000
Universitair Ziekenhuis Gent
Ghent, B-9000
U.Z. Gasthuisberg
Leuven, B-3000
Centre Hospitalier Regional de la Citadelle
Liège, 4000
Clinique de l'Esperance
Montegnée, 4420
Portugal2 sites
Hospital Escolar San Joao
Porto, 4200
Instituto Portugues de Oncologia Centro do Porto, SA
Porto, 4200
About this study
Official title: The Value of Dexamethasone Versus Prednisolone During Induction and Maintenance Therapy of Prolonged Versus Conventional Duration of L-Asparaginase Therapy During Consolidation and Late Intensification, and of Corticosteroid + VCR Pulses During Maintenance in Acute Lymphoblastic Leukemia and Lymphoblastic Non-Hodgkin Lymphoma of Childhood
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which regimen of combination chemotherapy plus steroid therapy is more effective for acute lymphoblastic leukemia or lymphoblastic non-Hodgkin's lymphoma.
PURPOSE: Randomized phase III trial to compare the effectiveness of different regimens of combination chemotherapy plus steroid therapy in treating children who have acute lymphoblastic leukemia or lymphoblastic non-Hodgkin's lymphoma.
Read the detailed description
OBJECTIVES:
- Compare the value of dexamethasone (DM) vs prednisolone (PRDL) administered during induction therapy, in terms of event-free and overall survival, in children with acute lymphoblastic leukemia (ALL) or lymphoblastic non-Hodgkin's lymphoma (LNHL).
- Assess the value of increasing the number of administrations of asparaginase during consolidation and late intensification therapy, in terms of disease-free and overall survival, in children without very high-risk (VHR) features.
- Compare the response rate in children treated with prephase therapy comprising DM vs PRDL and intrathecal methotrexate.
- Compare the incidence and grade of toxic effects of these treatment regimens in these children.
- Compare the long-term effects of these treatment regimens on growth and pubertal development, neurocognitive, cardiac, and endocrine function, and incidence of aseptic bone necrosis in these children.
- Evaluate the proportion of children with VHR disease when defined according to extended VHR criteria, and assess the prognostic importance of the new VHR features (cytogenetics and minimal-residual disease).
- Compare the feasibility of the VHR chemotherapy protocol in patients treated with DM vs PRDL.
OUTLINE: This is a randomized, multicenter study. Patients are stratified for prephase therapy according to center, disease (acute lymphoblastic leukemia [ALL] vs non-Hodgkin's lymphoma [NHL]), WBC for ALL patients (less than 10,000/mm^3 vs 10,000/mm^3 to less than 100,000/mm^3 vs greater than 100,000/mm^3), stage for NHL patients (I or II vs III or IV), and whether prephase already started (yes vs no). Patients are stratified for protocol II therapy according to center, risk group (very low risk [VLR] vs average risk 1 [AR1] vs average risk 2 [AR2]), and treatment arm at first randomization.
- Prephase: Patients are randomized to 1 of 2 treatment arms
- Arm I: Patients receive oral prednisolone (PRDL) twice daily or methylprednisolone IV over 1 hour every 12 hours on days 1-7.
- Arm II: Patients receive dexamethasone (DM) orally twice daily or IV over 1 hour every 12 hours on days 1-7.
Patients in both arms also receive methotrexate (MTX) intrathecally (IT) on day 1.
- Protocol IA (days 8-35):
- VLR patients: Patients receive either oral PRDL or oral DM (depending on earlier randomization) on days 8-28; vincristine (VCR) IV on days 8, 15, 22, and 29; daunorubicin (DNR) IV over 1-4 hours on days 8 and 15; MTX IT on days 12 and 25; and asparaginase (ASP) IV over 1 hour or intramuscularly (IM) on days 12, 15, 18, 22, 25, 29, 32, and 35.
- AR1 patients: Patients receive PRDL or DM, VCR, and ASP in the same manner as VLR patients. Patients also receive DNR IV over 1-4 hours on days 8, 15, 22, and 29 and triple intrathecal therapy (TIT) comprising MTX, cytarabine (ARA-C), and hydrocortisone on days 12 and 25.
- AR2 and very high-risk (VHR) patients:Patients receive PRDL or DM, VCR, and ASP in the same manner as VLR patients and high-dose MTX (HD-MTX) IV over 24 hours on day 8; cyclophosphamide (CTX) IV over 1 hour on day 9; DNR IV over 1-4 hours on days 15, 22, and 29; and TIT on days 12 and 25.
Patients with VLR, AR1, or AR2 disease after protocol IA proceed to protocol IB, interval therapy, and then protocol II. Patients with VHR disease after protocol IA proceed to the VHR patient protocol.
- Protocol IB (for VLR, AR1, or AR2 patients): Patients with precursor B-cell ALL must be in complete remission (CR) and patients with NHL must be in CR or good partial remission.
- VLR patients: Patients receive oral mercaptopurine (MP) on days 36-63; ARA-C IV on days 38-41, 45-48, 52-55, and 59-62; and MTX IT on days 38 and 52.
- AR1 and AR2 patients: Patients receive oral MP and ARA-C in the same manner as VLR patients; CTX IV over 1 hour on days 36 and 63; and TIT on days 38 and 52.
- VLR, AR1, and AR2 patients are also randomized to 1 of 2 treatment arms.
- Arm I: Patients receive ASP IV or IM on days 38, 41, 45, 48, 52, 55, 59, and 62.
- Arm II: Patients receive no ASP.
- Interval therapy for VLR, AR1, or AR2 patients (begins 14 days after completion of protocol I): Patients receive oral MP daily on days 1-56; HD-MTX IV over 24 hours on days 8, 22, 36, and 50; leucovorin calcium (CF) (or levofolinic acid) orally or IV beginning 36 hours after initiation of MTX infusion and repeating every 6 hours until hour 72 or until serum MTX level is adequate; and TIT on days 9, 23, 37, and 51.
- Protocol II (reinduction therapy IIA and reconsolidation therapy IIB):
- VLR patients: Patients receive oral DM twice daily on days 1-21; VCR IV on days 8, 15, 22, and 29; doxorubicin (DOX) IV over 1-4 hours on days 8 and 15; ARA-C IV on days 38-41 and 45-48; oral thioguanine (TG) once daily on days 36-49; and MTX IT on day 38.
- AR patients: Patients receive DM, VCR, ARA-C, and TG in the same manner as VLR patients; DOX IV over 1-4 hours on days 8, 15, 22, and 29; CTX IV over 30-60 minutes on day 36; and TIT on day 38.
- VLR and AR patients are also randomized to 1 of 2 treatment arms.
- Arm I: Patients receive short-term ASP IV over 1 hour or IM on days 8, 11, 15, and 18.
- Arm II: Patients receive long-term ASP IV over 1 hour or IM on days 8, 11, 15, 18, 22, 25, 29, and 32.
- Maintenance therapy for VLR and AR patients (begins 14 days after completion of protocol II):
- VLR patients: Patients receive oral MP once daily and oral MTX once weekly for a total of 74 weeks.
- AR1 patients: Patients receive oral MP once daily on days 1-70; oral MTX on days 1, 8, 15, 29, 36, 43, 50, 57, and 64; and TIT on day 22. Treatment repeats every 10 weeks for 6 courses.
- AR2 patients: Patients receive MP and oral MTX (as for AR1 patients); HD-MTX IV over 24 hours on day 22; CF as in interval therapy on days 23 and 24; and TIT and ASP on day 23.
After course 6, AR1 and AR2 patients receive further maintenance therapy comprising oral MP once daily and oral MTX once a week.
- VHR patient protocol (recommended treatment): Patients with VHR disease after protocol IA receive reinforced consolidation (protocol IB') and VANDA regimens.
- Protocol IB': Patients receive oral DM twice daily on days 36-40 and 50-54; oral MP daily on days 36-40; VCR IV on days 36 and 41; HD-MTX IV over 24 hours on days 36 and 50; TIT on days 37 and 51; ARA-C IV over 3 hours every 12 hours on day 40; ASP IV over 1 hour or IM on days 41, 43, 45, 55, 57, and 59; oral TG once daily on days 50-54; vindesine (DAVA) IV on day 50; DNR IV over 1-4 hours on day 54; and CTX IV over 1 hour on days 52 and 53. Patients who achieve CR after protocol IB' proceed to VANDA regimen.
- VANDA regimen: Patients receive oral DM twice daily on days 1-5; ARA-C IV over 3 hours every 12 hours on days 1 and 2; mitoxantrone IV over 1 hour on days 3 and 4; etoposide (VP-16) IV over 1 hour on days 3-5; TIT on day 5; and ASP IV or IM on days 7, 9, 11, and 13.
After protocol IB' and VANDA, VHR patients who are eligible for stem cell transplantation (SCT) and have an HLA-compatible familial donor undergo transplantation. Patients who are ineligible for SCT receive interval therapy, followed by 2 sequences of blocks R1, R2, and R3 (2 courses of each block for a total of 6 courses), and then maintenance therapy for a total treatment duration of 2 years.
- Interval therapy: Patients receive oral MP once daily on days 1-42; HD-MTX IV over 24 hours on days 8, 22, and 36; CF as in interval therapy (described above); and TIT on days 9, 23, and 37.
- Blocks R1, R2, and R3 (this sequential regimen is repeated once):
- R1: Patients receive oral DM twice daily and oral MP once daily on days 1-5; VCR IV on days 1 and 6; HD-MTX IV over 24 hours on day 1; CF as in interval therapy on days 1 and 2; TIT on day 2; ARA-C IV over 3 hours every 12 hours on day 5; and ASP IV over 1 hour or IM on day 6.
- R2: Patients receive DM, HD-MTX, CF, TIT, and ASP as in block R1 and oral TG once daily on days 1-5; DAVA IV on day 1; CTX IV over 1 hour on days 3 and 4; and DNR IV over 1-4 hours on day 5.
- R3: Patients receive DM and ASP as in block R1 and ARA-C IV over 3 hours every 12 hours on days 1 and 2; VP-16 IV over 1 hour on days 3-5; and TIT on day 5.
- Maintenance therapy: (begins 14 days after the second course of block R3 and ends 2 years after initiation of study therapy): Patients receive treatment as in maintenance therapy for AR1 patients. Treatment repeats every 10 weeks for 5 courses.
Patients are followed every 3 months for 5 years and then annually thereafter.
PROJECTED ACCRUAL: A total of 1,400-1,500 patients will be accrued for this study within 5.5 years.
- Being tested
- asparaginase, cyclophosphamide, cytarabine, daunorubicin hydrochloride, dexamethasone
- Keywords
- stage I childhood lymphoblastic lymphoma, stage II childhood lymphoblastic lymphoma, stage III childhood lymphoblastic lymphoma, stage IV childhood lymphoblastic lymphoma, untreated childhood acute lymphoblastic leukemia, L1 childhood acute lymphoblastic leukemia, L2 childhood acute lymphoblastic leukemia, T-cell childhood acute lymphoblastic leukemia, B-cell childhood acute lymphoblastic leukemia, acute undifferentiated leukemia
- Medical subject headings
- Leukemia, Lymphoma, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Biphenotypic, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
asparaginaseDrug
cyclophosphamideDrug
cytarabineDrug
daunorubicin hydrochlorideDrug
dexamethasoneDrug
etoposideDrug
mercaptopurineDrug
methotrexateDrug
mitoxantrone hydrochlorideDrug
prednisoloneDrug
therapeutic hydrocortisoneDrug
thioguanineDrug
vindesineDrug
allogeneic bone marrow transplantationProcedure or surgery
peripheral blood stem cell transplantationProcedure or surgery
What is being measured
The primary outcome is the main question the study is designed to answer.
Event-free survival after first randomization
Disease-free survival after second and third randomization
Secondary outcomes (4)
Overall survival
Response to prephase as assessed by number of blasts/mm³ in peripheral blood (< 1,000 vs ≥ 1,000) after randomization
Response as assessed by bone marrow (BM) blasts after first randomization, at evaluation of prephase, and on day 15 of induction
Toxicity and long-term toxicity as assessed by CTC v2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2003 (estimated)
- Study startDec 1998
- Primary completionMay 2008 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (17)Papers the sponsor has linked to this study.
- Other trials for LeukemiaStudies of the same condition, open and under way.
- More trials run by European Organisation for Research and Treatment of Cancer - EORTCThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Enrolment
- 1,500 participants (estimated)
Sponsor and investigators
- Sponsor type
- Research network
- Investigators
- Jacques Otten, MD, Academisch Ziekenhuis der Vrije Universiteit Brussel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00003728
- Sponsor's protocol ID
- CDR0000066840
- Other IDs
- EORTC-58951
- Status last verified
- Jun 2009
- First submitted
- 1 Nov 1999
- Last updated
- 21 Jan 2011
- Results posted
- No
Publications
Ducassou S, Ferlay C, Bergeron C, Girard S, Laureys G, Pacquement H, Plantaz D, Lutz P, Vannier JP, Uyttebroeck A, Bertrand Y. Clinical presentation, evolution, and prognosis of precursor B-cell lymphoblastic lymphoma in trials LMT96, EORTC 58881, and EORTC 58951. Br J Haematol. 2011 Feb;152(4):441-51. doi: 10.1111/j.1365-2141.2010.08541.x. Epub 2011 Jan 7.
PubMed 21210776Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G, Kaltenbach S, Yakouben K, Mazingue F, Robert A, Boutard P, Plantaz D, Rohrlich P, van Vlierberghe P, Preudhomme C, Otten J, Speleman F, Dastugue N, Suciu S, Benoit Y, Bertrand Y, Cave H; EORTC-CLG. NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia. 2010 Dec;24(12):2023-31. doi: 10.1038/leu.2010.205. Epub 2010 Sep 23.
PubMed 20861920Clappier E, Collette S, Grardel N, et al.: Prognostic significance of NOTCH1 and FBXW7 mutations in childhood T-cell acute lymphoblastic leukemia (T-ALL): results from the EORTC Children Leukemia Group. [Abstract] Blood 114 (22): A-909, 2009.
Renneville A, Kaltenbach S, Clappier E, Collette S, Micol JB, Nelken B, Lepelley P, Dastugue N, Benoit Y, Bertrand Y, Preudhomme C, Cave H. Wilms tumor 1 (WT1) gene mutations in pediatric T-cell malignancies. Leukemia. 2010 Feb;24(2):476-80. doi: 10.1038/leu.2009.221. Epub 2009 Oct 22. No abstract available.
PubMed 19847202Cave H, Suciu S, Preudhomme C, Poppe B, Robert A, Uyttebroeck A, Malet M, Boutard P, Benoit Y, Mauvieux L, Lutz P, Mechinaud F, Grardel N, Mazingue F, Dupont M, Margueritte G, Pages MP, Bertrand Y, Plouvier E, Brunie G, Bastard C, Plantaz D, Vande Velde I, Hagemeijer A, Speleman F, Lessard M, Otten J, Vilmer E, Dastugue N; EORTC-CLG. Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood. 2004 Jan 15;103(2):442-50. doi: 10.1182/blood-2003-05-1495. Epub 2003 Sep 22.
PubMed 14504110Mirebeau D, Acquaviva C, Suciu S, Bertin R, Dastugue N, Robert A, Boutard P, Mechinaud F, Plouvier E, Otten J, Vilmer E, Cave H; EORTC-CLG. The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. Haematologica. 2006 Jul;91(7):881-5.
PubMed 16818274Cavé H, Suciu S, Preudhomme C, et al.: HOX11L2 expression linked to t(5;14)(q35;q32) is not associated with poor prognosis in childhood T-ALL treated in EORTC trials 58 881 and 58 951. [Abstract] Blood 100(11 pt 1): A-576, 153a, 2002.
De Moerloose B, Suciu S, Bertrand Y, Mazingue F, Robert A, Uyttebroeck A, Yakouben K, Ferster A, Margueritte G, Lutz P, Munzer M, Sirvent N, Norton L, Boutard P, Plantaz D, Millot F, Philippet P, Baila L, Benoit Y, Otten J; Children's Leukemia Group of the European Organisation for Research and Treatment of Cancer (EORTC). Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010 Jul 8;116(1):36-44. doi: 10.1182/blood-2009-10-247965. Epub 2010 Apr 20.
PubMed 20407035Bertrand Y, Suciu S, Benoit Y, et al.: Dexamethasone(DEX)(6mg/sm/d) and prednisolone(PRED)(60mg/sm/d) in induction therapy of childhood ALL are equally effective: results of the 2nd interim analysis of EORTC trial 58951. [Abstract] Blood 112 (11): A-8, 2008.
Sirvent N, Suciu S, Benoit Y, et al.: Prognostic significance of central nervous system (CNS) status of children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58951. [Abstract] Blood 112 (11): A-303, 2008.
Bertrand Y, Goutagny MP, Poulat AL, et al.: Asparagine depletion, safety and antibody production after E coli asparaginase treatment in children with newly diagnosed acute lymphoblastic leukaemia treated with EORTC 58951 protocol: a single center report. [Abstract] Blood 110 (11): A-4337, 2007.
Sirvent N, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Paillard C, Costa V, Simon P, Pluchart C, Poiree M, Minckes O, Millot F, Freycon C, Maes P, Hoyoux C, Cave H, Rohrlich P, Bertrand Y, Benoit Y; Children's Leukemia Group of the European Organisation for Research Treatment of Cancer. CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951. Arch Pediatr. 2021 Jul;28(5):411-416. doi: 10.1016/j.arcped.2021.04.009. Epub 2021 May 24.
PubMed 34034929Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poiree M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cave H, Rohrlich P, Bertrand Y, Benoit Y; Children-s Leukemia Group (CLG) of the European Organization for Research and Treatment of Cancer (EORTC). Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. doi: 10.3324/haematol.2017.165845. Epub 2017 Jul 27.
PubMed 28751566Ghazavi F, Clappier E, Lammens T, Suciu S, Caye A, Zegrari S, Bakkus M, Grardel N, Benoit Y, Bertrand Y, Minckes O, Costa V, Ferster A, Mazingue F, Plat G, Plouvier E, Poiree M, Uyttebroeck A, van der Werff-Ten Bosch J, Yakouben K, Helsmoortel H, Meul M, Van Roy N, Philippe J, Speleman F, Cave H, Van Vlierberghe P, De Moerloose B. CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol. Haematologica. 2015 Oct;100(10):1311-9. doi: 10.3324/haematol.2015.126953. Epub 2015 Jul 2.
PubMed 26137961Clappier E, Grardel N, Bakkus M, Rapion J, De Moerloose B, Kastner P, Caye A, Vivent J, Costa V, Ferster A, Lutz P, Mazingue F, Millot F, Plantaz D, Plat G, Plouvier E, Poiree M, Sirvent N, Uyttebroeck A, Yakouben K, Girard S, Dastugue N, Suciu S, Benoit Y, Bertrand Y, Cave H; European Organisation for Research and Treatment of Cancer, Children's Leukemia Group (EORTC-CLG). IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951. Leukemia. 2015 Nov;29(11):2154-61. doi: 10.1038/leu.2015.134. Epub 2015 Jun 8.
PubMed 26050650
Study at a glance
From the registry record, last updated by the sponsor on 21 Jan 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Value of Dexamethasone Versus Prednisolone During Induction and Maintenance Therapy of Prolonged Versus Conventional Duration of L-Asparaginase Therapy During Consolidation and Late Intensification, and of Corticosteroid + VCR Pulses During Maintenance in Acute Lymphoblastic Leukemia and Lymphoblastic Non-Hodgkin Lymphoma of Childhood
- ClinicalTrials.gov ID
- NCT00003728
- Acronym / sponsor ID
- CDR0000066840
- Keywords
- stage I childhood lymphoblastic lymphoma, stage II childhood lymphoblastic lymphoma, stage III childhood lymphoblastic lymphoma, stage IV childhood lymphoblastic lymphoma, untreated childhood acute lymphoblastic leukemia, L1 childhood acute lymphoblastic leukemia, L2 childhood acute lymphoblastic leukemia, T-cell childhood acute lymphoblastic leukemia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 1,500 participants (estimated)
- Lead sponsor
- European Organisation for Research and Treatment of Cancer - EORTCResearch network
- Study start
- Dec 1998
- Primary completion
- May 2008 (estimated)
- First posted
- 27 Jan 2003 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which regimen of combination chemotherapy plus steroid therapy is more effective for acute lymphoblastic leukemia or lymphoblastic non-Hodgkin's lymphoma.
PURPOSE: Randomized phase III trial to compare the effectiveness of different regimens of combination chemotherapy plus steroid therapy in treating children who have acute lymphoblastic leukemia or lymphoblastic non-Hodgkin's lymphoma.
Detailed description
OBJECTIVES:
- Compare the value of dexamethasone (DM) vs prednisolone (PRDL) administered during induction therapy, in terms of event-free and overall survival, in children with acute lymphoblastic leukemia (ALL) or lymphoblastic non-Hodgkin's lymphoma (LNHL).
- Assess the value of increasing the number of administrations of asparaginase during consolidation and late intensification therapy, in terms of disease-free and overall survival, in children without very high-risk (VHR) features.
- Compare the response rate in children treated with prephase therapy comprising DM vs PRDL and intrathecal methotrexate.
- Compare the incidence and grade of toxic effects of these treatment regimens in these children.
- Compare the long-term effects of these treatment regimens on growth and pubertal development, neurocognitive, cardiac, and endocrine function, and incidence of aseptic bone necrosis in these children.
- Evaluate the proportion of children with VHR disease when defined according to extended VHR criteria, and assess the prognostic importance of the new VHR features (cytogenetics and minimal-residual disease).
- Compare the feasibility of the VHR chemotherapy protocol in patients treated with DM vs PRDL.
OUTLINE: This is a randomized, multicenter study. Patients are stratified for prephase therapy according to center, disease (acute lymphoblastic leukemia [ALL] vs non-Hodgkin's lymphoma [NHL]), WBC for ALL patients (less than 10,000/mm^3 vs 10,000/mm^3 to less than 100,000/mm^3 vs greater than 100,000/mm^3), stage for NHL patients (I or II vs III or IV), and whether prephase already started (yes vs no). Patients are stratified for protocol II therapy according to center, risk group (very low risk [VLR] vs average risk 1 [AR1] vs average risk 2 [AR2]), and treatment arm at first randomization.
- Prephase: Patients are randomized to 1 of 2 treatment arms
- Arm I: Patients receive oral prednisolone (PRDL) twice daily or methylprednisolone IV over 1 hour every 12 hours on days 1-7.
- Arm II: Patients receive dexamethasone (DM) orally twice daily or IV over 1 hour every 12 hours on days 1-7.
Patients in both arms also receive methotrexate (MTX) intrathecally (IT) on day 1.
- Protocol IA (days 8-35):
- VLR patients: Patients receive either oral PRDL or oral DM (depending on earlier randomization) on days 8-28; vincristine (VCR) IV on days 8, 15, 22, and 29; daunorubicin (DNR) IV over 1-4 hours on days 8 and 15; MTX IT on days 12 and 25; and asparaginase (ASP) IV over 1 hour or intramuscularly (IM) on days 12, 15, 18, 22, 25, 29, 32, and 35.
- AR1 patients: Patients receive PRDL or DM, VCR, and ASP in the same manner as VLR patients. Patients also receive DNR IV over 1-4 hours on days 8, 15, 22, and 29 and triple intrathecal therapy (TIT) comprising MTX, cytarabine (ARA-C), and hydrocortisone on days 12 and 25.
- AR2 and very high-risk (VHR) patients:Patients receive PRDL or DM, VCR, and ASP in the same manner as VLR patients and high-dose MTX (HD-MTX) IV over 24 hours on day 8; cyclophosphamide (CTX) IV over 1 hour on day 9; DNR IV over 1-4 hours on days 15, 22, and 29; and TIT on days 12 and 25.
Patients with VLR, AR1, or AR2 disease after protocol IA proceed to protocol IB, interval therapy, and then protocol II. Patients with VHR disease after protocol IA proceed to the VHR patient protocol.
- Protocol IB (for VLR, AR1, or AR2 patients): Patients with precursor B-cell ALL must be in complete remission (CR) and patients with NHL must be in CR or good partial remission.
- VLR patients: Patients receive oral mercaptopurine (MP) on days 36-63; ARA-C IV on days 38-41, 45-48, 52-55, and 59-62; and MTX IT on days 38 and 52.
- AR1 and AR2 patients: Patients receive oral MP and ARA-C in the same manner as VLR patients; CTX IV over 1 hour on days 36 and 63; and TIT on days 38 and 52.
- VLR, AR1, and AR2 patients are also randomized to 1 of 2 treatment arms.
- Arm I: Patients receive ASP IV or IM on days 38, 41, 45, 48, 52, 55, 59, and 62.
- Arm II: Patients receive no ASP.
- Interval therapy for VLR, AR1, or AR2 patients (begins 14 days after completion of protocol I): Patients receive oral MP daily on days 1-56; HD-MTX IV over 24 hours on days 8, 22, 36, and 50; leucovorin calcium (CF) (or levofolinic acid) orally or IV beginning 36 hours after initiation of MTX infusion and repeating every 6 hours until hour 72 or until serum MTX level is adequate; and TIT on days 9, 23, 37, and 51.
- Protocol II (reinduction therapy IIA and reconsolidation therapy IIB):
- VLR patients: Patients receive oral DM twice daily on days 1-21; VCR IV on days 8, 15, 22, and 29; doxorubicin (DOX) IV over 1-4 hours on days 8 and 15; ARA-C IV on days 38-41 and 45-48; oral thioguanine (TG) once daily on days 36-49; and MTX IT on day 38.
- AR patients: Patients receive DM, VCR, ARA-C, and TG in the same manner as VLR patients; DOX IV over 1-4 hours on days 8, 15, 22, and 29; CTX IV over 30-60 minutes on day 36; and TIT on day 38.
- VLR and AR patients are also randomized to 1 of 2 treatment arms.
- Arm I: Patients receive short-term ASP IV over 1 hour or IM on days 8, 11, 15, and 18.
- Arm II: Patients receive long-term ASP IV over 1 hour or IM on days 8, 11, 15, 18, 22, 25, 29, and 32.
- Maintenance therapy for VLR and AR patients (begins 14 days after completion of protocol II):
- VLR patients: Patients receive oral MP once daily and oral MTX once weekly for a total of 74 weeks.
- AR1 patients: Patients receive oral MP once daily on days 1-70; oral MTX on days 1, 8, 15, 29, 36, 43, 50, 57, and 64; and TIT on day 22. Treatment repeats every 10 weeks for 6 courses.
- AR2 patients: Patients receive MP and oral MTX (as for AR1 patients); HD-MTX IV over 24 hours on day 22; CF as in interval therapy on days 23 and 24; and TIT and ASP on day 23.
After course 6, AR1 and AR2 patients receive further maintenance therapy comprising oral MP once daily and oral MTX once a week.
- VHR patient protocol (recommended treatment): Patients with VHR disease after protocol IA receive reinforced consolidation (protocol IB') and VANDA regimens.
- Protocol IB': Patients receive oral DM twice daily on days 36-40 and 50-54; oral MP daily on days 36-40; VCR IV on days 36 and 41; HD-MTX IV over 24 hours on days 36 and 50; TIT on days 37 and 51; ARA-C IV over 3 hours every 12 hours on day 40; ASP IV over 1 hour or IM on days 41, 43, 45, 55, 57, and 59; oral TG once daily on days 50-54; vindesine (DAVA) IV on day 50; DNR IV over 1-4 hours on day 54; and CTX IV over 1 hour on days 52 and 53. Patients who achieve CR after protocol IB' proceed to VANDA regimen.
- VANDA regimen: Patients receive oral DM twice daily on days 1-5; ARA-C IV over 3 hours every 12 hours on days 1 and 2; mitoxantrone IV over 1 hour on days 3 and 4; etoposide (VP-16) IV over 1 hour on days 3-5; TIT on day 5; and ASP IV or IM on days 7, 9, 11, and 13.
After protocol IB' and VANDA, VHR patients who are eligible for stem cell transplantation (SCT) and have an HLA-compatible familial donor undergo transplantation. Patients who are ineligible for SCT receive interval therapy, followed by 2 sequences of blocks R1, R2, and R3 (2 courses of each block for a total of 6 courses), and then maintenance therapy for a total treatment duration of 2 years.
- Interval therapy: Patients receive oral MP once daily on days 1-42; HD-MTX IV over 24 hours on days 8, 22, and 36; CF as in interval therapy (described above); and TIT on days 9, 23, and 37.
- Blocks R1, R2, and R3 (this sequential regimen is repeated once):
- R1: Patients receive oral DM twice daily and oral MP once daily on days 1-5; VCR IV on days 1 and 6; HD-MTX IV over 24 hours on day 1; CF as in interval therapy on days 1 and 2; TIT on day 2; ARA-C IV over 3 hours every 12 hours on day 5; and ASP IV over 1 hour or IM on day 6.
- R2: Patients receive DM, HD-MTX, CF, TIT, and ASP as in block R1 and oral TG once daily on days 1-5; DAVA IV on day 1; CTX IV over 1 hour on days 3 and 4; and DNR IV over 1-4 hours on day 5.
- R3: Patients receive DM and ASP as in block R1 and ARA-C IV over 3 hours every 12 hours on days 1 and 2; VP-16 IV over 1 hour on days 3-5; and TIT on day 5.
- Maintenance therapy: (begins 14 days after the second course of block R3 and ends 2 years after initiation of study therapy): Patients receive treatment as in maintenance therapy for AR1 patients. Treatment repeats every 10 weeks for 5 courses.
Patients are followed every 3 months for 5 years and then annually thereafter.
PROJECTED ACCRUAL: A total of 1,400-1,500 patients will be accrued for this study within 5.5 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
Who may qualify
- Ages
- Up to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| asparaginase | Drug | – |
| cyclophosphamide | Drug | – |
| cytarabine | Drug | – |
| daunorubicin hydrochloride | Drug | – |
| dexamethasone | Drug | – |
| doxorubicin hydrochloride | Drug | – |
| etoposide | Drug | – |
| leucovorin calcium | Drug | – |
| mercaptopurine | Drug | – |
| methotrexate | Drug | – |
| methylprednisolone | Drug | – |
| mitoxantrone hydrochloride | Drug | – |
| prednisolone | Drug | – |
| therapeutic hydrocortisone | Drug | – |
| thioguanine | Drug | – |
| vincristine sulfate | Drug | – |
| vindesine | Drug | – |
| allogeneic bone marrow transplantation | Procedure or surgery | – |
| peripheral blood stem cell transplantation | Procedure or surgery | – |
Primary outcome
Event-free survival after first randomization
Disease-free survival after second and third randomization
4 secondary outcomes
Overall survival
Response to prephase as assessed by number of blasts/mm³ in peripheral blood (< 1,000 vs ≥ 1,000) after randomization
Response as assessed by bone marrow (BM) blasts after first randomization, at evaluation of prephase, and on day 15 of induction
Toxicity and long-term toxicity as assessed by CTC v2
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jan 2011.
- Background: PubMed 21210776Ducassou S, Ferlay C, Bergeron C, Girard S, Laureys G, Pacquement H, Plantaz D, Lutz P, Vannier JP, Uyttebroeck A, Bertrand Y. Clinical presentation, evolution, and prognosis of precursor B-cell lymphoblastic lymphoma in trials LMT96, EORTC 58881, and EORTC 58951. Br J Haematol. 2011 Feb;152(4):441-51. doi: 10.1111/j.1365-2141.2010.08541.x. Epub 2011 Jan 7.
- Background: PubMed 20861920Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G, Kaltenbach S, Yakouben K, Mazingue F, Robert A, Boutard P, Plantaz D, Rohrlich P, van Vlierberghe P, Preudhomme C, Otten J, Speleman F, Dastugue N, Suciu S, Benoit Y, Bertrand Y, Cave H; EORTC-CLG. NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia. 2010 Dec;24(12):2023-31. doi: 10.1038/leu.2010.205. Epub 2010 Sep 23.
- BackgroundClappier E, Collette S, Grardel N, et al.: Prognostic significance of NOTCH1 and FBXW7 mutations in childhood T-cell acute lymphoblastic leukemia (T-ALL): results from the EORTC Children Leukemia Group. [Abstract] Blood 114 (22): A-909, 2009.
- Background: PubMed 19847202Renneville A, Kaltenbach S, Clappier E, Collette S, Micol JB, Nelken B, Lepelley P, Dastugue N, Benoit Y, Bertrand Y, Preudhomme C, Cave H. Wilms tumor 1 (WT1) gene mutations in pediatric T-cell malignancies. Leukemia. 2010 Feb;24(2):476-80. doi: 10.1038/leu.2009.221. Epub 2009 Oct 22. No abstract available.
- Background: PubMed 14504110Cave H, Suciu S, Preudhomme C, Poppe B, Robert A, Uyttebroeck A, Malet M, Boutard P, Benoit Y, Mauvieux L, Lutz P, Mechinaud F, Grardel N, Mazingue F, Dupont M, Margueritte G, Pages MP, Bertrand Y, Plouvier E, Brunie G, Bastard C, Plantaz D, Vande Velde I, Hagemeijer A, Speleman F, Lessard M, Otten J, Vilmer E, Dastugue N; EORTC-CLG. Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood. 2004 Jan 15;103(2):442-50. doi: 10.1182/blood-2003-05-1495. Epub 2003 Sep 22.
- Background: PubMed 16818274Mirebeau D, Acquaviva C, Suciu S, Bertin R, Dastugue N, Robert A, Boutard P, Mechinaud F, Plouvier E, Otten J, Vilmer E, Cave H; EORTC-CLG. The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. Haematologica. 2006 Jul;91(7):881-5.
- BackgroundCavé H, Suciu S, Preudhomme C, et al.: HOX11L2 expression linked to t(5;14)(q35;q32) is not associated with poor prognosis in childhood T-ALL treated in EORTC trials 58 881 and 58 951. [Abstract] Blood 100(11 pt 1): A-576, 153a, 2002.
- Results publication: PubMed 20407035De Moerloose B, Suciu S, Bertrand Y, Mazingue F, Robert A, Uyttebroeck A, Yakouben K, Ferster A, Margueritte G, Lutz P, Munzer M, Sirvent N, Norton L, Boutard P, Plantaz D, Millot F, Philippet P, Baila L, Benoit Y, Otten J; Children's Leukemia Group of the European Organisation for Research and Treatment of Cancer (EORTC). Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010 Jul 8;116(1):36-44. doi: 10.1182/blood-2009-10-247965. Epub 2010 Apr 20.
- Results publicationBertrand Y, Suciu S, Benoit Y, et al.: Dexamethasone(DEX)(6mg/sm/d) and prednisolone(PRED)(60mg/sm/d) in induction therapy of childhood ALL are equally effective: results of the 2nd interim analysis of EORTC trial 58951. [Abstract] Blood 112 (11): A-8, 2008.
- Results publicationSirvent N, Suciu S, Benoit Y, et al.: Prognostic significance of central nervous system (CNS) status of children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58951. [Abstract] Blood 112 (11): A-303, 2008.
- Results publicationBertrand Y, Goutagny MP, Poulat AL, et al.: Asparagine depletion, safety and antibody production after E coli asparaginase treatment in children with newly diagnosed acute lymphoblastic leukaemia treated with EORTC 58951 protocol: a single center report. [Abstract] Blood 110 (11): A-4337, 2007.
- Derived from this study: PubMed 34034929Sirvent N, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Paillard C, Costa V, Simon P, Pluchart C, Poiree M, Minckes O, Millot F, Freycon C, Maes P, Hoyoux C, Cave H, Rohrlich P, Bertrand Y, Benoit Y; Children's Leukemia Group of the European Organisation for Research Treatment of Cancer. CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951. Arch Pediatr. 2021 Jul;28(5):411-416. doi: 10.1016/j.arcped.2021.04.009. Epub 2021 May 24.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jacques Otten, MD
Academisch Ziekenhuis der Vrije Universiteit Brussel
23 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing asparaginase, cyclophosphamide and cytarabine in people with Leukemia and Lymphoma, run by European Organisation for Research and Treatment of Cancer - EORTC at 23 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
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: status not confirmed, as of the sponsor's last update on 21 Jan 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in France, Belgium, Portugal. 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?
Results are not available in the source record.
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 after first randomization. The study lists 2 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 NCT00003728, which also lists 17 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 21 Jan 2011.