Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III-IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia

Childhood Diffuse Large Cell Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01595048
• Other study ID #: ANHL1131
• Secondary ID: NCI-2012-01963CD
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• First received: May 8, 2012
• Last updated: October 24, 2016
• Start date: June 2012
• Est. completion date: December 2020

Study information

• Verified date: October 2016
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This randomized phase II/III trial studies how well combination chemotherapy with or without rituximab works in treating younger patients with stage III-IV non-Hodgkin lymphoma or B-cell acute leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibody, such as rituximab, may block cancer growth in different ways by targeting certain cells. It is not yet known whether combination chemotherapy together with rituximab is more effective in treating patients with non-Hodgkin lymphoma or B-cell acute leukemia.

Description:

PRIMARY OBJECTIVES:

I. For the patients with advanced stage B-cell non-Hodgkin lymphoma (NHL)/Burkitt acute leukemia (B-AL) (stage III and lactate dehydrogenase (LDH) > twice the institutional upper limit of the adult normal values (Nx2), any stage IV or B-AL), to test whether adding 6 injections of rituximab to standard Lymphome Malin B (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 etoposide, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride (DA-EPOCH)-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) version (V)4 (non hematological toxicity grade >= 3, infections grade 3 to 5), cardiac toxicity (CTC grade 2-5 and evolution of left ventricular ejection fraction and left ventricular shortening fraction), number of days with platelets transfusion, intensive care unit admission and number of days with red cells transfusion, 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, and to study the need for immunoglobulin 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 and adolescents 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 left ventricular ejection fraction and left ventricular shortening fraction). (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 LMB chemotherapy 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:

Phase II (patients with PMLBL): Patients receive rituximab intravenously (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:

Group I (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 II (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.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 640
• Est. completion date: December 2020
• Est. primary completion date: December 2020
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 17 Years

Eligibility

Inclusion Criteria:

• Histologically or cytologically proven B-cell malignancies; either Burkitt leukemia or B-AL (= Burkitt leukemia = L3-AL), or diffuse large B-cell NHL, or aggressive mature B-cell NHL non 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)

• Histolo-cytologically proven PMLBL (phase II)

• PMLBL without central nervous system (CNS) involvement

• Slides will be reviewed by the national pathology panel, but review is not mandatory before registration

• Males and females of reproductive potential must agree to use an effective contraceptive method during the treatment, and after the end of treatment: during twelve months for women, taking into account the characteristics of rituximab and during five months for men, taking into account the characteristics of methotrexate

• Complete initial work-up within 8 days prior to treatment that allows definite staging

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

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

Exclusion Criteria:

• Follicular lymphoma, Mucosa-Associated Lymphoid Tissue (MALT) and nodular marginal zone are not included into this therapeutic study

• In phase II study (PMLBL) patients with CNS involvement are not eligible

• Patients with congenital immunodeficiency, chromosomal breakage syndrome, prior organ transplantation, previous malignancy of any type, or known positive human immunodeficiency virus (HIV) serology

• Evidence of pregnancy or lactation period

• There will be no exclusion criteria based on organ function

• Past or current anti-cancer treatment except corticosteroids of less than 7 days duration in total

• Tumor cell negative for cluster of differentiation (CD)20 (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)

• Prior exposure to rituximab

• Severe active viral infection, especially hepatitis B; severe infection (such as sepsis, pneumonia, etc.) should be clinically controlled at the time of randomization; contact the national co-investigator for further advice if necessary

• Hepatitis B carrier status history of hepatitis B virus (HBV) or positive serology; a patient is considered as HBV carrier or to have (had) HBV infection in case of:

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

• Immunized and HBsAG and/or anti-HBc antibody positive

• Important note: for the phase III trial, a patient without a known history of hepatitis B 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 would be due to receive rituximab, if so randomized), the patient must be withdrawn from the study whatever the allocated treatment arm; the data center must be informed immediately; for the phase II trial, the hepatitis B serology results must be available before registration; in each case indicating a carrier status or history for hepatitis B infection, the patients must not receive rituximab, and therefore must not be included in the rituximab trials on any treatment arm; in case of high-risk patients, the recommendation is to treat these patients with the standard LMB regimen corresponding to the patient prognostic group; in the case of PMLBL the physician is left to choose the most appropriate therapy

• Participation in another investigational drug clinical trial

• Patients who, for any reason, are not able to comply with the national legislation

Study Design

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

Related Conditions & MeSH terms

• Burkitt Lymphoma
• Childhood B Acute Lymphoblastic Leukemia
• Childhood Burkitt Leukemia
• Childhood Diffuse Large Cell Lymphoma
• Leukemia
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Non-Hodgkin
• Mediastinal (Thymic) Large B-Cell Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Stage III Childhood Large Cell Lymphoma
• Stage IV Childhood Large Cell Lymphoma

Intervention

Biological:
• Rituximab
Given IV

Drug:
• Prednisone
Given PO or IV
• Etoposide
Given IV
• Doxorubicin Hydrochloride
Given IV
• Cytarabine
Given IV
• Vincristine Sulfate
Given IV
• Cyclophosphamide
Given IV
• Methotrexate
Given IT
• Methylprednisolone
Given IV
• Leucovorin Calcium
Given PO
• Therapeutic Hydrocortisone
Given IT

Other:
• Laboratory Biomarker Analysis
Correlative studies

Locations

Country	Name	City	State
Australia	John Hunter Children's Hospital	New Lambton	New South Wales
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	Lady Cilento Children's Hospital	South Brisbane	Queensland
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Centre Hospitalier Universitaire de Quebec	Ste-Foy	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico	Albuquerque	New Mexico
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital-Memorial Campus	Asheville	North Carolina
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Georgia Regents University Medical Center	Augusta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Mountain States Tumor Institute	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	T C Thompson Children's Hospital	Chattanooga	Tennessee
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Columbia Regional	Columbia	Missouri
United States	Palmetto Health Richland	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	University of Florida	Gainesville	Florida
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Hershey Children's Hospital	Hershey	Pennsylvania
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Saint Vincent Hospital and Health Services	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville South	Jacksonville	Florida
United States	The Childrens Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's Hospital	Long Beach	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	Winthrop University Hospital	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of South Alabama	Mobile	Alabama
United States	Morristown Memorial Hospital	Morristown	New Jersey
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Childrens Hospital-King's Daughters	Norfolk	Virginia
United States	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	Kaiser Permanente-Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Childrens Hospital of Orange County	Orange	California
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Florida Hospital Orlando	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Saint John's Mercy Medical Center	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	University of California San Francisco Medical Center-Parnassus	San Francisco	California
United States	Memorial University Medical Center	Savannah	Georgia
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Southern Illinois University	Springfield	Illinois
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Tampa General Hospital	Tampa	Florida
United States	Scott and White Memorial Hospital	Temple	Texas
United States	Mercy Children's Hospital	Toledo	Ohio
United States	Children's National Medical Center	Washington	District of Columbia
United States	Lombardi Comprehensive Cancer Center at Georgetown University	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	EFS	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.	3 years	Yes
Secondary	Survival	Estimated by the Kaplan-Meier method and the 95% confidence intervals (95% CI) of the actuarial rates calculated by the Rothman method.	Up to 5 years	Yes
Secondary	Complete remission rate compared between arms by logistic regression	Compared between arms by logistic regression.	Up to 5 years	Yes
Secondary	Acute and long-term toxicity as assessed by the National Cancer Institute Common Terminology Criteria version 4.0		Up to 5 years	Yes
Secondary	Immune reconstitution as assessed by Ig (G, A, and M) levels and lymphocyte counts		Up to 5 years	Yes