Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: 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. Monoclonal antibody, such as rituximab, can block cancer cells growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving combination chemotherapy together with rituximab is more effective in treating patients with non-Hodgkin lymphoma or B-cell acute leukemia.

PURPOSE: This randomized phase II/III trial studies how well giving combination chemotherapy with or without rituximab works in treating younger patients with stage III or stage IV non-Hodgkin lymphoma or B-cell acute leukemia.

Further Study Information

OBJECTIVES:

Primary

• 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)

• 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

• To study the complete remission (CR) rate and the overall survival (OS).

• 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.

• 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.

• 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)

• 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)

• To obtain data on positron emission tomography (PET)-computed tomography (CT) scan in childhood pediatric B-cell NHL. (Exploratory)

• To evaluate the potential prognostic value of Minimal Disseminated Disease (MDD) and Minimal Residual disease (MRD) in correlation with outcome. (Exploratory - Phase III)

• To perform an economic study comparing the cost-effectiveness ratio between 2 therapeutic strategies: LMB chemotherapy with versus without rituximab. (Exploratory - Phase III)

• 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.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• 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)

PATIENT CHARACTERISTICS:

• 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

PRIOR CONCURRENT THERAPY:

• 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

Trial Contact Information

Trial Lead Organizations/Sponsors

Children's Oncology Group

Thomas G. Gross

Principal Investigator

U.S.A.
Alabama
	Birmingham
	Children's Hospital of Alabama at University of Alabama at Birmingham
		Joseph G. Pressey	Ph: 205-939-9285
	Mobile
	University of South Alabama Mitchell Cancer Institute
		Felicia L. Wilson	Ph: 251-405-5115
California
	Long Beach
	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
		Amanda M. Termuhlen	Ph: 562-933-8605
	Los Angeles
	Childrens Hospital Los Angeles
		Leo Mascarenhas	Ph: 323-361-2529
	Orange
	Children's Hospital of Orange County
		Violet Shen	Ph: 714-532-8636
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Clinical Trials Office - UCSF Helen Diller Family Comprehensi	Ph: 877-827-3222
Colorado
	Denver
	Presbyterian - St. Luke's Medical Center
		Clinical Trials Office - Presbyterian - St. Luke's Medical Cen	Ph: 303-839-6000
Connecticut
	Hartford
	Connecticut Children's Medical Center
		Clinical Trials Office - Connecticut Children's Medical Center	Ph: 860-545-9967
Florida
	Fort Myers
	Lee Cancer Care of Lee Memorial Health System
		Clinical Trials Office - Lee Cancer Care of Lee Memorial Healt	Ph: 877-680-0008
	Orlando
	M.D. Anderson Cancer Center at Orlando
		Vincent F. Giusti	Ph: 321-841-8588
	Saint Petersburg
	All Children's Hospital
		Gregory A. Hale	Ph: 727-767-4176
Hawaii
	Honolulu
	Cancer Research Center of Hawaii
		Clinical Trials Office - Cancer Research Center of Hawaii	Ph: 808-586-2979
Illinois
	Springfield
	Simmons Cooper Cancer Institute
		Clinical Trials Office - Simmons Cooper Cancer Institute	Ph: 217-545-7929
Indiana
	Indianapolis
	Riley's Children Cancer Center at Riley Hospital for Children
		James M. Croop	Ph: 317-944-8784
	St. Vincent Indianapolis Hospital
		Clinical Trials Office - St. Vincent Indianapolis Hospital	Ph: 317-338-2194
Iowa
	Des Moines
	Blank Children's Hospital
		Clinical Trials Office - Blank Children's Hospital	Ph: 515-241-6729
Kentucky
	Louisville
	Kosair Children's Hospital
		Clinical Trials Office - Kosair Children's Hospital	Ph: 502-629-5500
			Email: CancerResource@nortonhealthcare.org
Maryland
	Baltimore
	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
		Joseph M. Wiley	Ph: 410-601-6266
Michigan
	Grand Rapids
	Helen DeVos Children's Hospital at Spectrum Health
		Clinical Trials Office - Helen DeVos Children's Hospital	Ph: 616-391-3050
	Grosse Pointe Woods
	Van Elslander Cancer Center at St. John Hospital and Medical Center
		Clincial Trials Office - Van Elslander Cancer Center at St. Jo	Ph: 313-343-3166
	Lansing
	Breslin Cancer Center at Ingham Regional Medical Center
		Clinical Trials Office - Breslin Cancer Center at Ingham Regio	Ph: 517-334-2765
Minnesota
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph: 507-538-7623
Mississippi
	Jackson
	University of Mississippi Cancer Clinic
		Gail C. Megason	Ph: 601-984-5220
Missouri
	Saint Louis
	David C. Pratt Cancer Center at St. John's Mercy
		Clinical Trials Office - David C. Pratt Cancer Center at St. J	Ph: 314-251-6770
	St. Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Robert J. Hayashi	Ph: 314-454-2041
New Hampshire
	Lebanon
	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
		Clinical Trials Office - Norris Cotton Cancer Center	Ph: 603-650-7609
			Email: cancerhelp@dartmouth.edu
New Jersey
	Hackensack
	Hackensack University Medical Center Cancer Center
		Clinical Trials Office - Hackensack University Medical Center	Ph: 201-996-2879
	New Brunswick
	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
		Clinical Trials Office - Cancer Institute of New Jersey	Ph: 732-235-8675
	Paterson
	St. Joseph's Hospital and Medical Center
		Mary A. Bonilla	Ph: 973-754-3349
	Summit
	Carol G. Simon Cancer Center at Morristown Memorial Hospital
		Steven L. Halpern	Ph: 973-971-6720
New Mexico
	Albuquerque
	University of New Mexico Cancer Center
		Clinical Trials Office - University of New Mexico Cancer Cente	Ph: 505-272-6972
New York
	Buffalo
	Roswell Park Cancer Institute
		Clinical Trials Office - Roswell Park Cancer Institute	Ph: 877-275-7724
	Syracuse
	SUNY Upstate Medical University Hospital
		Clinical Trials Office - SUNY Upstate Medical University Hospi	Ph: 315-464-5476
North Carolina
	Asheville
	Mission Hospitals - Memorial Campus
		Clinical Trials Office - Mission Hospitals - Memorial Campus	Ph: 828-213-4150
	Chapel Hill
	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
		Clinical Trials Office - Lineberger Comprehensive Cancer Cente	Ph: 877-668-0683; 919-966-4432
	Charlotte
	Blumenthal Cancer Center at Carolinas Medical Center
		Clinical Trials Office - Blumenthal Cancer Center at Carolinas	Ph: 704-355-2884
	Durham
	Duke Cancer Institute
		Clinical Trials Office - Duke Cancer Institute	Ph: 888-275-3853
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		Clinical Trials Office - Wake Forest University Comprehensive	Ph: 336-713-6771
Ohio
	Columbus
	Nationwide Children's Hospital
		Laura T. Martin	Ph: 614-722-3582
	Dayton
	Dayton Children's - Dayton
		Emmett H. Broxson	Ph: 937-641-3111
Oklahoma
	Oklahoma City
	Oklahoma University Cancer Institute
		Rene Y. McNall-Knapp	Ph: 405-271-5311
Oregon
	Portland
	Knight Cancer Institute at Oregon Health and Science University
		Clinical Trials Office - Knight Cancer Institute at Oregon Hea	Ph: 503-494-1080
			Email: trials@ohsu.edu
	Legacy Emanuel Hospital and Health Center and Children's Hospital
		Clinical Trials Office - Legacy Emanuel Children's Hospital	Ph: 503-413-2560
Pennsylvania
	Philadelphia
	Children's Hospital of Philadelphia
		Elizabeth Fox	Ph: 267-425-3010
South Carolina
	Columbia
	Palmetto Health South Carolina Cancer Center
		Clinical Trials Office - Palmetto Health South Carolina Cancer	Ph: 803-434-3680
South Dakota
	Sioux Falls
	Sanford Cancer Center at Sanford USD Medical Center
		Clinical Trials Office - Sanford Cancer Center	Ph: 605-328-1367
Tennessee
	Knoxville
	East Tennessee Children's Hospital
		Ray C. Pais	Ph: 865-541-8266
	Nashville
	Vanderbilt-Ingram Cancer Center
		Clinical Trials Office - Vanderbilt-Ingram Cancer Center	Ph: 800-811-8480
Texas
	Austin
	Dell Children's Medical Center of Central Texas
		Clinical Trials Office - Dell Children's Medical Center of Cen	Ph: 512-324-8022
	Dallas
	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
		Clinical Trials Office - Simmons Comprehensive Cancer Center a	Ph: 866-460-4673; 214-648-7097
	Temple
	CCOP - Scott and White Hospital
		Guy H. Grayson	Ph: 254-724-2006
Virginia
	Richmond
	Virginia Commonwealth University Massey Cancer Center
		Clinical Trials Office -Virginia Commonwealth University Masse	Ph: 804-628-1939
Washington
	Spokane
	Providence Cancer Center at Sacred Heart Medical Center
		Judy L. Felgenhauer	Ph: 509-474-2777
Wisconsin
	Green Bay
	St. Vincent Hospital Regional Cancer Center
		Clinical Trials Office - St. Vincent Hospital Regional Cancer	Ph: 920-433-8889
Australia
	Perth
	Princess Margaret Hospital for Children
		Catherine H. Cole	Ph: 011-6189340-8238
Canada
	Quebec
	Centre Hospitalier Universitaire de Quebec
		Bruno Michon	Ph: 418-656-4141X47191
Ontario
	Kingston
	Cancer Centre of Southeastern Ontario at Kingston General Hospital
		Mariana P. Silva	Ph: 613-5496666x3833
Quebec
	Montreal
	Montreal Children's Hospital at McGill University Health Center
		Sharon B. Abish	Ph: 514-412-4400x22219

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01595048
Information obtained from ClinicalTrials.gov on November 20, 2012

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