Iodine-131 Anti-B1 Antibody (Tositumomab and Iodine I 131 Tositumomab) for Previously Untreated, Advanced-stage, Low Grade Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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This is a single-arm, single-institution, phase II study of Iodine-131 Anti-B1 Antibody for patients with previously untreated, advanced-stage (stage III or IV) low-grade non-Hodgkin's B-cell lymphoma. A total of 75-80 patients will be enrolled. Patients will undergo two phases of the study. In the first phase, termed the dosimetric dose, patients will receive an infusion of unlabeled Anti-B1 Antibody (450 mg) over 70 minutes (including a 10-minute flush) immediately followed by a 30-minute infusion (including a 10-minute flush) of Anti-B1 Antibody (35 mg) which has been trace-labeled with 5 mCi of Iodine-131. Whole body gamma camera scans will be obtained 5 to 8 times between Days 0 and 7 following the dosimetric dose. Using the dosimetric data from 3 imaging timepoints (the imaging timepoints to be used in decreasing order of preference depending on availability of data are Days 0, 3, and 7; Days 0, 4, and 7; Days 0, 3 and 6; Days 0, 4, and 6; Days 0, 2, and 7; and Days 0, 2, and 6), a patient-specific dose of Iodine- 131 to deliver the desired total body dose of radiotherapy will be calculated. In the second phase, termed the therapeutic dose, patients will receive a 70-minute infusion (including a 10-minute flush) of unlabeled Anti-B1 Antibody (450 mg) immediately followed by a 30-minute infusion (including a 10-minute flush) of Anti-B1 Antibody (35 mg) labeled with the patient-specific dose of Iodine-131 to deliver a whole body dose of 75 cGy. Patients who are obese will be dosed based upon 137% of their calculated lean body mass. Patients will be treated with either saturated solution potassium iodide (SSKI), Lugol's solution, or potassium iodide tablets starting at least 24 hours prior to the first infusion of the Iodine-131 Anti-B1 Antibody (i.e., dosimetric dose) and continuing for 14 days following the last infusion of Iodine-131 Anti-B1 Antibody (i.e., therapeutic dose). The primary endpoint of the study is the determination of the response rate with Iodine-131 Anti-B1 Antibody in previously untreated patients with low-grade non-Hodgkin's lymphoma (NHL). The secondary endpoints include duration of response, safety, radiation dosimetry, and the predictive value of detection of the presence or absence minimal residual disease by molecular techniques on response duration.

Official Title
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Phase II Trial of Iodine-131 Anti-B1 Antibody for Previously Untreated, Advanced Stage, Low Grade Non-Hodgkin's Lymphoma

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Biological: Tositumomab and Iodine I 131 Tositumomab (Anti-B1 Antibody and Iodine-131 Anti-B1 Antibody)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients must have a histologically confirmed diagnosis of lowgrade non-Hodgkin's B-cell lymphoma. The following low-grade histologies are included: small lymphocytic (with or without plasmacytoid differentiation); follicular, small cleaved; follicular, mixed small cleaved and follicular large cell (less than 50% large cell component); and monocytoid B-cell lymphoma. Patients must have evidence that their tumor tissue expresses the CD20 antigen. Immunoperoxidase stains of paraffin-embedded tissue showing positive reactivity with L26 antibody or immunoperoxidase stains of frozen tissue showing positive reactivity with Anti-B1 Antibody (Coulter Clone®) or similar commercially available CD20 antibody (>50% of tumor cells are positive) or evidence of CD20 positivity by flow cytometry (>50% of tumor cells are positive) are acceptable evidence of CD20 positivity. Testing of tumor tissue from any time in the course of the patient's disease is acceptable. Patients must have Ann Arbor stage III or IV extent of disease after complete staging. Patients must not have had any previous treatment for low-grade lymphoma including chemotherapy or radiation. They may be newly diagnosed or observed without treatment after diagnosis. Symptomatic and asymptomatic patients will be eligible. Patients must have a performance status of at least 60% on the Karnofsky Scale and an anticipated survival of at least 3 months. Patients must have an absolute neutrophil count (ANC) >1500 cells/mm3 and a platelet count >100,000 cells/mm3 within 14 days of study entry. These blood counts must be sustained without support of hematopoietic cytokines or transfusion of blood products. Patients must have 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 14 days of study entry. Patients must have bi-dimensionally measurable disease. At least one lesion must be ≥2 x 2 cm (by computed tomography [CT] scan). Patients must be at least 18 years of age. Patients must give written informed consent and sign an IRB- approved informed consent form prior to study entry. Exclusion Criteria Patients with more than an average of 25% of the intratrabecular marrow space involved by lymphoma in bone marrow biopsy specimens as assessed microscopically within 42 days of study entry. Bilateral posterior iliac crest core biopsies are required if the percentage of intratrabecular space involved exceeds 10% on a unilateral biopsy. The mean of bilateral biopsies must be no more than 25%. Patients with evidence of active infection requiring intravenous (IV) antibiotics at the time of study entry. Patients with New York Heart Association class III or IV heart disease or other serious illness that would preclude evaluation. Patients with active obstructive hydronephrosis. Patients with prior malignancy other than lymphoma, except for adequately treated skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 years. Patients with known HIV infection. Patients with known brain or leptomeningeal metastases. Patients who are pregnant or nursing. Patients of childbearing potential must undergo a pregnancy test within 7 days of study entry and radiolabeled antibody is not to be administered until a negative result is obtained. Males and females must agree to use effective contraception for 6 months following the radioimmunotherapy. Patients with previous allergic reactions to iodine. This does not include reacting to IV iodine-containing contrast materials. Patients who were previously given any monoclonal or polyclonal antibodies of any non-human species for either diagnostic or therapeutic purposes. This includes engineered chimeric and humanized antibodies. Patients who are concurrently receiving either approved or nonapproved (through another protocol) anti-cancer drugs or biologics.

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: open-label, single arm<br>Tositumomab and Iodine I 131 Tositumomab | Biological: Tositumomab and Iodine I 131 Tositumomab (Anti-B1 Antibody and Iodine-131 Anti-B1 Antibody)<br>* Dosimetric Dose: 450 mg of Anti-B1 Antibody infused over 70 minutes (inclusive of a 10-minute flush) immediately followed by 5 mCi (35 mg) of Iodine-131 Anti-B1 Antibody infused over 30 minutes (inclusive of a 10-minute flush). Therapeutic Dose: Seven to 14 days after the dosimetric dose, 450 mg of Anti-B1 Antibody infused over 70 minutes (inclusive of a 10-minute flush), immediately followed by the patient-specific milliCurie activity (35 mg) of Iodine-131 Anti-B1 Antibody to deliver a total body dose (TBD) of 75 cGy infused over 30 minutes (inclusive of a 10-minute flush). Obese patients were dosed based upon 137% of their calculated lean body mass.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Confirmed Response, Including Participants With Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR) | Confirmed response required CR, CCR, or PR, which were confirmed by 2 separate response evaluations >=4 weeks apart. CR: Complete resolution of all disease-related radiological abnormalities and disappearance of all signs and symptoms related to the disease. CCR: Complete resolution of all disease-related symptoms, but residual foci, thought to be residual scar tissue, are present. PR: >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions. | From Study Day 0 (start of treatment) up to 12 years (long-term follow up) | 
| Number of Participants With Response, Including Participants With Complete Response (CR), Clinical Complete Response (CCR), or Partial Response (PR) | CR: Complete resolution of all disease-related radiological abnormalities and disappearance of all signs and symptoms related to the disease. CCR: Complete resolution of all disease-related symptoms, but residual foci, thought to be residual scar tissue, are present. PR: >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions. | From Study Day 0 (start of treatment) up to 12 years (long-term follow up) | 
| Number of Participants With Confirmed Complete Response (CR, CCR, and CR+CCR) and Partial Response (PR) | Responses were confirmed by two separate response evaluations at least 4 weeks apart. CR: Complete resolution of all disease-related radiological abnormalities and disappearance of all signs and symptoms related to the disease. CCR: Complete resolution of all disease-related symptoms, but residual foci, thought to be residual scar tissue, are present. PR: >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions. | From Study Day 0 (start of treatment) up to 12 years (long-term follow up) | 
| Number of Participants With Complete Response (CR, CCR, and CR+CCR) and Partial Response (PR) | CR: Complete resolution of all disease-related radiological abnormalities and disappearance of all signs and symptoms related to the disease. CCR: Complete resolution of all disease-related symptoms, but residual foci, thought to be residual scar tissue, are present. PR: >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions. | From Study Day 0 (start of treatment) up to 12 years (long-term follow up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Estimated Value Represents the Percentage of Participants With a PR | Duration of response (CR, CCR, or PR) is defined as the time from the first documented response to the first documented progression. Progressive Disease (PD) is defined as a >=25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. | From Study Day 0 (start of treatment) up to 12 years (long-term follow up) | 
| Overall Survival | Overall survival is defined as the time from the treatment start date to the date of death from any cause. | From Study Day 0 (start of treatment) up to 12 years (long-term follow up) | 
| Time to Progression of Disease or Death (Progression-free Survival) | Time to progression is defined as the time from the treatment start date to the first documented progression or death. Progressive Disease is defined as a >=25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. | From Study Day 0 (start of treatment) up to 12 years (long-term follow up) | 
| Number of Participants With Resolution of All Baseline B-symptoms by the End of the Study | The Ann Arbor staging system of lymphomas is used to summarize the extent of the cancer's spread. Stages are classified by Roman numerals I (less spread) to IV (more spread). If the following symptoms (called B-symptoms) are present, a B classification is added to the stage: night sweats, intermittant fever, and weight loss. B-symptoms indicate the presence of systemic symptoms. The presence or absence of B-symptoms has prognostic significance and is reflected in the staging of these lymphomas. | Baseline and up to 12 years (long-term follow up) | 
| Number of Participants Who Were Polymerase Chain Reaction (PCR)-Positive at Baseline With Bone Marrow Conversion to a Status of PCR Positive and Negative Any Time After Treatment | PCR is a scientific technique in molecular biology to amplify a single copy or a few copies of a piece of deoxyribonucleic acid (DNA) across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. Applications of PCR technique include: selective DNA isolation, amplification and quantification of DNA, and the diagnosis of diseases. PCR positive: interchromosomal translocation t(14;18) is present. PCR negative: t(14;18) is absent. | Baseline and up to 12 years (long-term follow up) | 
| Duration of Response (the Time From the First Documented Response to the First Documented Progression) for Participants Who Were PCR Positive at Baseline and Converted to PCR Negative Status After Treatment | PCR is a scientific technique in molecular biology to amplify a single copy or a few copies of a piece of deoxyribonucleic acid (DNA) across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. Applications of PCR technique include: selective DNA isolation, amplification and quantification of DNA, and the diagnosis of diseases. PCR positive: interchromosomal translocation t(14;18) is present. PCR negative: t(14;18) is absent. | Baseline and up to 12 years (long-term follow up) | 
| Progression-free Survival (PFS) Based on Participants' Baseline PCR Status | PCR is a scientific technique in molecular biology to amplify a single copy or a few copies of a piece of deoxyribonucleic acid (DNA) across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. Applications of PCR technique include: selective DNA isolation, amplification and quantification of DNA, and the diagnosis of diseases. PCR positive: interchromosomal translocation t(14;18) is present. PCR negative: t(14;18) is absent. PFS is defined as the time from the dosimetric dose to the first documented occurrence of disease progression or death. | Baseline and up to 12 years (long-term follow up) | 
| Initial Half-life (t1/2alpha) | t1/2 alpha is the estimated initial or alpha phase half-life in a two-compartmental pharmacokinetic model. Half-life measures how long it takes for the concentration of drug in the blood to decrease by half. | 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) | 
| Terminal Half-life (t1/2beta) | t1/2 beta is the estimated terminal or beta phase half-life in a two-compartmental pharmacokinetic model. Half-life measures how long it takes for the concentration of drug in the blood to decrease by half. | 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) | 
| Area Under the Curve (AUC) at 0 to 120 Hours and 0 to Infinity Hours | Area under the concentration-time curve for I-131 tositumomab from time 0 to 120 hours and time 0 to infinity hours (extrapolated) after the end of the dosimetric dose infusion was measured. Unit: %ID*h/ml, where %ID/ml is the percentage of the injected dose per milliliter of blood. AUC measures how much drug is in the system over time after infusion. | 0-120 hours and 0-infinity hours from the dosimetric dose (given only on Day 0) and 0-120 hours and 0-infinity hours from the therapeutic dose (given only on Day 7) | 
| Clearance Values | Clearance of I-131 tositumomab after intravenous administration was measured. The clearance of a drug measures the rate at which the drug is removed from the body after the dose. | 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) | 
| Maximum Concentration (Cmax) Values | Cmax is the maximum observed I-131 tositumomab concentration from time zero (end of the dosimetric dose infusion) to 120 hours after the end of the infusion. Unit: %ID/ml, where %ID/ml is the percentage of the injected dose per milliliter of blood. Cmax is the highest drug concentration in the blood after infusion. | 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) | 
| Volume of Distribution at Infusion Time 0 (Vd0) and Steady State (Vdss) | Volume of distribution at the start of infusion and at steady state of I-131 tositumomab. The volume of distribution measures how much the drug spreads through the body after the dose. Steady state is defined as that state at which the overall intake of a drug is fairly in dynamic equilibrium with its elimination. | 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) | 
| Total Body Effective Half-life (EHL) | Total body EHL is the time required for a radioactive element in the body to be diminished by 50% as a result of radioactive decay and biologic elimination. The EHL is equal to the product of the biologic half-life (BHL) and the radioactive half-life (RHL) divided by the sum of the BHL and the RHL: EHL=(BHL * RHL)/(BHL + RHL). BHL is the time it takes for a drug to lose half of its pharmacologic, physiologic, or radiologic activity. RHL is the time taken for half of the radioactive nuclei to decay. | 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) | 
| Normal Organ Dosimetry for the Indicated Organs | Organ dosimetry was performed in participants using the kidneys, liver, lungs, spleen, red marrow, urinary bladder, and the remainder of the body as source organs. Organ doses and Iodine I-131 Anti-B1 Antibody biodistribution were comparable across the three Anti-B1 Antibody manufacturers. Gamma camera images of participants were used to calculate the amount of radiation that accumulated in the target tumor and normal organs (tumor/organ dosimetry). For the spleen (corrected) category, participant-specific corrections were made to account for individual spleen size. | 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) | 
| Number of Participants With the Indicated Fatal Serious Adverse Events (SAE) | An SAE is any event occurring at any dose that results in any of the following: death, a life-threatening adverse drug experience (ADE; at immediate risk of death from the experience as it occurred), inpatient hospitalization/prolongation of existing hospitalization, a persistent/significant disability/incapacity, or a congenital anomaly/birth defect. A fatal SAE is a medical event that results in death. | From Baseline up to 12 years from the start of treatment (long-term follow up) | 
| Number of Participants Evaluable and Not Evaluable for Human Anti-Murine Antibodies (HAMA) | Tositumomab is a murine (mouse) antibody (immunoglobulin) of the IgG2a subclass. Participants were evaluated to determine whether they developed an immune response to study treatment, as evident by human anti-mouse antibodies (HAMA) after administration of tositumomab and iodine I-131 tositumomab. A positive HAMA value indicates that the participant developed HAMA above the HAMA assay threshold, and a negative HAMA value indicates either the absence or below threshold level of HAMA. | From Baseline up to 2 years from the start of treatment | 
| Number of Participants With Conversion to HAMA Positivity Any Time During the Study From Baseline | Tositumomab is a murine (mouse) antibody (immunoglobulin) of the IgG2a subclass. Participants were evaluated to determine whether they developed an immune response to study treatment, as evident by human anti-mouse antibodies (HAMA) after administration of tositumomab and iodine I-131 tositumomab. A positive HAMA value indicates that the participant developed HAMA above the HAMA assay threshold, and a negative HAMA value indicates either the absence or below threshold level of HAMA. HAMA assays were conducted in the laboratory to measure conversion to HAMA positivity following treatment. | From Baseline up to 2 years from the start of treatment | 
| Time to HAMA Positivity From the First Dosimetric Dose | Tositumomab is a murine (mouse) antibody (immunoglobulin) of the IgG2a subclass. Participants were evaluated to determine whether they developed an immune response to study treatment, as evident by human anti-mouse antibodies (HAMA) after administration of tositumomab and iodine I-131 tositumomab. A positive HAMA value indicates that the participant developed HAMA above the HAMA assay threshold, and a negative HAMA value indicates either the absence or below threshold level of HAMA. HAMA assays were conducted in the laboratory to measure conversion to HAMA positivity following treatment. | From Baseline up to 2 years from the start of treatment | 
| Number of Participants With Elevated, Low, and Normal Thyroid Stimulating Hormone (TSH) Levels at Baseline | TSH is a hormone that stimulates the thyroid gland to produce thyroxine (T4) and then triiodothyronine (T3), which stimulates the metabolism of almost every tissue in the body. Participants were considered to have normal, high, or low TSH levels per the standard TSH ranges of the testing laboratory. | Baseline | 
| Participants With Elevated TSH Levels at Baseline With Post Baseline TSH Levels of Low/Normal and Elevated | TSH is a hormone that stimulates the thyroid gland to produce thyroxine (T4) and then triiodothyronine (T3), which stimulates the metabolism of almost every tissue in the body. Participants were considered to have normal, high, or low TSH levels per the standard TSH ranges of the testing laboratory. | Baseline and up to 12 years (long-term follow up) | 
| Time to Elevated TSH Post Baseline for Participants Who Had Low or Normal TSH Levels at Baseline and Elevated Levels Post Baseline | TSH is a hormone that stimulates the thyroid gland to produce thyroxine (T4) and then triiodothyronine (T3), which stimulates the metabolism of almost every tissue in the body. Participants were categorized to have elevated or normal/low TSH values per the standard TSH ranges of the testing laboratory. | Baseline and up to 12 years from the start of treatment | 
| Number of Participants With the Adverse Event (AEs) of Hypothyroidism | Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone and is defined as either developing elevated TSH levels or initiating thyroid medication. An AE is defined as any unfavorable and unintended sign, including an abnormal laboratory finding, symptom, or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered to be related to the medical treatment or procedure, that occurs during the course of the study. | Baseline and up to 12 years from the start of treatment | 
| Number of Participants With Low or Normal Baseline TSH Levels That Developed Hypothyroidism | Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone and is defined as either developing elevated TSH levels or initiating thyroid medication. | Baseline and up to 12 years from the start of treatment | 
| Number of Participants Who Received Thyroid Medication After Treatment | Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone and is defined as either developing elevated TSH levels or initiating thyroid medication. | From Study Day 0 (start of treatment) up to 12 years (long-term follow up) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radioimmunotherapy, Anti-B1 Antibody and Iodine-131 Anti-B1 Antibody, Tositumomab and Iodine I 131 Tositumomab, non-Hodgkin's Lymphoma, Bexxar