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Intergroup Trial for Children or Adolescents With B-Cell NHL or B-AL: Evaluation of Rituximab Efficacy and Safety in High Risk Patients


Phase 2/Phase 3
N/A
18 Years
Open (Enrolling)
Both
B-cell Childhood Acute Lymphoblastic Leukemia, Childhood Diffuse Large Cell Lymphoma, L3 Childhood Acute Lymphoblastic Leukemia, Stage III Childhood Large Cell Lymphoma, Stage IV Childhood Large Cell Lymphoma, Untreated Childhood Acute Lymphoblastic Leukemia

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Trial Information

Intergroup Trial for Children or Adolescents With B-Cell NHL or B-AL: Evaluation of Rituximab Efficacy and Safety in High Risk Patients


PRIMARY OBJECTIVES:

I. For the patients with advanced stage B-cell non-Hodgkin lymphoma (NHL)/Burkitt leukemia
(B-AL) (stage III and lactate dehydrogenase (LDH) > Nx2, any stage IV or B-AL), to test
whether adding 6 injections of rituximab to standard LMB chemotherapy regimen, improves the
event-free survival (EFS) compared with LMB chemotherapy alone. (Phase III) II. For patients
with primary mediastinal large B-cell lymphoma (PMLBL), to evaluate the EFS following
treatment with the regimen dose-adjusted (DA)-etoposide, prednisone, vincristine sulfate,
cyclophosphamide, doxorubicin hydrochloride (EPOCH), and rituximab. (Phase II)

SECONDARY OBJECTIVES:

I. To study the complete remission (CR) rate and the overall survival (OS). II. To evaluate
safety on all study arms including toxic deaths, adverse events recorded using the National
Cancer Institute (NCI)-Common Terminology Criteria (CTC) V4 (non-hematological toxicity
grade 3, infections grade 3 to 5), cardiac toxicity (CTC grade 2-5 and evolution of left
ventricular ejection fraction [LVEF] and left ventricular shortening fraction [LVSF]),
number of days with platelets transfusion, intensive-care unit admission, number of days
with red cells transfusion, and rituximab infusion reactions.

III. To study the rate of patients with immunoglobulin (Ig; G, A, and M) levels abnormally
low and lymphocyte count abnormally low at 1 year and until 5-year follow-up, to study the
need for Ig infusions, and levels of post (previous and re-) vaccination antibodies at 1
year.

IV. To study long-term (at least 5 years) risks of the use of rituximab plus chemotherapy
compared with LMB chemotherapy alone in children with advanced stage B-NHL/B-AL (all events
related [certain and probable] to therapy). (Phase III) V. To study the long-term risk of
DA-EPOCH-R regimen, especially the cardiac risk related to doxorubicin given at higher dose
than usual in children, but infused over 96 hours (i.e., evaluation of CTC grade 2-5 and
evolution of LVEF and LVSF). (Phase II)

TERTIARY OBJECTIVES:

I. To obtain data on positron emission tomography (PET)-computed tomography (CT) scan in
childhood pediatric B-cell NHL. (Exploratory) II. To evaluate the potential prognostic value
of Minimal Disseminated Disease (MDD) and Minimal Residual disease (MRD) in correlation with
outcome. (Exploratory - Phase III) III. To perform an economic study comparing the
cost-effectiveness ratio between 2 therapeutic strategies: LMB chemotherapy with versus
without rituximab. (Exploratory - Phase III) IV. To characterize the pharmacokinetics of
rituximab in combination with LMB chemotherapy in a subset of patients. (Exploratory - Phase
III)

OUTLINE: This is a multicenter study.

Phase II (patients with PMLBL): Patients receive rituximab IV on day 1; prednisone orally
(PO) twice daily (BID) or IV on day on days 1-5; etoposide IV continuously on days 1-4;
doxorubicin hydrochloride IV continuously on days 1-4; vincristine sulfate IV continuously
on days 1-4; and cyclophosphamide IV on day 5. Patients also receive filgrastim
subcutaneously (SC) once daily (QD) beginning on day 6 until blood count recovers. Treatment
repeats every 21 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

Phase III: Patients are stratified according to National Group (COG vs SFCE vs UK NCRI CCL
CSG vs AIEOP vs BSPHO vs DCOG vs SEHOP vs PPLLSG vs Hungarian Society of Pediatric
Oncologist and Pediatric Hematologist), histology (large cell vs non large cell [Burkitt,
atypical Burkitt, B-AL, or L3-AL]), and chemotherapy group (1 vs 2). Patients are assigned
to 1 of 2 treatment groups.

Group 1 (pre-phase central nervous system [CNS]-negative, cerebral spinal fluid
[CSF]-negative): Patients receive vincristine sulfate IV on day 1; cyclophosphamide IV over
15 minutes on day 1; prednisone PO BID or methylprednisolone IV on days 1-7; methotrexate
intrathecally (IT) and hydrocortisone IT on day 1. Patients are randomized to 1 of 2
treatment arms.

Arm I (R-COPADM induction therapy): Beginning 8 days later, patients receive rituximab IV on
day 1; vincristine sulfate IV on day 1; prednisone PO BID or methylprednisolone IV on days
1-5; methotrexate IV over 3 hours on day 1; leucovorin calcium PO every 6 hours on days 2-4;
cyclophosphamide IV over 15 minutes on days 2-4; doxorubicin hydrochloride over 1 hour on
day 2; and methotrexate IT and hydrocortisone IT on days 2 and 6. Treatment repeats every
18-21 days for 2 courses. Consolidation therapy (R-COPADM): Patients receive rituximab IV
on day 1; methotrexate IV over 3 hours on day 1; leucovorin calcium PO every 6 hours on days
2-4; cytarabine IV continuously on days 2-6; methotrexate IT on day 2; hydrocortisone IT on
days 2 and 7; and cytarabine IT on day 7. Treatment repeats every 21 days for 2 courses.

Arm II (COPADM induction therapy): Beginning 8 days later, patients receive vincristine
sulfate, prednisone or methylprednisolone, methotrexate, leucovorin calcium,
cyclophosphamide, doxorubicin, methotrexate IT, and hydrocortisone IT as in arm I. Treatment
repeats every 18-21 days for 2 courses.

Consolidation therapy (COPADM): Patients receive methotrexate IV over 3 hours on day 1;
leucovorin calcium PO every 6 hours on days 2-4; cytarabine IV over 12 hours on days 2-6;
methotrexate IT on day 2; hydrocortisone IT on days 2 and 7; and cytarabine IT on day 7.
Treatment repeats every 21 days for 2 courses.

Group 2 (pre-phase B-AL, CNS-negative OR CNS-positive, CSF-negative OR CSF-positive):
Patients receive vincristine sulfate IV on day 1; cyclophosphamide IV over 15 minutes on day
1; prednisone PO BID or methylprednisolone IV on days 1-7; methotrexate IT, hydrocortisone
IT, and cytarabine IT on days 1, 3, and 5; and leucovorin calcium PO BID on days 2 and 4.
Patients are randomized to 1 of 2 treatment arms.

Arm III (R-COPADM induction therapy): Patients receive rituximab IV on days -2 (course 1)
and 1; vincristine sulfate IV on day 1; prednisone PO or methylprednisolone IV on days 1-5;
high-dose methotrexate IV over 4 hours* on day 1; leucovorin calcium PO every 6 hours on
days 2-4; cyclophosphamide IV over 15 minutes on days 2-4; doxorubicin hydrochloride IV on
day 2; and methotrexate IT, hydrocortisone IT, and cytarabine IT on days 2, 4, and 6.
Treatment repeats every 21 days for 2 courses.

NOTE: *During the second course, patients with CSF-positive disease receive high-dose
methotrexate IV over 24 hours (instead of 4 hours).

Consolidation therapy (R-COPADM): Patients receive rituximab IV on day 1; hydrocortisone IT
and methotrexate IT on day 1; cytarabine IV over 12 hours on days 1-5; high-dose cytarabine
IV over 3 hours on day 2-5; and etoposide IV over 2 hours on days 2-5. If CSF-positive,
patients receive high-dose methotrexate IV over 24 hours on day 18, methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 19, and leucovorin calcium PO every 6 hours on
days 19-21. Treatment repeats every 21 days for 2 courses.

Maintenance therapy (R-COPADM): Patients receive vincristine sulfate IV on day 1; prednisone
PO or methylprednisolone IV on days 1-5; high-dose methotrexate IV over 4 hours on day 1;
leucovorin calcium PO every 6 hours on days 2-4; cyclophosphamide IV over 15 minutes on days
2-3; doxorubicin hydrochloride over 1 hour on day 2; and methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 2. Beginning 28 days later, patients receive cytarabine
subcutaneously (SC) every 12 hours on days 1-5 and etoposide IV over 90 minutes on days 1-3.

Arm IV (COPADM induction therapy): Patients receive vincristine sulfate, prednisone or
methylprednisolone, high-dose methotrexate*, leucovorin calcium, cyclophosphamide,
doxorubicin hydrochloride, and methotrexate, hydrocortisone, and cytarabine IT as in arm
III. NOTE: *Patients with CSF-positive disease receive high-dose methotrexate IV over 24
hours (instead of 4 hours).

Consolidation therapy (COPADM): Patients receive hydrocortisone and methotrexate IT,
cytarabine, high-dose cytarabine, and etoposide as in arm III consolidation therapy.

Maintenance therapy (COPADM): Patients receive vincristine sulfate, prednisone or
methylprednisolone, high-dose methotrexate*, leucovorin calcium, cyclophosphamide,
doxorubicin hydrochloride, methotrexate IT, hydrocortisone IT, cytarabine IT, cytarabine SC,
and etoposide as in arm III maintenance therapy.

NOTE: *Patients with CSF-positive disease receive high-dose methotrexate IV over 24 hours.

Blood and tumor tissue samples are collected at baseline, during, and at the completion of
study therapy for correlative studies.

After completion of study treatment, patients are followed-up for 5 years.


Inclusion Criteria:



- Histologically or cytologically proven B-cell malignancies; Burkitt leukemia or
B-cell acute leukemia (B-AL) (Burkitt leukemia = L3-AL), or diffuse large B-cell
non-Hodgkin lymphoma (NHL), or aggressive mature B-cell NHL not otherwise specified
or specifiable (phase III)

- Stage III with elevated LDH level (B-high) [LDH > twice the institutional upper
limit of the adult normal values (> Nx2)], any stage IV, or B-AL (phase III)

- Histologically or cytologically proven primary mediastinal large B-cell lymphoma
(PMLBL) (phase II)

- No central nervous system (CNS) involvement

- No follicular lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, or nodular
marginal zone lymphoma

- Tumor cell negative for CD20 (absence of result due to technical problems in the
presence of other characteristics suggestive of BL/DLBCL, including genetic and
phenotypic features, is not an exclusion criteria)

- Males and females of reproductive potential must agree to use an effective
contraceptive method during the treatment, and after the end of treatment: 12 months
for women and 5 months for men

- Able to comply with scheduled follow-up and with management of toxicity

- Signed informed consent from patients and/or their parents or legal guardians

- No patients with congenital immunodeficiency, chromosomal breakage syndrome, prior
organ transplantation, previous malignancy of any type, or known positive human
immunodeficiency virus (HIV) serology

- Not pregnant or nursing

- No severe active viral infection, especially hepatitis B virus (HBV)

- Severe infection (such as sepsis, pneumonia, etc.) should be clinically
controlled at the time of randomization

- No HBV carrier status or positive serology; a patient is considered as HBV carrier
or to have (had) HBV infection by any of the following criteria:

- Unimmunized and hepatitis B surface antigen (HBsAg) and/or anti-HBs antibody
and/or anti-hepatitis B core (HBc)-antibody positive

- Immunized and HBsAg and/or anti-HBc antibody positive

- For the Phase III trial, a patient without a known history of HBV could be
randomized in the study if the serology results are not available at the time of
the randomization; however, if the serology results are positive or not
available at day 6 (the first day to receive rituximab, if so randomized), the
patient must be withdrawn from the study whatever the allocated treatment arm;
for the phase II trial, the hepatitis B serology results must be available
before registration

- No patients who, for any reason, are not able to comply with the national legislation

- No past or current anti-cancer treatment except corticosteroids for less than one
week

- No participation in another investigational drug clinical trial

- No prior exposure to rituximab

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

EFS

Outcome Description:

Will be estimated with the Kaplan Meier method. The 95% confidence intervals (95% CI) of the actuarial rates will be calculated with the Rothman method.

Outcome Time Frame:

3 years

Safety Issue:

Yes

Principal Investigator

Thomas Gross

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

ANHL1131

NCT ID:

NCT01595048

Start Date:

June 2012

Completion Date:

Related Keywords:

  • B-cell Childhood Acute Lymphoblastic Leukemia
  • Childhood Diffuse Large Cell Lymphoma
  • L3 Childhood Acute Lymphoblastic Leukemia
  • Stage III Childhood Large Cell Lymphoma
  • Stage IV Childhood Large Cell Lymphoma
  • Untreated Childhood Acute Lymphoblastic Leukemia
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin

Name

Location

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
Washington University School of MedicineSaint Louis, Missouri  63110
Medical University of South CarolinaCharleston, South Carolina  29425-0721
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Sinai Hospital of BaltimoreBaltimore, Maryland  21225
Geisinger Medical CenterDanville, Pennsylvania  17822-0001
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Loyola University Medical CenterMaywood, Illinois  60153
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
Morristown Memorial HospitalMorristown, New Jersey  07962-1956
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's Hospital Los AngelesLos Angeles, California  90027-0700
All Children's HospitalSt. Petersburg, Florida  33701
Saint Jude Midwest AffiliatePeoria, Illinois  61637
Ochsner Clinic FoundationNew Orleans, Louisiana  70121
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Driscoll Children's HospitalCorpus Christi, Texas  78466
Scott and White Memorial HospitalTemple, Texas  76508
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Hospital Medical Center of AkronAkron, Ohio  44308
Winthrop University HospitalMineola, New York  11501
Mount Sinai Medical CenterNew York, New York  10029
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
Montefiore Medical CenterBronx, New York  10467-2490
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
Lehigh Valley Hospital - MuhlenbergBethlehem, Pennsylvania  18017
Presbyterian HospitalCharlotte, North Carolina  28233-3549
Lee Memorial Health SystemFort Myers, Florida  33902
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
Legacy Emanuel Children's HospitalPortland, Oregon  97227
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
Dartmouth Hitchcock Medical CenterLebanon, New Hampshire  03756
University of Texas Southwestern Medical CenterDallas, Texas  
University of KentuckyLexington, Kentucky  40536-0098
Oregon Health and Science UniversityPortland, Oregon  97201
Virginia Commonwealth UniversityRichmond, Virginia  
Florida HospitalOrlando, Florida  32803
Seattle Children's HospitalSeattle, Washington  98105
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Kaiser Permanente-OaklandOakland, California  94611
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 Vincent Hospital and Health ServicesIndianapolis, Indiana  46260
Saint John Hospital and Medical CenterDetroit, Michigan  48236
Michigan State University - Breslin Cancer CenterEast Lansing, Michigan  48824-1313
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
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 South AlabamaMobile, Alabama  36693
University of IllinoisChicago, Illinois  60612
The Children's Medical Center of DaytonDayton, Ohio  45404
Children's Oncology GroupArcadia, California  91006-3776
Southern Illinois UniversitySpringfield, Illinois  62702
University Of Missouri-ColumbiaColumbia, Missouri  65212
Riley Hospital for ChildrenIndianapolis, Indiana  46202
UMDNJ - Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
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
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Rainbow Babies and Childrens HospitalCleveland, Ohio  44106
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916
Saint Joseph's Regional Medical CenterPaterson, New Jersey  07503
Childrens Hospital-King's DaughtersNorfolk, Virginia  23507
Floating Hospital for Children at Tufts Medical CenterBoston, Massachusetts  02111
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
Saint Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania  19134
Sanford USD Medical Center - Sioux FallsSioux Falls, South Dakota  57117-5134
T C Thompson Children's HospitalChattanooga, Tennessee  37403
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204