Acute Lymphoblastic LeukemiaPhase 3NCT00187005
Total Therapy Study XIV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
A Phase 3 study testing Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase and L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine in people with Acute Lymphoblastic Leukemia, run by St. Jude Children's Research Hospital at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Acute Lymphoblastic Leukemia
- What is being tested?
- Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase and L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 53 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 1998to Jul 2002
- 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 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Diagnosis of non-B-cell leukemia by immunophenotyping (e.g. T-cell, B-cell precursor, or acute undifferentiated leukemia)
- Ages less than or equal to 18 years of age
- One week or less of prior therapy, limited to glucocorticoids, vinca alkaloids, emergency radiation therapy to the mediastinum and one dose of intrathecal chemotherapy Exclusion Criteria
- Participants greater than 18 years of age
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country.
United States1 site
St.Jude Children's Research Hospital
Memphis, Tennessee, 38105
About this study
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.
Read the 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, (e.g., 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 (e.g. 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 mg/m2 for standard risk and 250 mg/m2 for low-risk cases will be given over 1 hour, followed immediately by maintenance infusion (4500 mg/m2 for standard/high-risk or 2250 mg/m2 for low-risk cases) over 23 hours.
Remission Induction Therapy (6-7 weeks) The remaining induction treatment will begin with Prednisone 40 mg/m2/day PO (tid) Days 5-32, Vincristine 1.5 mg/m2/week IV days 5, 12, 19, 26, Daunorubicin 25 mg/m2/week IV days 5, 12, L-asparaginase 10,000 U/m2/dose IM (thrice weekly) days 6, 8, 10, 12, 14, 16 (19, 21, 23), and triple intrathecal treatment, followed by Etoposide 300 mg/m2/dose IV over 2 hr days 26, 29, 33, plus Cytarabine 300 mg/m2/dose 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 patient's risk of CNS relapse.
Consolidation (2 weeks) Patients receive High dose Methotrexate (HDMTX) 2.5 gm/m2 (low-risk) or 5 gm/m2 (standard-or-high-risk) IV over 24 hr days 1 and 8 and 6-Mercaptopurine 25 mg/m2/day 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 ≥300/mm3 and platelet count ≥ 50 x 109/L. 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 standard/high risk cases; weeks 12 to 15 and weeks 28-31 for low-risk cases. Leucovorin rescue (5 mg/m2) 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 standard/high risk patients.
Standard- or High-Risk Leukemia
- DEX (dexamethasone) 8 mg/m2 PO daily (tid) x 7 days and VCR (vincristine) 1.5 mg/m2 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 mg/m2 IV over 2 hours and CTX (cyclophosphamide) 300 mg/m2 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 mg/m2 PO daily x 7 days and MTX (methotrexate) 40 mg/m2 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 mg/m2 IV or IM and Ara-C (cytarabine) 300 mg/m2 IV push will be given weeks4, 20, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, and 116.
- 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and HDMTX 5 gm/ gm/m2 will be given week 7 and 23.
- HDMTX 5 gm/ gm/m2 and Ara-C (cytarabine) 300 mg/m2 IV push will be given weeks 15 and 31.
Reinduction Treatment-Standard/High Risk
- DEX (dexamethasone) 8 mg/m2 PO daily (tid) days 1-21,
- VCR (vincristine) 1.5 mg/m2/week IV (max. 2 mg) days 1, 8, and 15
- PEG-asparaginase 2500 U/m2/week IM weeks 28-31, days 8, and 15
- Idarubicin 5 mg/m2/week IV days 1 and 8
- HDMTX 5 gm/m2 IV day 22
- ITMHA (methotrexate+hydrocortisone+ara-C), age dependent, IT day 1
- High-dose cytarabine 2 gm/m2 IV q 12 hr Days 23, and 24 Low Risk
- 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and MTX (methotrexate) 40 mg/m2 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 mg/m2 PO daily x 7 days, MTX (methotrexate) 40 mg/m2 IV or IM, DEX (dexamethasone) 8 mg/m2 PO daily (tid) x 7 days and VCR (vincristine) 1.5 mg/m2 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 mg/m2 PO daily x 7 days and HDMTX 2.5 gm/m2 weeks 7, 15, 23 and 31.
Reinduction Treatment-Low Risk
- DEX (dexamethasone) 8 mg/m2 PO daily days 1-21,
- VCR (vincristine) 1.5 mg/m2/week IV push (max. 2 mg) days 1, 8, and 15
- PEG-asparaginase 2500 U/m2/week IM days 8, and 15
- Idarubicin 5 mg/m2/week IV day 1
- HDMTX 2.5 gm/m2 day 22
- ITMHA (methotrexate+hydrocortisone+ara-C), age dependent, IT day 1 and 22
- 6 MP 75 mg/m2/day 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 standard/high-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 standard/high-risk cases with WBC ≥100 x 109/L, T-cell ALL with WBC ≥50 x 109/L, 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.
- Conditions
- Acute Lymphoblastic Leukemia
- Being tested
- Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase, L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine
- Keywords
- Leukemia
- Medical subject headings
- Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginaseDrug
See Detailed Description section for details of treatment interventions.
L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, MercaptopurineDrug
See Detailed Description section for details of treatment interventions.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Other | Not described Receives: Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase; Drug: L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine |
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine if CNS irradiation can be safely omitted with early intensification of systemic and intrathecal chemotherapy.
Measured: Unable to determine
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Sep 2005 (estimated)
- Study startJul 1998
- Primary completionJul 2002
- Study completionJul 2002
Why it stopped: Toxicity
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (31)Papers the sponsor has linked to this study.
- Other trials for Acute Lymphoblastic LeukemiaStudies of the same condition, open and under way.
- More trials run by St. Jude Children's Research HospitalThe 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
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 53 participants (actual)
Sponsor and investigators
- Lead sponsor
- St. Jude Children's Research Hospital
- Sponsor type
- University, hospital or other
- Investigators
- Ching-Hon Pui, MD, Principal investigator, St. Jude Children's Research Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00187005
- Sponsor's protocol ID
- TOTXIV
- Status last verified
- Jun 2008
- First submitted
- 12 Sep 2005
- Last updated
- 30 Mar 2011
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Hammond TG, Hu A, Hammond JM, Relling MV, Underwood JL. Detection of point mutations on a DNA microchip Clinical Immunology Newsletter 19(12):121-6, 1999.
Pui CH, Mahmoud HH, Wiley JM, Woods GM, Leverger G, Camitta B, Hastings C, Blaney SM, Relling MV, Reaman GH. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma. J Clin Oncol. 2001 Feb 1;19(3):697-704. doi: 10.1200/JCO.2001.19.3.697.
PubMed 11157020Pui CH, Jeha S, Irwin D, Camitta B. Recombinant urate oxidase (rasburicase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results of a compassionate-use trial. Leukemia. 2001 Oct;15(10):1505-9. doi: 10.1038/sj.leu.2402235.
PubMed 11587206Panetta JC, Yanishevski Y, Pui CH, Sandlund JT, Rubnitz J, Rivera GK, Ribeiro R, Evans WE, Relling MV. A mathematical model of in vivo methotrexate accumulation in acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2002 Nov;50(5):419-28. doi: 10.1007/s00280-002-0511-x. Epub 2002 Sep 24.
PubMed 12439601Coustan-Smith E, Sancho J, Behm FG, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, Pui CH, Campana D. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood. 2002 Jul 1;100(1):52-8. doi: 10.1182/blood-2002-01-0006.
PubMed 12070008Coustan-Smith E, Sancho J, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, Pui CH, Campana D. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood. 2002 Oct 1;100(7):2399-402. doi: 10.1182/blood-2002-04-1130.
PubMed 12239148Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, Evans WE, Naeve C, Wong L, Downing JR. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002 Mar;1(2):133-43. doi: 10.1016/s1535-6108(02)00032-6.
PubMed 12086872Panetta JC, Wall A, Pui CH, Relling MV, Evans WE. Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity. Clin Cancer Res. 2002 Jul;8(7):2423-9.
PubMed 12114448Cheok MH, Yang W, Pui CH, Downing JR, Cheng C, Naeve CW, Relling MV, Evans WE. Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nat Genet. 2003 May;34(1):85-90. doi: 10.1038/ng1151.
PubMed 12704389Kishi S, Griener J, Cheng C, Das S, Cook EH, Pei D, Hudson M, Rubnitz J, Sandlund JT, Pui CH, Relling MV. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol. 2003 Aug 15;21(16):3084-91. doi: 10.1200/JCO.2003.07.056.
PubMed 12915598Hinds PS, Gattuso JS, Fletcher A, Baker E, Coleman B, Jackson T, Jacobs-Levine A, June D, Rai SN, Lensing S, Pui CH. Quality of life as conveyed by pediatric patients with cancer. Qual Life Res. 2004 May;13(4):761-72. doi: 10.1023/B:QURE.0000021697.43165.87.
PubMed 15129886Hak LJ, Relling MV, Cheng C, Pei D, Wang B, Sandlund JT, Rubnitz J, Pui CH. Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia. Leukemia. 2004 Jun;18(6):1072-7. doi: 10.1038/sj.leu.2403351.
PubMed 15057247Neale GA, Coustan-Smith E, Stow P, Pan Q, Chen X, Pui CH, Campana D. Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia. 2004 May;18(5):934-8. doi: 10.1038/sj.leu.2403348.
PubMed 15029212Cheng Q, Wu B, Kager L, Panetta JC, Zheng J, Pui CH, Relling MV, Evans WE. A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenetics. 2004 Aug;14(8):557-67. doi: 10.1097/01.fpc.0000114761.78957.7e.
PubMed 15284538Rubnitz JE, Lensing S, Zhou Y, Sandlund JT, Razzouk BI, Ribeiro RC, Pui CH. Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience. Cancer. 2004 Oct 1;101(7):1677-84. doi: 10.1002/cncr.20532.
PubMed 15378506
Study at a glance
From the registry record, last updated by the sponsor on 30 Mar 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Total Therapy Study XIV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
- ClinicalTrials.gov ID
- NCT00187005
- Acronym / sponsor ID
- TOTXIV
- Conditions
- Acute Lymphoblastic Leukemia
- Keywords
- Leukemia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Toxicity
- Enrolment
- 53 participants (actual)
- Lead sponsor
- St. Jude Children's Research HospitalUniversity, hospital or other
- Study start
- Jul 1998
- Primary completion
- Jul 2002 (actual)
- Study completion
- Jul 2002 (actual)
- First posted
- 16 Sep 2005 (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.
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, (e.g., 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 (e.g. 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 mg/m2 for standard risk and 250 mg/m2 for low-risk cases will be given over 1 hour, followed immediately by maintenance infusion (4500 mg/m2 for standard/high-risk or 2250 mg/m2 for low-risk cases) over 23 hours.
Remission Induction Therapy (6-7 weeks) The remaining induction treatment will begin with Prednisone 40 mg/m2/day PO (tid) Days 5-32, Vincristine 1.5 mg/m2/week IV days 5, 12, 19, 26, Daunorubicin 25 mg/m2/week IV days 5, 12, L-asparaginase 10,000 U/m2/dose IM (thrice weekly) days 6, 8, 10, 12, 14, 16 (19, 21, 23), and triple intrathecal treatment, followed by Etoposide 300 mg/m2/dose IV over 2 hr days 26, 29, 33, plus Cytarabine 300 mg/m2/dose 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 patient's risk of CNS relapse.
Consolidation (2 weeks) Patients receive High dose Methotrexate (HDMTX) 2.5 gm/m2 (low-risk) or 5 gm/m2 (standard-or-high-risk) IV over 24 hr days 1 and 8 and 6-Mercaptopurine 25 mg/m2/day 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 ≥300/mm3 and platelet count ≥ 50 x 109/L. 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 standard/high risk cases; weeks 12 to 15 and weeks 28-31 for low-risk cases. Leucovorin rescue (5 mg/m2) 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 standard/high risk patients.
Standard- or High-Risk Leukemia
- DEX (dexamethasone) 8 mg/m2 PO daily (tid) x 7 days and VCR (vincristine) 1.5 mg/m2 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 mg/m2 IV over 2 hours and CTX (cyclophosphamide) 300 mg/m2 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 mg/m2 PO daily x 7 days and MTX (methotrexate) 40 mg/m2 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 mg/m2 IV or IM and Ara-C (cytarabine) 300 mg/m2 IV push will be given weeks4, 20, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, and 116.
- 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and HDMTX 5 gm/ gm/m2 will be given week 7 and 23.
- HDMTX 5 gm/ gm/m2 and Ara-C (cytarabine) 300 mg/m2 IV push will be given weeks 15 and 31.
Reinduction Treatment-Standard/High Risk
- DEX (dexamethasone) 8 mg/m2 PO daily (tid) days 1-21,
- VCR (vincristine) 1.5 mg/m2/week IV (max. 2 mg) days 1, 8, and 15
- PEG-asparaginase 2500 U/m2/week IM weeks 28-31, days 8, and 15
- Idarubicin 5 mg/m2/week IV days 1 and 8
- HDMTX 5 gm/m2 IV day 22
- ITMHA (methotrexate+hydrocortisone+ara-C), age dependent, IT day 1
- High-dose cytarabine 2 gm/m2 IV q 12 hr Days 23, and 24 Low Risk
- 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and MTX (methotrexate) 40 mg/m2 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 mg/m2 PO daily x 7 days, MTX (methotrexate) 40 mg/m2 IV or IM, DEX (dexamethasone) 8 mg/m2 PO daily (tid) x 7 days and VCR (vincristine) 1.5 mg/m2 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 mg/m2 PO daily x 7 days and HDMTX 2.5 gm/m2 weeks 7, 15, 23 and 31.
Reinduction Treatment-Low Risk
- DEX (dexamethasone) 8 mg/m2 PO daily days 1-21,
- VCR (vincristine) 1.5 mg/m2/week IV push (max. 2 mg) days 1, 8, and 15
- PEG-asparaginase 2500 U/m2/week IM days 8, and 15
- Idarubicin 5 mg/m2/week IV day 1
- HDMTX 2.5 gm/m2 day 22
- ITMHA (methotrexate+hydrocortisone+ara-C), age dependent, IT day 1 and 22
- 6 MP 75 mg/m2/day 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 standard/high-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 standard/high-risk cases with WBC ≥100 x 109/L, T-cell ALL with WBC ≥50 x 109/L, 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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Other | Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase, Drug: L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine |
Who may qualify
- Ages
- Up to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (4 listed)
- Diagnosis of non-B-cell leukemia by immunophenotyping (e.g. T-cell, B-cell precursor, or acute undifferentiated leukemia)
- Ages less than or equal to 18 years of age
- One week or less of prior therapy, limited to glucocorticoids, vinca alkaloids, emergency radiation therapy to the mediastinum and one dose of intrathecal chemotherapy Exclusion Criteria
- Participants greater than 18 years of age
Key exclusion criteria (0 listed)
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 |
|---|---|---|
| Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginaseSee Detailed Description section for details of treatment interventions. | Drug | 1 |
| L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, MercaptopurineSee Detailed Description section for details of treatment interventions. | Drug | 1 |
Primary outcome
To determine if CNS irradiation can be safely omitted with early intensification of systemic and intrathecal chemotherapy.
Time frame: Unable to determine
Results and safety
The study was stopped early (reason given: Toxicity). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Mar 2011.
- BackgroundHammond TG, Hu A, Hammond JM, Relling MV, Underwood JL. Detection of point mutations on a DNA microchip Clinical Immunology Newsletter 19(12):121-6, 1999.
- Background: PubMed 11157020Pui CH, Mahmoud HH, Wiley JM, Woods GM, Leverger G, Camitta B, Hastings C, Blaney SM, Relling MV, Reaman GH. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma. J Clin Oncol. 2001 Feb 1;19(3):697-704. doi: 10.1200/JCO.2001.19.3.697.
- Background: PubMed 11587206Pui CH, Jeha S, Irwin D, Camitta B. Recombinant urate oxidase (rasburicase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results of a compassionate-use trial. Leukemia. 2001 Oct;15(10):1505-9. doi: 10.1038/sj.leu.2402235.
- Background: PubMed 12439601Panetta JC, Yanishevski Y, Pui CH, Sandlund JT, Rubnitz J, Rivera GK, Ribeiro R, Evans WE, Relling MV. A mathematical model of in vivo methotrexate accumulation in acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2002 Nov;50(5):419-28. doi: 10.1007/s00280-002-0511-x. Epub 2002 Sep 24.
- Background: PubMed 12070008Coustan-Smith E, Sancho J, Behm FG, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, Pui CH, Campana D. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood. 2002 Jul 1;100(1):52-8. doi: 10.1182/blood-2002-01-0006.
- Background: PubMed 12239148Coustan-Smith E, Sancho J, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, Pui CH, Campana D. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood. 2002 Oct 1;100(7):2399-402. doi: 10.1182/blood-2002-04-1130.
- Background: PubMed 12086872Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, Evans WE, Naeve C, Wong L, Downing JR. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002 Mar;1(2):133-43. doi: 10.1016/s1535-6108(02)00032-6.
- Background: PubMed 12114448Panetta JC, Wall A, Pui CH, Relling MV, Evans WE. Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity. Clin Cancer Res. 2002 Jul;8(7):2423-9.
- Background: PubMed 12704389Cheok MH, Yang W, Pui CH, Downing JR, Cheng C, Naeve CW, Relling MV, Evans WE. Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nat Genet. 2003 May;34(1):85-90. doi: 10.1038/ng1151.
- Background: PubMed 12915598Kishi S, Griener J, Cheng C, Das S, Cook EH, Pei D, Hudson M, Rubnitz J, Sandlund JT, Pui CH, Relling MV. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol. 2003 Aug 15;21(16):3084-91. doi: 10.1200/JCO.2003.07.056.
- Background: PubMed 15129886Hinds PS, Gattuso JS, Fletcher A, Baker E, Coleman B, Jackson T, Jacobs-Levine A, June D, Rai SN, Lensing S, Pui CH. Quality of life as conveyed by pediatric patients with cancer. Qual Life Res. 2004 May;13(4):761-72. doi: 10.1023/B:QURE.0000021697.43165.87.
- Background: PubMed 15057247Hak LJ, Relling MV, Cheng C, Pei D, Wang B, Sandlund JT, Rubnitz J, Pui CH. Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia. Leukemia. 2004 Jun;18(6):1072-7. doi: 10.1038/sj.leu.2403351.
- St. Jude Children's Research HospitalLink provided by the sponsor.
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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.
Ching-Hon Pui, MD principal investigator
St. Jude Children's Research Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase and L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine in people with Acute Lymphoblastic Leukemia, run by St. Jude Children's Research Hospital at 1 site in United States.
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 4 inclusion and 0 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: stopped early, as of the sponsor's last update on 30 Mar 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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 was stopped early (reason given: Toxicity). 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?
To determine if CNS irradiation can be safely omitted with early intensification of systemic and intrathecal chemotherapy. (time frame: Unable to determine). 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 NCT00187005, which also lists 31 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 30 Mar 2011.