Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00187005
Status:
TERMINATED
Last Update Posted:
2011-03-30
First Post:
2005-09-12
Brief Title:
Total Therapy Study XIV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Sponsor:
St Jude Childrens Research Hospital
Organization:
St Jude Childrens Research Hospital
Study Overview
Official Title:
Total Therapy Study XIV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Status:
TERMINATED
Status Verified Date:
2008-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Toxicity
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The main purpose of this study is to find out if radiation to the central nervous system CNS can be safely omitted with early intensification of chemotherapy and chemotherapy given directly to the CNS Another purpose is to find out if survival of children with ALL can be improved with risk-directed therapy given on this protocol
Detailed Description:
There are multiple secondary objectives in this trial
To estimate the overall event-free survival of patients treated with risk-directed therapy
To identify the plasma methotrexate MTX concentrations that produce maximum intracellular accumulation of active metabolites methotrexate polyglutamates MTXPG in vivo in relation to major cell lineage and genotype
To determine the relation between MTXPG accumulation in leukemic lymphoblasts and antileukemic effects as measured by the inhibition of de novo purine synthesis and by the decrease in circulating blasts during the 4 days after initiation of single-agent high-dose methotrexate treatment
To determine if plasma MTX concentrations exceeding those required for maximum MTXPG accumulation cause a paradoxical decrease in the accumulation of long-chain MTXPG in lymphoblasts eg due to feedback inhibition of folypolyglutamate synthetase
To determine if there are significant differences in lymphoblast uptake of MTX and expression of the reduced folate carrier in T-lineage vs B-lineage lymphoblasts and in hyperdiploid vs non-hyperdiploid B-lineage lymphoblasts
To investigate whether atovaquone ATQ is as effective as trimethoprim-sulfamethoxazole TMP-SMZ in preventing Pneumocystis carinii pneumonitis PCP
To investigate whether or not the administration of G-CSF at the onset of febrile episodes in neutropenia patients after induction or any of the two reinductions will affect the extent and duration of fever
To determine whether levels of minimal residual disease in peripheral blood PB reflect those measured in the bone marrow BM by immunologic or molecular techniques
To assess the degree of DNA damage in somatic cells leukocytes during treatment
To explore whether genetic polymorphisms of enzymes important in metabolism of antileukemic agents eg methylene tetrahydrofolate reductase thiopurine methyltransferase glutathione transferases are correlated with MTX pharmacology in lymphoblasts acute toxicities and long-term outcome
To explore whether the development of anti-asparaginase antibodies or CSF depletion of asparaginase is correlated with acute toxicities and long-term outcome
To assess the relation between MRI changes of brain especially white matter abnormalities from HDMTX and intrathecal treatment neurologic and cognitive deficits CSF levels of homocysteines and diminished quality of life
To investigate whether early MRI changes are related to late MRI abnormalities neurologic and cognitive deficits and diminished quality of life
To correlate changes in MRI neurologic or cognitive deficits and diminished quality of life with selected pharmacokinetic variables
To determine the prevalence of low bone density and to correlate this complication with potential risk factors
Details of Treatment Interventions
Treatment will consist of three main phases Remission Induction including an Upfront HDMTX Window Consolidation and Continuation
Window Therapy Upfront HDMTX is considered the first part of remission induction treatment HDMTX will be given by vein over 24 hours one day MTX 500 mgm2 for standard risk and 250 mgm2 for low-risk cases will be given over 1 hour followed immediately by maintenance infusion 4500 mgm2 for standardhigh-risk or 2250 mgm2 for low-risk cases over 23 hours
Remission Induction Therapy 6-7 weeks The remaining induction treatment will begin with Prednisone 40 mgm2day PO tid Days 5-32 Vincristine 15 mgm2week IV days 5 12 19 26 Daunorubicin 25 mgm2week IV days 5 12 L-asparaginase 10000 Um2dose IM thrice weekly days 6 8 10 12 14 16 19 21 23 and triple intrathecal treatment followed by Etoposide 300 mgm2dose IV over 2 hr days 26 29 33 plus Cytarabine 300 mgm2dose IV over 2 hr Days 26 29 33
Triple intrathecal chemotherapy MHA is used for the remaining treatment with dosages based on age Frequency and total number of triple intrathecal treatment for Remission Induction are based on the patients risk of CNS relapse
Consolidation 2 weeks Patients receive High dose Methotrexate HDMTX 25 gmm2 low-risk or 5 gmm2 standard-or-high-risk IV over 24 hr days 1 and 8 and 6-Mercaptopurine 25 mgm2day PO days 1 to 14 All patients will receive triple intrathecal therapy weekly for two doses on Days 1 and 8
Continuation treatment 120 weeks for girls and 146 weeks for boys Post-remission continuation treatment begins 7 days after the second course of HDMTX of the consolidation treatment provided that the ANC 300mm3 and platelet count 50 x 109L Continuation treatment will be 120 weeks for girls and 146 weeks for boys and differs according to the risk classification
Reinduction Treatment This phase of treatment will be started at weeks 12 and 28 after bone marrow examination confirms complete remission
Reinduction treatment will be given twice
Weeks 12 to 16 and week 28 to 32 for standardhigh risk cases weeks 12 to 15 and weeks 28-31 for low-risk cases Leucovorin rescue 5 mgm2 will be given at 24 and 30 hours after the intrathecal treatment during both remission reinduction treatments No chemotherapy will be given weeks 16 and 32 for standardhigh risk patients
Standard- or High-Risk Leukemia
DEX dexamethasone 8 mgm2 PO daily tid x 7 days and VCR vincristine 15 mgm2 IV push max 2 mg will be given weeks 1 5 9 17 21 25 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101 105 109 113 and 117
VP16 etoposide 300 mgm2 IV over 2 hours and CTX cyclophosphamide 300 mgm2 IV short infusion will be given weeks 2 6 10 18 22 26 34 38 42 46 50 54 58 62 66 70 74 78 82 86 90 and 94
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days and MTX methotrexate 40 mgm2 IV or IM weeks 3 8 11 19 24 27 35 39 40 43 47 48 51 55 56 59 63 64 67 71 72 75 79 80 83 87 88 91 95 96 98 99 102 103 104 106 107 110 111 112 114 115 118 119 and 120 and weeks 121-146 for boys
MTX methotrexate 40 mgm2 IV or IM and Ara-C cytarabine 300 mgm2 IV push will be given weeks4 20 36 44 52 60 68 76 84 92 100 108 and 116
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days and HDMTX 5 gm gmm2 will be given week 7 and 23
HDMTX 5 gm gmm2 and Ara-C cytarabine 300 mgm2 IV push will be given weeks 15 and 31
Reinduction Treatment-StandardHigh Risk
DEX dexamethasone 8 mgm2 PO daily tid days 1-21
VCR vincristine 15 mgm2week IV max 2 mg days 1 8 and 15
PEG-asparaginase 2500 Um2week IM weeks 28-31 days 8 and 15
Idarubicin 5 mgm2week IV days 1 and 8
HDMTX 5 gmm2 IV day 22
ITMHA methotrexatehydrocortisoneara-C age dependent IT day 1
High-dose cytarabine 2 gmm2 IV q 12 hr Days 23 and 24 Low Risk
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days and MTX methotrexate 40 mgm2 IV or IM weeks 1 2 3 4 6 8 10 11 16 18- 20 22 24 26 27 32 34- 36 38-40 42- 44 46-48 50-52 54-56 58-60 62-64 66-68 70-72 74-76 78-80 82-84 86-88 90-92 94-96 98-100 102-104 106-108 110-112 114-116 118-120 and weeks 121-146 for boys
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days MTX methotrexate 40 mgm2 IV or IM DEX dexamethasone 8 mgm2 PO daily tid x 7 days and VCR vincristine 15 mgm2 IV push max 2 mg weeks 5 9 17 21 25 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101 105 109 113 and 117
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days and HDMTX 25 gmm2 weeks 7 15 23 and 31
Reinduction Treatment-Low Risk
DEX dexamethasone 8 mgm2 PO daily days 1-21
VCR vincristine 15 mgm2week IV push max 2 mg days 1 8 and 15
PEG-asparaginase 2500 Um2week IM days 8 and 15
Idarubicin 5 mgm2week IV day 1
HDMTX 25 gmm2 day 22
ITMHA methotrexatehydrocortisoneara-C age dependent IT day 1 and 22
6 MP 75 mgm2day PO days 22-28 IT Chemotherapy
Triple intrathecal treatment will be given to low-risk cases with CNS-1 status on weeks 1 2 7 12 15 23 28 31 39 47 and 54
Triple intrathecal treatment will be given to low-risk cases with CNS-2 or traumatic CSF status on weeks 1 2 7 12 15 19 23 28 31 36 39 43 47 and 54
Triple intrathecal treatment will be given to standardhigh-risk cases on weeks 1 2 7 12 19 23 28 36 39 43 47 and 54
Triple intrathecal treatment will be given to other standardhigh-risk cases with WBC 100 x 109L T-cell ALL with WBC 50 x 109L presence of Philadelphia chromosome MLL rearrangement near haploidy or CNS-3 status on weeks 1 2 7 12 19 23 28 36 39 43 47 54 64 72 80 and 88
Hematopoietic Stem Cell Transplantation Patients who meet the criteria of high-risk ALL will be offered the option of transplantation with a matched related or unrelated donor However if the option is declined or if a suitable donor is not available the patient will remain on study and continue to receive chemotherapy
To estimate the overall event-free survival of patients treated with risk-directed therapy
To identify the plasma methotrexate MTX concentrations that produce maximum intracellular accumulation of active metabolites methotrexate polyglutamates MTXPG in vivo in relation to major cell lineage and genotype
To determine the relation between MTXPG accumulation in leukemic lymphoblasts and antileukemic effects as measured by the inhibition of de novo purine synthesis and by the decrease in circulating blasts during the 4 days after initiation of single-agent high-dose methotrexate treatment
To determine if plasma MTX concentrations exceeding those required for maximum MTXPG accumulation cause a paradoxical decrease in the accumulation of long-chain MTXPG in lymphoblasts eg due to feedback inhibition of folypolyglutamate synthetase
To determine if there are significant differences in lymphoblast uptake of MTX and expression of the reduced folate carrier in T-lineage vs B-lineage lymphoblasts and in hyperdiploid vs non-hyperdiploid B-lineage lymphoblasts
To investigate whether atovaquone ATQ is as effective as trimethoprim-sulfamethoxazole TMP-SMZ in preventing Pneumocystis carinii pneumonitis PCP
To investigate whether or not the administration of G-CSF at the onset of febrile episodes in neutropenia patients after induction or any of the two reinductions will affect the extent and duration of fever
To determine whether levels of minimal residual disease in peripheral blood PB reflect those measured in the bone marrow BM by immunologic or molecular techniques
To assess the degree of DNA damage in somatic cells leukocytes during treatment
To explore whether genetic polymorphisms of enzymes important in metabolism of antileukemic agents eg methylene tetrahydrofolate reductase thiopurine methyltransferase glutathione transferases are correlated with MTX pharmacology in lymphoblasts acute toxicities and long-term outcome
To explore whether the development of anti-asparaginase antibodies or CSF depletion of asparaginase is correlated with acute toxicities and long-term outcome
To assess the relation between MRI changes of brain especially white matter abnormalities from HDMTX and intrathecal treatment neurologic and cognitive deficits CSF levels of homocysteines and diminished quality of life
To investigate whether early MRI changes are related to late MRI abnormalities neurologic and cognitive deficits and diminished quality of life
To correlate changes in MRI neurologic or cognitive deficits and diminished quality of life with selected pharmacokinetic variables
To determine the prevalence of low bone density and to correlate this complication with potential risk factors
Details of Treatment Interventions
Treatment will consist of three main phases Remission Induction including an Upfront HDMTX Window Consolidation and Continuation
Window Therapy Upfront HDMTX is considered the first part of remission induction treatment HDMTX will be given by vein over 24 hours one day MTX 500 mgm2 for standard risk and 250 mgm2 for low-risk cases will be given over 1 hour followed immediately by maintenance infusion 4500 mgm2 for standardhigh-risk or 2250 mgm2 for low-risk cases over 23 hours
Remission Induction Therapy 6-7 weeks The remaining induction treatment will begin with Prednisone 40 mgm2day PO tid Days 5-32 Vincristine 15 mgm2week IV days 5 12 19 26 Daunorubicin 25 mgm2week IV days 5 12 L-asparaginase 10000 Um2dose IM thrice weekly days 6 8 10 12 14 16 19 21 23 and triple intrathecal treatment followed by Etoposide 300 mgm2dose IV over 2 hr days 26 29 33 plus Cytarabine 300 mgm2dose IV over 2 hr Days 26 29 33
Triple intrathecal chemotherapy MHA is used for the remaining treatment with dosages based on age Frequency and total number of triple intrathecal treatment for Remission Induction are based on the patients risk of CNS relapse
Consolidation 2 weeks Patients receive High dose Methotrexate HDMTX 25 gmm2 low-risk or 5 gmm2 standard-or-high-risk IV over 24 hr days 1 and 8 and 6-Mercaptopurine 25 mgm2day PO days 1 to 14 All patients will receive triple intrathecal therapy weekly for two doses on Days 1 and 8
Continuation treatment 120 weeks for girls and 146 weeks for boys Post-remission continuation treatment begins 7 days after the second course of HDMTX of the consolidation treatment provided that the ANC 300mm3 and platelet count 50 x 109L Continuation treatment will be 120 weeks for girls and 146 weeks for boys and differs according to the risk classification
Reinduction Treatment This phase of treatment will be started at weeks 12 and 28 after bone marrow examination confirms complete remission
Reinduction treatment will be given twice
Weeks 12 to 16 and week 28 to 32 for standardhigh risk cases weeks 12 to 15 and weeks 28-31 for low-risk cases Leucovorin rescue 5 mgm2 will be given at 24 and 30 hours after the intrathecal treatment during both remission reinduction treatments No chemotherapy will be given weeks 16 and 32 for standardhigh risk patients
Standard- or High-Risk Leukemia
DEX dexamethasone 8 mgm2 PO daily tid x 7 days and VCR vincristine 15 mgm2 IV push max 2 mg will be given weeks 1 5 9 17 21 25 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101 105 109 113 and 117
VP16 etoposide 300 mgm2 IV over 2 hours and CTX cyclophosphamide 300 mgm2 IV short infusion will be given weeks 2 6 10 18 22 26 34 38 42 46 50 54 58 62 66 70 74 78 82 86 90 and 94
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days and MTX methotrexate 40 mgm2 IV or IM weeks 3 8 11 19 24 27 35 39 40 43 47 48 51 55 56 59 63 64 67 71 72 75 79 80 83 87 88 91 95 96 98 99 102 103 104 106 107 110 111 112 114 115 118 119 and 120 and weeks 121-146 for boys
MTX methotrexate 40 mgm2 IV or IM and Ara-C cytarabine 300 mgm2 IV push will be given weeks4 20 36 44 52 60 68 76 84 92 100 108 and 116
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days and HDMTX 5 gm gmm2 will be given week 7 and 23
HDMTX 5 gm gmm2 and Ara-C cytarabine 300 mgm2 IV push will be given weeks 15 and 31
Reinduction Treatment-StandardHigh Risk
DEX dexamethasone 8 mgm2 PO daily tid days 1-21
VCR vincristine 15 mgm2week IV max 2 mg days 1 8 and 15
PEG-asparaginase 2500 Um2week IM weeks 28-31 days 8 and 15
Idarubicin 5 mgm2week IV days 1 and 8
HDMTX 5 gmm2 IV day 22
ITMHA methotrexatehydrocortisoneara-C age dependent IT day 1
High-dose cytarabine 2 gmm2 IV q 12 hr Days 23 and 24 Low Risk
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days and MTX methotrexate 40 mgm2 IV or IM weeks 1 2 3 4 6 8 10 11 16 18- 20 22 24 26 27 32 34- 36 38-40 42- 44 46-48 50-52 54-56 58-60 62-64 66-68 70-72 74-76 78-80 82-84 86-88 90-92 94-96 98-100 102-104 106-108 110-112 114-116 118-120 and weeks 121-146 for boys
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days MTX methotrexate 40 mgm2 IV or IM DEX dexamethasone 8 mgm2 PO daily tid x 7 days and VCR vincristine 15 mgm2 IV push max 2 mg weeks 5 9 17 21 25 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101 105 109 113 and 117
6MP 6-mercaptopurine 75 mgm2 PO daily x 7 days and HDMTX 25 gmm2 weeks 7 15 23 and 31
Reinduction Treatment-Low Risk
DEX dexamethasone 8 mgm2 PO daily days 1-21
VCR vincristine 15 mgm2week IV push max 2 mg days 1 8 and 15
PEG-asparaginase 2500 Um2week IM days 8 and 15
Idarubicin 5 mgm2week IV day 1
HDMTX 25 gmm2 day 22
ITMHA methotrexatehydrocortisoneara-C age dependent IT day 1 and 22
6 MP 75 mgm2day PO days 22-28 IT Chemotherapy
Triple intrathecal treatment will be given to low-risk cases with CNS-1 status on weeks 1 2 7 12 15 23 28 31 39 47 and 54
Triple intrathecal treatment will be given to low-risk cases with CNS-2 or traumatic CSF status on weeks 1 2 7 12 15 19 23 28 31 36 39 43 47 and 54
Triple intrathecal treatment will be given to standardhigh-risk cases on weeks 1 2 7 12 19 23 28 36 39 43 47 and 54
Triple intrathecal treatment will be given to other standardhigh-risk cases with WBC 100 x 109L T-cell ALL with WBC 50 x 109L presence of Philadelphia chromosome MLL rearrangement near haploidy or CNS-3 status on weeks 1 2 7 12 19 23 28 36 39 43 47 54 64 72 80 and 88
Hematopoietic Stem Cell Transplantation Patients who meet the criteria of high-risk ALL will be offered the option of transplantation with a matched related or unrelated donor However if the option is declined or if a suitable donor is not available the patient will remain on study and continue to receive chemotherapy
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