A Study Of Pharmacokinetics, Whole Body And Organ Dosimetry, And Biodistribution Of Fission-Derived Iodine I 131 Tositumomab (BEXXAR®) For Patients With Previously Untreated Or Relapsed Follicular Or Transformed Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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Patients will receive a standard 5 mCi dosimetric dose of fission-derived Iodine I 131 Tositumomab. Pharmacokinetic data for the primary endpoint analysis will be derived from testing done on blood samples drawn at 12 timepoints over the first 7 days following administration of the dosimetric dose. Whole body gamma camera images will be obtained on six days following the dosimetric dose. Organ and tumor dosimetry data will be generated from gamma camera counts of specific organs and tumor. All scans will be examined by an independent review panel to evaluate biodistribution of the radionuclide. Using the dosimetric data from three of the six imaging time points and the patient's weight, a patient-specific activity (mCi) of Iodine-131 will be calculated to deliver the desired total body dose of radiation (75 cGy). Patients will receive an infusion of unlabeled Tositumomab (450 mg) immediately followed by an infusion of the patient specific dose of tellurium-derived Iodine I 131 Tositumomab (35 mg) to deliver a total body dose (TBD) of 75 cGy. Patients will be followed closely obtaining safety information during the post-treatment period, and for response and safety at 3,6,and 12 months during the first year, annually thereafter up to five years, and annually for additional safety and outcomes information up to 10 years.

Official Title
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A Multi-Center Study to Examine the Pharmacokinetics, Whole Body and Organ Dosimetry, and Biodistribution of Fission-Derived Iodine I 131 Tositumomab for Patients With Previously Untreated or Relapsed Follicular or Transformed Follicular Non-Hodgkin's Lymphoma

Conditions
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Lymphoma, Follicular

Intervention / Treatment
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* Biological: Follicular Lymphoma


Participation Criteria
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Eligibility Criteria
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Inclusion criteria At least 18 years of age A histologically confirmed diagnosis of the following: Follicular lymphoma, Grade 1, 2, or 3 or diffuse large cell lymphoma concurrent with or following the diagnosis of follicular lymphoma (World Health Organization/Revised European-American Lymphoma [WHO/REAL] classification). International Working Formulation histological equivalents included: Follicular, small-cleaved; Follicular, mixed small-cleaved and large-cell; Follicular large-cell; or Transformed diffuse large-cell lymphoma following or concurrent with a diagnosis of follicular lymphoma. Stage III or IV disease at the time of study entry (based on Ann Arbor Staging Classification) Previously untreated or recurrent lymphoma after no more than 4 prior qualifying therapy regimens; steroids alone, as treatment for lymphoma, not considered a treatment regimen Performance status of at least 70% on the Karnofsky Performance Scale and an anticipated survival of at least 3 months. Bi dimensionally measurable disease with at least one lesion measuring greater than or equal to 2.0 cm x 2.0 cm (greater than or equal to 4.0 cm2) by computed tomography (CT) scan Absolute B lymphocyte count (as determined by CD19 reactivity [flow cytometric determination of CD19+ B lymphocyte count]) of 30 to 350 cell/mm3 within 21 days prior to study enrollment Absolute neutrophil count greater than or equal to 1500 cells/mm3; platelet count greater than or equal to 150,000/mm3; and hemoglobin greater than or equal to 10 g/dL within 21 days prior to study enrollment; blood products and/or growth factors not taken within 4 weeks prior to blood draw Adequate renal function, defined as serum creatinine <1.5 x upper limit of normal (ULN), and hepatic function, defined as total bilirubin <1.5 x ULN and aspartate transaminase (AST) <5 x ULN, within 21 days of study enrollment HAMA negative within 21 days prior to study enrollment Signed IRB approved consent form prior to any study-specific procedures being implemented Exclusion criteria Greater than 25% of the intratrabecular marrow space involved by lymphoma in bone marrow biopsy specimens as assessed microscopically within 90 days of study enrollment; a unilateral bone marrow biopsy was adequate; marrow core was greater than or equal to 2.0 cm in length Prior chemotherapy, biologic therapy, steroids, or radiation therapy as treatment for NHL within 28 days prior to study enrollment; subjects receiving low doses of steroids for non neoplastic disease acceptable to enter this study (Low dose steroids was defined as less than or equal to 10 mg of prednisone or equivalent per day.) Prior rituximab therapy within 120 days prior to study enrollment Prior radioimmunotherapy Prior splenectomy Splenomegaly defined as spleen mass greater than 700 grams, where splenic mass was defined as follows: Spleen mass = л(X x Y x Z)/6 Where X and Y are the greatest perpendicular diameters in cm on any single CT scan slice, and Z is the number of CT scan slices upon which the spleen is visible times the slice thickness in cm Bulky disease as defined as any uni-dimensional measurement of lymphomatous mass exceeding 7 cm Prior malignancy other than lymphoma, except for adequately treated skin cancer, in situ cervical cancer, or other cancer for which the subject had a generally accepted risk of recurrence less than 20% Central nervous system involvement by lymphoma Evidence of active infection requiring IV antibiotics at the time of study enrollment Known human immunodeficiency virus (HIV) infection New York Heart Association Class III or IV heart disease or other serious illness that would preclude evaluation. Active obstructive hydronephrosis Evidence of clinically significant ascites or pleural effusion observed on screening physical examination or baseline CT scan Prior myeloablative therapy History of failed stem cell collection Pregnant or nursing subjects (Subjects of childbearing potential had to have a negative serum pregnancy test within 21 days of study enrollment. Males and females of childbearing age had to agree to use effective contraception for up to 12 months after the radioimmunotherapy.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tositumomab and iodine I 131 tositumomab<br>Subjects participating in this study will receive a standard 5 mCi dosimetric dose of fission-derived Iodine I-131 tositumomab, immediately following an infusion of 450 mg of unlabeled tositumomab. Using the dosimetric data from three of the six imaging time points and the subject's weight, a patient-specific activity (mCi) of Iodine I-131 will be calculated to deliver the desired total body dose of radiation (75 cGy). All subjects will then receive an infusion of unlabeled tositumomab (450 mg) immediately followed by an infusion of the subject specific dose of tellurium-derived Iodine I-131 tositumomab (35 mg) to deliver a total body dose (TBD) of 75 cGy. | Biological: Follicular Lymphoma<br>* For subjects with previously untreated or relapsed follicular or transformed follicular non-Hodgkin's<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) at 0 to 120, 0 to 168, and 0 to Infinity Hours | Area under the concentration-time curve for 131I-tositumomab from time 0 to 120, 0 to 168, and time 0 to infinity hours (extrapolated), after the end of the dosimetric dose infusion. Unit: %ID.h/mL, where %ID/mL is the percentage of the injected dose per milliliter blood. AUC measures how much drug is in the system over time after infusion. | 0-120, 0-168, and 0-infinity hours from dosimetric dose (given only once on Day 0) | 
| Maximum Concentration (Cmax) Values | Cmax is the maximum observed 131I-tositumomab concentration from time zero (end of the dosimetric dose infusion) to 7 days after the end of the infusion. Unit: %ID/mL, where %ID/mL is the percentage of the injected dose per milliliter blood. Cmax is the highest drug concentration in the blood after infusion. | 0 to 7 days from dosimetric dose (given only once on Day 0) | 
| Terminal Phase Half-life (t½) | The terminal phase half-life of 131 I tositumomab in hours. Half-life measures how long it takes for the concentration of drug in the blood to decrease by half. | 0 to 7 days from dosimetric dose (given only once on Day 0) | 
| Clearance (CL) Values | Clearance of 131I-tositumomab after intravenous administration. The clearance of a drug measures the rate at which the drug is removed from the body after the dose. | 0 to 7 days from dosimetric dose given only once on Day 0 | 
| Volume of Distribution at Steady State (Vss) | Volume of distribution at steady state of 131I-tositumomab. Volume of distribution measures how much the drug spreads through the body after the dose. | 0 to 7 days from dosimetric dose given only once on Day 0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) at 0 to 120 Hours | Area under the concentration-time curve from time 0 to 120 hours after the end of the dosimetric dose infusion. Unit: %ID.h/mL, where %ID/mL is the percentage of the injected dose per milliliter blood. AUC measures how much drug is in the system over time after infusion. | 0-120 hours from dosimetric dose (given only once on Day 0) | 
| Area Under the Curve (AUC) at 0 to 168 Hours | Ratio and 90% confidence interval for AUC(0-168) after dosimetric dose of fission-derived 131I-tositumomab to historical data from tellurium-derived 131I-tositumomab. AUC measures how much drug is in the blood over time after the dose. | 0-168 h from dosimetric dose (given only once on Day 0) | 
| Area Under the Curve (AUC) at 0 to Infinity (Extrapolated) | Ratio and 90% CI for AUC (0 to infinity) after dosimetric dose of fission-derived 131I-tositumomab to historical data from tellurium derived 131I-tositumomab. AUC measures how much drug is in the blood over time after the dose is given. | 0 to infinity h from dosimetric dose (given only once on Day 0) | 
| Maximum Concentration (Cmax) Values | Maximum observed concentration from time zero (end of the dosimetric dose infusion) to 7 days after the end of the infusion. Unit: %ID/mL, where %ID/mL is the percentage of the injected dose per milliliter blood. Cmax is the highest drug concentration in the blood after the dose. | 0 to 7 days from dosimetric dose (given only once on Day 0) | 
| Mean Residence Times From Day 0 to Day 7 | Whole body images from anterior and posterior gamma camera scans were collected to assess dosimetry. Assessment of organ dosimetry required gamma camera scans from at least 4 time points. Nuclear medicine reviewers conducted a visual examination of the gamma camera scans and calculated the total body residence times. Residence time is calculated from the rate of total body clearance of iodine I-131 radioactivity during the dosimetric dose. Residence time is a measure of how long the drug resides in the body. | 0 to 7 days from dosimetric dose (given only once on Day 0) | 
| Mean Absorbed Dose in the Source Organs and the Target Organs | The radiation absorbed dose to source organs were determined with Organ Level Internal Dose Assessment/Exponential Modeling (OLINDA/EXM) software using residence times directly determined by an independent reviewer for kidneys, liver, lungs, spleen, urinary bladder, and total body; the radiation absorbed dose for the remaining target organs was based on a mathematical model used to calculate source organ radiation dose estimates using the same OLINDA/EXM software. OLINDA/EXM is a registered proprietary computer program. | 0 to 7 days from dosimetric dose | 
| Number of Participants With Expected Distribution of Radioactivity in the Circulatory System Compared With Uptake by Other Organs. | Expected biodistribution (images): most radioactivity (RA) in blood pool, with uptake in normal liver and spleen less than the heart. Later time points, RA in blood pool decrease and uptake in normal liver and spleen decrease. Images may show uptake by the thyroid gland, kidneys, urinary bladder, and lungs. Altered biodistribution: Blood pool not visualized or diffuse, intense uptake in the liver and/or spleen, or uptake suggestive of urinary obstruction, diffuse lung uptake greater than the blood pool | 0 to 7 days from dosimetric dose (given only once on Day 0) | 
| Percentage of Participants Evaluable for Confirmed Response With Complete Response (CR), CR Unconfirmed (CRu), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) | Evaluation based on the Int'l Workshop to Standardize Response Criteria for non-Hodgkin's Lymphoma (NHL). CR, complete disappearance of all detectable clinical/radiographic evidence of disease, disappearance of all disease-related symptoms if present before therapy, and normalization of biochemical abnormalities definitely assignable to NHL. CRu, complete response unconfirmed, included complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities definitely assignable to NHL. PR, >=50% decrease in sum of perpendicular diameters (SPD) of all measurable lesions determined at baseline. SD, less than a PR but not progressive disease (>=50% increase from nadir in SPD for all measurable disease or the appearance of any new lesion that was >=1.4 cm x 1.4 cm by radiographic evaluation or >=1.0 cm by palpation per physical examination). | From Baseline up to 99 Months | 
| Duration of Response | Duration of response is defined as the time from first documented response (CR, CRu, or PR) until disease progression. | Week 7 to Week 260 post treatment | 
| Progression-free Survival | Progression-free survival, or time to progression, is defined as the time from the dosimetric dose to the first documented disease progression (PD) or death. PD is defined as a >= 50% increase from nadir in the SPPD for all measurable disease. | Week 7 to Week 260 post treatment | 
| Overall Survival | Time to death is defined as the time from the dosimetric dose to the date of death. | Week 7 to Week 260 post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bexxar, tositumomab and iodine I 131 tositumomab therapeutic regiment, fission, Non-Hodgkin's lymphoma, Iodine I 131 Tositumomab, pharmacokinetics, tellurium