AzTrials
AzTrials

Acute Lymphoblastic LeukemiaPhase 3NCT00549848

Total Therapy Study XVI for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

A Phase 3 study testing Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine and Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib in people with Acute Lymphoblastic Leukemia, run by St. Jude Children's Research Hospital at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The primary objective of this study (TOTXVI) is to compare the clinical benefit, the pharmacokinetics, and the pharmacodynamics of polyethylene glycol-conjugated (PEG) asparaginase given in higher dose (HD PEG) versus those of PEG-asparaginase given in conventional dose (CD PEG) during the continuation phase. 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, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine and Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
600 participants
Where
1 siteUnited States
Study dates
29 Oct 2007to 26 Mar 2022
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 Up to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Participant has a confirmed diagnosis of precursor B-cell or precursor T-cell acute lymphocytic leukemia (ALL) by immunophenotyping
  • Participant is less than or equal to 18 years of age
  • Limited prior therapy, including systemic glucocorticoids for one week or less, one dose of vincristine, emergency radiation therapy to the mediastinum and one dose of intrathecal chemotherapy. Other circumstances must be cleared by principal investigator (PI) or co-PI.
  • Written, informed consent and assent following Institutional Review Board, NCI, FDA, and Office for Human Research Protections (OHRP) Guidelines.

Who cannot join

  • Participants with prior therapy, other than that listed above
  • Pregnant or lactating
  • Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • St. Jude Children's Research Hospital

    Memphis, Tennessee, 38105

Other trials in United States

About this study

The primary objective of this study (TOTXVI) is to compare the clinical benefit, the pharmacokinetics, and the pharmacodynamics of polyethylene glycol-conjugated (PEG) asparaginase given in higher dose (HD PEG) versus those of PEG-asparaginase given in conventional dose (CD PEG) during the continuation phase.

This study has several secondary objectives:

Read more

Therapeutic Objectives:

To estimate the event-free survival and overall survival of children with ALL who are treated with risk-directed therapy.

To study whether intensifying induction, including fractionated cyclophosphamide and thioguanine, in patients with day 15 MRD > 5%, will result in improved leukemia cytoreduction in this subgroup compared to TOTXV.

To assess whether intensification of central nervous system (CNS)-directed intrathecal and systemic chemotherapy will improve outcome in patients at high risk of CNS relapse.

Exploratory Pharmacologic Objectives:

To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for treatment-related outcomes in the context of the systemic therapy used in the protocol.

To compare the pharmacokinetics and pharmacodynamics of PEG-asparaginase given in higher dose (3,500 or 3,000 units/m2) versus those of PEG-asparaginase given in conventional dose (2,500 units/m2) in the continuation phase.

Exploratory Biologic Objectives:

To determine the prognostic value of levels of minimal residual disease in peripheral blood at day 8 of remission induction.

To validate new markers and methods for MRD detection. To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis and before reinduction, and to associate these features with treatment outcome.

To identify new prognostic factors by applying new technologies to study patient material (e.g., stored plasma, serum, cerebrospinal fluid, and normal and leukemic cells).

Exploratory Neuroimaging Objectives:

To use quantitative MR measures (Diffusion Tensor Imaging and high resolution volumetric imaging) to assess differences in myelin and cortical thickness development in patients treated for ALL relative to healthy controls matched for age and gender.

To assess the impact of folate pathway genetic polymorphisms on myelin and cortical thickness development and neurocognitive performance.

To assess the impact of frontal-parietal lobe myelin and cortical thickness development on neurocognitive performance in attention, working memory, fluency, visual-spatial reasoning and processing speed.

Read the detailed description

Details of the Treatment Plan:

Treatment will consist of three main phases: Remission Induction, Consolidation, and Continuation.

  1. Remission Induction
  • Intrathecal Treatment during Induction Frequency and total number of triple intrathecal treatments for Remission Induction is based on the patient's risk of CNS relapse.All patients will receive triple intrathecal treatment on days 1 and 15. Patients with high risk features may receive additional triple intrathecal treatment on days 4, 8, 11, and 22.[t(1;19)/E2A-PBX1. Induction treatment will begin with prednisone, vincristine, daunorubicin, PEG-asparaginase and triple intrathecal treatment, followed by cyclophosphamide plus cytarabine plus thioguanine. Remission Induction Chemotherapy (6-7 weeks) Prednisone 40 mg/m2/day PO (divided t.i.d.) Days 1 - 28 Dexamethasone will be substituted for prednisone in patients with early T-cell precursor (ETP) immunophenotype. Mercaptopurine will be substituted for thiopurine in TPMT HET/deficient patients Dexamethasone (for ETP immunophenotype only) 10 mg/m2/day PO (divided t.i.d.)Days 1-21; 4 mg/m2/day PO (divided t.i.d) Days 22-24; 2 mg/m2/day PO(divided t.i.d) Days 25-28 Vincristine 1.5 mg/m2 IV (max 2 mg) Days 1, 8, 15, 22 Daunorubicin 25 mg/m2 IV Days 1 and 8 PEG-asparaginase 3,000 Units/m2 IV Day 3
  • Participants with Day 15 MRD greater than or equal to 1%: PEG-asparaginase 3,000 Units/m2 IV Day 15
  • Participants with Day 15 MRD less than 5% (excluding MLL positive infants): Cyclophosphamide 1000 mg/m2 IV Day 22 Cytarabine 75 mg/m2/dose IV Days 23-26, 30-33 Thioguanine [Mercaptopurine (TPMT HET/deficient patients only)]60 mg/m2/dose PO Days 22-35 Dasatinib (Ph+ participants only) 40 mg/m2 b.i.d starting Day 22 of induction to continue until end of treatment Day 15 MRD > or equal to 5% (excluding MLL+ infants) Cyclophosphamide† 300 mg/m2 IV/ q12 hrs on Days 22-23 Cytarabine 75 mg/m2/dose IV Days 23-26, 30-33 Thioguanine [Mercaptopurine (TPMT HET/deficient patients only) 60 mg/m2/dose PO Days 22-35 Dasatinib‡ (Ph+ participants only) 40 mg/m2 b.i.d Daily Starting Day 22 of induction to continue until end of treatment
  • Infants with MLL positive rearrangement: Clofarabine 40 mg/m2/dose IV Days 22-26 Etoposide 100 mg/m2/dose IV Days 22-26 Cyclophosphamide 300 mg/m2/dose IV Days 22-26
  1. Consolidation Treatment (8 weeks) High Dose Methotrexate (HDMTX) 2.5 gm/ (low risk), or targeted 65 μM (std/high-risk) days 1, 15, 29 and 43. Mercaptopurine 50 mg/m2/day Days 1 to 56. All patients will receive triple intrathecal therapy every other week for four doses on Days 1, 15, 29, and 43. Dose is age dependent.
  • Reintensification Patients with high-risk leukemia may receive reintensification therapy and then will be offered the option of transplant. This treatment will attempt to maximize leukemic cell kill before allogeneic hematopoietic stem cell transplantation. Dexamethasone 20 mg/m2/day PO or IV Days 1-6.Cytarabine 2 grams/m2, 3-hour IV infusion every 12 hours Days 1-2. Etoposide 100 mg/m2, 1-hour IV infusion every 12 hours Days 3-5. Intrathecal methotrexate+hydrocortisone+cytarabine (ITMHA) Day 5; PEG-asparaginase 3,000 units/m2 IV Day 6 Patients with suboptimal response to reintensification may receive one to two cycles of clofarabine/cyclophosphamide/etoposide/dexamethasone: Clofarabine 40 mg/m2/day, 2-hour IV infusion Days 1-5 Etoposide 100 mg/m2/day, 2-hour IV infusion Days 1-5 Cyclophosphamide 300 mg/m2/day, 30-60 minute IV infusion Days 1-5 Dexamethasone 8 mg/m2/day (divided t.i.d) Days 1-5
  1. Continuation Treatment (120 weeks)

Abbreviations used below: DEX=dexamethasone; DOX=doxorubicin; VCR=vincristine; MP=mercaptopurine; PEG-ASP=polyethylene glycol-conjugated asparaginase; MTX=methotrexate; 6MP=mercaptopurine

Weeks 1 through 20 - treatment depends on risk assignment standard-high versus low-risk

Week Standard-/High-Risk Low-Risk

  1. DEX+DOX+VCR+MP + PEG-ASP/MP + DEX + VCR
  2. MP MP + MTX
  3. MP + PEG-ASP/MP + MTX
  4. DEX + DOX + VCR + MP/MP + DEX + VCR
  5. MP + PEG-ASP MP + MTX
  6. MP MP + MTX
  7. Reinduction I
  8. Reinduction I
  9. Reinduction I
  10. MP/MP + MTX
  11. DOX + VCR +MP + PEG-ASP/MP + MTX
  12. MP/MP + MTX
  13. MP + PEG-ASP/MP + MTX
  14. DEX + DOX + VCR +6MP/MP + DEX + VCR
  15. MP + PEG-ASP/MP + MTX
  16. MP/MP + MTX
  17. Reinduction II
  18. Reinduction II
  19. Reinduction II
  20. No chemotherapy/MP + MTX Drug Dosages, Schedules and Routes for Continuation Therapy Weeks 1 to 6 and 10 to 16: Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (divided t.i.d.) for 5 days, Days 1-5. Doxorubicin 30 mg/m2 IV, Day 1. Vincristine 2 mg/m2 IV push (max. 2 mg), Day 1 (0.05 mg/kg for patients < 1 year of age or < 10kg in weight). MP (mercaptopurine) 50 mg/m2 PO daily for 7 days (std/high risk), Days 1-7, 75 mg/m2 PO daily for 7 days (low risk), Days 1-7. PEG-ASP (PEG-asparaginase) 2,500 vs. 3,500 units/m2 IV randomization, Day 1. Methotrexate 40 mg/m2 IV Day 1. Dexamethasone, vincristine, and asparaginase will be given regardless of blood counts, provided that the patient is clinically well. Doxorubicin, mercaptopurine and methotrexate will be held if white blood count (WBC) <1000/mm3 or absolute neutrophil count (ANC) <300/mm3. Doxorubicin, mercaptopurine and methotrexate will be reduced for WBC < 1500/mm3, or if WBC and ANC not increase by at least 2 folds a week after the start date of dexamethasone pulse. Reinduction Treatment - This phase of treatment is part of continuation and will be started at weeks 7 and 17 after bone marrow examination confirms complete remission. Doxorubicin and HD-cytarabine will be held if ANC < or equal to 300/mm3 or WBC < 1000/mm3.It is preferable to start HD-cytarabine when WBC > or equal to 1800/mm3 and ANC > 300/mm3 Reinduction treatment will be given twice: weeks 7 to 9 and weeks 17 to 19 for all patients. Intrathecal treatment will be followed by leucovorin rescue (5 mg/m2/dose PO, max 5 mg) at 24 and 30 hours only in patients with prior CNS toxicities or in patients with WBC < 1500/mm3, or ANC < 500/mm3.
  • Reinduction I for Standard/High Risk ALL excluding MLL infants: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15 Doxorubicin 30 mg/m2 IV Days 1, 8. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. Intrathecal chemotherapy, Methotrexate + hydrocortisone + Ara-C dose age dependent, Day 1.
  • Reinduction II for Standard/High Risk ALL including MLL infants: Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. High-dose cytarabine 2 gm/m2 IV q 12 hr Days 15, 16. Intrathecal chemotherapy, dose age dependent, Day 1.
  • Reinduction I for Low-Risk ALL: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. Doxorubicin 30 mg/m2/IV Day 1. Intrathecal chemotherapy, dose age dependent, Day 1.
  • Reinduction II for Low-Risk ALL: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. Intrathecal chemotherapy, dose age dependent, Day 1.
  • Reinduction I for MLL Infants: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days 1-8 and 15-21. Clofarabine 40 mg/m2/day, -hour IV Days 1-5. Etoposide 100 mg/m2/day, 2-hour IV Days 1-5. cyclophosphamide 300 mg/m2/day, 1-hour IV Days 1-5. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. Intrathecal chemotherapy, dose age dependent, on Day 1.
  • Intrathecal Chemotherapy:
  • Triple intrathecal treatment will be given to low-risk cases with CNS-1 status (no identifiable blasts in CSF) on weeks 7, 12, 17, 25, 33, 41, and 49.
  • Triple intrathecal treatment will be given to low-risk cases with CNS-2, traumatic CSF with blasts status, or WBC > 100 x 109/L on weeks 3, 7, 12, 17, 25, 29, 33, 37, 41, 45 and 49.
  • Triple intrathecal treatment will be given to standard/high-risk cases on weeks 7, 12, 17, 25, 29, 33, 37, 41, 45 and 49.
  • Triple intrathecal treatment will be given to other standard/high-risk cases with WBC > or equal to 100 x 109/L, T-cell ALL, t (1;19)/E2A-PBX1, presence of Philadelphia chromosome, MLL rearrangement, hypodiploidy <44, CNS-2 or CNS-3 status, or traumatic lumbar puncture with blasts on weeks 3, 7, 12, 17, 25, 29, 33, 37, 41, 45, 49, 57, 65, 73, 81, 89 and 97 Treatment (weeks 21 to 29) Week Standard/High Risk Low Risk
  1. MP + PEG-ASP+Dasatinib MP + MTX
  2. MP +Dasatinib MP + MTX
  3. MP + PEG-ASP + Dasatinib MP + MTX
  4. Cyclo + Ara-C + Dasatinib MP + MTX
  5. DEX + VCR + PEG-ASP + Dasatinib MP + DEX + VCR
  6. MP + Dasatinib MP + MTX
  7. MP + PEG-ASP+Dasatinib MP + MTX
  8. Cyclo + Ara-C + Dasatinib MP + MTX
  9. DEX + VCR +PEG-ASP + Dasatinib MP + DEX + VCR Dasatinib in Ph+ only Treatment (weeks 30 to end of therapy) Week Standard/High Risk Low Risk
  10. MP + MTX + Dasatinib MP + MTX
  11. MP + MTX + Dasatinib MP + MTX
  12. Cyclo + Ara-C+Dasatinib MP + MTX
  13. DEX + VCR + Dasatinib MP + DEX + VCR
  14. MP + MTX + Dasatinib MP + MTX
  15. MP + MTX + Dasatinib MP + MTX
  16. Cyclo + Ara-C + Dasatinib/MP + MTX
  17. DEX + VCR + Dasatinib /MP + DEX + VCR Dasatinib in Ph positive patients only

Drug Dosages, Schedules and Routes for Continuation Therapy from Week 21 to End of Therapy:

Mercaptopurine 75 mg/m2 PO daily for 7 days, Days 1-7. Methotrexate 40 mg/m2 IV or intramuscularly (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 (divided t.i.d.) for 5 days, Day 1-5 (between week 21 and week 68).Decrease dexamethasone to 6 mg/m2 PO daily (divided t.i.d.) x 5 days,Day 1-5 between week 69 and week 101 for all risk groups.

Vincristine2 mg/m2 IV push (max 2 mg), Day 1 (0.05mg/kg for patients < 1 year or < 10 kg).

PEG-ASP 2,500 vs 3,500 units/m2 IV randomization (until week 30)

Dexamethasone, vincristine, and asparaginase will be given regardless of blood counts, provided that the patient is clinically well. Cyclophosphamide, cytarabine, mercaptopurine and methotrexate will be held if WBC <1000/mm3 or ANC <300/mm3. Mercaptopurine and methotrexate will be reduced for WBC < 1500/mm3, or if WBC and ANC do not increase by at least 2 folds a week after the start date of dexamethasone pulse. Doses of cyclophosphamide and cytarabine may need to be reduced if patient misses 25% of chemotherapy and if the low counts deem to be related to this combination.

The same treatment (weeks 30-37) will be repeated for a total of 5 times, until week 69 (see Section 5.5.3 for intrathecal therapy). After week 69, all patients will receive daily mercaptopurine and weekly methotrexate interrupted with pulses of dexamethasone, vincristine, and mercaptopurine every 4 weeks. The dose of dexamethasone will be decreased to 6 mg/m2 between week 69 and week 101, after which only mercaptopurine and methotrexate will be given. Intrathecal treatment will be given every 8 weeks only to patients at risk of CNS relapse after week 49 and will be discontinued after week 97. Continuation therapy will be discontinued after 120 weeks.

Hematopoietic Stem Cell Transplantation (for 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.

Being tested
Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine, Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
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, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, ThioguanineDrug

    Also called Prednisone: prednisolone, Vincristine: Oncovin(R), Daunorubicin: daunomycin, Cerubidine(R), PEG-L-asparaginase: pegaspargase, Oncaspar(R)

    See Detailed Description section for details of treatment interventions.

  • Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, DasatinibDrug

    Also called Clofarabine: clofarex, Clolar(TM), Methotrexate: MTX, Mercaptopurine: 6-MP, Purinethol(R), Dexamethasone: Decadron(R)

    See Detailed Description section for details of treatment interventions.

Study groups in NCT00549848
Study groupRoleWhat they receive
HD PEGExperimentalParticipants randomized to receive higher dose PEG-asparaginase during the continuation phase. Interventions: * Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine * Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
Receives: Drug: Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine; Drug: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
CD PEGActive comparatorParticipants randomized to receive conventional dose PEG-asparaginase during the continuation phase.. Interventions: * Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine * Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
Receives: Drug: Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine; Drug: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With Continuous Complete Remission of Patients Receiving High-dose and Conventional Dose PEG-asparaginase.

    The primary objective of this study is to compare the distributions of continuous complete remission of patients randomized on the first day of the continuation phase to receive a higher dose of PEG-asparaginase or to receive the conventional dose (2,500 units/m2).

    The randomization will occur on the starting day of the continuation phase, at which time all information necessary for performing the randomization should be available. In the rare case that immunophenotype and/or Day-15 MRD is not available, we will make the following assumptions: If immunophenotype is unknown at the time the randomization is to be executed, then it will be assumed B-lineage. If Day-15 MRD is unknown at the time of randomization, then it will be assumed negative (<0.01%). Past experience indicate that few patients will fall into these unknown categories.

    Measured: 3.5 years after the last enrollment up to 12.5 years

Secondary outcomes (5)

  1. Probability of Event-free Survival

    To estimate the event-free survival of children with ALL who are treated with risk-directed therapy and to compare the EFS results of TOTXVI with that of TOTXV (NCT00137111).

    EFS will be measured from the date of complete response to the date of initial failure for patients who fail. Failure includes the traditional endpoints of failure to achieve a complete remission, relapse in any site, secondary malignancy, and death during induction or remission. EFS time will be measured to the date of last contact for patients who are failure free at the time of analysis. The EFS time is defined to be zero (0) for patients who die during induction therapy or fail to achieve a complete remission.

    Measured: For Total XVI: 3.5 years after the last enrollment, up to approximately 13.5 years For Total XV: patients are followed continuously, up to 20.5 years

  2. Probability of Overall Survival

    To estimate the overall survival of children with ALL who are treated with risk-directed therapy and to compare the EFS results of TOTXVI with that of TOTXV.

    Measured: For Total XVI: 3.5 years after the last enrollment, up to approximately 13.5 years For Total XV: patients are followed continuously, up to 20.5 years

  3. Proportion of Participants With Minimal Residual Disease (MRD) on the 15th Day of Remission Induction ≥ 5%

    To study whether intensifying induction, including fractionated cyclophosphamide and thioguanine, in patients with day 15 MRD ≥ 5% will result in improved leukemia cytoreduction in this subgroup compared to therapy followed in the TOTXV protocol.

    Measured: Middle of remission induction, Day 15 in Total XVI and Day 19 in Total XV

  4. Proportion of Participants With Minimal Residual Disease (MRD) at End of Remission Induction ≥ 0.01%

    To study whether intensifying induction, including fractionated cyclophosphamide and thioguanine, in patients with day 15 MRD ≥ 5% will result in improved leukemia cytoreduction in this subgroup compared to therapy followed in the TOTXV protocol.

    Measured: End of remission induction; day 42 in Total XVI and day 46 in Total XV

  5. Probability of CNS Relapse

    To assess whether intensification of CNS-directed intrathecal and systemic chemotherapy will improve outcome in patients at high-risk of CNS relapse.

    Measured: For Total XVI: 3.5 years after the last enrollment, up to approximately 13.5 years For Total XV: patients are followed continuously, up to 20.5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Oct 2007 (estimated)
  2. Study start29 Oct 2007
  3. Primary completion26 Sep 2020
  4. Study completion26 Mar 2022

Resources

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
600 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00549848
Sponsor's protocol ID
TOTXVI
Other IDs
R01CA140729, F32CA141762, R37CA036401, R01CA090246, Aspar PK-PD-T16, NCI-2011-01254, P50GM115279
Status last verified
Jul 2022
First submitted
25 Oct 2007
Last updated
23 Aug 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Bidoli C, Yang W, Karol SE, Lucafo M, Stocco G, Yang JJ. Unraveling Novel Genetic Determinants of Thiopurine Response Via TWAS. Clin Pharmacol Ther. 2026 Jan;119(1):84-88. doi: 10.1002/cpt.70053. Epub 2025 Sep 5.

    PubMed 40908865

  • Purvis K, Zhou Y, Karol SE, Rubnitz JE, Ribeiro RC, Lee S, Yang JJ, Bowman WP, Wang L, Dixon SB, Roberts KG, Gao Q, Cheng C, Mullighan CG, Jeha S, Pui CH, Inaba H. Outcomes in patients with ETV6::RUNX1 or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies. Blood. 2025 Jan 9;145(2):190-201. doi: 10.1182/blood.2024024936.

    PubMed 39316653

  • Chang TC, Chen W, Qu C, Cheng Z, Hedges D, Elsayed A, Pounds SB, Shago M, Rabin KR, Raetz EA, Devidas M, Cheng C, Angiolillo A, Baviskar P, Borowitz M, Burke MJ, Carroll A, Carroll WL, Chen IM, Harvey R, Heerema N, Iacobucci I, Wang JR, Jeha S, Larsen E, Mattano L, Maloney K, Pui CH, Ramirez NC, Salzer W, Willman C, Winick N, Wood B, Hunger SP, Wu G, Mullighan CG, Loh ML. Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia. J Clin Oncol. 2024 Oct 10;42(29):3491-3503. doi: 10.1200/JCO.23.02238. Epub 2024 Aug 9.

    PubMed 39121442

  • Panetta JC, Liu Y, Bottiglieri T, Arning E, Cheng C, Karol SE, Yang JJ, Zhou Y, Inaba H, Pui CH, Jeha S, Relling MV. Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase. Cancer Chemother Pharmacol. 2021 Oct;88(4):655-664. doi: 10.1007/s00280-021-04315-0. Epub 2021 Jun 25.

    PubMed 34170389

  • Finch ER, Smith CA, Yang W, Liu Y, Kornegay NM, Panetta JC, Crews KR, Molinelli AR, Cheng C, Pei D, Ramsey LB, Karol SE, Inaba H, Sandlund JT, Metzger M, Evans WE, Jeha S, Pui CH, Relling MV. Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer. 2020 Jan;67(1):e28040. doi: 10.1002/pbc.28040. Epub 2019 Oct 14.

    PubMed 31612640

  • Liu Y, Smith CA, Panetta JC, Yang W, Thompson LE, Counts JP, Molinelli AR, Pei D, Kornegay NM, Crews KR, Swanson H, Cheng C, Karol SE, Evans WE, Inaba H, Pui CH, Jeha S, Relling MV. Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge. J Clin Oncol. 2019 Aug 10;37(23):2051-2061. doi: 10.1200/JCO.18.02439. Epub 2019 Jun 12.

    PubMed 31188727

  • Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, Johnson C, Karlsson EA, Chang TC, Jeha S, Pui CH, Sun Y, Pounds S, Hayden RT, Tuomanen E, Rosch JW. Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia. Clin Infect Dis. 2018 Aug 1;67(4):541-548. doi: 10.1093/cid/ciy153.

    PubMed 29518185

  • Wolf J, Tang L, Flynn PM, Pui CH, Gaur AH, Sun Y, Inaba H, Stewart T, Hayden RT, Hakim H, Jeha S. Levofloxacin Prophylaxis During Induction Therapy for Pediatric Acute Lymphoblastic Leukemia. Clin Infect Dis. 2017 Nov 13;65(11):1790-1798. doi: 10.1093/cid/cix644.

    PubMed 29020310

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Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine and Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib 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 3 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 23 Aug 2022. 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?

Yes. Results are posted in the registry (first posted 10 Feb 2022). 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?

Percentage of Participants With Continuous Complete Remission of Patients Receiving High-dose and Conventional Dose PEG-asparaginase. (time frame: 3.5 years after the last enrollment up to 12.5 years). 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 NCT00549848, which also lists 10 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 23 Aug 2022; AzTrials last refreshed its copy on 6 Nov 2026.

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