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

Primary Purpose

Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
cyclophosphamide
fludarabine phosphate
vincristine sulfate
prednisone
rituximab
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Stage III Grade 1 Follicular Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients must have Stage III-IV (Ann Arbor classification) low-grade Non-Hodgkin's lymphoma Baseline measurements and evaluations must be obtained within 4 weeks prior to registration; all areas of disease (evaluable and measurable) should be recorded and mapped out in order to assess response and uniformity of response to therapy; must have at least one objective MEASURABLE disease parameter Radiographic findings are acceptable providing that clear-cut measurement can be made Abnormalities on scans may be used to document the presence of disease for staging purposes; a clearly defined, bidimensionally measurable defect or mass measuring at least 2 cm in diameter on a radionuclide or a CT scan will be acceptable as measurable disease An enlarged spleen extending at least 2 cm below the costal margin will constitute measurable disease providing that no explanation other than lymphomatous involvement is likely; for an enlarged liver to constitute the only evident measurable disease parameter, liver biopsy proof of lymphoma in the liver is required Patients must have a tissue diagnosis of low-grade malignant lymphoma obtained within 12 months prior to registration (according to the International Working Formulation) as below: ML- small lymphocytic (Category A) ML-follicular-small cleaved (Category B) ML-follicular-mixed small cleaved and large cell (Category C) Patients having both diffuse and follicular architectural elements will be considered eligible if the histology is predominantly follicular (i.e. >= 50% of the cross-sectional area); if the interval since tissue diagnosis of low-grade malignant lymphoma is > 12 months, diagnostic confirmation using either FNA or nodal biopsy is required to confirm that the histology remains in one of the eligible categories Women of child bearing potential and sexually active males are strongly advised to use an accepted and effective method of birth control No prior chemotherapy, radiotherapy, or immunotherapy No active, uncontrolled infections (afebrile for > 48 hours off antibiotics) No evidence of a previous or concurrent malignancy, with the exception of 1) treated carcinoma in situ of the cervix, 2) treated squamous cell or basal cell skin cancer OR 3) any other surgically cured malignancy from which the patient has been disease free for at least 5 years ECOG performance status 0-1 WBC > 3000/mm^3 Plts > 100,000/mm^3 Creatinine =< 1.5 mg/dl Bilirubin < 2.0 mg/dl LFTs =< 5x ULN (SGOT and Alkaline Phosphate) These lab values must be obtained within 4 weeks prior to protocol entry; patients with documented marrow involvement at the time of registration are not required to meet the hematologic parameters above Patient must give signed informed consent

Sites / Locations

  • Eastern Cooperative Oncology Group

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

No Intervention

Arm Label

Arm I (cyclophosphamide, fludarabine)

Arm II (cyclophosphamide, vincristine, prednisone)

Arm III (rituximab)

Arm IV (no intervention)

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Time to treatment failure
This comparison will be made using a one-sided logrank test with a 5% type I error rate.

Secondary Outcome Measures

Full Information

First Posted
May 2, 2000
Last Updated
February 26, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00003204
Brief Title
Combination Chemotherapy With or Without Monoclonal Antibody Therapy in Treating Patients With Stage III or Stage IV Low-Grade Non-Hodgkin's Lymphoma
Official Title
Randomized Phase III Study in Low Grade Lymphoma Comparing Maintenance Anti-CD20 Antibody Versus Observation Following Induction Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
February 2013
Overall Recruitment Status
Completed
Study Start Date
March 1998 (undefined)
Primary Completion Date
May 2006 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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. 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
Detailed Description
PRIMARY OBJECTIVES: I. To compare the response rate, time to progression, time to treatment failure, and survival for patients with low grade lymphoma treated with the cyclophosphamide - fludarabine regimen with a control arm consisting of standard treatment with CVP. II. To determine the effect of maintenance with anti-CD20 (IDEC C2B8) on time to progression, time to treatment failure, and survival and its effects on lymphocyte number, subsets, and quantitative immunoglobulin levels over time. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage III Small Lymphocytic Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Small Lymphocytic Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
515 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (cyclophosphamide, fludarabine)
Arm Type
Experimental
Arm Description
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 Title
Arm II (cyclophosphamide, vincristine, prednisone)
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm III (rituximab)
Arm Type
Experimental
Arm Description
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 Title
Arm IV (no intervention)
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
CPM, CTX, Cytoxan, Endoxan, Endoxana
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
vincristine sulfate
Other Intervention Name(s)
leurocristine sulfate, VCR, Vincasar PFS
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
prednisone
Other Intervention Name(s)
DeCortin, Deltra
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
rituximab
Other Intervention Name(s)
IDEC-C2B8, IDEC-C2B8 monoclonal antibody, Mabthera, MOAB IDEC-C2B8, Rituxan
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Time to treatment failure
Description
This comparison will be made using a one-sided logrank test with a 5% type I error rate.
Time Frame
From maintenance randomization to the earlier of progression or death, assessed up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have Stage III-IV (Ann Arbor classification) low-grade Non-Hodgkin's lymphoma Baseline measurements and evaluations must be obtained within 4 weeks prior to registration; all areas of disease (evaluable and measurable) should be recorded and mapped out in order to assess response and uniformity of response to therapy; must have at least one objective MEASURABLE disease parameter Radiographic findings are acceptable providing that clear-cut measurement can be made Abnormalities on scans may be used to document the presence of disease for staging purposes; a clearly defined, bidimensionally measurable defect or mass measuring at least 2 cm in diameter on a radionuclide or a CT scan will be acceptable as measurable disease An enlarged spleen extending at least 2 cm below the costal margin will constitute measurable disease providing that no explanation other than lymphomatous involvement is likely; for an enlarged liver to constitute the only evident measurable disease parameter, liver biopsy proof of lymphoma in the liver is required Patients must have a tissue diagnosis of low-grade malignant lymphoma obtained within 12 months prior to registration (according to the International Working Formulation) as below: ML- small lymphocytic (Category A) ML-follicular-small cleaved (Category B) ML-follicular-mixed small cleaved and large cell (Category C) Patients having both diffuse and follicular architectural elements will be considered eligible if the histology is predominantly follicular (i.e. >= 50% of the cross-sectional area); if the interval since tissue diagnosis of low-grade malignant lymphoma is > 12 months, diagnostic confirmation using either FNA or nodal biopsy is required to confirm that the histology remains in one of the eligible categories Women of child bearing potential and sexually active males are strongly advised to use an accepted and effective method of birth control No prior chemotherapy, radiotherapy, or immunotherapy No active, uncontrolled infections (afebrile for > 48 hours off antibiotics) No evidence of a previous or concurrent malignancy, with the exception of 1) treated carcinoma in situ of the cervix, 2) treated squamous cell or basal cell skin cancer OR 3) any other surgically cured malignancy from which the patient has been disease free for at least 5 years ECOG performance status 0-1 WBC > 3000/mm^3 Plts > 100,000/mm^3 Creatinine =< 1.5 mg/dl Bilirubin < 2.0 mg/dl LFTs =< 5x ULN (SGOT and Alkaline Phosphate) These lab values must be obtained within 4 weeks prior to protocol entry; patients with documented marrow involvement at the time of registration are not required to meet the hematologic parameters above Patient must give signed informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Howard Hochster
Organizational Affiliation
Eastern Cooperative Oncology Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
Eastern Cooperative Oncology Group
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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