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INTENSIVE TREATMENT FOR INTERMEDIATE-RISK RELAPSE OF CHILDHOOD B-PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): A RANDOMIZED TRIAL OF VINCRISTINE STRATEGIES


Phase 3
1 Year
29 Years
Not Enrolling
Both
B-cell Childhood Acute Lymphoblastic Leukemia, L1 Childhood Acute Lymphoblastic Leukemia, L2 Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia

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Trial Information

INTENSIVE TREATMENT FOR INTERMEDIATE-RISK RELAPSE OF CHILDHOOD B-PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): A RANDOMIZED TRIAL OF VINCRISTINE STRATEGIES


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. Compare the 3-year event-free survival and frequency and severity of adverse effects in
patients treated with high-dose (closed to accrual as of 9/2010) vs low-dose vincristine.

II. 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.

III. 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).

IV. 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).

V. 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 arms (randomization closed as of 09/2010).

INDUCTION THERAPY 1 (WEEKS 1-5):

ARM I: 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.

ARM II (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 arm I.

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 arm II are crossover to arm I.

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 arm in induction therapy 1).

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

ARM I: 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).

ARM II: Patients receive high-dose vincristine IV on day 1 and high-dose methotrexate,
leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide, and methotrexate
IT* as in arm I. (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 arm II are crossover to arm I.

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

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

ARM I: 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.

ARM II: Patients receive high-dose vincristine IV on days 1, 8, and 15 and doxorubicin
hydrochloride, dexamethasone, pegaspargase, and methotrexate IT* as in arm I. (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 arm II are crossover to arm I. Patients in both arms
then proceed to intensification therapy 2 (as per their randomized arm in induction therapy
1).

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

ARM I: 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).

ARM II: Patients receive high-dose cytarabine, high-dose methotrexate, leucovorin calcium,
pegaspargase, mercaptopurine, etoposide phosphate, cyclophosphamide, methotrexate IT*, and
G-CSF as in arm I. 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 arms then proceed to maintenance therapy (as per their randomized arm in
induction therapy 1).

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

ARM I: 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.

ARM II: Patients receive methotrexate*, mercaptopurine, dexamethasone, and cyclophosphamide
as in arm I. 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.


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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Efficacy of therapy of an intensive chemotherapy regimen (based on POG 9412) for patients with intermediate-risk relapse of childhood B-precursor ALL

Outcome Description:

Power calculations are based on the assumption of proportional hazards, and using the log rank test (alpha=0.1, one-sided test). The efficacy stopping boundaries to be used will be based on the alpha x (time)^2 spending function. The study will also be monitored for futility. The lower boundaries are based on testing the alternative hypothesis at the 0.005 level.

Outcome Time Frame:

Assessed up to 5 years

Safety Issue:

No

Principal Investigator

Glen Lew

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

AALL0433

NCT ID:

NCT00381680

Start Date:

March 2007

Completion Date:

Related Keywords:

  • B-cell Childhood Acute Lymphoblastic Leukemia
  • L1 Childhood Acute Lymphoblastic Leukemia
  • L2 Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Burkitt Lymphoma
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma

Name

Location

Baylor College of MedicineHouston, Texas  77030
Johns Hopkins UniversityBaltimore, Maryland  21205
Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Mayo ClinicRochester, Minnesota  55905
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Hurley Medical CenterFlint, Michigan  48503
Rhode Island HospitalProvidence, Rhode Island  02903
Medical City Dallas HospitalDallas, Texas  75230
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Sinai Hospital of BaltimoreBaltimore, Maryland  21225
Bronson Methodist HospitalKalamazoo, Michigan  49007
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Loyola University Medical CenterMaywood, Illinois  60153
Morristown Memorial HospitalMorristown, New Jersey  07962-1956
Marshfield ClinicMarshfield, Wisconsin  54449
Loma Linda University Medical CenterLoma Linda, California  92354
Baptist Hospital of MiamiMiami, Florida  33176-2197
Newark Beth Israel Medical CenterNewark, New Jersey  07112
New York Medical CollegeValhalla, New York  10595
Cedars-Sinai Medical CenterLos Angeles, California  90048
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Brooke Army Medical CenterFort Sam Houston, Texas  78234-6200
Madigan Army Medical CenterTacoma, Washington  98431-5048
Eastern Maine Medical CenterBangor, Maine  04401
University of Nebraska Medical CenterOmaha, Nebraska  68198-3330
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's National Medical CenterWashington, District of Columbia  20010-2970
Miami Children's HospitalMiami, Florida  33155-4069
All Children's HospitalSt. Petersburg, Florida  33701
Advocate Hope Children's HospitalOak Lawn, Illinois  60453
Ochsner Clinic FoundationNew Orleans, Louisiana  70121
Maine Children's Cancer ProgramScarborough, Maine  04074-9308
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health CenterPortland, Oregon  97227
Driscoll Children's HospitalCorpus Christi, Texas  78466
Scott and White Memorial HospitalTemple, Texas  76508
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Santa Barbara Cottage HospitalSanta Barbara, California  93102
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Hospital Medical Center of AkronAkron, Ohio  44308
Covenant Children's HospitalLubbock, Texas  79410
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Overlook HospitalSummit, New Jersey  07902-0220
Mount Sinai Medical CenterNew York, New York  10029
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Montefiore Medical CenterBronx, New York  10467-2490
Saint Peter's University HospitalNew Brunswick, New Jersey  08901-1780
Rady Children's Hospital - San DiegoSan Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central TexasAustin, Texas  78723
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
Mary Bridge Children's Hospital and Health CenterTacoma, Washington  98415-0299
City of Hope Medical CenterDuarte, California  91010
Lehigh Valley Hospital - MuhlenbergBethlehem, Pennsylvania  18017
Presbyterian HospitalCharlotte, North Carolina  28233-3549
Lee Memorial Health SystemFort Myers, Florida  33902
University of VirginiaCharlottesville, Virginia  22908
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Children's Hospital of AlabamaBirmingham, Alabama  35233
Connecticut Children's Medical CenterHartford, Connecticut  06106
University of North CarolinaChapel Hill, North Carolina  27599
Duke University Medical CenterDurham, North Carolina  27710
University of FloridaGainesville, Florida  32610-0277
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, Michigan  49503
Yale UniversityNew Haven, Connecticut  06520
Wayne State UniversityDetroit, Michigan  48202
Mercy Children's HospitalToledo, Ohio  43608
Legacy Emanuel Children's HospitalPortland, Oregon  97227
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
University of Arizona Health Sciences CenterTucson, Arizona  85724
University of Massachusetts Medical SchoolWorcester, Massachusetts  01605
Dartmouth Hitchcock Medical CenterLebanon, New Hampshire  03756
University of Texas Southwestern Medical CenterDallas, Texas  
University of KentuckyLexington, Kentucky  40536-0098
UC Davis Comprehensive Cancer CenterSacramento, California  95817
Oregon Health and Science UniversityPortland, Oregon  97201
Tulane University Health Sciences CenterNew Orleans, Louisiana  70112
Florida HospitalOrlando, Florida  32803
Memorial Health University Medical CenterSavannah, Georgia  31404
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Childrens Memorial HospitalChicago, Illinois  60614
Kaiser Permanente-OaklandOakland, California  94611
Sutter General HospitalSacramento, California  95816
Lombardi Comprehensive Cancer Center at Georgetown UniversityWashington, District of Columbia  20057
M D Anderson Cancer Center- OrlandoOrlando, Florida  32806
University of HawaiiHonolulu, Hawaii  96813
Saint Luke's Mountain States Tumor InstituteBoise, Idaho  83712
Saint Vincent Hospital and Health ServicesIndianapolis, Indiana  46260
Michigan State University - Breslin Cancer CenterEast Lansing, Michigan  48824-1313
Kalamazoo Center for Medical StudiesKalamazoo, Michigan  49008
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Nevada Cancer Research Foundation CCOPLas Vegas, Nevada  89106
Saint Barnabas Medical CenterLivingston, New Jersey  07039
New York University Langone Medical CenterNew York, New York  10016
Columbia University Medical CenterNew York, New York  10032
State University of New York Upstate Medical UniversitySyracuse, New York  13210
Mission Hospitals IncAsheville, North Carolina  28801
Saint Vincent HospitalGreen Bay, Wisconsin  54301
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201
University of IllinoisChicago, Illinois  60612
Cook Children's Medical CenterFort Worth, Texas  76104
East Carolina UniversityGreenville, North Carolina  27858
West Virginia University CharlestonCharleston, West Virginia  25304
The Children's Medical Center of DaytonDayton, Ohio  45404
Advocate Lutheran General HospitalPark Ridge, Illinois  60068
University of Miami Miller School of Medicine-Sylvester Cancer CenterMiami, Florida  33136
University of Minnesota Medical Center-FairviewMinneapolis, Minnesota  55455
Children's Oncology GroupArcadia, California  91006-3776
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Southern Illinois UniversitySpringfield, Illinois  62702
University Of Missouri-ColumbiaColumbia, Missouri  65212
Walter Reed National Military Medical CenterBethesda, Maryland  20889
Riley Hospital for ChildrenIndianapolis, Indiana  46202
UMDNJ - Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
Phoenix Childrens HospitalPhoenix, Arizona  85016
Miller Children's HospitalLong Beach, California  90806
Childrens Hospital of Orange CountyOrange, California  92868-3874
Alfred I duPont Hospital for ChildrenWilmington, Delaware  19803
Nemours Children's Clinic - JacksonvilleJacksonville, Florida  32207-8426
Nemours Childrens Clinic - OrlandoOrlando, Florida  32806
Saint Joseph Children's Hospital of TampaTampa, Florida  33607
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Rainbow Babies and Childrens HospitalCleveland, Ohio  44106
Penn State Hershey Children's HospitalHershey, Pennsylvania  17033
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916
Saint Mary's HospitalWest Palm Beach, Florida  33407
Children's Hospital and Medical Center of OmahaOmaha, Nebraska  68114
Saint Joseph's Regional Medical CenterPaterson, New Jersey  07503
Texas Tech University Health Science Center-AmarilloAmarillo, Texas  79106
Childrens Hospital-King's DaughtersNorfolk, Virginia  23507
Children's Hospital ColoradoAurora, Colorado  80045
Lucile Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical CenterDenver, Colorado  80218
Raymond Blank Children's HospitalDes Moines, Iowa  50309
Children's Hospital-Main CampusNew Orleans, Louisiana  70118
Saint Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania  19134
Greenville Cancer Treatment CenterGreenville, South Carolina  29605
Sanford USD Medical Center - Sioux FallsSioux Falls, South Dakota  57117-5134
T C Thompson Children's HospitalChattanooga, Tennessee  37403
Carilion Clinic Children's HospitalRoanoke, Virginia  24014
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204
Broward Health Medical CenterFort Lauderdale, Florida  33316
The Steven and Alexandra Cohen Children's Medical Center of New YorkNew Hyde Park, New York  11040
Georgia Regents UniversityAugusta, Georgia  30912