Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

Overview[ - collapse ][ - ]

Purpose 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.
ConditionLymphoblastic Leukemia, Acute
InterventionDrug: 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
PhasePhase 3
SponsorSt. Jude Children's Research Hospital
Responsible PartySt. Jude Children's Research Hospital
ClinicalTrials.gov IdentifierNCT00137111
First ReceivedAugust 25, 2005
Last UpdatedMay 28, 2013
Last verifiedMay 2013

Tracking Information[ + expand ][ + ]

First Received DateAugust 25, 2005
Last Updated DateMay 28, 2013
Start DateJune 2000
Estimated Primary Completion DateNovember 2020
Current Primary Outcome Measures
  • Overall Event-free Survival (EFS) [Time Frame: Median follow-up time (range) 5.6 (1.3 to 8.9) years] [Designated as safety issue: No]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] [Designated as safety issue: No]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.
Current Secondary Outcome Measures
  • Minimal Residual Disease (MRD) [Time Frame: End of Induction (Day 46 MRD measurement)] [Designated as safety issue: No]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)] [Designated as safety issue: No]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] [Designated as safety issue: No]White blood cell (leukocytes) counts in peripheral blood by Complete Blood Count
    Measurement: Percentage change of leukemia cells from baseline

Descriptive Information[ + expand ][ + ]

Brief TitleTherapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Official TitleTotal 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 TypeInterventional
Study PhasePhase 3
Study DesignAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionLymphoblastic Leukemia, Acute
InterventionDrug: 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 Arm (s)
  • Other: 1
  • Other: 2

Recruitment Information[ + expand ][ + ]

Recruitment StatusActive, not recruiting
Estimated Enrollment501
Estimated Completion DateNovember 2020
Estimated Primary Completion DateNovember 2010
Eligibility Criteria
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.
GenderBoth
Ages12 Months
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesUnited States

Administrative Information[ + expand ][ + ]

NCT Number NCT00137111
Other Study ID NumbersTOTXV
Has Data Monitoring CommitteeYes
Information Provided BySt. Jude Children's Research Hospital
Study SponsorSt. Jude Children's Research Hospital
CollaboratorsNational Cancer Institute (NCI)
Investigators Principal Investigator: Ching-Hon Pui, M.D. St. Jude Children's Research Hospital
Verification DateMay 2013

Locations[ + expand ][ + ]

St Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Cook Children's Medical Center
Fort Worth, Texas, United States, 76104