RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with radiation therapy may kill more cancer cells.

PURPOSE: Phase II trial to study the effectiveness of radiation therapy following chemotherapy in treating children with CNS relapse from acute lymphoblastic leukemia.

Condition	Treatment or Intervention	Phase
B-cell childhood acute lymphocytic leukemia TdT positive childhood acute lymphocytic leukemia recurrent childhood acute lymphocytic leukemia T-cell childhood acute lymphocytic leukemia	Drug: asparaginase  Drug: cyclophosphamide  Drug: cytarabine (liposomal)  Drug: daunorubicin  Drug: dexamethasone  Drug: etoposide  Drug: filgrastim  Drug: hydrocortisone  Drug: leucovorin calcium  Drug: mercaptopurine  Drug: mesna  Drug: methotrexate  Drug: thiotepa  Drug: vincristine	Phase II

Further Study Details: 

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.

PROTOCOL 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.

PROJECTED ACCRUAL: 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.

Ages Eligible for Study:  up to  20 Years

Criteria

PROTOCOL 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

Alabama
      MBCCOP - University of South Alabama, Mobile,  Alabama,  36688,  United States
      University of Alabama Comprehensive Cancer Center, Birmingham,  Alabama,  35294,  United States
Arkansas
      University of Arkansas for Medical Sciences, Little Rock,  Arkansas,  72205,  United States
California
      Children's Hospital and Health Center, San Diego,  California,  92123-4282,  United States
      Lucile Packard Children's Hospital at Stanford, Palo Alto,  California,  94304,  United States
      University of California Davis Medical Center, Sacramento,  California,  95817,  United States
      University of California San Diego Cancer Center, La Jolla,  California,  92093-0658,  United States
Connecticut
      Yale Comprehensive Cancer Center, New Haven,  Connecticut,  06520-8028,  United States
District of Columbia
      Walter Reed Army Medical Center, Washington,  District of Columbia,  20307-5000,  United States
Florida
      CCOP - Florida Pediatric, Tampa,  Florida,  33682-7757,  United States
      Miami Children's Hospital, Miami,  Florida,  33155,  United States
      Shands Hospital and Clinics, University of Florida, Gainesville,  Florida,  32610-100277,  United States
      Sylvester Cancer Center, University of Miami, Miami,  Florida,  33136,  United States
Georgia
      Emory University Hospital - Atlanta, Atlanta,  Georgia,  30322,  United States
Illinois
      Children's Memorial Hospital, Chicago, Chicago,  Illinois,  60614,  United States
Kansas
      CCOP - Wichita, Wichita,  Kansas,  67214-3882,  United States
      University of Kansas Medical Center, Kansas City,  Kansas,  66160-7357,  United States
      Via Christi Regional Medical Center, Wichita,  Kansas,  67214,  United States
Louisiana
      CCOP - Ochsner, New Orleans,  Louisiana,  70121,  United States
      MBCCOP - LSU Medical Center, New Orleans,  Louisiana,  70112,  United States
      Tulane University School of Medicine, New Orleans,  Louisiana,  70112,  United States
Maryland
      Johns Hopkins Oncology Center, Baltimore,  Maryland,  21287,  United States
      Marlene & Stewart Greenebaum Cancer Center, University of Maryland, Baltimore,  Maryland,  21201,  United States
Massachusetts
      Boston Floating Hospital Infants and Children, Boston,  Massachusetts,  02111,  United States
      Dana-Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States
      University of Massachusetts Memorial Medical Center, Worcester,  Massachusetts,  01655,  United States
Michigan
      Children's Hospital of Michigan, Detroit,  Michigan,  48201,  United States
Mississippi
      University of Mississippi Medical Center, Jackson,  Mississippi,  39216-4505,  United States
Missouri
      Cardinal Glennon Children's Hospital, Saint Louis,  Missouri,  63104,  United States
      Washington University School of Medicine, Saint Louis,  Missouri,  63110,  United States
New Jersey
      CCOP - Northern New Jersey, Hackensack,  New Jersey,  07601,  United States
      Hackensack University Medical Center, Hackensack,  New Jersey,  07601,  United States
New York
      Mount Sinai School of Medicine, New York,  New York,  10029,  United States
      Roswell Park Cancer Institute, Buffalo,  New York,  14263-0001,  United States
      Schneider Children's Hospital, New Hyde Park,  New York,  11042,  United States
      State University of New York - Upstate Medical University, Syracuse,  New York,  13210,  United States
      State University of New York Health Sciences Center - Stony Brook, Stony Brook,  New York,  11790-9832,  United States
      University of Rochester Cancer Center, Rochester,  New York,  14642,  United States
North Carolina
      Carolinas Medical Center, Charlotte,  North Carolina,  28232-2861,  United States
      Comprehensive Cancer Center of Wake Forest University Baptist Medical Center, Winston Salem,  North Carolina,  27157-1082,  United States
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States
      East Carolina University School of Medicine, Greenville,  North Carolina,  27858-4354,  United States
      Memorial Mission Hospital, Asheville,  North Carolina,  28801,  United States
      Presbyterian Healthcare, Charlotte,  North Carolina,  28233-3549,  United States
Oklahoma
      Oklahoma Memorial Hospital, Oklahoma City,  Oklahoma,  73126-0307,  United States
Oregon
      CCOP - Columbia River Program, Portland,  Oregon,  97213,  United States
Pennsylvania
      St. Christopher's Hospital for Children, Philadelphia,  Pennsylvania,  19134-1095,  United States
Rhode Island
      Rhode Island Hospital, Providence,  Rhode Island,  02903,  United States
South Carolina
      Children's Hospital of Greenville Hospital System, Greenville,  South Carolina,  29605,  United States
      Medical University of South Carolina, Charleston,  South Carolina,  29425-0721,  United States
Tennessee
      Saint Jude Children's Research Hospital, Memphis,  Tennessee,  38105-2794,  United States
Texas
      Baylor College of Medicine, Houston,  Texas,  77030,  United States
      MBCCOP - South Texas Pediatric, San Antonio,  Texas,  78284-7810,  United States
      Medical City Dallas Hospital, Dallas,  Texas,  75230,  United States
      San Antonio Military Pediatric Cancer and Blood Disorders Center, Lackland Air Force Base,  Texas,  78236-5300,  United States
      Simmons Cancer Center - Dallas, Dallas,  Texas,  75235-9154,  United States
      University of Texas Health Science Center at San Antonio, San Antonio,  Texas,  78284-7811,  United States
Virginia
      Cancer Center, University of Virginia HSC, Charlottesville,  Virginia,  22908,  United States
      Massey Cancer Center, Richmond,  Virginia,  23298-0037,  United States
      Naval Medical Center, Portsmouth, Portsmouth,  Virginia,  23708-2197,  United States
West Virginia
      West Virginia University Hospitals, Morgantown,  West Virginia,  26506-9162,  United States
Wisconsin
      Midwest Children's Cancer Center, Milwaukee,  Wisconsin,  53226,  United States
Canada, Alberta
      Cross Cancer Institute, Edmonton,  Alberta,  T6G 1Z2,  Canada
Canada, Ontario
      Hospital for Sick Children, Toronto,  Ontario,  M5G 1X8,  Canada
      McMaster Division, Hamilton,  Ontario,  L8N 3Z5,  Canada
Canada, Quebec
      Hopital Sainte Justine, Montreal,  Quebec,  H3T 1C5,  Canada
      Montreal Children's Hospital, Montreal,  Quebec,  H3H 1P3,  Canada
Puerto Rico
      University of Puerto Rico School of Medicine Medical Sciences Campus, San Juan,  00936-5067,  Puerto Rico
Switzerland
      Clinique de Pediatrie, Geneva,  1211,  Switzerland
      Swiss Pediatric Oncology Group Bern, Bern,  CH 3010,  Switzerland

Study chairs or principal investigators

Julio Barredo,  Study Chair,  Pediatric Oncology Group   

Study ID Numbers:  CDR0000064509; POG-9412
Record last reviewed:  June 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002704
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08