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Trial record 1 of 1 for:    26580448 [PUBMED-IDS]
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Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT00137111
Recruitment Status : Completed
First Posted : August 29, 2005
Results First Posted : April 26, 2011
Last Update Posted : August 28, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Tracking Information
First Submitted Date  ICMJE August 25, 2005
First Posted Date  ICMJE August 29, 2005
Results First Submitted Date  ICMJE February 28, 2011
Results First Posted Date  ICMJE April 26, 2011
Last Update Posted Date August 28, 2019
Actual Study Start Date  ICMJE July 8, 2000
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 22, 2011)
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 26, 2005)
To improve the cure rate of children with non-B-cell acute lymphoblastic leukemia without the use of irradiation
Change History Complete list of historical versions of study NCT00137111 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2012)
  • Minimal Residual Disease (MRD) [ Time Frame: End of Induction (Day 46 MRD measurement) ]
    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%).
  • 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) ]
    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.
  • 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 ]
    White blood cell (leukocytes) counts in peripheral blood by Complete Blood Count Measurement: Percentage change of leukemia cells from baseline
Original Secondary Outcome Measures  ICMJE
 (submitted: August 26, 2005)
To assess the prognostic value of biologic markers and the influence of host factors on treatment outcome
Current Other Pre-specified Outcome Measures
 (submitted: June 1, 2016)
  • Median Difference in CASP1 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs Glucocorticoid-sensitive Cells [ Time Frame: Pre-treatment ]
    Prednisolone sensitivity was measured in primary leukemia cells from bone marrow collected at diagnosis. Expression of CASP1 was determined by HG-U133A microarray. Values given are gene expression values, and the unit is arbitrary units (AU) defined as scaled fluorescence measured on microarray.
  • Median Difference in NLRP3 Gene Expression in Primary Leukemia Cells of Patients in Glucocorticoid-resistant Cells vs. Glucocorticoid-sensitive Cells [ Time Frame: Pre-treatment ]
    Prednisolone sensitivity was measured in primary leukemia cells from bone marrow collected at diagnosis. Expression of NLRP3 was determined by HG-U133A microarray. Values given are gene expression values, and the unit is arbitrary units (AU) defined as scaled fluorescence measured on microarray.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Official Title  ICMJE Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Brief 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.
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

  1. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
  2. 6MP + ASP 6MP + MTX
  3. 6MP + ASP 6MP + MTX
  4. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
  5. 6MP + ASP 6MP + MTX
  6. 6MP + ASP 6MP + MTX
  7. Reinduction I§ Reinduction I
  8. Reinduction I Reinduction I
  9. Reinduction I Reinduction I
  10. 6MP + ASP 6MP + MTX
  11. DOX + VCR + 6MP + ASP 6MP + MTX
  12. 6MP + ASP 6MP + MTX
  13. 6MP + ASP 6MP + MTX
  14. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR
  15. 6MP + ASP 6MP + MTX
  16. 6MP + ASP 6MP + MTX
  17. Reinduction II Reinduction II
  18. Reinduction II Reinduction II
  19. Reinduction II Reinduction II
  20. 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

  21. 6MP + MTX 6MP + MTX
  22. 6MP + MTX 6MP + MTX
  23. Cyclo + Ara-C 6MP + MTX
  24. DEX + VCR 6MP + DEX + VCR
  25. 6MP + MTX 6MP + MTX
  26. 6MP + MTX 6MP + MTX
  27. Cyclo + Ara-C 6MP + MTX
  28. 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Lymphoblastic Leukemia, Acute
Intervention  ICMJE
  • Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin
    See Detailed Description sections for details on treatment interventions.
  • Drug: Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase
    See Detailed Description sections for details on treatment interventions.
  • Drug: Methotrexate, Cyclophosphamide, Cytarabine, Etoposide
    See Detailed Description sections for details on treatment interventions.
  • Drug: Mercaptopurine, Imatinib
    See Detailed Description sections for details on treatment interventions.
  • Procedure: chemotherapy, intrathecal chemotherapy
    See Detailed Description sections for details on treatment interventions.
  • Procedure: steroid therapy, hematopoietic stem cell transplantation
    See Detailed Description sections for details on treatment interventions.
Study Arms  ICMJE
  • 1
    Interventions:
    • 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
    Interventions:
    • 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
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 20, 2007)
501
Original Enrollment  ICMJE
 (submitted: August 26, 2005)
430
Actual Study Completion Date  ICMJE April 2014
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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).

Exclusion Criteria:

• Previously treated with chemotherapy for one week or longer.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Months to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00137111
Other Study ID Numbers  ICMJE TOTXV
R37CA036401 ( U.S. NIH Grant/Contract )
P30CA021765 ( U.S. NIH Grant/Contract )
F32CA141762 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party St. Jude Children's Research Hospital
Study Sponsor  ICMJE St. Jude Children's Research Hospital
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Ching-Hon Pui, M.D. St. Jude Children's Research Hospital
PRS Account St. Jude Children's Research Hospital
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP