Ignite Creation Date:
2024-05-05 @ 10:27 PM
Last Modification Date:
2024-10-26 @ 10:19 AM
Study NCT ID:
NCT01117441
Status:
COMPLETED
Last Update Posted:
2022-05-24
First Post:
2010-05-03
Brief Title:
International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia
Sponsor:
University Hospital Schleswig-Holstein
Organization:
University Hospital Schleswig-Holstein
Study Overview
Official Title:
International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia
Status:
COMPLETED
Status Verified Date:
2022-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
RationalePurpose 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
Study objectives
Primary study questions
Non high-risk non-HR precursor-B ALL pB-ALL patients with TELAML1-negative ALL or unknown TELAML1 status and flow cytometry minimal residual disease MRD in bone marrow on day 15 01 or with TELAML1-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 AESAE 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-ALLMR 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
This trial is studying several different combination chemotherapy regimens to compare how well they work in treating young patients with ALL
Study objectives
Primary study questions
Non high-risk non-HR precursor-B ALL pB-ALL patients with TELAML1-negative ALL or unknown TELAML1 status and flow cytometry minimal residual disease MRD in bone marrow on day 15 01 or with TELAML1-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 AESAE 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-ALLMR 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
Detailed Description:
Risk Stratification
Tnon-HR T-ALL in absence of any HR criteria see below
pBnon-HR pB-ALL in absence of any HR criteria see below
SR polymerase chain reactionPCR-MRD-SR MRD-negative on day 33 and 78 or if no PCR-MRD result available FCM d15 01
MR no SR
HR Prednisone poor-response 1000 blast cellsµl 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 MLLAF4 or t411 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
Tnon-HR Protocol I Protocol M Protocol II and Maintenance pBnon-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
InterimMaintenance until week 104
6-MP po daily MTX po 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 000μl
pB-ALL with PPR andor FCM-MRD day 15 10 andor PCR-MRDMR SER as only HR criteria
Radiotherapy Patients without CNS involvement and
T-ALLnon-HR WBC 100 000μl 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 andor FCM-MRD day 15 10 andor 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
Tnon-HR T-ALL in absence of any HR criteria see below
pBnon-HR pB-ALL in absence of any HR criteria see below
SR polymerase chain reactionPCR-MRD-SR MRD-negative on day 33 and 78 or if no PCR-MRD result available FCM d15 01
MR no SR
HR Prednisone poor-response 1000 blast cellsµl 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 MLLAF4 or t411 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
Tnon-HR Protocol I Protocol M Protocol II and Maintenance pBnon-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
InterimMaintenance until week 104
6-MP po daily MTX po 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 000μl
pB-ALL with PPR andor FCM-MRD day 15 10 andor PCR-MRDMR SER as only HR criteria
Radiotherapy Patients without CNS involvement and
T-ALLnon-HR WBC 100 000μl 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 andor FCM-MRD day 15 10 andor 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None