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Escalating Dose Intravenous Methotrexate Without Leucovorin Rescue Versus Oral Methotrexate and Single Versus Double Delayed Intensification for Children With Standard Risk Acute Lymphoblastic Leukemia


Phase 3
1 Year
9 Years
Not Enrolling
Both
Leukemia

Thank you

Trial Information

Escalating Dose Intravenous Methotrexate Without Leucovorin Rescue Versus Oral Methotrexate and Single Versus Double Delayed Intensification for Children With Standard Risk Acute Lymphoblastic Leukemia


OBJECTIVES:

- Compare the event-free survival and overall survival of children with standard-risk
acute lymphoblastic leukemia treated with escalating-dose IV methotrexate without
leucovorin calcium versus oral methotrexate during the interim maintenance phase of
therapy.

- Compare the event-free survival and overall survival of these patients after receiving
treatment in two delayed intensification phases versus one delayed intensification
phase.

- Compare the toxic effects of oral versus escalating-dose intravenous methotrexate in
these patients.

- Determine the prognostic significance of the rate of disappearance of peripheral
lymphoblasts and lymphocytes during the first week of treatment in these patients.

- Determine the prognostic significance of trisomies of chromosomes 4, 5, 10, and 17 and
early treatment response in patients treated with these regimens.

- Determine the prognostic significance of the TEL-AML1 fusion transcript and early
treatment response in patients treated with these regimens.

- Determine the minimal residual disease (MRD) by polymerase chain reaction in bone
marrow and cerebrospinal fluid at various stages of therapy in these patients.

- Determine the prognostic significance of MRD during various stages of therapy in these
patients.

- Determine whether a second delayed intensification therapy improves the prognosis of
patients who have MRD at the end of induction therapy.

OUTLINE: This is a randomized, multicenter study. Patients without CNS disease at diagnosis,
achieving a specified early marrow response profile and M1 marrow status of less than 5%
blasts in the bone marrow (regardless of the proportion of mature lymphocytes) by day 28 of
induction therapy, and remaining event free with favorable bone marrow status and
cytogenetics between day 21 and 28 of consolidation therapy are randomized to one of four
treatment arms. Patients with CNS disease at diagnosis are assigned to treatment arm II and
undergo cranial irradiation. Patients with any of the following unfavorable bone marrow
features and/or unfavorable cytogenetic features are assigned to the augmented treatment
regimen by day 21 of induction chemotherapy or at the beginning of consolidation
chemotherapy:

NOTE: All T-cell precursor patients that are not more than 4 months past completion of the
delayed intensification phase of therapy should be switched to the augmented regimen as of
3/8/2004. These patients may be switched to the augmented regimen. The protocol gives
specific instructions according to the phase of therapy the patients are actually in.

- Unfavorable marrow status:

- M2: 5-25% blasts in bone marrow at day 28 of induction chemotherapy (or at day 14
of induction chemotherapy if day 7 status is M3) OR

- M3: More than 25% blast cell in bone marrow, regardless of the proportion of
mature lymphocytes at day 14 of induction chemotherapy

- Unfavorable cytogenetics: Must have 1 of the following:

- t(9;22)(q34;q11)

- t(4;11)(q21;q23)

- Balanced t(1;19)(q23;p13)

- Hypodiploidy with less than 45 chromosomes

- Other 11q23 translocations involving MLL Patients receive standard induction
chemotherapy comprising cytarabine (ARA-C) intrathecally (IT) on day 0 or up to 72
hours before day 0; oral dexamethasone (DM) twice daily on days 0-27; vincristine
(VCR) IV on days 0, 7, 14, and 21; and pegaspargase (PEG-ASP) intramuscularly (IM)
once between days 3-5. Patients without CNS disease at diagnosis receive
methotrexate (MTX) IT on days 7 and 28. Patients with CNS disease at diagnosis
receive MTX IT on days 7, 14, 21, and 28.

Patients who have achieved M1 marrow status by day 28 of induction therapy and have
favorable early bone marrow response and cytogenetics proceed to standard consolidation
therapy once blood counts have recovered. Patients with M3 bone marrow status at day 28 of
induction therapy are taken off the protocol. All other patients are assigned to the
augmented treatment regimen.

Beginning on day 28 of induction chemotherapy, patients receive standard consolidation
chemotherapy comprising VCR IV on day 0 and oral mercaptopurine (MP) on days 0-27. Patients
without CNS disease at diagnosis receive MTX IT on days 7, 14, 21, and 28. Patients with CNS
disease at diagnosis receive MTX IT on day 7 and cranial irradiation 5 days a week for 2
weeks. Patients with testicular disease receive bilateral testicular radiotherapy 5 days a
week for 1 week and then for 3 consecutive days during the next week.

NOTE: As of 3/8/2004, patients with T-cell disease who did not achieve M1 marrow status by
day 14 of induction OR who did not receive augmented induction and/or consolidation
(regardless of early marrow status) receive cranial irradiation.

- Arm I: Beginning on day 28 of consolidation chemotherapy, patients receive interim
maintenance I chemotherapy comprising oral DM twice daily on days 0-4 and 28-32; VCR IV
on days 0 and 28; oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49; oral MP on days
0-49; and MTX IT on day 28.

Beginning on day 56 of interim maintenance I chemotherapy, patients receive delayed
intensification chemotherapy comprising oral DM twice daily on days 0-6 and 14-20; VCR IV
and doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14; PEG-ASP IM on day
3; cyclophosphamide (CTX) IV over 20-30 minutes on day 28; oral thioguanine (TG) on days
28-41; ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38; and MTX IT on days 0
and 28.

Beginning on day 56 of delayed intensification chemotherapy, patients receive interim
maintenance II chemotherapy identical to interim maintenance I chemotherapy except patients
receive MTX IT on days 0 and 28.

Beginning on day 56 of interim maintenance II chemotherapy, patients receive maintenance
chemotherapy comprising oral DM twice daily on days 0-4, 28-32, and 56-60; VCR IV on days 0,
28, and 56; oral MP on days 0-83; oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70,
and 77; and MTX IT on day 0.

- Arm II: Patients receive interim maintenance I chemotherapy, delayed intensification
chemotherapy, and interim maintenance II chemotherapy as in arm I. Beginning on day 56
of interim maintenance II chemotherapy, patients then receive a second course of
delayed intensification chemotherapy followed by maintenance chemotherapy as in arm I.

- Arm III: Beginning on day 28 of consolidation chemotherapy, patients receive interim
maintenance I chemotherapy comprising VCR IV; escalating doses of MTX IV on days 0, 10,
20, 30, and 40; and MTX IT on day 30. Patients then receive delayed intensification
chemotherapy as in arm I. Patients receive interim maintenance II chemotherapy as in
interim maintenance I chemotherapy, but with IV MTX starting at 2/3 of the maximum
tolerated dose (MTD) attained in interim maintenance I chemotherapy. Patients then
receive maintenance chemotherapy as in arm I.

- Arm IV: Patients receive interim maintenance I chemotherapy as in arm III, delayed
intensification chemotherapy as in arm I, interim maintenance II chemotherapy as in arm
III, delayed intensification II chemotherapy as in arm II, and maintenance chemotherapy
as in arm I.

- Augmented Treatment: Patients receive induction chemotherapy comprising daunorubicin IV
continuously for 48 hours beginning no later than day 21; oral DM twice daily on days
14-27; and VCR IV on days 14 and 21. Patients without CNS disease at diagnosis receive
MTX IT on days 21 and 35. Patients with CNS disease at diagnosis receive MTX IT on days
21 and 28.

NOTE: Patients with T-cell disease should re-start with augmented consolidation and proceed
as per the augmented regimen.

Beginning on day 35 of induction chemotherapy, patients receive consolidation therapy
comprising CTX IV over 20-30 minutes on days 0 and 28; oral MP on days 0-13 and 28-41; ARA-C
IV or SC daily on days 0-3, 7-10, 28-31, and 35-38; VCR IV on days 14, 21, 42, and 49; and
PEG-ASP IM on days 14 and 42. Patients without CNS disease at diagnosis receive MTX IT on
days 7, 14, and 21. Patients with CNS disease at diagnosis receive MTX IT on day 7 and
cranial irradiation as in the randomized treatment section. Patients with testicular
leukemia receive radiotherapy as in the randomized treatment section.

Beginning on day 63 of consolidation chemotherapy, patients receive interim maintenance I
chemotherapy comprising VCR IV on days 0, 10, 20, 30, and 40; escalating doses of MTX IV on
days 10, 20, 30, and 40; PEG-ASP IM on days 1 and 21; and MTX IT on days 0 and 30.

Beginning on day 56 of interim maintenance I chemotherapy, patients receive delayed
intensification I chemotherapy comprising oral DM twice daily on days 0-6 and 14-20; VCR IV
on days 0, 7, 14, 42, and 49; DOX IV over 15 minutes to 2 hours on days 0, 7, and 14;
PEG-ASP IM on days 3 and 42; CTX IV over 20-30 minutes on day 28; oral TG on days 28-41;
ARA-C IV or SC daily on days 28-31 and 35-38; and MTX IT on days 0 and 28.

NOTE: Patients with T-cell disease who are in interim maintenance I chemotherapy with
escalating IV methotrexate should continue this phase and then proceed as per the augmented
regimen. If these patients are receiving conventional interim maintenance chemotherapy with
oral methotrexate, they should stop and restart the interim maintenance as per the augmented
regimen. These patients receive cranial irradiation starting on day 28 of delayed
intensification II chemotherapy.

Beginning on day 56 of delayed intensification I chemotherapy, patients receive interim
maintenance II chemotherapy as in interim maintenance I chemotherapy, but with IV MTX
starting at 2/3 of the MTD attained in interim maintenance I chemotherapy.

NOTE: Patients with T-cell disease who are in delayed intensification I chemotherapy proceed
with this phase, with the addition of 2 vincristine doses on days 42 and 49 and PEG-ASP on
day 42. These patients then proceed as per the augmented regimen with the addition of
cranial irradiation starting on day 28 of delayed intensification II chemotherapy.

NOTE: Patients with T-cell disease who are within 4 months of completing delayed
intensification I chemotherapy and have not received interim maintenance II chemotherapy
with escalating IV methotrexate or delayed intensification II chemotherapy receive a course
of interim maintenance chemotherapy and delayed intensification II chemotherapy according to
the augmented regimen. If these patients have received interim maintenance II chemotherapy
with escalating IV methotrexate, they receive delayed intensification II chemotherapy
according to the augmented regimen. These patients also receive cranial irradiation starting
on day 28 of delayed intensification II chemotherapy and then proceed to maintenance
therapy.

Beginning on day 56 of interim maintenance II chemotherapy, patients receive delayed
intensification II chemotherapy as in delayed intensification I chemotherapy.

Beginning on day 56 of delayed intensification II chemotherapy, patients receive maintenance
chemotherapy comprising oral DM twice daily on days 0-4, 28-32, and 56-60; VCR IV on days 0,
28, and 56; oral MP on days 0-83; oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70,
and 77; and MTX IT on day 0.

Patients are followed every 4-8 weeks for one year, every 3 months for one year, every 6
months for one year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,037 randomized patients will be accrued for this study
within 3.75 years.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Diagnosis of previously untreated B-cell precursor acute lymphoblastic leukemia

- More than 25% L1 or L2 lymphoblasts

- No more than 25% L3 lymphoblasts

- WBC < 50,000/mm^3

- No T-cell precursor acute lymphoblastic leukemia by immunophenotyping

- Massive lymphadenopathy, massive splenomegaly, or large mediastinal mass allowed

- CNS or testicular leukemia allowed

- No patients found to have t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11-p12;q24)
(characteristic of Burkitt's lymphoma)

PATIENT CHARACTERISTICS:

Age:

- 1 to 9

Performance status:

- Not specified

Life expectancy:

- Not specified

Hematopoietic:

- See Disease Characteristics

Hepatic:

- Not specified

Renal:

- Not specified

Other:

- Not pregnant

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- Not specified

Chemotherapy:

- No more than 72 hours since prior intrathecal cytarabine

Endocrine therapy:

- At least 30 days since prior systemic corticosteroids given for more than 48 hours

- Prior corticosteroids for mediastinal mass causing superior mediastinal syndrome
allowed

- Prior or concurrent inhaled corticosteroids allowed

Radiotherapy:

- Prior radiotherapy for mediastinal mass causing superior mediastinal syndrome allowed

- No concurrent spinal radiotherapy

Surgery:

- Not specified

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Event Free Survival

Outcome Description:

The primary outcome index used in examining the randomized treatment groups will be event free survival (EFS) from the time of randomization (i.e., end of Consolidation), where the life table events will consist of the first occurrence of leukemic relapse at any site, death, or occurrence of a second malignancy.

Outcome Time Frame:

Time of randomization

Safety Issue:

No

Principal Investigator

Yousif H. Matloub, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of Wisconsin, Madison

Authority:

United States: Federal Government

Study ID:

1991

NCT ID:

NCT00005945

Start Date:

June 2000

Completion Date:

Related Keywords:

  • Leukemia
  • untreated childhood acute lymphoblastic leukemia
  • L1 childhood acute lymphoblastic leukemia
  • L2 childhood acute lymphoblastic leukemia
  • L3 childhood acute lymphoblastic leukemia
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
University of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan  48109-0752
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Mayo Clinic Cancer CenterRochester, Minnesota  55905
Jonsson Comprehensive Cancer Center, UCLALos Angeles, California  90095-1781
University of Chicago Cancer Research CenterChicago, Illinois  60637
University of Minnesota Cancer CenterMinneapolis, Minnesota  55455
Cancer Center of Albany Medical CenterAlbany, New York  12208
Rhode Island HospitalProvidence, Rhode Island  02903
Medical City Dallas HospitalDallas, Texas  75230
Yale Comprehensive Cancer CenterNew Haven, Connecticut  06520-8028
Presbyterian - St. Luke's Medical CenterDenver, Colorado  80218
Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health CenterFarmington, Connecticut  06360-2875
Baystate Regional Cancer Program at D'Amour Center for Cancer CareSpringfield, Massachusetts  01199
Bronson Methodist HospitalKalamazoo, Michigan  49007
Geisinger Medical CenterDanville, Pennsylvania  17822-0001
Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical CenterLa Crosse, Wisconsin  54601
Marshfield Clinic - Marshfield CenterMarshfield, Wisconsin  54449
Lutheran General Cancer Care CenterPark Ridge, Illinois  60068
Newark Beth Israel Medical CenterNewark, New Jersey  07112
New York Medical CollegeValhalla, New York  10595
Meritcare Roger Maris Cancer CenterFargo, North Dakota  58122
Deaconess Medical CenterSpokane, Washington  99210-0248
University of Wisconsin Comprehensive Cancer CenterMadison, Wisconsin  53792
Holden Comprehensive Cancer Center at University of IowaIowa City, Iowa  52242-1002
Long Island Cancer Center at Stony Brook University HospitalStony Brook, New York  11790-7775
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570
CCOP - Columbia River Oncology ProgramPortland, Oregon  97225
CCOP - Scott and White HospitalTemple, Texas  76508
St. Barnabas Medical CenterLivingston, New Jersey  07039
MBCCOP - LSU Health Sciences CenterNew Orleans, Louisiana  70112
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's Hospital of Orange CountyOrange, California  92668
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Mercy HospitalKansas City, Missouri  64108
St. Joseph's Hospital and Medical CenterPaterson, New Jersey  07503
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Kaiser Permanente Medical Center/Kaiser Foundation Hospital - San DiegoSan Diego, California  92120
Kaiser Permanente Medical Center - Santa ClaraSanta Clara, California  95051-5386
Schneider Children's HospitalNew Hyde Park, New York  11042
City of Hope Comprehensive Cancer CenterDuarte, California  91010
UCSF Comprehensive Cancer CenterSan Francisco, California  94115
Phoenix Children's HospitalPhoenix, Arizona  85016-7710
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Santa Barbara Cottage HospitalSanta Barbara, California  93102
Medical Center of Central GeorgiaMacon, Georgia  31201
Southern Illinois University School of MedicineSpringfield, Illinois  62794-9658
Kosair Children's HospitalLouisville, Kentucky  40202-3830
CCOP - BeaumontRoyal Oak, Michigan  48073-6769
Children's Hospital of OmahaOmaha, Nebraska  68114
Sunrise Hospital and Medical CenterLas Vegas, Nevada  89109-2306
Brookdale University Hospital and Medical CenterBrooklyn, New York  11212
Brooklyn Hospital CenterBrooklyn, New York  11201
Children's Hospital Medical Center of AkronAkron, Ohio  44308
Children's Medical Center - DaytonDayton, Ohio  45404
St. Vincent Mercy Medical CenterToledo, Ohio  43608
Toledo Children's HospitalToledo, Ohio  43601
East Tennessee Children's HospitalKnoxville, Tennessee  37901
Texas Tech University Health Sciences Center School of MedicineAmarillo, Texas  79106
Children's Hospital of AustinAustin, Texas  78701
Covenant Children's HospitalLubbock, Texas  79410
Children's Hospital of the King's DaughtersNorfolk, Virginia  23507
Bellin Memorial HospitalGreen Bay, Wisconsin  54301
Markey Cancer Center at University of Kentucky Chandler Medical CenterLexington, Kentucky  40536-0084
Herbert Irving Comprehensive Cancer Center at Columbia UniversityNew York, New York  10032
Blumenthal Cancer Center at Carolinas Medical CenterCharlotte, North Carolina  28232-2861
SUNY Downstate Medical CenterBrooklyn, New York  11203
Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve UniversityCleveland, Ohio  44106
Sioux Valley Hospital and University of South Dakota Medical CenterSioux Falls, South Dakota  57117-5134
Loma Linda University Cancer Institute at Loma Linda University Medical CenterLoma Linda, California  92354
Curtis & Elizabeth Anderson Cancer Institute at Memorial Health University Medical CenterSavannah, Georgia  31403-3089
Blank Children's HospitalDes Moines, Iowa  50309
Alvin and Lois Lapidus Cancer Institute at Sinai HospitalBaltimore, Maryland  21215
Breslin Cancer Center at Ingham Regional Medical CenterLansing, Michigan  48910
Albert Einstein Cancer Center at Albert Einstein College of MedicineBronx, New York  10461
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Presbyterian Cancer Center at Presbyterian HospitalCharlotte, North Carolina  28233-3549
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
West Virginia University - Robert C. Byrd Health Sciences Center - Charleston DivisionCharleston, West Virginia  25302
CCOP - Marshfield Clinic Research FoundationMarshfield, Wisconsin  54449
St. Mary's - Duluth Clinic Cancer CenterDuluth, Minnesota  55805
Group Health Central HospitalSeattle, Washington  98104
Lombardi Cancer Center at Georgetown University Medical CenterWashington, District of Columbia  20007
Josephine Ford Cancer Center at Henry Ford Health SystemDetroit, Michigan  48202
UNMC Eppley Cancer Center at the University of Nebraska Medical CenterOmaha, Nebraska  68198-7680
New York Weill Cornell Cancer Center at Cornell UniversityNew York, New York  10021
Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical CenterLos Angeles, California  90048-1865
Alfred I. duPont Hospital for ChildrenWilmington, Delaware  19803
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite CampusAtlanta, Georgia  30342
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical SchoolNew Brunswick, New Jersey  08903
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
Kaiser Permanente Medical Center - SacramentoSacramento, California  95825
Mountain States Tumor Institute - BoiseBoise, Idaho  83712
University of Illinois Medical CenterChicago, Illinois  60612
Riley Children Cancer Center at Riley Hospital for ChildrenIndianapolis, Indiana  46202-5225
William Beaumont Hospital - Royal OakRoyal Oak, Michigan  48073-6769
Valerie Fund Children's Center at Atlantic HealthSummit, New Jersey  07901
Comprehensive Cancer Center at Maimonides Medical CenterBrooklyn, New York  11219
Dakota Cancer Institute at Innovis Health - Dakota ClinicFargo, North Dakota  58103-4940
Doernbecher Children's Hospital at Oregon Health & Science UniversityPortland, Oregon  97239-3098
East Tennessee State University Cancer Center at Johnson City Medical CenterJohnson City, Tennessee  37604
Vanderbilt Children's HospitalNashville, Tennessee  37232-6310
Methodist Cancer Center at Methodist Specialty and Transplant HospitalSan Antonio, Texas  78229-3902
MBCCOP - South Texas PediatricsSan Antonio, Texas  78229-3900
Mary Bridge Children's Hospital and Health CenterTacoma, Washington  98415-0299
Cabell Huntington HospitalHuntington, West Virginia  25701
Chao Family Comprehensive Cancer Center at University of California Irvine Medical CenterOrange, California  92868
General Robert Huyser Cancer Center at David Grant Medical CenterTravis Air Force Base, California  94535
Children's Hospital Cancer CenterDenver, Colorado  80218
DeVos Children's HospitalGrand Rapids, Michigan  49503
Children's Hospitals and Clinics - Minneapolis/St. PaulMinneapolis, Minnesota  55404
Columbus Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital at Milton S. Hershey Medical CenterHershey, Pennsylvania  17033
MD Anderson Cancer Center at University of TexasHouston, Texas  77030-4009