Radiolabeled Monoclonal Antibody Plus Rituximab With and Without Filgrastim and Interleukin-11 in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

Study Overview
=================
Brief Summary
-----------------
Phase I/II trial to study the effectiveness of combining radiolabeled monoclonal antibody therapy and rituximab with and without filgrastim and interleukin-11 in treating patients who have relapsed or refractory non-Hodgkin's lymphoma. Radiolabeled monoclonal antibodies can locate cancer cells and deliver cancer-killing substances to them without harming normal cells. Biological therapies such as filgrastim and interleukin-11 use different ways to stimulate the immune system and stop cancer cells from growing.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of yttrium Y 90 ibritumomab tiuxetan (IDEC-90Y2B8) administered with rituximab with and without filgrastim (G-CSF) and interleukin-11 (IL-11) in patients with relapsed low-grade or follicular CD20+ non-Hodgkin's lymphoma. (Phase I) II. Determine the toxicity of this regimen in these patients. III. Determine the response rate in patients treated with this regimen. IV. Compare tumor and normal organ dosimetry with positron emission tomography and computerized tomography scans, subsequent tumor response, and normal organ toxicity by utilizing indium In 111 ibritumomab tiuxetan radioimmunoconjugate scans before each IDEC-90Y2B8 dose in these patients. (Phase I) V. Determine the immune response to this regimen, in terms of human anti-mouse and human anti-chimeric antibody formation, in these patients. (Phase I) VI. Determine whether G-CSF and IL-11 can ameliorate the effect of the MTD of IDEC-90Y2B8 on bone marrow function in these patients. (Phase I) VII. Determine progression-free survival at 3 years. (Phase II) OUTLINE: PHASE I: Patients receive rituximab IV on days 1 and 8, indium In 111 ibritumomab tiuxetan IV over 10 minutes on day 1 (for radioimaging), and IDEC-90Y2B8 IV over 10 minutes on day 8. Treatment repeats 24-36 weeks later for a total of 2 courses in the absence of disease progression or unacceptable toxicity. Once the maximum tolerated dose (MTD) of IDEC-90Y2B8 is determined, patients also receive filgrastim (G-CSF) subcutaneously (SC) daily beginning when absolute neutrophil count is less than 1,500/mm3 and continuing until blood counts recover. Patients also receive interleukin-11 (IL-11) SC beginning when platelet count is less than 75,000/mm^3 and continuing until blood counts recover. Patients undergo PBSC transplantation only if marrow recovery is inadequate. Cohorts of 3-6 patients receive escalating doses of IDEC-90Y2B8 until the MTD is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, additional patients are accrued to determine the MTD of this radioimmunotherapy with the addition of the prophylactic cytokines, G-CSF and IL-11. PHASE II: Patients receive rituximab, indium In 111 ibritumomab tiuxetan, and IDEC-90Y2B8 IV as determined at the MTD in phase I. Treatment repeats 24-36 weeks later for a total of 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually for 2 years.

Official Title
-----------------
Phase I/II Study of Two Sequential Doses of IDEC-Y2B8 in Patients With Relapsed Low-Grade and Follicular 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 Grade 3 Follicular Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Splenic Marginal Zone Lymphoma, Waldenström Macroglobulinemia

Intervention / Treatment
-----------------
* Biological: rituximab
* Biological: yttrium Y 90 ibritumomab tiuxetan
* Biological: indium In 111 ibritumomab tiuxetan
* Biological: oprelvekin
* Biological: filgrastim


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven relapsed or refractory low-grade or follicular CD+ non-Hodgkin lymphoma, including 1 of the following: Small lymphocytic lymphoma Lymphoplasmacytoid lymphoma Follicular center lymphoma (grades I, II, and III) Extranodal marginal zone B-cell lymphoma Nodal marginal zone B-cell lymphoma Splenic marginal zone B-cell lymphoma (monocytoid B-cell lymphoma) Less than 25% bone marrow involvement of cellular marrow with lymphoma by bilateral bone marrow aspirate and biopsy ECOG performance status 0-2 Bidimensionally measurable disease with at least 1 lesion >= 2 cm in the greatest diameter No prior myeloablative therapy with autologous or allogeneic bone marrow transplantation or peripheral blood stem cell support No concurrent corticosteroid therapy, except prednisone (or equivalent) for adrenal failure or < 20mg of prednisone daily No prior external beam radiotherapy to >25% of active bone marrow More than 4 weeks since prior surgery other than diagnostic surgery No other concurrent myelosuppressive antineoplastic agents No prior radioimmunotherapy, including yttrium Y 90 ibritumomab tiuxetan or iodine I 131 monoclonal antibody tositumomab or Lym-1 No CNS lymphoma No myelodysplastic syndromes or marrow chromosomal changes suggesting myelodysplasia No HIV or AIDS-related lymphoma No pleural effusion or ascites with lymphoma cells No active infection No other serious non-malignant disease that would preclude study participation No other active primary malignancy No known human anti-mouse or human anti-chimeric antibody No prior skin rash (e.g., Stevens-Johnsons syndrome or toxic epidermal necrolysis) from rituximab therapy Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Absolute neutrophil count >= 1,500/mm^3 Platelet count >= 150,000/mm^3 Total lymphocyte count < 5,000/mm^3 for patients with small lymphocytic lymphoma Bilirubin =< 2 mg/dL Creatinine =< 2 mg/dL

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (radiolabeled monoclonal antibody therapy)<br>Patients receive rituximab IV on days 1 and 8, indium In 111 ibritumomab tiuxetan IV over 10 minutes on day 1, and yttrium Y 90 ibritumomab tiuxetan (IDEC-90Y2B8) IV over 10 minutes on day 8. Patients also receive filgrastim (G-CSF) subcutaneously (SC) and interleukin-11 SC until blood counts recover. | Biological: rituximab<br>* Given IV<br>* Other names: Rituxan;Biological: yttrium Y 90 ibritumomab tiuxetan<br>* Given IV<br>* Other names: Y90-labeled ibritumomab tiuxetan;Biological: indium In 111 ibritumomab tiuxetan<br>* Given IV<br>* Other names: IDEC-In2B8;Biological: oprelvekin<br>* Given subcutaneously<br>* Other names: Neumega;Biological: filgrastim<br>* Given subcutaneously<br>* Other names: Neupogen;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Yttrium Y-90 Ibritumomab Tiuxetan (Y2B8) With and Without Filgrastim (G-CSF) and Interleukin-11 (IL-11) (Phase I) | This study is a series of 3 single-arm phase-I trials designed to determine the maximum tolerated dose (MTD) of a 2-cycle combination regimen containing Rituxan + Y2B8 radioimmunotherapy with and without the use of G-CSF and IL-11. Trial 1 will determine the Y2B8 MTD in the combined regimen without growth factors. Trial 2 will evaluate the combined regimen with growth factors. Trial 3 starts IL-11 earlier (when platelet count drops below 150000) and reduces the dosing interval to twice weekly. > Dose-limiting toxicity (DLT) is defined as an adverse event in the second cycle attributed to treatment and meeting the following criteria: Grade 4 ANC or platelet decrease for 14 days, or grade 3 for 28 days, or any other grade 3 Non-Heme event. > If at any time 2 or more patients (of a maximum of 6) at any dose level experience DLT, then the MTD will be defined as the previous dose level during that trial. The number of patients with a DLT are reported here. | At 8 weeks | 
| Toxicity of Single-dose Y2B8 Radioimmunotherapy With and Without the Use of Growth Factors (Phase I) | Evaluated using the Common Toxicity Criteria (CTC) version 2.0. This data is presented as the number of patients reporting grade 3 or higher, grade 4 or higher, or grade 5 adverse events regardless of event attribution. | Assessed up to week 24 | 
| Proportion of Patients Who Receive 2 Sequential Doses of Y2B8 Immunotherapy and Are Progression-free (Phase II) | Estimated by the number of successes divided by the total number of evaluable patients. Exact binomial confidence intervals for the true success proportion will be calculated. | At 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Association Between the Amounts of Tumor Radiation Indicated by the In2B8 Scan and Tumor Response (Phase I) | Assessed using a correlated logistic regression model and generalized estimating equations (GEE). Covariates such as dose level and use of prophylactic cytokines may also be included in this model. A Wilcoxon test will be used to assess the equality of the distributions of the continuous levels of predicted tumor radiation from the In2B8 scans by response. | At week 12 | 
| Association Between In2B8 Scan and Positron Emission Tomography Scan Results (Phase I) | Explored using a contingency table and sensitivity and specificity will be calculated using 90% exact confidence intervals. | At week 12 | 
| Appearance of Tumor and Normal Organ Images on the Second In2B8 Scan (Phase I) | Calculated from the serial gamma camera images. Compared using a signed-rank-test. Scatter plots will be used to further explore relationships between these residence times and Bland- Altman methods can be used to assess the agreement between the first and second In2B8 scan residence times. | At week 12 | 
| Survival (Phase II) | Estimated using the method of Kaplan-Meier. | From registration to death due to any cause, assessed up to 5 years | 
| Time to Disease Progression (Phase II) | Estimated using the method of Kaplan-Meier. | From registration to the earliest date documentation of>disease progression, assessed up to 5 years | 
| Tumor Response Rate (Phase II) | Calculated by the number of tumor responses divided by the total number of evaluable patients. An exact binomial confidence interval will be calculated. | Assessed up to 5 years |