Combination Chemotherapy With or Without Monoclonal Antibody Therapy in Treating Patients With Stage III or Stage IV Low-Grade Non-Hodgkin's Lymphoma - Full Text View

Sponsor:	Eastern Cooperative Oncology Group
Collaborators:	National Cancer Institute (NCI) Cancer and Leukemia Group B
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00003204

Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. It is not yet known which regimen of combination chemotherapy, with or without rituximab, is more effective for non-Hodgkin's lymphoma.

PURPOSE: Randomized phase III trial to compare the effectiveness of two regimens of combination chemotherapy followed by rituximab or observation in treating patients who have stage III or stage IV low-grade non-Hodgkin's lymphoma.

Condition	Intervention	Phase
Lymphoma	Biological: rituximab Drug: cyclophosphamide Drug: prednisone Drug: vincristine sulfate	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Active Control
Official Title:	Randomized Phase III Study in Low Grade Lymphoma Comparing Cyclophosphamide/Fludarabine to Standard Therapy Followed by Maintenance Anti-CD20 Antibody

Resource links provided by NLM:

MedlinePlus related topics: Cancer Lymphoma

Drug Information available for: Cyclophosphamide Prednisone Vincristine Rituximab Vincristine sulfate

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Estimated Enrollment:	515
Study Start Date:	March 1998
Primary Completion Date:	April 2009 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Compare response rate, time to progression, time to treatment failure, and survival of patients with low grade non-Hodgkin's lymphoma treated with a cyclophosphamide and fludarabine regimen (closed as of 9/2000) or standard treatment with cyclophosphamide, vincristine, and prednisone.
Determine the effect of maintenance with rituximab (IDEC-C2B8 monoclonal antibody) on time to progression, times to treatment failure, and survival, as well as its effects on lymphocyte number, subsets, and quantitative immunoglobulin levels over time in these patients.

OUTLINE: This a two step, stratified, randomized study.

Patients are stratified for arms I and II (step 1) by age (under 60 vs 60 and over), tumor burden (high vs low), histology (follicular vs other), and B symptoms (present vs absent). After arms I and II have been completed, patients are stratified in arms III and IV (step 2) by extent of residual disease (minimal vs gross), histology (follicular vs other), and initial tumor burden.

Arm I (closed as of 9/2000): Patients receive cyclophosphamide IV over 30-45 minutes on day 1 and fludarabine IV over 10-20 minutes on days 1-5. Treatment repeats every 28 days in the absence of disease progression for a minimum of 4 courses and a maximum of 6 courses.
Arm II: Patients receive cyclophosphamide IV over 30-45 minutes and vincristine IV on day 1, and oral prednisone on days 1-5. Treatment repeats every 21 days in the absence of disease progression for a minimum of 6 courses and a maximum of 8 courses.

After completion of therapy on arm I or II, patients are randomized into step 2 of this study comprising arms III and IV.

Arm III: Patients receive maintenance therapy with rituximab (IDEC-C2B8 monoclonal antibody) IV weekly for 4 weeks. Courses repeat every 6 months for 2 years. Maintenance therapy begins 4 weeks after the last chemotherapy.
Arm IV: Patients undergo no maintenance therapy and are observed. Patients are followed every 3 months for 2 years, every 6 months for the next 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 515 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed stage III-IV low grade non-Hodgkin's lymphoma
- Small lymphocytic
- Follicular small cleaved cell
- Follicular mixed cleaved cell
- Follicular large cell
Measurable disease by at least one of the following:
- Radiographic findings must provide clear-cut measurements
- Bidimensionally measurable, clearly defined defect or mass measuring at least 2 cm in diameter on a radionuclide or CT scan
- An enlarged spleen extending at least 2 cm below the costal margin, provided that no explanation other than lymphomatous involvement is likely
- An enlarged liver with proof of lymphoma in the liver by biopsy
May have low or high tumor burden
- High tumor burden defined as:
  - Nodal or extranodal mass at least 7 cm
  - 3 or more nodal masses greater than 3 cm
  - Systemic symptoms or B symptoms
  - Risk of extrinsic compression of vital organ
  - Leukemia phase with lymphocyte count of greater than 5,000/mm3
  - Absolute neutrophil count less than 1,500/mm3
  - Hemoglobin less than 10 g/dL
  - Platelet count less than 100,000/mm3
Patients with both diffuse and follicular architectural elements are eligible if histology is predominantly follicular (at least 50% of the cross-sectional area)
If diagnosis of low grade non-Hodgkin's lymphoma had been made over 1 year ago, diagnostic confirmation using either fine needle aspiration or nodal biopsy is required NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age:

18 and over

Performance status:

ECOG 0-1

Life expectancy:

Not specified

Hematopoietic:

See Disease Characteristics
WBC greater than 3,000/mm^3 (unless documented bone marrow involvement)
Platelet count greater than 100,000/mm^3 (unless documented bone marrow involvement)

Hepatic:

Bilirubin less than 2.0 mg/dL
SGOT no greater than 5 times upper limit of normal (ULN)
Alkaline phosphatase no greater than 5 times ULN

Renal:

Creatinine no greater than 1.5 mg/dL

Other:

No other malignancy within the past 5 years except treated carcinoma in situ of the cervix or basal or squamous cell carcinoma of the skin
No active, uncontrolled infections
Adequate contraception required of all fertile patients

PRIOR CONCURRENT THERAPY:

Biologic therapy:

No prior immunotherapy

Chemotherapy:

No prior chemotherapy

Endocrine therapy:

Not specified

Radiotherapy:

No prior radiotherapy

Surgery:

Not specified

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00003204

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Locations

United States, Alabama
University of Alabama at Birmingham Comprehensive Cancer Center
Birmingham, Alabama, United States, 35294-3300
United States, Arizona
CCOP - Scottsdale Oncology Program
Scottsdale, Arizona, United States, 85259-5404
United States, California
Rebecca and John Moores UCSD Cancer Center
La Jolla, California, United States, 92093-0658
UCSF Comprehensive Cancer Center
San Francisco, California, United States, 94143-0128
Veterans Affairs Medical Center - San Francisco
San Francisco, California, United States, 94121
United States, Delaware
CCOP - Christiana Care Health Services
Wilmington, Delaware, United States, 19899
United States, District of Columbia
Lombardi Cancer Center
Washington, District of Columbia, United States, 20007
Walter Reed Army Medical Center
Washington, District of Columbia, United States, 20307-5000
United States, Florida
CCOP - Mount Sinai Medical Center
Miami Beach, Florida, United States, 33140
United States, Illinois
University of Chicago Cancer Research Center
Chicago, Illinois, United States, 60637-1470
Veterans Affairs Medical Center - Chicago (Westside Hospital)
Chicago, Illinois, United States, 60612
United States, Indiana
Indiana University Cancer Center
Indianapolis, Indiana, United States, 46202-5289
Veterans Affairs Medical Center - Indianapolis (Roudebush)
Indianapolis, Indiana, United States, 46202
United States, Iowa
Holden Comprehensive Cancer Center
Iowa City, Iowa, United States, 52242-1009
United States, Maryland
Marlene and Stewart Greenebaum Cancer Center, University of Maryland
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
University of Massachusetts Memorial Medical Center - University Campus
Worcester, Massachusetts, United States, 01655
United States, Minnesota
Veterans Affairs Medical Center - Minneapolis
Minneapolis, Minnesota, United States, 55417
University of Minnesota Cancer Center
Minneapolis, Minnesota, United States, 55455
CCOP - Metro-Minnesota
Saint Louis Park, Minnesota, United States, 55416
United States, Missouri
Barnes-Jewish Hospital
Saint Louis, Missouri, United States, 63110
Ellis Fischel Cancer Center - Columbia
Columbia, Missouri, United States, 65203
Veterans Affairs Medical Center - Columbia (Truman Memorial)
Columbia, Missouri, United States, 65201
United States, Nebraska
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198-7680
United States, Nevada
CCOP - Southern Nevada Cancer Research Foundation
Las Vegas, Nevada, United States, 89106
United States, New Hampshire
Norris Cotton Cancer Center
Lebanon, New Hampshire, United States, 03756-0002
United States, New Jersey
Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08903
United States, New York
CCOP - North Shore University Hospital
Manhasset, New York, United States, 11030
CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
Syracuse, New York, United States, 13217
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10021
Mount Sinai Medical Center, NY
New York, New York, United States, 10029
State University of New York - Upstate Medical University
Syracuse, New York, United States, 13210
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263-0001
North Shore University Hospital
Manhasset, New York, United States, 11030
Veterans Affairs Medical Center - Buffalo
Buffalo, New York, United States, 14215
Veterans Affairs Medical Center - Syracuse
Syracuse, New York, United States, 13210
Weill Medical College of Cornell University
New York, New York, United States, 10021
United States, North Carolina
CCOP - Southeast Cancer Control Consortium
Winston-Salem, North Carolina, United States, 27104-4241
Lineberger Comprehensive Cancer Center, UNC
Chapel Hill, North Carolina, United States, 27599-7295
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
Comprehensive Cancer Center at Wake Forest University
Winston-Salem, North Carolina, United States, 27157-1082
Veterans Affairs Medical Center - Durham
Durham, North Carolina, United States, 27705
United States, Ohio
Arthur G. James Cancer Hospital - Ohio State University
Columbus, Ohio, United States, 43210-1240
United States, Oklahoma
CCOP - Oklahoma
Tulsa, Oklahoma, United States, 74136
United States, Pennsylvania
CCOP - MainLine Health
Wynnewood, Pennsylvania, United States, 19096
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States, 15213-3489
United States, Rhode Island
Lifespan: The Miriam Hospital
Providence, Rhode Island, United States, 02906
United States, South Dakota
CCOP - Sioux Community Cancer Consortium
Sioux Falls, South Dakota, United States, 57104
United States, Texas
CCOP - Scott and White Hospital
Temple, Texas, United States, 76508
United States, Vermont
Green Mountain Oncology Group
Bennington, Vermont, United States, 05201
Vermont Cancer Center
Burlington, Vermont, United States, 05401-3498
Veterans Affairs Medical Center - White River Junction
White River Junction, Vermont, United States, 05009
United States, Virginia
MBCCOP - Massey Cancer Center
Richmond, Virginia, United States, 23298-0037
United States, Wisconsin
CCOP - St. Vincent Hospital Cancer Center, Green Bay
Green Bay, Wisconsin, United States, 54301

Sponsors and Collaborators

Eastern Cooperative Oncology Group

National Cancer Institute (NCI)

Cancer and Leukemia Group B

Investigators

Study Chair:	Howard S. Hochster, MD	New York University School of Medicine
Study Chair:	Stanley R. Frankel, MD	University of Maryland Greenebaum Cancer Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2.

Colocci N, Weller E, Hochster HS, et al.: Prognostic significance of the Follicular Lymphoma International Prognostic Index (FLIPI) in the E1496 trial of chemotherapy with or without maintenance rituximab. [Abstract] J Clin Oncol 23 (Suppl 16): A-6526, 566s, 2005.

Hochster HS, Weller E, Gascoyne RD, et al.: Maintenance rituximab after CVP results in superior clinical outcome in advanced follicular lymphoma (FL): results of the E1496 phase III trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B. [Abstract] Blood 106 (11): A-349, 2005.

Hochster HS, Weller E, Ryan T, et al.: Results of E1496: a phase III trial of CVP with or without maintenance rituximab in advanced indolent lymphoma (NHL). [Abstract] J Clin Oncol 22 (Suppl 14): A-6502, 558s, 2004.

Hochster H, Weller E, Kuzel T, et al.: Increased mortality associated with higher dose cyclophosphamide plus fludarabine (CF) in advanced stage indolent lymphoma patients treated on E1496, an Eastern Cooperative Oncology Group (ECOG) and CALGB study. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1125, 2002.

Study ID Numbers:	CDR0000066056, E-1496, CLB-59902
Study First Received:	May 2, 2000
Last Updated:	June 16, 2009
ClinicalTrials.gov Identifier:	NCT00003204 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Cancer Institute (NCI):

stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage IV grade 1 follicular lymphoma

stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Prednisone
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Cyclophosphamide
Hormones
Therapeutic Uses
Lymphoma
Alkylating Agents
Immunoproliferative Disorders
Neoplasms by Histologic Type
Antineoplastic Agents, Hormonal

Immune System Diseases
Rituximab
Mitosis Modulators
Vincristine
Antimitotic Agents
Immunosuppressive Agents
Glucocorticoids
Pharmacologic Actions
Lymphatic Diseases
Neoplasms
Tubulin Modulators
Myeloablative Agonists
Antineoplastic Agents, Alkylating
Lymphoproliferative Disorders
Lymphoma, Non-Hodgkin

ClinicalTrials.gov processed this record on November 27, 2009