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

This study has been terminated.
(Toxicity)
Sponsor:
Information provided by:
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT00187005
First received: September 12, 2005
Last updated: March 29, 2011
Last verified: June 2008
  Purpose

The main purpose of this study is to find out if radiation to the central nervous system (CNS) can be safely omitted with early intensification of chemotherapy and chemotherapy given directly to the CNS. Another purpose is to find out if survival of children with ALL can be improved with risk-directed therapy given on this protocol.


Condition Intervention Phase
Acute Lymphoblastic Leukemia
Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase
Drug: L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Total Therapy Study XIV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • To determine if CNS irradiation can be safely omitted with early intensification of systemic and intrathecal chemotherapy. [ Time Frame: Unable to determine ]

Enrollment: 53
Study Start Date: July 1998
Study Completion Date: July 2002
Primary Completion Date: July 2002 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1 Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase
See Detailed Description section for details of treatment interventions.
Drug: L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine
See Detailed Description section for details of treatment interventions.

  Hide Detailed Description

Detailed Description:

There are multiple secondary objectives in this trial:

  • To estimate the overall event-free survival of patients treated with risk-directed therapy
  • To identify the plasma methotrexate (MTX) concentrations that produce maximum intracellular accumulation of active metabolites (methotrexate polyglutamates, MTXPG) in vivo, in relation to major cell lineage and genotype
  • To determine the relation between MTXPG accumulation in leukemic lymphoblasts and antileukemic effects, as measured by the inhibition of de novo purine synthesis, and by the decrease in circulating blasts during the 4 days after initiation of single-agent high-dose methotrexate treatment
  • To determine if plasma MTX concentrations exceeding those required for maximum MTXPG accumulation cause a paradoxical decrease in the accumulation of long-chain MTXPG in lymphoblasts, (e.g., due to "feedback inhibition" of folypolyglutamate synthetase)
  • To determine if there are significant differences in lymphoblast uptake of MTX and expression of the reduced folate carrier in T-lineage vs B-lineage lymphoblasts, and in hyperdiploid vs non-hyperdiploid B-lineage lymphoblasts
  • To investigate whether atovaquone (ATQ) is as effective as trimethoprim-sulfamethoxazole (TMP-SMZ) in preventing Pneumocystis carinii pneumonitis (PCP)
  • To investigate whether or not the administration of G-CSF at the onset of febrile episodes in neutropenia patients after induction or any of the two reinductions will affect the extent and duration of fever.
  • To determine whether levels of minimal residual disease in peripheral blood (PB) reflect those measured in the bone marrow (BM) by immunologic or molecular techniques
  • To assess the degree of DNA damage in somatic cells (leukocytes) during treatment
  • To explore whether genetic polymorphisms of enzymes important in metabolism of antileukemic agents (e.g. methylene tetrahydrofolate reductase, thiopurine methyltransferase, glutathione transferases) are correlated with MTX pharmacology in lymphoblasts, acute toxicities and long-term outcome
  • To explore whether the development of anti-asparaginase antibodies or CSF depletion of asparaginase is correlated with acute toxicities and long-term outcome
  • To assess the relation between MRI changes of brain (especially white matter abnormalities) from HDMTX and intrathecal treatment, neurologic and cognitive deficits, CSF levels of homocysteines and diminished quality of life
  • To investigate whether early MRI changes are related to late MRI abnormalities, neurologic and cognitive deficits, and diminished quality of life
  • To correlate changes in MRI, neurologic or cognitive deficits and diminished quality of life with selected pharmacokinetic variables
  • To determine the prevalence of low bone density and to correlate this complication with potential risk factors

Details of Treatment Interventions:

Treatment will consist of three main phases, Remission Induction (including an Upfront HDMTX Window), Consolidation, and Continuation.

Window Therapy Upfront HDMTX is considered the first part of remission induction treatment. HDMTX will be given by vein over 24 hours (one day). MTX 500 mg/m2 for standard risk and 250 mg/m2 for low-risk cases will be given over 1 hour, followed immediately by maintenance infusion (4500 mg/m2 for standard/high-risk or 2250 mg/m2 for low-risk cases) over 23 hours.

Remission Induction Therapy (6-7 weeks) The remaining induction treatment will begin with Prednisone 40 mg/m2/day PO (tid) 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 U/m2/dose IM (thrice weekly) days 6, 8, 10, 12, 14, 16 (19, 21, 23), and triple intrathecal treatment, followed by Etoposide 300 mg/m2/dose IV over 2 hr days 26, 29, 33, plus Cytarabine 300 mg/m2/dose IV over 2 hr Days 26, 29, 33.

Triple intrathecal chemotherapy (MHA) is used for the remaining treatment with dosages based on age Frequency and total number of triple intrathecal treatment for Remission Induction are based on the patient's risk of CNS relapse.

Consolidation (2 weeks) Patients receive High dose Methotrexate (HDMTX) 2.5 gm/m2 (low-risk) or 5 gm/m2 (standard-or-high-risk) IV over 24 hr days 1 and 8 and 6-Mercaptopurine 25 mg/m2/day PO days 1 to 14. All patients will receive triple intrathecal therapy weekly for two doses on Days 1 and 8.

Continuation treatment (120 weeks for girls and 146 weeks for boys) Post-remission continuation treatment begins 7 days after the second course of HDMTX of the consolidation treatment, provided that the ANC ≥300/mm3 and platelet count ≥ 50 x 109/L. Continuation treatment will be 120 weeks for girls and 146 weeks for boys and differs according to the risk classification.

Reinduction Treatment This phase of treatment will be started at weeks 12 and 28 after bone marrow examination confirms complete remission.

Reinduction treatment will be given twice:

Weeks 12 to 16 and week 28 to 32 for standard/high risk cases; weeks 12 to 15 and weeks 28-31 for low-risk cases. Leucovorin rescue (5 mg/m2) will be given at 24 and 30 hours after the intrathecal treatment during both remission reinduction treatments. No chemotherapy will be given weeks 16 and 32 for standard/high risk patients.

Standard- or High-Risk Leukemia

  • DEX (dexamethasone) 8 mg/m2 PO daily (tid) x 7 days and VCR (vincristine) 1.5 mg/m2 IV push (max. 2 mg) will be given weeks 1, 5, 9, 17, 21, 25, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, and 117.
  • VP16 (etoposide) 300 mg/m2 IV over 2 hours and CTX (cyclophosphamide) 300 mg/m2 IV short infusion will be given weeks 2, 6, 10, 18, 22, 26, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, and 94.
  • 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and MTX (methotrexate) 40 mg/m2 IV or IM weeks 3, 8, 11, 19, 24, 27, 35, 39, 40, 43, 47, 48, 51, 55, 56, 59, 63, 64, 67, 71, 72, 75, 79, 80, 83, 87, 88, 91, 95, 96, 98, 99, 102, 103, 104, 106, 107, 110, 111, 112, 114, 115, 118, 119, and 120, and weeks 121-146 for boys.
  • MTX (methotrexate) 40 mg/m2 IV or IM and Ara-C (cytarabine) 300 mg/m2 IV push will be given weeks4, 20, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, and 116.
  • 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and HDMTX 5 gm/ gm/m2 will be given week 7 and 23.
  • HDMTX 5 gm/ gm/m2 and Ara-C (cytarabine) 300 mg/m2 IV push will be given weeks 15 and 31.

Reinduction Treatment-Standard/High Risk

  • DEX (dexamethasone) 8 mg/m2 PO daily (tid) days 1-21,
  • VCR (vincristine) 1.5 mg/m2/week IV (max. 2 mg) days 1, 8, and 15
  • PEG-asparaginase 2500 U/m2/week IM weeks 28-31, days 8, and 15
  • Idarubicin 5 mg/m2/week IV days 1 and 8
  • HDMTX 5 gm/m2 IV day 22
  • ITMHA (methotrexate+hydrocortisone+ara-C), age dependent, IT day 1
  • High-dose cytarabine 2 gm/m2 IV q 12 hr Days 23, and 24 Low Risk
  • 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and MTX (methotrexate) 40 mg/m2 IV or IM weeks 1, 2, 3, 4, 6, 8, 10,, 11, 16, 18- 20, 22, 24, 26, 27, 32, 34- 36, 38-40, 42- 44, 46-48, 50-52, 54-56, 58-60, 62-64, 66-68, 70-72, 74-76, 78-80, 82-84, 86-88, 90-92, 94-96, 98-100, 102-104, 106-108, 110-112, 114-116, 118-120 and weeks 121-146 for boys.
  • 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days, MTX (methotrexate) 40 mg/m2 IV or IM, DEX (dexamethasone) 8 mg/m2 PO daily (tid) x 7 days and VCR (vincristine) 1.5 mg/m2 IV push (max. 2 mg) weeks 5, 9, 17, 21, 25, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, and 117.
  • 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and HDMTX 2.5 gm/m2 weeks 7, 15, 23 and 31.

Reinduction Treatment-Low Risk

  • DEX (dexamethasone) 8 mg/m2 PO daily days 1-21,
  • VCR (vincristine) 1.5 mg/m2/week IV push (max. 2 mg) days 1, 8, and 15
  • PEG-asparaginase 2500 U/m2/week IM days 8, and 15
  • Idarubicin 5 mg/m2/week IV day 1
  • HDMTX 2.5 gm/m2 day 22
  • ITMHA (methotrexate+hydrocortisone+ara-C), age dependent, IT day 1 and 22
  • 6 MP 75 mg/m2/day PO days 22-28 IT Chemotherapy
  • Triple intrathecal treatment will be given to low-risk cases with CNS-1 status on weeks 1, 2, 7, 12, 15, 23, 28, 31, 39, 47, and 54.
  • Triple intrathecal treatment will be given to low-risk cases with CNS-2 or traumatic CSF status on weeks 1, 2, 7, 12, 15, 19, 23, 28, 31, 36, 39, 43, 47, and 54.
  • Triple intrathecal treatment will be given to standard/high-risk cases on weeks 1, 2, 7, 12, 19, 23, 28, 36, 39, 43, 47, and 54.
  • Triple intrathecal treatment will be given to other standard/high-risk cases with WBC ≥100 x 109/L, T-cell ALL with WBC ≥50 x 109/L, presence of Philadelphia chromosome, MLL rearrangement, near haploidy, or CNS-3 status on weeks 1, 2, 7, 12, 19, 23, 28, 36, 39, 43, 47, 54, 64, 72, 80, and 88.

Hematopoietic Stem Cell Transplantation Patients who meet the criteria of high-risk ALL will be offered the option of transplantation with a matched, related or unrelated donor. However, if the option is declined or if a suitable donor is not available, the patient will remain on study and continue to receive chemotherapy.

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of non-B-cell leukemia by immunophenotyping (e.g. T-cell, B-cell precursor, or acute undifferentiated leukemia)
  • Ages less than or equal to 18 years of age
  • One week or less of prior therapy, limited to glucocorticoids, vinca alkaloids, emergency radiation therapy to the mediastinum and one dose of intrathecal chemotherapy Exclusion Criteria
  • Participants greater than 18 years of age
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00187005

Locations
United States, Tennessee
St.Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
Principal Investigator: Ching-Hon Pui, MD St. Jude Children's Research Hospital
  More Information

Additional Information:
Publications:
Hammond TG, Hu A, Hammond JM, Relling MV, Underwood JL. Detection of point mutations on a DNA microchip Clinical Immunology Newsletter 19(12):121-6, 1999.

Responsible Party: Ching-Hon Pui, MD / Principal Investigator, St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00187005     History of Changes
Other Study ID Numbers: TOTXIV
Study First Received: September 12, 2005
Last Updated: March 29, 2011
Health Authority: United States: Food and Drug Administration

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
Cyclophosphamide
Pegaspargase
Asparaginase
Daunorubicin
Dexamethasone
Etoposide
Idarubicin
Prednisone
Vincristine
BB 1101
Dexamethasone acetate
Dexamethasone 21-phosphate
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 20, 2014