Lymphoblastic Leukemia, AcutePhase 3NCT00137111
Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
A Phase 3 study testing Prednisone, Dexamethasone, Vincristine, Daunorubicin, Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase and Methotrexate, Cyclophosphamide, Cytarabine, Etoposide in people with Lymphoblastic Leukemia, Acute, run by St. Jude Children's Research Hospital at 2 sites in United States.
Trial summary
The primary objective is to estimate the overall event-free survival of children at least one year of age at diagnosis who are treated with risk-directed therapy and to monitor the molecular remission induction rate. Read more about this study
- Who is it for?
- Ages 12 months to 18 years
- Conditions the study is for
- Lymphoblastic Leukemia, Acute
- What is being tested?
- Prednisone, Dexamethasone, Vincristine, Daunorubicin, Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase and Methotrexate, Cyclophosphamide, Cytarabine, Etoposide
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 501 participants
- Where
- 2 sitesUnited States
- Study dates
- 8 Jul 2000to Apr 2014
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 12 months to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Diagnosis of non-B-cell ALL by immunophenotyping, as determined by the reactivity pattern to a panel of monoclonal antibodies with flow cytometry as well as morphology and cytochemical staining.
- Age range: 1 to 18 years (inclusive).
Who cannot join
- Previously treated with chemotherapy for one week or longer.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Cook Children's Medical Center
Fort Worth, Texas, 76104
St Jude Children's Research Hospital
Memphis, Tennessee, 38105
About this study
Official title: Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
The primary objective is to estimate the overall event-free survival of children at least one year of age at diagnosis who are treated with risk-directed therapy and to monitor the molecular remission induction rate.
Read the detailed description
These are the following secondary objectives:
- To determine if CNS irradiation can be safely omitted in the context of the systemic therapy used in the protocol.
- To identify whether prolonged (24 hour) intravenous infusions of HDMTX produce greater methotrexate polyglutamate (MTXPG) accumulation than short (4 hour) infusions 42 hours after 1 gm/m2 of HDMTX, stratified for lineage (T- vs B-lineage) and ploidy (hyperdiploid vs non-hyperdiploid B-lineage).
- To determine whether prolonged (24 hour) intravenous infusions of HDMTX produce greater antileukemic effects than short (4 hour) infusions, based on the inhibition of de novo purine synthesis in bone marrow blasts and the decrease in circulating blasts during the 4 day "window" prior to initiation of conventional remission induction therapy.
- MRD
- Other exploratory objectives
Details of Treatment Plan
Treatment will consist of three main phases, Remission Induction, Consolidation, and Continuation. Treatment with an Upfront HDMTX Window for research purposes will be optional.
All patients will receive IT therapy on day 1, dose is age dependent.
Upfront High-Dose Methotrexate Window
HDMTX (1 g/m2) as a 4 hour infusion versus as a 24 hour infusion. Leucovorin rescue will be given.
Remission Induction
Prednisone 40 mg/m2/day PO 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 Unit/m2/dose IM Days 6, 8, 10, 12, 14, 16 (19, 21, 23) Cyclophosphamide 1000 mg/m2/dose IV Day 26 Cytarabine 75 mg/m2/dose IV Days 27-30, 34-37 6-Mercaptopurine 60 mg/m2/dose PO Days 26-39 Imatinib 40 mg/m2 bid for Ph positive patients starting Day 22 of induction. Intrathecal therapy will be administered on day 1 and 19, dose age dependent. Patients with high risk of CNS relapse will receive additional IT treatments on days 8 and 26.
Consolidation Treatment
High dose methotrexate targeted dose depending on risk status, days 1, 15, 29, and 43 and mercaptopurine 50 mg/m2/day, days 1-56.
Reintensification treatment for patients with high risk disease:
Patients with high risk disease will be offered the option of hematopoietic stem cell transplant (HSCT) and may receive an additional 1-2 cycles of reintensification treatment prior to maximize the anti-leukemic kill before transplant.
Dexamethasone 20 mg/m2 PO days 1-3 Cytarabine 2 g/m2 IV x 4 doses, days 3-5 Etoposide 100 mg/m2 IV x 5 doses, days 3-5 L-asparaginase 25,000 Units/m2 IM day 6 Intrathecal treatment Day 5
Continuation Treatment (lasts 120 weeks for girls and 146 weeks for boys)
Treatment will depend on risk classification: low versus standard versus high risk
Treatment weeks 1 to 20:
Week Standard/High Risk Low Risk
- DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
- 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
- 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- Reinduction I§ Reinduction I
- Reinduction I Reinduction I
- Reinduction I Reinduction I
- 6MP + ASP 6MP + MTX
- DOX + VCR + 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
- 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- Reinduction II Reinduction II
- Reinduction II Reinduction II
- Reinduction II Reinduction II
- No chemotherapy 6MP + MTX Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5 days, Days 1-5 Doxorubicin 30 mg/m2 IV, Day 1 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1 Mercaptopurine 50 mg/m2 PO daily x 7 days (std/high risk), Days 1-7 75 mg/m2 PO daily x 7 days (low risk), Days 1-7 L-asparaginase 25,000 Unit/m2 IM, Day 1 Methotrexate 40 mg/m2 IV or IM, Day 1 Reinduction I and II This phase of treatment will be started at weeks 7 and 17 after bone marrow examination confirms complete remission. Reinduction treatment will be given twice: weeks 7 to 9 and weeks 17 to 19 for all patients. Reinduction I for Standard/High Risk ALL: Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15, 21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, Doxorubicin 30 mg/m2 Days 1, 8, L-asparaginase 25,000 Unit/m2 IM Days 1, 8, 15, Intrathecal chemotherapy, dose age dependent Day 1. Reinduction II for Standard/High Risk ALL: Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, L-asparaginase 25,000 Unit/m2, weekly IM Days 1, 8, 17, Intrathecal chemotherapy, dose age dependent Day 1 High-dose cytarabine 2 gm/m2 IV q 12 Days 15, 16 Reinduction I and II for Low Risk ALL Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21 Vincristine 1.5 mg/m2/week IV (max 2 mg), Days 1, 8, 15 L-asparaginase 10,000 Unit/m2/thrice weekly IM Days 2, 4, 6, 8, 10, 12, 15, 17, 19 Doxorubicin 30 mg/m2/week IV Day 1 Intrathecal chemotherapy, dose age dependent on Day 1 Treatment Weeks 21 to end of therapy Week Standard/High Risk Low Risk
- 6MP + MTX 6MP + MTX
- 6MP + MTX 6MP + MTX
- Cyclo + Ara-C 6MP + MTX
- DEX + VCR 6MP + DEX + VCR
- 6MP + MTX 6MP + MTX
- 6MP + MTX 6MP + MTX
- Cyclo + Ara-C 6MP + MTX
- DEX + VCR 6MP + DEX + VCR
Mercaptopurine 75 mg/m2 PO, daily x 7 days, Days 1-7 Methotrexate 40 mg/m2 IV or IM, Day 1 Cyclophosphamide 300 mg/m2 IV, Day 1 Cytarabine 300 mg/m2 IV, Day 1 Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5, Day 1-5 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1
The same treatment (weeks 21-28) will be repeated for a total of 6 times (until week 68). After week 68, all patients will receive daily 6MP and weekly MTX with pulses of dexamethasone and vincristine every 4 weeks until week 100, after which only 6MP and methotrexate will be given. Intrathecal treatment will be given every 8 weeks only to patients at high risk of CNS relapse after week 48 and will be discontinued after week 96. Continuation therapy will be discontinued after 120 weeks in girls and after 146 weeks in boys
Patients who meet the criteria of high-risk ALL are candidates for allogeneic hematopoietic stem cell transplantation. However, if the option is declined by the patients or guardians, or the procedure is deemed unsuitable by the attending physician and the principal investigator, the patient will remain on study and continue to receive chemotherapy
- Conditions
- Lymphoblastic Leukemia, Acute
- Being tested
- Prednisone, Dexamethasone, Vincristine, Daunorubicin, Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase, Methotrexate, Cyclophosphamide, Cytarabine, Etoposide, Mercaptopurine, Imatinib, chemotherapy, intrathecal chemotherapy
- 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, DaunorubicinDrug
See Detailed Description sections for details on treatment interventions.
Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginaseDrug
See Detailed Description sections for details on treatment interventions.
Methotrexate, Cyclophosphamide, Cytarabine, EtoposideDrug
See Detailed Description sections for details on treatment interventions.
Mercaptopurine, ImatinibDrug
See Detailed Description sections for details on treatment interventions.
chemotherapy, intrathecal chemotherapyProcedure or surgery
See Detailed Description sections for details on treatment interventions.
steroid therapy, hematopoietic stem cell transplantationProcedure or surgery
See Detailed Description sections for details on treatment interventions.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Other | Not described Receives: Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin; Drug: Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase; Drug: Methotrexate, Cyclophosphamide, Cytarabine, Etoposide; Drug: Mercaptopurine, Imatinib; Procedure: chemotherapy, intrathecal chemotherapy; Procedure: steroid therapy, hematopoietic stem cell transplantation |
| 2 | Other | Not described Receives: Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin; Drug: Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase; Drug: Methotrexate, Cyclophosphamide, Cytarabine, Etoposide; Drug: Mercaptopurine, Imatinib; Procedure: chemotherapy, intrathecal chemotherapy; Procedure: steroid therapy, hematopoietic stem cell transplantation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Event-free Survival (EFS)
EFS was measured from the start of on-study to the date of first treatment failure of any kind (relapse, death, lineage switch, or second malignancy) or to the last date of follow-up. Failure to enter remission was considered an event at time zero. Measurement was determined by Kaplan-Meyer estimate.
Measured: Median follow-up time (range) 5.6 (1.3 to 8.9) years
Continuous Complete Remission Since Week 56 Therapy.
CCR was measured from end of week 56 therapy to the date of first treatment failure of any kind (relapse, death, lineage switch, or second malignancy) or to the last date of follow-up. Measurement was determined by Kaplan-Meyer estimate.
Measured: Median follow up time (range) 4.5 (1 to 7.8) years
Secondary outcomes (3)
Minimal Residual Disease (MRD)
Detection of MRD at end of induction where positive MRD was defined as one or more leukemic cell per 10,000 mononuclear bone-marrow cells (>=0.01%).
Measured: End of Induction (Day 46 MRD measurement)
Mean Difference of Active Methotrexate Polyglutamates (MTXPG) in Leukemia Cells Between Two Arms (4 Hours vs. 24 Hours).
Children were randomly assigned to receive initial single-agent treatment with HDMTX (1g/m^2) as either a 24-hour infusion or a 4-hour infusion and the outcome measure was the accumulation of MTXPG in leukemia cells.
Measured: 42 hours after start of high dose methotrexate infusion (HDMTX)
Circulating Leukemia Cells in Peripheral Blood Change From Prior to the Methotrexate Infusion to Three Days After Between Two Arms (4 Hours vs. 24 Hours)
White blood cell (leukocytes) counts in peripheral blood by Complete Blood Count
Measurement: Percentage change of leukemia cells from baseline
Measured: Immediately before the methotrexate infusion and three days after subsequent infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Aug 2005 (estimated)
- Study start8 Jul 2000
- Primary completionNov 2010
- Study completionApr 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (208)Papers the sponsor has linked to this study.
- Other trials for Lymphoblastic Leukemia, AcuteStudies 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
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 501 participants (actual)
Sponsor and investigators
- Lead sponsor
- St. Jude Children's Research Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Ching-Hon Pui, M.D., Principal investigator, St. Jude Children's Research Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00137111
- Sponsor's protocol ID
- TOTXV
- Other IDs
- R37CA036401, P30CA021765, F32CA141762
- Status last verified
- Sep 2020
- First submitted
- 25 Aug 2005
- Last updated
- 11 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Yeoh 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 12086872Coustan-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 12239148Cheok 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 12704389Neale 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 15029212Pauley JL, Panetta JC, Schmidt J, Kornegay N, Relling MV, Pui CH. Late-onset delayed excretion of methotrexate. Cancer Chemother Pharmacol. 2004 Aug;54(2):146-52. doi: 10.1007/s00280-004-0797-y. Epub 2004 May 18.
PubMed 15148625Pui CH, Relling MV, Sandlund JT, Downing JR, Campana D, Evans WE. Rationale and design of Total Therapy Study XV for newly diagnosed childhood acute lymphoblastic leukemia. Ann Hematol. 2004;83 Suppl 1:S124-6. doi: 10.1007/s00277-004-0850-2.
PubMed 15124703Cheng 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 15284538Zaza G, Yang W, Kager L, Cheok M, Downing J, Pui CH, Cheng C, Relling MV, Evans WE. Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis. Blood. 2004 Sep 1;104(5):1435-41. doi: 10.1182/blood-2003-12-4306. Epub 2004 May 13.
PubMed 15142881Hijiya N, Onciu M, Howard SC, Zhang Z, Cheng C, Sandlund JT, Kyzer EP, Behm FG, Pui CH. Utility of automated counting to determine absolute neutrophil counts and absolute phagocyte counts for pediatric cancer treatment protocols. Cancer. 2004 Dec 1;101(11):2681-6. doi: 10.1002/cncr.20677.
PubMed 15517573Kager L, Cheok M, Yang W, Zaza G, Cheng Q, Panetta JC, Pui CH, Downing JR, Relling MV, Evans WE. Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J Clin Invest. 2005 Jan;115(1):110-7. doi: 10.1172/JCI22477.
PubMed 15630450Lowe EJ, Pui CH, Hancock ML, Geiger TL, Khan RB, Sandlund JT. Early complications in children with acute lymphoblastic leukemia presenting with hyperleukocytosis. Pediatr Blood Cancer. 2005 Jul;45(1):10-5. doi: 10.1002/pbc.20178.
PubMed 15547931McCarville MB, Adelman CS, Li C, Xiong X, Furman WL, Razzouk BI, Pui CH, Sandlund JT. Typhlitis in childhood cancer. Cancer. 2005 Jul 15;104(2):380-7. doi: 10.1002/cncr.21134.
PubMed 15952190Cheng Q, Yang W, Raimondi SC, Pui CH, Relling MV, Evans WE. Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes. Nat Genet. 2005 Aug;37(8):878-82. doi: 10.1038/ng1612. Epub 2005 Jul 24.
PubMed 16041371Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006 Jan 12;354(2):166-78. doi: 10.1056/NEJMra052603. No abstract available.
PubMed 16407512Coustan-Smith E, Ribeiro RC, Stow P, Zhou Y, Pui CH, Rivera GK, Pedrosa F, Campana D. A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have a superior clinical outcome. Blood. 2006 Jul 1;108(1):97-102. doi: 10.1182/blood-2006-01-0066. Epub 2006 Mar 14.
PubMed 16537802
Study at a glance
From the registry record, last updated by the sponsor on 11 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
- ClinicalTrials.gov ID
- NCT00137111
- Acronym / sponsor ID
- TOTXV
- Conditions
- Lymphoblastic Leukemia, Acute
- Keywords
- Leukemia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 501 participants (actual)
- Lead sponsor
- St. Jude Children's Research HospitalUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- 8 Jul 2000 (actual)
- Primary completion
- Nov 2010 (actual)
- Study completion
- Apr 2014 (actual)
- First posted
- 29 Aug 2005 (estimated)
- Results
- Posted 26 Apr 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective is to estimate the overall event-free survival of children at least one year of age at diagnosis who are treated with risk-directed therapy and to monitor the molecular remission induction rate.
Detailed description
These are the following secondary objectives:
- To determine if CNS irradiation can be safely omitted in the context of the systemic therapy used in the protocol.
- To identify whether prolonged (24 hour) intravenous infusions of HDMTX produce greater methotrexate polyglutamate (MTXPG) accumulation than short (4 hour) infusions 42 hours after 1 gm/m2 of HDMTX, stratified for lineage (T- vs B-lineage) and ploidy (hyperdiploid vs non-hyperdiploid B-lineage).
- To determine whether prolonged (24 hour) intravenous infusions of HDMTX produce greater antileukemic effects than short (4 hour) infusions, based on the inhibition of de novo purine synthesis in bone marrow blasts and the decrease in circulating blasts during the 4 day "window" prior to initiation of conventional remission induction therapy.
- MRD
- Other exploratory objectives
Details of Treatment Plan
Treatment will consist of three main phases, Remission Induction, Consolidation, and Continuation. Treatment with an Upfront HDMTX Window for research purposes will be optional.
All patients will receive IT therapy on day 1, dose is age dependent.
Upfront High-Dose Methotrexate Window
HDMTX (1 g/m2) as a 4 hour infusion versus as a 24 hour infusion. Leucovorin rescue will be given.
Remission Induction
Prednisone 40 mg/m2/day PO 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 Unit/m2/dose IM Days 6, 8, 10, 12, 14, 16 (19, 21, 23) Cyclophosphamide 1000 mg/m2/dose IV Day 26 Cytarabine 75 mg/m2/dose IV Days 27-30, 34-37 6-Mercaptopurine 60 mg/m2/dose PO Days 26-39 Imatinib 40 mg/m2 bid for Ph positive patients starting Day 22 of induction. Intrathecal therapy will be administered on day 1 and 19, dose age dependent. Patients with high risk of CNS relapse will receive additional IT treatments on days 8 and 26.
Consolidation Treatment
High dose methotrexate targeted dose depending on risk status, days 1, 15, 29, and 43 and mercaptopurine 50 mg/m2/day, days 1-56.
Reintensification treatment for patients with high risk disease:
Patients with high risk disease will be offered the option of hematopoietic stem cell transplant (HSCT) and may receive an additional 1-2 cycles of reintensification treatment prior to maximize the anti-leukemic kill before transplant.
Dexamethasone 20 mg/m2 PO days 1-3 Cytarabine 2 g/m2 IV x 4 doses, days 3-5 Etoposide 100 mg/m2 IV x 5 doses, days 3-5 L-asparaginase 25,000 Units/m2 IM day 6 Intrathecal treatment Day 5
Continuation Treatment (lasts 120 weeks for girls and 146 weeks for boys)
Treatment will depend on risk classification: low versus standard versus high risk
Treatment weeks 1 to 20:
Week Standard/High Risk Low Risk
- DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
- 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
- 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- Reinduction I§ Reinduction I
- Reinduction I Reinduction I
- Reinduction I Reinduction I
- 6MP + ASP 6MP + MTX
- DOX + VCR + 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
- 6MP + ASP 6MP + MTX
- 6MP + ASP 6MP + MTX
- Reinduction II Reinduction II
- Reinduction II Reinduction II
- Reinduction II Reinduction II
- No chemotherapy 6MP + MTX Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5 days, Days 1-5 Doxorubicin 30 mg/m2 IV, Day 1 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1 Mercaptopurine 50 mg/m2 PO daily x 7 days (std/high risk), Days 1-7 75 mg/m2 PO daily x 7 days (low risk), Days 1-7 L-asparaginase 25,000 Unit/m2 IM, Day 1 Methotrexate 40 mg/m2 IV or IM, Day 1 Reinduction I and II This phase of treatment will be started at weeks 7 and 17 after bone marrow examination confirms complete remission. Reinduction treatment will be given twice: weeks 7 to 9 and weeks 17 to 19 for all patients. Reinduction I for Standard/High Risk ALL: Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15, 21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, Doxorubicin 30 mg/m2 Days 1, 8, L-asparaginase 25,000 Unit/m2 IM Days 1, 8, 15, Intrathecal chemotherapy, dose age dependent Day 1. Reinduction II for Standard/High Risk ALL: Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, L-asparaginase 25,000 Unit/m2, weekly IM Days 1, 8, 17, Intrathecal chemotherapy, dose age dependent Day 1 High-dose cytarabine 2 gm/m2 IV q 12 Days 15, 16 Reinduction I and II for Low Risk ALL Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21 Vincristine 1.5 mg/m2/week IV (max 2 mg), Days 1, 8, 15 L-asparaginase 10,000 Unit/m2/thrice weekly IM Days 2, 4, 6, 8, 10, 12, 15, 17, 19 Doxorubicin 30 mg/m2/week IV Day 1 Intrathecal chemotherapy, dose age dependent on Day 1 Treatment Weeks 21 to end of therapy Week Standard/High Risk Low Risk
- 6MP + MTX 6MP + MTX
- 6MP + MTX 6MP + MTX
- Cyclo + Ara-C 6MP + MTX
- DEX + VCR 6MP + DEX + VCR
- 6MP + MTX 6MP + MTX
- 6MP + MTX 6MP + MTX
- Cyclo + Ara-C 6MP + MTX
- DEX + VCR 6MP + DEX + VCR
Mercaptopurine 75 mg/m2 PO, daily x 7 days, Days 1-7 Methotrexate 40 mg/m2 IV or IM, Day 1 Cyclophosphamide 300 mg/m2 IV, Day 1 Cytarabine 300 mg/m2 IV, Day 1 Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5, Day 1-5 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1
The same treatment (weeks 21-28) will be repeated for a total of 6 times (until week 68). After week 68, all patients will receive daily 6MP and weekly MTX with pulses of dexamethasone and vincristine every 4 weeks until week 100, after which only 6MP and methotrexate will be given. Intrathecal treatment will be given every 8 weeks only to patients at high risk of CNS relapse after week 48 and will be discontinued after week 96. Continuation therapy will be discontinued after 120 weeks in girls and after 146 weeks in boys
Patients who meet the criteria of high-risk ALL are candidates for allogeneic hematopoietic stem cell transplantation. However, if the option is declined by the patients or guardians, or the procedure is deemed unsuitable by the attending physician and the principal investigator, the patient will remain on study and continue to receive chemotherapy
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Other | Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin, Drug: Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase, Drug: Methotrexate, Cyclophosphamide, Cytarabine, Etoposide, Drug: Mercaptopurine, Imatinib, Procedure: chemotherapy, intrathecal chemotherapy, Procedure: steroid therapy, hematopoietic stem cell transplantation |
| 2 | Other | Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin, Drug: Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase, Drug: Methotrexate, Cyclophosphamide, Cytarabine, Etoposide, Drug: Mercaptopurine, Imatinib, Procedure: chemotherapy, intrathecal chemotherapy, Procedure: steroid therapy, hematopoietic stem cell transplantation |
Who may qualify
- Ages
- 12 months to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (2 listed)
- Diagnosis of non-B-cell ALL by immunophenotyping, as determined by the reactivity pattern to a panel of monoclonal antibodies with flow cytometry as well as morphology and cytochemical staining.
- Age range: 1 to 18 years (inclusive).
Key exclusion criteria (1 listed)
- Previously treated with chemotherapy for one week or longer.
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, DaunorubicinSee Detailed Description sections for details on treatment interventions. | Drug | 1, 2 |
| Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginaseSee Detailed Description sections for details on treatment interventions. | Drug | 1, 2 |
| Methotrexate, Cyclophosphamide, Cytarabine, EtoposideSee Detailed Description sections for details on treatment interventions. | Drug | 1, 2 |
| Mercaptopurine, ImatinibSee Detailed Description sections for details on treatment interventions. | Drug | 1, 2 |
| chemotherapy, intrathecal chemotherapySee Detailed Description sections for details on treatment interventions. | Procedure or surgery | 1, 2 |
| steroid therapy, hematopoietic stem cell transplantationSee Detailed Description sections for details on treatment interventions. | Procedure or surgery | 1, 2 |
Primary outcome
Overall Event-free Survival (EFS)
Time frame: Median follow-up time (range) 5.6 (1.3 to 8.9) years
EFS was measured from the start of on-study to the date of first treatment failure of any kind (relapse, death, lineage switch, or second malignancy) or to the last date of follow-up. Failure to enter remission was considered an event at time zero. Measurement was determined by Kaplan-Meyer estimate.
Continuous Complete Remission Since Week 56 Therapy.
Time frame: Median follow up time (range) 4.5 (1 to 7.8) years
CCR was measured from end of week 56 therapy to the date of first treatment failure of any kind (relapse, death, lineage switch, or second malignancy) or to the last date of follow-up. Measurement was determined by Kaplan-Meyer estimate.
3 secondary outcomes
Minimal Residual Disease (MRD)
Time frame: End of Induction (Day 46 MRD measurement)
Mean Difference of Active Methotrexate Polyglutamates (MTXPG) in Leukemia Cells Between Two Arms (4 Hours vs. 24 Hours).
Time frame: 42 hours after start of high dose methotrexate infusion (HDMTX)
Circulating Leukemia Cells in Peripheral Blood Change From Prior to the Methotrexate Infusion to Three Days After Between Two Arms (4 Hours vs. 24 Hours)
Time frame: Immediately before the methotrexate infusion and three days after subsequent infusion
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- 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 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 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 15029212Neale 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.
- Background: PubMed 15148625Pauley JL, Panetta JC, Schmidt J, Kornegay N, Relling MV, Pui CH. Late-onset delayed excretion of methotrexate. Cancer Chemother Pharmacol. 2004 Aug;54(2):146-52. doi: 10.1007/s00280-004-0797-y. Epub 2004 May 18.
- Background: PubMed 15124703Pui CH, Relling MV, Sandlund JT, Downing JR, Campana D, Evans WE. Rationale and design of Total Therapy Study XV for newly diagnosed childhood acute lymphoblastic leukemia. Ann Hematol. 2004;83 Suppl 1:S124-6. doi: 10.1007/s00277-004-0850-2.
- Background: PubMed 15284538Cheng 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.
- Background: PubMed 15142881Zaza G, Yang W, Kager L, Cheok M, Downing J, Pui CH, Cheng C, Relling MV, Evans WE. Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis. Blood. 2004 Sep 1;104(5):1435-41. doi: 10.1182/blood-2003-12-4306. Epub 2004 May 13.
- Background: PubMed 15517573Hijiya N, Onciu M, Howard SC, Zhang Z, Cheng C, Sandlund JT, Kyzer EP, Behm FG, Pui CH. Utility of automated counting to determine absolute neutrophil counts and absolute phagocyte counts for pediatric cancer treatment protocols. Cancer. 2004 Dec 1;101(11):2681-6. doi: 10.1002/cncr.20677.
- Background: PubMed 15630450Kager L, Cheok M, Yang W, Zaza G, Cheng Q, Panetta JC, Pui CH, Downing JR, Relling MV, Evans WE. Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J Clin Invest. 2005 Jan;115(1):110-7. doi: 10.1172/JCI22477.
- Background: PubMed 15547931Lowe EJ, Pui CH, Hancock ML, Geiger TL, Khan RB, Sandlund JT. Early complications in children with acute lymphoblastic leukemia presenting with hyperleukocytosis. Pediatr Blood Cancer. 2005 Jul;45(1):10-5. doi: 10.1002/pbc.20178.
- Background: PubMed 15952190McCarville MB, Adelman CS, Li C, Xiong X, Furman WL, Razzouk BI, Pui CH, Sandlund JT. Typhlitis in childhood cancer. Cancer. 2005 Jul 15;104(2):380-7. doi: 10.1002/cncr.21134.
- St Jude Children's Research HospitalLink provided by the sponsor.
- Clinical Trials Open at St. JudeLink 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, M.D. principal investigator
St. Jude Children's Research Hospital
2 sites 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, Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase and Methotrexate, Cyclophosphamide, Cytarabine, Etoposide in people with Lymphoblastic Leukemia, Acute, run by St. Jude Children's Research Hospital at 2 sites 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 2 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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?
Yes. Results are posted in the registry (first posted 26 Apr 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Overall Event-free Survival (EFS) (time frame: Median follow-up time (range) 5.6 (1.3 to 8.9) years). 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 NCT00137111, which also lists 208 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 11 Sep 2020.