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

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

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.

Study Overview

• Status: Completed
• 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; Splenic Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: questionnaire administration; Procedure: quality-of-life assessment; Biological: rituximab; Biological: recombinant interleukin-12

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.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • North Central Cancer Treatment Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (rituximab and recombinant interleukin-12); 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.	Other: laboratory biomarker analysis; Correlative studies; Other: questionnaire administration; Ancillary studies; Procedure: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment; Biological: rituximab; Given IV; Other Names: Rituxan; Mabthera; IDEC-C2B8; IDEC-C2B8 monoclonal antibody; MOAB IDEC-C2B8; Biological: recombinant interleukin-12; Given SC; Other Names: cytotoxic lymphocyte maturation factor; IL-12; interleukin-12; natural killer cell stimulatory factor; Ro 24-7472
Experimental: Arm II (rituximab and recombinant interleukin-12); 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.	Other: laboratory biomarker analysis; Correlative studies; Other: questionnaire administration; Ancillary studies; Procedure: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment; Biological: rituximab; Given IV; Other Names: Rituxan; Mabthera; IDEC-C2B8; IDEC-C2B8 monoclonal antibody; MOAB IDEC-C2B8; Biological: recombinant interleukin-12; Given SC; Other Names: cytotoxic lymphocyte maturation factor; IL-12; interleukin-12; natural killer cell stimulatory factor; Ro 24-7472

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Stephen Ansell, North Central Cancer Treatment Group

Study record dates

Study Major Dates

• Study Start: October 1, 2001
• Primary Completion (Actual): February 1, 2005

Study Registration Dates

• First Submitted: November 9, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): August 26, 2013
• Last Update Submitted That Met QC Criteria: August 23, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Disease Attributes; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Lymphoma; Lymphoma, Follicular; Lymphoma, B-Cell; Recurrence; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Leukemia, Lymphocytic, Chronic, B-Cell; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Adjuvants, Immunologic; Rituximab; Interleukin-12
• Other Study ID Numbers: NCI-2012-01865 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA025224 (U.S. NIH Grant/Contract); NCCTG-N0087; CDR0000068994; N0087 (Other Identifier: CTEP)