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  • Last Modified: 11/26/2007

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Phase I/II Study of an "Up-Front" Therapeutic Window with 6-MP Followed by Intensified Systemic Induction, Consolidation, and Intensification with Intrathecal Therapy Followed by Delayed Craniospinal Irradiation in Children with Isolated CNS Leukemia

Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase II, Phase ITreatmentCompletedover 1 to 21NCIPOG-9061

Objectives

I.  Determine the efficacy and toxicity of intensified systemic treatment with 
delayed craniospinal irradiation in children with acute lymphoblastic leukemia 
and isolated central nervous system (CNS) disease.

II.  Describe the pharmacokinetics and cytotoxic effect within the 
cerebrospinal fluid (CSF) of intravenous 6-mercaptopurine given as a single 
agent in an up-front window, and determine the level at which 100% of the 
blasts are cleared from the CSF.

III.  Measure parameters of CNS tissue injury (free fatty acids and 
phospholipids in the CSF), and associate these with the effects of CNS 
leukemia and treatments.

Entry Criteria

Disease Characteristics:


ALL in first bone marrow remission (on or off therapy) with
isolated initial CNS relapse

  Confirmation of CNS relapse in CSF by the presence of more
  than 5 WBC/mcl with blasts on cytospin/Wright stain exam
  required (cytomorphology must be confirmed by reference
  laboratory)

     If 5 or fewer WBC with blasts or more than 5 WBC with
     equivocal blasts are detected, LP should be repeated q 2-4
     weeks while the patient is off intrathecal chemotherapy
     until the criterion for CNS disease is met

  CSF samples may be sent for immunophenotyping


Prior/Concurrent Therapy:


Biologic therapy:
  Not specified

Chemotherapy:
  Prior anthracycline dose less than 375 mg/sqm
  Interval of at least 1 week between prior intrathecal or
     intravenous chemotherapy and initiation of treatment with
     intravenous 6-mercaptopurine

Endocrine therapy:
  Not specified

Radiotherapy:
  No prior brain irradiation

Surgery:
  Not specified


Patient Characteristics:


Age:
  Children greater than 1 at time of CNS relapse

Performance status:
  Not specified

Hematopoietic:
  ANC greater than 500
  Platelets greater than 100,000

Hepatic:
  Bilirubin less than 2.0 mg/dl
  SGPT less than 2.5 x normal

Renal:
  Not specified


Expected Enrollment

A maximum of 40 patients will be studied to determine the MTD or optimum dose 
of 6-MP in the Phase I portion of the study, and a minimum of 30 patients will 
be entered in the Phase II portion.  If 4 or more patients experience CNS 
failure within 6 months of follow-up, the study may be terminated.  An accrual 
rate of 18 patients/month is anticipated, with an estimated 20-27 months 
required for completion of accrual.

Outline

Nonrandomized study.  Patients with significant symptoms (e.g., cranial nerve 
palsy, seizures, or paresis) or with abnormal liver function are entered 
directly on the Induction regimen; all other patients begin on the 
Preinduction regimen.

Preinduction:  Single-Agent Chemotherapy.  6-Mercaptopurine, 6-MP, NSC-755.

Induction:  3-Drug Combination Chemotherapy plus Triple Intrathecal Therapy.  
Dexamethasone, DM, NSC-34521; Vincristine, VCR, NSC-67574; Daunorubicin, DNR, 
NSC-82151; plus TIT:  Methotrexate, MTX, NSC-740; Hydrocortisone, HC, 
NSC-10483; Cytarabine, Cytosine arabinoside, ARA-C, NSC-63878.

Consolidation:  2-Drug Combination Chemotherapy with Hematologic Toxicity 
Attenuation plus Triple Intrathecal Therapy.  High-dose ARA-C; 
PEG-L-Asparaginase, PEG-ASP, NSC-624239; with Granulocyte Colony Stimulating 
Factor (Amgen), G-CSF, NSC-614629; plus TIT.

Intensification:  4-Drug Combination Chemotherapy with Leucovorin Rescue and 
Urothelial Protection plus Triple Intrathecal Therapy.  MTX; 6-MP; Etoposide, 
VP-16, NSC-141540; Cyclophosphamide, CTX, NSC-26271; with Leucovorin calcium, 
LV, NSC-3590; and Mesna, NSC-113891; plus TIT.

Delayed Craniospinal Irradiation:  Radiotherapy plus 3-Drug Combination 
Chemotherapy with (as indicated) Hematologic Toxicity Attenuation.  
Craniospinal Irradiation using megavoltage equipment (accelerator beams with 
energies of 4-6 MeV or Co60); plus DM; VCR; PEG-ASP; with (as indicated) G-CSF.

Maintenance:  2-Drug Combination Chemotherapy Alternating with 2-Drug 
Combination Chemotherapy.  6-MP; MTX; alternating with VCR; CTX.

Published Results

Ritchey AK, Pollock BH, Lauer SJ, et al.: Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a pediatric oncology group study . J Clin Oncol 17 (12): 3745-52, 1999.[PUBMED Abstract]

Related Publications

Eapen M, Zhang MJ, Devidas M, et al.: Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. Leukemia 22 (2): 281-6, 2008.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Pediatric Oncology Group

Arthur Ritchey, MD, Protocol chair (Contact information may not be current)
Ph: 304-293-1217; 877-427-2894
Email: ritchey@wvnvm.wvnet.edu

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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