Rituximab and Interleukin-12 in Treating Patients With B-Cell Non-Hodgkin's Lymphoma

Study Overview
=================
Brief Summary
-----------------
Monoclonal antibodies, such as rituximab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Interleukin-12 may kill cancer cells by stopping blood flow to the tumor and by stimulating a person's white blood cells to kill cancer cells. Combining rituximab with interleukin-12 may kill more cancer cells. This randomized phase II trial is comparing how well giving rituximab together with two different schedules of interleukin-12 works in treating patients with B-cell non-Hodgkin lymphoma.

Detailed Description
-----------------
OBJECTIVES: I. Compare the objective response in patients with B-cell non-Hodgkin's lymphoma treated with rituximab and 2 different schedules of interleukin-12*. II. Compare the toxic effects of these regimens in these patients. III. Determine the objective response rate in patients with mantle cell lymphoma treated with these regimens. IV. Determine the overall and progression-free survival of patients treated with these regimens. V, Compare the quality of life of patients treated with these regimens. NOTE: *Interleukin-12 will no longer be available after 6/30/05. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to histology (mantle cell lymphoma vs other [closed to accrual as of 3/10/04]) and International Prognostic Factor Index (low and low-intermediate risk [closed to accrual as of 3/10/04] vs high-intermediate and high risk). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive rituximab IV on days 1, 8, 15, and 22. Patients receive interleukin-12* subcutaneously (SC) twice weekly beginning on day 2 and continuing until disease progression. ARM II (closed to accrual as of 11/14/03): Patients receive rituximab as in arm I. Patients are evaluated at week 12. Patients with stable or progressive disease receive interleukin-12* SC twice weekly until disease progression or for 24 weeks. Patients with a complete or partial response after rituximab are monitored until disease progression and then begin interleukin-12 SC twice weekly until further disease progression. NOTE: *Interleukin-12 will no longer be available after 06/30/05. Patients proceed to follow-up as outlined below. Quality of life is assessed at baseline and at 3 and 6 months. Patients are followed every 3 months for 1 year and then every 6 months for up to 4 years. PROJECTED ACCRUAL: A total of 90 patients (45 per treatment arm [arm II closed to accrual as of 11/14/03]) will be accrued for this study within 3 years.

Official Title
-----------------
Randomized Phase II Study Of Interleukin-12 In Combination With Rituximab In Patients With Non-Hodgkin's Lymphoma

Conditions
-----------------
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Small Lymphocytic Lymphoma, Splenic Marginal Zone Lymphoma

Intervention / Treatment
-----------------
* Biological: rituximab
* Biological: recombinant interleukin-12
* Other: laboratory biomarker analysis
* Other: questionnaire administration
* Procedure: quality-of-life assessment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed CD20-positive B-cell non-Hodgkin's lymphoma Previously treated low-grade lymphoma considered incurable with standard therapy Grade I or II follicular lymphoma* Lymphoplasmacytic lymphoma* Small lymphocytic lymphoma* Nodal marginal zone lymphoma* Extranodal marginal zone lymphoma of MALT type* Splenic marginal zone lymphoma* Previously treated mantle cell lymphoma allowed Meets one of the following criteria for measurable disease: Bidimensional diameter at least 1.5 cm by 1.5 cm on physical exam At least 2 cm in one dimension by CT scan, MRI, or plain radiograph imaging Palpable spleen at least 5 cm below the left costal margin No CNS involvement by lymphoma Performance status - ECOG 0-1 At least 12 weeks Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 75,000/mm^3 Hemoglobin ≥ 8 g/dL Bilirubin ≤ 3 times upper limit of normal (ULN) AST and ALT ≤ 3 times ULN Alkaline phosphatase ≤ 3 times ULN Creatinine ≤ 2 times ULN No New York Heart Association class III or IV heart disease No history of angina No uncontrolled peptic ulcer disease No uncontrolled infection No other active malignancy No autoimmune-related phenomena (e.g., antinuclear antibody less than 2 times ULN, rheumatoid factor less than 2 times ULN, and negative direct Coombs) HIV negative Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Prior stem cell transplantation allowed More than 12 months since prior rituximab No prior interleukin-12 No other concurrent immunotherapy Recovered from prior chemotherapy No concurrent chemotherapy No concurrent steroid therapy No concurrent radiotherapy Any number of prior therapies allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (rituximab and recombinant interleukin-12)<br>Patients receive rituximab IV on days 1, 8, 15, and 22. Patients receive interleukin-12 SC twice weekly beginning on day 2 and continuing until disease progression. | Biological: rituximab<br>* Given IV<br>* Other names: Rituxan;Biological: recombinant interleukin-12<br>* Given SC<br>* Other names: Ro 24-7472;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: questionnaire administration<br>* Ancillary studies<br>Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|
| Experimental: Arm II (rituximab and recombinant interleukin-12)<br>Patients receive rituximab as in arm I. Patients are evaluated at week 12. Patients with stable or progressive disease receive interleukin-12 SC twice weekly until disease progression or for 24 weeks. Patients with a complete or partial response after rituximab are monitored until disease progression and then begin interleukin-12 SC twice weekly until further disease progression. | Biological: rituximab<br>* Given IV<br>* Other names: Rituxan;Biological: recombinant interleukin-12<br>* Given SC<br>* Other names: Ro 24-7472;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: questionnaire administration<br>* Ancillary studies<br>Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response | The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. In addition, confidence intervals for the response probability will be calculated according to the approach of Duffy and Santner. | 12 weeks | 
| Objective response | The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. In addition, confidence intervals for the response probability will be calculated according to the approach of Duffy and Santner. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate for MCL patients | Corresponding 95% confidence intervals will also be calculated. | Up to 5 years | 
| Overall survival | The distribution this time measure will be estimated using the method of Kaplan-Meier. | From randomization to death due to any cause, assessed up to 5 years | 
| Time to treatment failure | The distribution this time measure will be estimated using the method of Kaplan-Meier. | From randomization to the treatment-specific definition of disease progression, death, or when the patient goes off study due to refusal or toxicity, assessed up to 5 years | 
| Complete response rate | Will be assessed and descriptively summarized. | Up to 5 years | 
| Quality of life assessed using FACT-BRM | Before and after treatment comparisons will be made using a paired samples t-test or its nonparametric equivalent. This two-sided test will have at least 80% power to detect a moderate effect size (0.42 times the standard deviation) in the FACT-BRM scores. | Baseline | 
| Quality of life assessed using FACT-BRM | Before and after treatment comparisons will be made using a paired samples t-test or its nonparametric equivalent. This two-sided test will have at least 80% power to detect a moderate effect size (0.42 times the standard deviation) in the FACT-BRM scores. | 3 months | 
| Quality of life assessed using FACT-BRM | Before and after treatment comparisons will be made using a paired samples t-test or its nonparametric equivalent. This two-sided test will have at least 80% power to detect a moderate effect size (0.42 times the standard deviation) in the FACT-BRM scores. | 6 months |