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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00549848
Recruitment Status : Completed
First Posted : October 26, 2007
Results First Posted : February 10, 2022
Last Update Posted : May 19, 2022
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Enzon Pharmaceuticals, Inc.
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Brief 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.

This study has several secondary objectives:

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.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Drug: Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine Drug: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib Phase 3

Show Show detailed description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Total Therapy Study XVI for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Actual Study Start Date : October 29, 2007
Actual Primary Completion Date : September 26, 2020
Actual Study Completion Date : March 26, 2022


Arm Intervention/treatment
Experimental: HD PEG

Participants 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
Drug: Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine
See Detailed Description section for details of treatment interventions.
Other Names:
  • Prednisone: prednisolone
  • Vincristine: Oncovin(R)
  • Daunorubicin: daunomycin, Cerubidine(R)
  • PEG-L-asparaginase: pegaspargase, Oncaspar(R)
  • Erwinia L-Asparaginase: Erwinase(R)
  • Doxorubicin: Adriamycin(R)
  • Cyclophosphamide: Cytoxan(R)
  • Cytarabine: Ara-C, Cytosar-U(R)
  • Thioguanine: 6-TG

Drug: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
See Detailed Description section for details of treatment interventions.
Other Names:
  • Clofarabine: clofarex, Clolar(TM)
  • Methotrexate: MTX
  • Mercaptopurine: 6-MP, Purinethol(R)
  • Dexamethasone: Decadron(R)
  • Etoposide: VP-16, Vepesid(R)
  • Dasatinib: Sprycel(R)

Active Comparator: CD PEG

Participants 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
Drug: Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine
See Detailed Description section for details of treatment interventions.
Other Names:
  • Prednisone: prednisolone
  • Vincristine: Oncovin(R)
  • Daunorubicin: daunomycin, Cerubidine(R)
  • PEG-L-asparaginase: pegaspargase, Oncaspar(R)
  • Erwinia L-Asparaginase: Erwinase(R)
  • Doxorubicin: Adriamycin(R)
  • Cyclophosphamide: Cytoxan(R)
  • Cytarabine: Ara-C, Cytosar-U(R)
  • Thioguanine: 6-TG

Drug: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
See Detailed Description section for details of treatment interventions.
Other Names:
  • Clofarabine: clofarex, Clolar(TM)
  • Methotrexate: MTX
  • Mercaptopurine: 6-MP, Purinethol(R)
  • Dexamethasone: Decadron(R)
  • Etoposide: VP-16, Vepesid(R)
  • Dasatinib: Sprycel(R)




Primary Outcome Measures :
  1. 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 ]

    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.



Secondary Outcome Measures :
  1. Probability of Event-free Survival [ Time Frame: 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 ]

    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.


  2. Probability of Overall Survival [ Time Frame: 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 ]
    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.

  3. Proportion of Participants With Minimal Residual Disease (MRD) on the 15th Day of Remission Induction ≥ 5% [ Time Frame: Middle of remission induction, Day 15 in Total XVI and Day 19 in Total XV ]
    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.

  4. Proportion of Participants With Minimal Residual Disease (MRD) at End of Remission Induction ≥ 0.01% [ Time Frame: End of remission induction; day 42 in Total XVI and day 46 in Total XV ]
    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.

  5. Probability of CNS Relapse [ Time Frame: 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 ]
    To assess whether intensification of CNS-directed intrathecal and systemic chemotherapy will improve outcome in patients at high-risk of CNS relapse.



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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00549848


Locations
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United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Sponsors and Collaborators
St. Jude Children's Research Hospital
National Cancer Institute (NCI)
Enzon Pharmaceuticals, Inc.
National Institute of General Medical Sciences (NIGMS)
Investigators
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Principal Investigator: Sima Jeha, MD St. Jude Children's Research Hospital
  Study Documents (Full-Text)

Documents provided by St. Jude Children's Research Hospital:
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00549848    
Other Study ID Numbers: TOTXVI
R01CA140729 ( U.S. NIH Grant/Contract )
F32CA141762 ( U.S. NIH Grant/Contract )
R37CA036401 ( U.S. NIH Grant/Contract )
R01CA090246 ( U.S. NIH Grant/Contract )
Aspar PK-PD-T16 ( Other Identifier: Enzon Pharmaceuticals, Inc. )
NCI-2011-01254 ( Registry Identifier: NCI Clinical Trial Registration Program )
P50GM115279 ( U.S. NIH Grant/Contract )
First Posted: October 26, 2007    Key Record Dates
Results First Posted: February 10, 2022
Last Update Posted: May 19, 2022
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Jude Children's Research Hospital:
Leukemia
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Dexamethasone
Dexamethasone acetate
Prednisone
Prednisolone
Cyclophosphamide
Doxorubicin
Liposomal doxorubicin
Methotrexate
Etoposide
Etoposide phosphate
Vincristine
Daunorubicin
Asparaginase
Dasatinib
Mercaptopurine
Clofarabine
Pegaspargase
Thioguanine
BB 1101
Immunosuppressive Agents