Chemotherapy With or Without Total-Body Irradiation Prior to Bone Marrow Transplantation in Treating Children With Acute Lymphoblastic Leukemia

This study has been terminated.
(poor accrual)
Sponsor:
Information provided by (Responsible Party):
Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
NCT00002961
First received: November 1, 1999
Last updated: October 14, 2013
Last verified: October 2013
  Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining chemotherapy, radiation therapy, and bone marrow transplantation may kill more cancer cells.

PURPOSE: Randomized phase III trial to compare high-dose chemotherapy with or without total-body irradiation before bone marrow transplantation in treating children with acute lymphoblastic leukemia.


Condition Intervention Phase
Leukemia
Drug: cyclophosphamide
Drug: cyclosporine
Drug: etoposide
Drug: methotrexate
Procedure: allogeneic bone marrow transplantation
Radiation: Total Body Irradiation
Drug: Busulfan
Drug: Mesna
Radiation: Radiation
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Primary Purpose: Treatment
Official Title: Randomized Trial of Busulfan or Total Body Irradiation Conditioning Regimens for Children With Acute Lymphoblastic Leukemia

Resource links provided by NLM:


Further study details as provided by Children's Hospital of Philadelphia:

Enrollment: 43
Study Start Date: October 1995
Study Completion Date: February 2001
Primary Completion Date: February 2001 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Total body irradiation
Total body irradiation 1200 centigray
Drug: cyclophosphamide
Arms A and B Day 2 and 3: Cyclophosphamide 60 mg/kg intravenously; Administer 20 mg/ml concentration over 2 hours.
Other Names:
  • cyclophosphamide
  • Cytoxin
Drug: etoposide
Day 4 (arms A/B): 40 mg/kg over four hours intravenously
Other Names:
  • etoposide
  • Etopophos
  • etoposide phosphate
  • VP-16
Procedure: allogeneic bone marrow transplantation
Bone marrow infusion given on day 0
Other Name: BMT
Radiation: Total Body Irradiation
Day 0: Marrow Transfusion; Day 1: rest; Day 2 and 3: Cyclophosphamide 60 mg/kg; Day 4: Etopophos 40 mg/kg over four hours; Day 5,6 and 7: Total Body Irradiation (TBI) [200 cGy twice a day (BID)].
Other Names:
  • Total body irradiation
  • TBI
Radiation: Radiation

Central Nervous System (CNS) therapy:

a) CNS Leukemia prior to study entry: No TBI i) No prior CNS irradiation: 2340 centigray (cGy) in 13 fractions of 180 cGy to the cranial field and 600 cGy in 200 cGy fractions to the spinal field prior to conditioning. II) >/= 1800 cGy prior CNS irradiation: 1800 cGy to cranial field and 600 cGy spinal prior to conditioning. If prior radiation therapy (RT) doses >3000 cGy have been administered or CNS Leukemia prior to study entry: TBI, consult with Principal Investigator (PI). Recommend: 1) no prior CNS irradiation: 600 cGy in 3 fractions to the cranial field prior to conditioning or overlapping with TBI.

Testicular Boost Irradiation: a) overt testicular leukemia at relapse: No TBI 2400 cGy in 12 fractions prior to conditioning; b) overt testicular leukemia at relapse: TBI 1200 cGy in 6 fractions over 8-10 days prior to conditioning. c) No overt testicular leukemia: 200 cGy first and last fractions of TBI-

Active Comparator: Busulfan
Busulfan 16 doses
Drug: cyclophosphamide
Arms A and B Day 2 and 3: Cyclophosphamide 60 mg/kg intravenously; Administer 20 mg/ml concentration over 2 hours.
Other Names:
  • cyclophosphamide
  • Cytoxin
Drug: cyclosporine

graft vs. host disease (GVHD)prophylaxis: starting on day-1, cyclosporin 1.5 mg/kg IV every 12 hours or by continuous infusion.

When the patient tolerates adequate oral intake, cyclosporin therapy may be changed from IV to oral administration. Cyclosporin therapy should be continued at full dose until day +50. if the patient has less than Grade 2 GVHD, cyclosporin may be tapered by 5-10% weekly until completely off cyclosporin therapy.

Other Name: cyclosporine
Drug: etoposide
Day 4 (arms A/B): 40 mg/kg over four hours intravenously
Other Names:
  • etoposide
  • Etopophos
  • etoposide phosphate
  • VP-16
Drug: methotrexate

methotrexate 15 mg/m2 IV on day +1 (do not give until 24 hours after marrow infusion), and 10mg/mg2 IV on days +3 and +6.

Methotrexate may be held after two doses for bilirubin .2 mg/dL. If serum creatinine is >2x baseline, methotrexate will be omitted. If the presence of ascites or pleural effusion, methotrexate will be omitted.

Other Names:
  • methotrexate
  • MTX
Procedure: allogeneic bone marrow transplantation
Bone marrow infusion given on day 0
Other Name: BMT
Drug: Busulfan

Conditioning Regimen Arm B:

Day 0: Marrow infusion; Day 1: Rest; Day 2 and 3: Cyclophosphamide 60 mg/kg; Day 4: Etopophos 40 mg/kg over four hours; Day 5,6,7 and 8: Busulfan 0.8 mg/kg intravenous (IV) every 6 hours x 4 doses.

Patients </= 20kg to receive busulfan 1.0 mg/kg/dose IV**Busulfan oral preparation may be substituted: 1mg/kg/dose by mouth (po) for patients >20kg and 1.25 mg/kg/dose by mouth (po) for patients </= 20 kg.

Other Names:
  • Busulfan
  • Myleran
Drug: Mesna
Dosing per institutional preference for hemorrhagic cystitis. Mesna 300 mg/m2 as a 15 minute infusion prior to each dose of cyclophosphamide, then at 3,6,9,12, 18 and 21 hours after initiation of each cyclophosphamide infusion. Alternative method of Mesna administration is 10 mg/kg prior to cyclophosphamide and 100 mg/kg/24 hours by continuous infusion.
Other Names:
  • Mesna
  • Mesnex
Radiation: Radiation

Central Nervous System (CNS) therapy:

a) CNS Leukemia prior to study entry: No TBI i) No prior CNS irradiation: 2340 centigray (cGy) in 13 fractions of 180 cGy to the cranial field and 600 cGy in 200 cGy fractions to the spinal field prior to conditioning. II) >/= 1800 cGy prior CNS irradiation: 1800 cGy to cranial field and 600 cGy spinal prior to conditioning. If prior radiation therapy (RT) doses >3000 cGy have been administered or CNS Leukemia prior to study entry: TBI, consult with Principal Investigator (PI). Recommend: 1) no prior CNS irradiation: 600 cGy in 3 fractions to the cranial field prior to conditioning or overlapping with TBI.

Testicular Boost Irradiation: a) overt testicular leukemia at relapse: No TBI 2400 cGy in 12 fractions prior to conditioning; b) overt testicular leukemia at relapse: TBI 1200 cGy in 6 fractions over 8-10 days prior to conditioning. c) No overt testicular leukemia: 200 cGy first and last fractions of TBI-


Detailed Description:

OBJECTIVES: I. Compare the efficacy of a busulfan containing conditioning regimen versus a total body irradiation (TBI) containing regimen for children with acute lymphoblastic leukemia (ALL) undergoing allogeneic bone marrow transplantation. II. Compare relapse rate between a chemotherapy only regimen versus a total body irradiation containing regimen for children with ALL. III. Assess and compare the acute and chronic neuropsychological effects of bone marrow transplantation (BMT) in children undergoing BMT with busulfan or TBI conditioning regimens. IV. Assess and compare the cardiac, pulmonary and growth effects of BMT in children undergoing this conditioning regimen. V. Assess the relationship between plasma busulfan levels and relapse and toxicity. VI. Assess and compare minimal residual disease patterns by quantitative polymerase chain reaction (PCR) in patients receiving busulfan or TBI conditioning regimens.

OUTLINE: This is a multicenter, randomized study comparing a chemotherapy only arm, including busulfan, with a TBI containing arm. Arm I patients receive TBI on days -7, -6, and -5 given in 2 fractions daily. Arm II patients receive busulfan every 6 hours on days -8, -7, -6, and -5. Both regimens are followed by etoposide over 4 hours on day -4 and cyclophosphamide intravenously (IV) on days -3 and -2. Marrow infusion begins following a day of rest. Starting on day -1, cyclosporine IV is administered every 12 hours or by continuous infusion and continues until day 50. Methotrexate IV is administered on days 1, 3, and 6

PROJECTED ACCRUAL: A total of 230 patients will be entered into this study.

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS: Histologically confirmed childhood acute lymphoblastic leukemia (ALL) in second hematologic remission or greater who have relapsed: On therapy OR Within one year of discontinuation of therapy OR Greater than 1 year from discontinuation of high risk intensive therapy (matched sibling donor only) Patients with central nervous system or testicular relapse: Occurred within 18 months of diagnosis OR Following prophylactic or therapeutic cranial irradiation T cell disease with isolated central nervous system (CNS) or bone marrow relapse at any time Patients in first remission with greater than 4 weeks to achieve remission or with high risk features such as: t(4,11) t(9,22) Hypodiploidy Patients under 12 months of age in first remission with any of the following features at diagnosis: CALLA (CD10) negative white blood count (WBC) at least 100,000/mm3 Day 14 M2 or M3 bone marrow CNS disease

PATIENT CHARACTERISTICS: Age: 21 and under Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: No active hepatitis B or C Bilirubin no greater than 1.5 times normal Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) less than 2.5 times normal Renal: Creatinine no greater than 1.5 times normal OR Creatinine clearance at least 65 mL/min Cardiovascular: Shortening fraction greater than 27% by echocardiogram OR Ejection fraction greater than 47% by radionuclide angiogram Pulmonary: [1] forced expiratory volume at one second (FEV1)/forced vital capacity (FVC) greater than 60% For uncooperative children: No evidence of dyspnea at rest No exercise intolerance Pulse oximetry greater than 94% Other: No active infection No occult untreated infection HIV negative Not eligible for Children's Cancer Group (CCG) or Pediatric Oncology Group (POG) transplant study Donor criteria: Genotypically matched sibling or phenotypically matched family member (bone marrow or peripheral blood stem cells may be used) One antigen mismatched related donor Matched or one antigen mismatched unrelated donor Cord blood (genotypic or phenotypic match or one antigen mismatch) Matched sibling or phenotypically matched family member peripheral stem cells

PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: Not specified Endocrine therapy: Not specified Radiotherapy: Not specified Surgery: Not specified

  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: NCT00002961

Locations
United States, Alabama
University of Alabama Comprehensive Cancer Center
Birmingham, Alabama, United States, 35294
United States, California
Children's Hospital and Health Center
San Diego, California, United States, 92123-4282
United States, Florida
Nemours Children's Clinic
Jacksonville, Florida, United States, 32207
All Children's Hospital
St. Petersburg, Florida, United States, 33701
United States, Illinois
University of Chicago Cancer Research Center
Chicago, Illinois, United States, 60637
United States, Kentucky
Albert B. Chandler Medical Center, University of Kentucky
Lexington, Kentucky, United States, 40536-0084
United States, Louisiana
Louisiana State University School of Medicine
New Orleans, Louisiana, United States, 70112-2822
Tulane University School of Medicine
New Orleans, Louisiana, United States, 70112
United States, Missouri
Children's Mercy Hospital
Kansas City, Missouri, United States, 64108
Cardinal Glennon Children's Hospital
Saint Louis, Missouri, United States, 63104
Washington University Medical Center
Saint Louis, Missouri, United States, 63110
United States, Ohio
Ireland Cancer Center
Cleveland, Ohio, United States, 44106-5065
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Palmetto Richland Memorial Hospital
Columbia, South Carolina, United States, 29203
United States, Texas
South Texas Cancer Institute
San Antonio, Texas, United States, 78229
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States, 78284-7811
United States, Utah
Huntsman Cancer Institute
Salt Lake City, Utah, United States, 84132
Canada, Alberta
Alberta Children's Hospital
Calgary, Alberta, Canada, T2T 5C7
Sponsors and Collaborators
Children's Hospital of Philadelphia
Investigators
Study Chair: Nancy Bunin, MD Children's Hospital of Philadelphia
  More Information

No publications provided

Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT00002961     History of Changes
Other Study ID Numbers: 1995-9-1013, CHP-BMT-583, BMS-CHP-BMT-583, NCI-V97-1183
Study First Received: November 1, 1999
Last Updated: October 14, 2013
Health Authority: United States: Federal Government
United States: Institutional Review Board

Keywords provided by Children's Hospital of Philadelphia:
recurrent childhood acute lymphoblastic leukemia
childhood acute lymphoblastic leukemia in remission

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
Mesna
Busulfan
Cyclophosphamide
Cyclosporins
Cyclosporine
Methotrexate
Etoposide phosphate
Etoposide
Protective Agents
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Antirheumatic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 24, 2014