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Phase II Study of Delayed Craniospinal Irradiation Following 6 Months of Intensive Chemotherapy, with a Phase I Study of an "Up-Front" Therapeutic Window with Thiotepa or Sustained Release Cytarabine in Children with Isolated CNS Leukemia

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

Alternate Title

Radiation Therapy and Chemotherapy in Treating Children With CNS Relapse From Acute Lymphoblastic Leukemia

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs
Phase II Treatment Closed 6 mo. to under 21 at relapse NCI POG-9412
NCT00002704

Objectives

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

II.  Determine the efficacy of systemic thiotepa in reducing or clearing 
blasts in the cerebrospinal fluid of these patients.

III.  Evaluate the toxicity of single dose thiotepa followed by dexamethasone, 
vincristine, daunorubicin, and triple intrathecal therapy in these patients.

IV.  Determine the response rate of intrathecal sustained release cytarabine 
(DTC101) in patients with first bone marrow remission with first isolated CNS 
relapse.

V.  Assess the safety and toxicity of DTC101 in these patients.

Entry Criteria

Disease Characteristics:


Acute lymphoblastic leukemia in first bone marrow remission (M1) with first
isolated initial CNS relapse, i.e.:
  More than 5 WBC/microliter in cerebrospinal fluid (CSF) with blasts on
     cytospin OR
  Immunophenotypic proof (encouraged) of relapse in CSF, i.e.:
     Identifiable blasts and presence on 2 CSF samples 3 weeks apart of:
        If B-cell:  terminal deoxynucleotidyl transferase (TdT) or CD-10
        If T-cell:  TdT alone or with CD-7

Prior/Concurrent Therapy:


Prior cumulative anthracycline dose less than 375 mg/sqm

Patients receiving sustained release cytarabine:
 At least 7 days since prior investigational drug 
 At least 3 weeks since prior CNS directed therapy (6 weeks is prior          

  nitrosourea)
 At least 1 week since intrathecal chemotherapy
 At least 8 weeks since prior craniospinal radiotherapy

Patient Characteristics:


Age:
  Over 6 months and under 21 years at relapse

Patients receiving sustained release cytarabine:

 Performance status:
  Older than 10 years:  Karnofsky greater than 50%
  Less than 10 years:  Lansky greater than 50%

 Hematopoietic:
  Platelet count greater than 40,000/mm3
 Hepatic:
  Bilirubin less than 2.0 mg/dL
  SGPT less than 5 times normal

 Renal:
  Creatinine less than 1.5 times normal for age
  
 Metabolic:
  Normal metabolic parameters (serum electrolytes, calcium, and phosphorus)

 Other:
  No clinical evidence of obstructive hydrocephalus, compartmentalization of  

   the CSF flow, ventriculoperitoneal or ventriculoatrial shunt

Expected Enrollment

156

156 patients will be accrued over approximately 4 years.  Up to 40 evaluable 
patients will be studied in the Therapeutic Window (20 patients with thiotepa; 
20 patients with DTC101), after which that regimen will close (thiotepa window 
closed 7/6/98; sustained release cytarabine window opened 11/15/99); if 5 of 
the first 10 patients experience > 50% increase in blasts 1 week after 
treatment, or if 3 patients exhibit 100% blast clearing, the Therapeutic 
Window will close early.

Outline

Patients with significant neurologic symptoms (e.g., seizures, cranial nerve 
palsy, paresis, mental status changes) are entered directly on the Induction 
regimen and do not receive the Therapeutic Window.

The following acronyms are used:
  ARA-C    Cytarabine, NSC-63878
  ASP      Asparaginase, NSC-109229 (E. coli) or 106977 (Erwinia)
  CF       Leucovorin calcium, NSC-3590
  CTX      Cyclophosphamide, NSC-26271
  DM       Dexamethasone, NSC-34521
  DNR      Daunorubicin, NSC-82151
  DTC101   Sustained release cytarabine
  G-CSF    Granulocyte Colony-Stimulating Factor (Amgen), NSC-614629
  HC       Hydrocortisone, NSC-10483
  Mesna    Mercaptoethane sulfonate, NSC-113891
  MP       Mercaptopurine, NSC-755
  MTX      Methotrexate, NSC-740
  TIT      Triple Intrathecal Therapy, IT MTX/IT HC/IT ARA-C
  TMP-SMX  Trimethoprim-sulfamethoxazole
  TSPA     Thiotepa, NSC-6396
  VCR      Vincristine, NSC-67574
  VP-16    Etoposide, NSC-141540

THERAPEUTIC WINDOW:  Single Agent Chemotherapy.  TSPA or DTC101.
  ** Thiotepa window closed as of 7/6/98 **
  ** DTC101 window opened 11/15/99 **

INDUCTION:  3-Drug Combination Chemotherapy plus Triple Intrathecal Therapy.  
DM/DNR/VCR; plus TIT.

CONSOLIDATION:  2-Drug Combination Chemotherapy plus Triple Intrathecal 
Therapy.  ARA-C/ASP; plus TIT.

INTENSIFICATION I:  4-Drug Combination Chemotherapy with Leucovorin Rescue 
plus Triple Intrathecal Therapy.  CTX/MP/MTX/VP-16; with CF; plus TIT.

RE-INDUCTION:  3-Drug Combination Chemotherapy plus Triple Intrathecal 
Therapy.  DM/DNR/VCR; plus TIT.

INTENSIFICATION II:  6-Drug Combination Chemotherapy with Leucovorin Rescue 
plus Triple Intrathecal Therapy.  ARA-C/ASP/CTX/MP/MTX/VP-16; with CF; plus 
TIT.

CHEMORADIOTHERAPY:  Radiotherapy plus 3-Drug Combination Chemotherapy.  
Craniospinal irradiation using x-rays with energies of 4-6 MV (electrons 
acceptable for spinal cord irradiation); plus ASP/DM/VCR.

MAINTENANCE:  2-Drug Combination Chemotherapy Alternating with 2-Drug 
Combination Chemotherapy.  MP/MTX; alternating with CTX/VCR.

Published Results

Barredo JC, Devidas M, Lauer SJ, et al.: Isolated CNS relapse of acute lymphoblastic leukemia treated with intensive systemic chemotherapy and delayed CNS radiation: a pediatric oncology group study. J Clin Oncol 24 (19): 3142-9, 2006.[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

Julio Barredo, MD, Protocol chair
Ph: 843-792-2957
Email: barredjc@musc.edu

Registry Information

Official Title		TREATMENT OF ISOLATED CNS RELAPSE OF ACUTE LYMPHOBLASTIC LEUKEMIA -- A PEDIATRIC ONCOLOGY GROUP-WIDE PHASE II STUDY

Trial Start Date		1996-01-16

Registered in ClinicalTrials.gov		NCT00002704

Date Submitted to PDQ		1996-01-16

Information Last Verified		2007-11-26

NCI Grant/Contract Number		U10-CA30969

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.