Low-Dose or High-Dose Vincristine and Combination Chemotherapy in Treating Young Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia

Intensive Treatment for Intermediate-Risk Relapse of Childhood B-precursor Acute Lymphoblastic Leukemia (ALL): A Randomized Trial of Vincristine Strategies

This randomized phase III trial is studying low-dose vincristine to see how well it works compared with high-dose vincristine when given together with different combination chemotherapy regimens in treating young patients with intermediate-risk relapsed B-cell acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving the drugs in different ways and different doses may kill more cancer cells..

Study Overview

• Status: Completed
• Conditions: B-cell Childhood Acute Lymphoblastic Leukemia; L1 Childhood Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; Intermediate Risk Recurrent Childhood Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: cyclophosphamide; Drug: etoposide; Drug: doxorubicin hydrochloride; Drug: vincristine sulfate; Drug: pegaspargase; Biological: filgrastim; Drug: prednisone; Drug: dexamethasone; Drug: leucovorin calcium; Drug: asparaginase; Drug: mercaptopurine; Drug: cytarabine; Drug: methotrexate

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the efficacy of an intensive chemotherapy regimen (based on POG-9412) for pediatric patients with intermediate-risk relapsed B-precursor acute lymphoblastic leukemia.

SECONDARY OBJECTIVES:

I. To determine levels of minimal residual disease (MRD) present at the end of the first & third blocks of Induction and determine if higher MRD levels at these times identify patients at higher risk of relapse who might be candidates for alternative therapies in future trials.

II. To determine whether common polymorphisms in candidate genes are associated with the frequency of vincristine adverse effects (peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion [SIADH], or constipation) and with anti-leukemic response (level of end-Induction MRD).

III. Compare, descriptively, the outcomes of patients treated with combination chemotherapy vs those treated with matched sibling-related donor hematopoietic stem cell transplantation (for those with eligible donors).

IV. To use deoxyribonucleic acid (DNA) arrays to characterize patterns of gene expression that predict treatment failure, and to compare gene expression profiles at the time of relapse with those at initial diagnosis to gain an understanding of the pathways that may be involved in disease resistance.

OUTLINE: This is a multicenter, randomized study. Patients are randomized to 1 of 2 treatment regimens (randomization closed as of 09/2010).

INDUCTION THERAPY 1 (WEEKS 1-5):

Regimen A: Patients receive low-dose vincristine intravenously (IV) on days 1, 8, 15, and 22; prednisone orally (PO) 3 times daily (TID) on days 1-28; doxorubicin hydrochloride IV over 15 minutes on day 1; pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22; cytarabine intrathecally (IT) on day 1; and methotrexate IT* on days 15 and 29.

Regimen B: (closed to accrual as of 09/2010)***: Patients receive high-dose vincristine IV on days 1, 8, 15, and 22 and prednisone, doxorubicin hydrochloride, pegaspargase, cytarabine, and methotrexate* as in Regimen A.

NOTE: *Central nervous system (CNS)-positive patients do not receive methotrexate IT. In both arms, CNS-positive patients receive intrathecal triple therapy (ITT) comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, 22, and 29. CNS-positive patients not achieving remission after induction therapy 1 receive one additional dose of ITT on day 36. Patients in both arms then proceed to induction therapy 2**.

NOTE: **Patients who are CNS-positive at relapse receive induction therapy 3 BEFORE induction therapy 2.

NOTE: ***Patients already enrolled on Regimen B are crossover to Regimen A.

INDUCTION THERAPY 2 (WEEKS 6-10 or 7-11): Once blood counts recover, all patients receive etoposide phosphate IV over = 1 hour and cyclophosphamide IV over 1 hour on days 1-5; high-dose methotrexate IV continuously over 24 hours on day 22; leucovorin calcium IV or PO beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; and methotrexate IT* on days 1 and 22. Patients also receive filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 6 and continuing until blood counts recover.

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 22. Patients with testicular-relapse with persistent testicular disease at the end of induction therapy 1 undergo testicular radiotherapy once daily (QD), 5 days a week, for 12 days during induction therapy 2**.

NOTE: **Radiotherapy should be completed before beginning high-dose methotrexate (week 9) chemotherapy.

All patients then proceed to induction therapy 3.

INDUCTION THERAPY 3 (WEEKS 11-15 or 12-16): All patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9, and asparaginase IM on days 2 and 9. Patients also receive G-CSF IV or SC beginning on day 10 and continuing until blood counts recover. Patients with a suitable HLA-matched related donor are removed from study and proceed to stem cell transplantation. Patients without a suitable HLA-matched related donor proceed to intensification therapy 1 (as per their randomized regimen in induction therapy 1).

INTENSIFICATION THERAPY 1 (WEEKS 16-27 or 17-28):

Regimen A: Patients receive low-dose vincristine IV and high-dose methotrexate IV continuously over 24 hours on day 1; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 2-6; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 8; and methotrexate IT* on day 15. Treatment repeats every 21 days for 4 courses (with the exception of IT methotrexate which repeats for only 3 courses).

Regimen B: Patients receive high-dose vincristine IV on day 1 and high-dose methotrexate, leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide, and methotrexate IT* as in Regimen A. (closed to accrual as of 09/2010)

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 15. ITT repeats every 3 weeks for 3 courses.

NOTE: ** Patients already enrolled on Regimen B are crossover to Regimen A.

Patients in both regimens then proceed to reinduction therapy (as per their randomized regimen in induction therapy 1).

REINDUCTION THERAPY (WEEKS 28-32 or 29-33):

Regimen A: Patients receive low-dose vincristine IV and doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15, oral dexamethasone twice daily on days 1-7 and 15-21, pegaspargase IM on days 2 and 15, and methotrexate IT* on days 1 and 28.

Regimen B: Patients receive high-dose vincristine IV on days 1, 8, and 15 and doxorubicin hydrochloride, dexamethasone, pegaspargase, and methotrexate IT* as in Regimen A. (closed to accrual as of 09/2010)

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 28.

NOTE: ** Patients already enrolled on Regimen B are crossover to Regimen A. Patients in both regimens then proceed to intensification therapy 2 (as per their randomized regimen in induction therapy 1).

INTENSIFICATION THERAPY 2 (WEEKS 33-56 or 34-57):

Regimen A: Once blood counts recover, patients receive high-dose cytarabine IV over 3 hours on days 1 and 2; pegaspargase IM on day 2; low-dose vincristine IV on days 22 and 29; high-dose methotrexate IV on day 22; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 23-27; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 29; and methotrexate IT* on day 36. Patients also receive G-CSF IV or SC beginning on day 3 and continuing until blood counts recover. Treatment repeats every 42 days for 4 courses (with the exception of IT methotrexate which only repeats for 3 courses).

Regimen B: Patients receive high-dose cytarabine, high-dose methotrexate, leucovorin calcium, pegaspargase, mercaptopurine, etoposide phosphate, cyclophosphamide, methotrexate IT*, and G-CSF as in Regimen A. Patients also receive high-dose vincristine IV on days 22 and 29.

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 36. Treatment repeats every 6 weeks for 3 courses.

Patients in both regimens then proceed to maintenance therapy (as per their randomized regimen in induction therapy 1).

MAINTENANCE THERAPY (week 57-106 or 58-107):

Regimen A: Patients receive methotrexate IT on day 1* and then PO on days 8, 15, 22, 29, and 36; mercaptopurine PO QD on days 1-42; dexamethasone PO twice daily (BID) on days 1-5; and low-dose vincristine IV and cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64. Treatment repeats every 70 days for 5 courses.

Regimen B: Patients receive methotrexate*, mercaptopurine, dexamethasone, and cyclophosphamide as in Regimen A. Patients also receive high-dose vincristine IV on days 43, 50, 57, and 64.

NOTE: *CNS-positive patients receive methotrexate IT on day 1, instead of oral methotrexate.

Beginning in week 1 of the first maintenance therapy course, patients with CNS relapse undergo cranial radiotherapy QD, 5 days a week, for 10 days. Patients with CNS relapse do not receive any IT therapy during maintenance therapy.

After completion of study therapy, patients are followed periodically for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 275
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Perth, Western Australia, Australia, 6008
      • Princess Margaret Hospital for Children
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3J 3G9
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • Hamilton, Ontario, Canada, L8S 4L8
      • Chedoke-McMaster Hospitals
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario At Kingston General Hospital
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hospital Sainte-Justine
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre
• Switzerland
  • Bern, Switzerland, 3010
    • Swiss Pediatric Oncology Group - Bern
  • Lausanne, Switzerland, 1011
    • Swiss Pediatric Oncology Group - Lausanne
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
    • Tucson, Arizona, United States, 85724
      • University of Arizona Health Sciences Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Arcadia, California, United States, 91006-3776
      • Children's Oncology Group
    • Downey, California, United States, 90242
      • Southern California Permanente Medical Group
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Long Beach, California, United States, 90806
      • Miller Children's Hospital
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Madera, California, United States, 93636-8762
      • Children's Hospital Central California
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • Oakland, California, United States, 94609-1809
      • Children's Hospital and Research Center at Oakland
    • Orange, California, United States, 92868-3874
      • Childrens Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • Sacramento, California, United States, 95816
      • Sutter General Hospital
    • Sacramento, California, United States, 95817
      • UC Davis Comprehensive Cancer Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center-Parnassus
    • Santa Barbara, California, United States, 93102
      • Santa Barbara Cottage Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
    • New Haven, Connecticut, United States, 06520-8032
      • Yale University
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
    • Washington, District of Columbia, United States, 20057
      • Lombardi Comprehensive Cancer Center at Georgetown University
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • Broward Health Medical Center
    • Fort Myers, Florida, United States, 33901
      • Lee Memorial Health System
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Jacksonville, Florida, United States, 32207-8426
      • Nemours Children's Clinic - Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Miami, Florida, United States, 33176
      • Baptist Hospital of Miami
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • Orlando, Florida, United States, 32803
      • Florida Hospital
    • Orlando, Florida, United States, 32806
      • M D Anderson Cancer Center- Orlando
    • Orlando, Florida, United States, 32806
      • Nemours Childrens Clinic - Orlando
    • Pensacola, Florida, United States, 32504
      • Nemours Children's Clinic - Pensacola
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • Saint Joseph Children's Hospital of Tampa
    • West Palm Beach, Florida, United States, 33407
      • Saint Mary's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
    • Augusta, Georgia, United States, 30912
      • Georgia Regents University
    • Savannah, Georgia, United States, 31403
      • Memorial Health University Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii
  • Idaho
    • Boise, Idaho, United States, 83712
      • Saint Luke's Mountain States Tumor Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois
    • Chicago, Illinois, United States, 60614
      • Childrens Memorial Hospital
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Hope Children's Hospital
    • Park Ridge, Illinois, United States, 60068
      • Advocate Lutheran General Hospital
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
    • Indianapolis, Indiana, United States, 46260
      • Saint Vincent Hospital and Health Services
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Raymond Blank Children's Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Children's Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital-Main Campus
  • Maine
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
    • Scarborough, Maine, United States, 04074
      • Maine Children's Cancer Program
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
    • Baltimore, Maryland, United States, 21287-8936
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21201-1595
      • University of Maryland Greenebaum Cancer Center
    • Bethesda, Maryland, United States, 20889-5600
      • Walter Reed National Military Medical Center
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
    • Detroit, Michigan, United States, 48202
      • Wayne State University
    • Flint, Michigan, United States, 48502
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital at Spectrum Health
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49008
      • Kalamazoo Center for Medical Studies
    • Lansing, Michigan, United States, 48910
      • Michigan State University - Breslin Cancer Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center-Fairview
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri-Columbia
    • Kansas City, Missouri, United States, 64108
      • The Childrens Mercy Hospital
    • Saint Louis, Missouri, United States, 63141
      • Saint John's Mercy Medical Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68114
      • Children's Hospital and Medical Center of Omaha
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Nevada Cancer Research Foundation CCOP
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
    • Morristown, New Jersey, United States, 07962
      • Morristown Memorial Hospital
    • New Brunswick, New Jersey, United States, 08901
      • Saint Peter's University Hospital
    • New Brunswick, New Jersey, United States, 08903
      • UMDNJ - Robert Wood Johnson University Hospital
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
    • Paterson, New Jersey, United States, 07503
      • Saint Joseph's Regional Medical Center
    • Summit, New Jersey, United States, 07902
      • Overlook Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
  • New York
    • Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New Hyde Park, New York, United States, 11040
      • The Steven and Alexandra Cohen Children's Medical Center of New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospitals Inc
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28204
      • Presbyterian Hospital
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 27858
      • East Carolina University
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Childrens Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • The Children's Medical Center of Dayton
    • Toledo, Ohio, United States, 43608
      • Mercy Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Children's Hospital
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Lehigh Valley Hospital - Muhlenberg
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19134
      • Saint Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health Richland
    • Greenville, South Carolina, United States, 29605
      • BI-LO Charities Children's Cancer Center
    • Greenville, South Carolina, United States, 29605
      • Greenville Cancer Treatment Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5134
      • Sanford USD Medical Center - Sioux Falls
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • T C Thompson Children's Hospital
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Childrens Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Science Center-Amarillo
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Corpus Christi, Texas, United States, 78411
      • Driscoll Children's Hospital
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229
      • Methodist Children's Hospital of South Texas
    • San Antonio, Texas, United States, 78229-3900
      • University of Texas Health Science Center at San Antonio
    • Temple, Texas, United States, 76508
      • Scott and White Memorial Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Norfolk, Virginia, United States, 23507
      • Childrens Hospital-King's Daughters
    • Roanoke, Virginia, United States, 24014
      • Carilion Clinic Children's Hospital
  • Washington
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center and Children's Hospital
    • Tacoma, Washington, United States, 98405
      • Mary Bridge Children's Hospital and Health Center
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • West Virginia University Charleston
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • Saint Vincent Hospital
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 29 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of acute lymphoblastic leukemia (ALL)

  • Bone marrow with > 25% L1 or L2 lymphoblasts (M3 marrow)

    • Patients with > 25% L3 marrow lymphoblasts and/or evidence of c-myc translocation are not eligible (considered Burkitt's or mature B-cell leukemia)

• Intermediate-risk relapsed disease, meeting 1 of the following criteria:

  • Bone marrow relapse ≥ 36 months after initial diagnosis (defined as M3 marrow after previous remission from ALL)
  • Combined bone marrow and extramedullary (CNS* and/or testicular**) relapse ≥ 36 months after initial diagnosis
  • Isolated extramedullary (CNS* and/or testicular**) relapse < 18 months after initial diagnosis

• The following subtypes are not allowed:

  • T-lineage ALL
  • Mature B-cell (Burkitt's) leukemia (defined as L3 morphology and/or evidence of c-myc translocation)
  • Philadelphia-chromosome positive disease
• No Down syndrome (trisomy 21)
• Shortening fraction >= 27% by echocardiogram OR ejection fraction >= 50% by radionuclide angiogram
• Bilirubin < 3.0 mg/dL
• Not pregnant
• Fertile patients must use effective contraception
• No history of peripheral neuropathy >= grade 3 within the past month
• No toxicity (i.e. peripheral neuropathy) >= grade 3 attributable to vincristine within the past month
• At least 5 days since prior intrathecal chemotherapy
• No prior hematopoietic stem cell or marrow transplantation
• No prior cranial radiotherapy > 1200 cGy (for patients with CNS relapse)
• No concurrent stem cell transplant
• No concurrent alternative therapy
• No concurrent itraconazole in patients receiving vincristine
• No concurrent intensity-modulated radiotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Regimen A: Standard vincristine dosing; See detailed description.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM; Adriamycin PFS; Adriamycin RDF; ADR; Adria; Drug: vincristine sulfate; Given IV; Other Names: VCR; leurocristine sulfate; Vincasar PFS; Drug: pegaspargase; Given IM; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-ASP; PEG-L-asparaginase; Biological: filgrastim; Given IV or SC; Other Names: G-CSF; Neupogen; Drug: prednisone; Given PO; Other Names: DeCortin; Deltra; Drug: dexamethasone; Given PO; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Drug: leucovorin calcium; Given IV or PO; Other Names: CF; CFR; LV; Drug: asparaginase; Given IM; Other Names: Elspar; Colaspase; L-ASP; ASNase; Crasnitin; Drug: mercaptopurine; Given PO; Other Names: 6-MP; Leukerin; 6-mercaptopurine; MP; Drug: cytarabine; Given IT or IV; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: methotrexate; Given IT or IV; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX
Experimental: Arm B: Randomized High Dose Vincristine regimen; See detailed description. Closed to accrual as of 09/2010).	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM; Adriamycin PFS; Adriamycin RDF; ADR; Adria; Drug: vincristine sulfate; Given IV; Other Names: VCR; leurocristine sulfate; Vincasar PFS; Drug: pegaspargase; Given IM; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-ASP; PEG-L-asparaginase; Biological: filgrastim; Given IV or SC; Other Names: G-CSF; Neupogen; Drug: prednisone; Given PO; Other Names: DeCortin; Deltra; Drug: dexamethasone; Given PO; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Drug: leucovorin calcium; Given IV or PO; Other Names: CF; CFR; LV; Drug: asparaginase; Given IM; Other Names: Elspar; Colaspase; L-ASP; ASNase; Crasnitin; Drug: mercaptopurine; Given PO; Other Names: 6-MP; Leukerin; 6-mercaptopurine; MP; Drug: cytarabine; Given IT or IV; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: methotrexate; Given IT or IV; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival. EFS	Percentage of patients who were event free at 3 years among those on Standard VCR dosing who did not undergo Hematopoietic Stem Cell Transplant (SCT).	3 years after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and Severity of Adverse Effects	Percentage of patients who developed at least 1 episode of grade 2 to 4 neuropathy.	Up to 107 weeks
Gene Expression Profile	Percent of unfavorable gene expression profile of early versus late marrow relapse.	Up to 36 months
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1	Percentage of patients who had minimal residual disease (MRD) < 0.01% among those with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 1	End of Block 1 (35 days) of Induction therapy
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3	Percentage of patients who had minimal residual disease (MRD) < 0.01% among those with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 3.	End of Block 3 (105 days) of Induction therapy
Event Free Survival (EFS)	Percentage of patients who were event free at 3 years among those with isolated BM or combined BM relapse >= 36 months.	3 years
Adjusted Event Free Survival	Adjusted percentage of patients who were event free at 3 years. For patients who received matched donor SCT, EFS was adjusted to start from the actual SCT date. For patients who did not undergo SCT, EFS was adjusted to start from median time to SCT based on patients who received matched related SCT (where patients who had events prior to SCT date were excluded from the calculation of median time to SCT).	3 years

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Glen Lew, MD, Children's Oncology Group

Publications and helpful links

General Publications

• Lew G, Chen Y, Lu X, Rheingold SR, Whitlock JA, Devidas M, Hastings CA, Winick NJ, Carroll WL, Wood BL, Borowitz MJ, Pulsipher MA, Hunger SP. Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433. Haematologica. 2021 Jan 1;106(1):46-55. doi: 10.3324/haematol.2019.237230.

Helpful Links

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: September 26, 2006
• First Submitted That Met QC Criteria: September 26, 2006
• First Posted (Estimated): September 28, 2006

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Micronutrients; Antibiotics, Antineoplastic; Vitamins; Reproductive Control Agents; Antidotes; Vitamin B Complex; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Dexamethasone; Cyclophosphamide; Etoposide; Etoposide phosphate; Leucovorin; Levoleucovorin; Prednisone; Doxorubicin; Liposomal doxorubicin; Cytarabine; Methotrexate; Vincristine; Asparaginase; Mercaptopurine; Pegaspargase
• Other Study ID Numbers: AALL0433; U10CA098543 (U.S. NIH Grant/Contract); NCI-2009-00306 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); COG-AALL0433 (Other Identifier: Children's Oncology Group); CDR0000495359 (Other Identifier: Clinical Trials.gov)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive