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

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.

Conditions

• Acute Lymphoblastic Leukemia

Interventions

DRUG

Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine

See Detailed Description section for details of treatment interventions.

DRUG

Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib

See Detailed Description section for details of treatment interventions.

Sponsors & Collaborators

• National Cancer Institute (NCI)

  collaborator NIH

• Enzon Pharmaceuticals, Inc.

  collaborator INDUSTRY

• National Institute of General Medical Sciences (NIGMS)

  collaborator NIH

• St. Jude Children's Research Hospital

  lead OTHER

Principal Investigators

• Sima Jeha, MD · St. Jude Children's Research Hospital

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Max Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2007-10-29

Primary Completion

2020-09-26

Completion

2022-03-26

FDA Drug

Yes

Countries

• United States

Study Locations