Total Therapy Study XVI for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
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Purpose
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.
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.
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).
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.
Infectious Disease Objective:
To determine the performance characteristics of broad-range, molecular diagnostic methods for detection of bacterial, fungal, and viral agents, in comparison to methods currently in routine clinical use.
| Condition | Intervention | 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 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Total Therapy Study XVI for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia |
- Continuous complete remission of patients receiving high-dose and conventional dose PEG-asparaginase. [ Time Frame: 3.5 years after the last enrollment ] [ Designated as safety issue: No ]
- Event-free survival [ Time Frame: 3.5 years after the last enrollment ] [ Designated as safety issue: No ]
- Overall survival [ Time Frame: 3.5 years after the last enrollment ] [ Designated as safety issue: No ]
- Level of minimal residual disease (MRD) on the 15th day of remission induction [ Time Frame: 3.5 years after enrollment of last patient ] [ Designated as safety issue: No ]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.
- Time to CNS relapse or the last follow up since diagnosis [ Time Frame: 3.5 years after enrollment of last patient ] [ Designated as safety issue: No ]To assess whether intensification of CNS-directed intrathecal and systemic chemotherapy will improve outcome in patients at high-risk of CNS relapse.
| Estimated Enrollment: | 420 |
| Study Start Date: | October 2007 |
| Estimated Study Completion Date: | November 2019 |
| Estimated Primary Completion Date: | November 2019 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: HD PEG
Participants randomized to receive higher dose PEG-asparaginase during the continuation phase. Interventions:
|
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:
Drug: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
See Detailed Description section for details of treatment interventions.
Other Names:
|
|
Active Comparator: CD PEG
Participants randomized to receive conventional dose PEG-asparaginase during the continuation phase.. Interventions:
|
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:
Drug: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
See Detailed Description section for details of treatment interventions.
Other Names:
|
Show Detailed Description Eligibility| Ages Eligible for Study: | up to 18 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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.
Contacts and Locations| Contact: Sima Jeha, MD | 1-866-278-5833 | info@stjude.org |
| United States, Tennessee | |
| St. Jude Children's Research Hospital | Recruiting |
| Memphis, Tennessee, United States, 38105 | |
| Principal Investigator: Sima Jeha, MD | |
| Principal Investigator: | Sima Jeha, MD | St. Jude Children's Research Hospital |
More Information
Additional Information:
No publications provided
| Responsible Party: | St. Jude Children's Research Hospital |
| ClinicalTrials.gov Identifier: | NCT00549848 History of Changes |
| Other Study ID Numbers: | TOTXVI, 5R01CA140729, 5F32CA141762, R37CA036401 |
| Study First Received: | October 25, 2007 |
| Last Updated: | May 22, 2013 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by St. Jude Children's Research Hospital:
|
Leukemia |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases 6-Mercaptopurine Cytarabine Methotrexate Thioguanine Cyclophosphamide Etoposide phosphate |
Pegaspargase Clofarabine Asparaginase Daunorubicin Dexamethasone Doxorubicin Etoposide Prednisolone Prednisone Vincristine BB 1101 Dasatinib Dexamethasone acetate Dexamethasone 21-phosphate Antimetabolites |
ClinicalTrials.gov processed this record on May 23, 2013