Study of Iodine-131 Anti-B1 Antibody for Patients With Non Hodgkin's Lymphoma Who Have Previously Received Rituximab

Study Overview
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Brief Summary
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This is a single-arm, open-label, multicenter study of Iodine I-131 Anti B1 Antibody (Tositumomab and Iodine I 131 Tositumomab) for treatment of non-Hodgkin's lymphoma (NHL) who were previously treated with rituximab antibody. Patients must have been treated with at least 4 doses of rituximab and have progressed during or following rituximab therapy. Patients will undergo two dosing phases of study. In the first phase, termed the dosimetric dose, patients will receive an infusion of unlabeled Anti-B1 Antibody (450 mg) over 70 minutes immediately followed by a 30-minute infusion of Anti-B1 Antibody (35 mg) which has been radiolabeled with 5 mCi of Iodine-131. Whole body gamma camera scans will be obtained on Day 0; Day 2, 3, or 4; and Day 6 or 7 following the dosimetric dose. Using the dosimetric data from three imaging timepoints, a patient-specific dose of Iodine-131 will be calculated to deliver the desired total body dose of radiotherapy. In the second phase, termed the therapeutic dose, patients will receive a 70-minute infusion of unlabeled Anti-B1 Antibody (450 mg) immediately followed by a 30-minute infusion of 35 mg Anti-B1 Antibody labeled with a patient-specific dose of Iodine-131 to deliver a whole body dose of 75 cGy to patients with no hematologic risk factors. Patients who have platelet counts of 100,001-149,999 cells/mm3 will receive 65 cGy and patients who are obese will be dosed based upon 137% of their 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 endpoints of the study are to determine the response rate, complete response rate, duration of response, and time to progression or death, based on both a Masked Independent Randomized Radiographic and Oncologic Review (MIRROR) panel and the Investigators, and the Investigators' assessment of safety and survival of survival of Iodine-131 Anti-B1 Antibody therapy in NHL patients who have previously been treated with rituximab.

Official Title
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Phase II Study of Iodine-131 Anti-B1 Antibody for Non Hodgkin's Lymphoma Patients Who Have Previously Received Rituximab

Conditions
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Lymphoma, Non-Hodgkin

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients must have a histologically confirmed diagnosis of low-grade non-Hodgkin's B-cell lymphoma according to International Working Formulation. 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 or evidence of CD20 positivity by flow cytometry are acceptable evidence of CD20 positivity. Patients must have been treated with at least 4 doses of rituximab at any time and failed to achieve an objective response (CR, CCR, PR) or relapse/progressed during treatment or following the completion of rituximab therapy. 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 granulocyte count >1500 cells/mm3 (US) and a platelet count >100,000 cells/mm3 (US) 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 greater than or equal to 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/EC- 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 who received cytotoxic chemotherapy, radiation therapy, immunosuppressants, or cytokine treatment within 4 weeks prior to study entry (6 weeks of nitrosourea compounds) or who exhibit persistent clinical evidence of toxicity. The use of systemic steroids must be discontinued at least 1 week prior to study entry. Patients with prior hematopoietic stem cell transplant following high-dose chemotherapy or chemo/radiotherapy. Patients with active obstructive hydronephrosis. 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 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 previously received radioimmunotherapy. Patients with progressive disease within 1 year of irradiation arising in a field that has been previously irradiated with > 3500 cGy. Patients who are HAMA positive. Patients who are concurrently receiving either approved or non-approved (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> | Biological: Anti-B1 Antibody and Iodine-131 Anti-B1 Antibody (Tositumomab and Iodine I 131 Tositumomab)<br>* Patients will receive an infusion of unlabeled Anti-B1 Antibody (450 mg) followed by an infusion of Anti-B1 Antibody (35 mg) containing 5 mCi of Iodine-131 (dosimetric dose). Whole body gamma camera scans will be obtained on Day 0; Day 2, 3, or 4; and Day 6 or 7 following the dosimetric dose. Patients will then receive an infusion of unlabeled Anti-B1 Antibody (450 mg) followed by an infusion of 35 mg Anti-B1 Antibody containing a patient-specific dose of Iodine-131 calculated to deliver a 75 cGy total body radiation dose (therapeutic dose). Patients who have platelet counts of 100,001-149,999 cells/mm3 will receive 65 cGy; obese patients will be dosed based upon 137% of their lean body mass. Patients will be treated with a thyroid blocking agent 24 hours prior to the dosimetric dose and continuing for 14 days following the therapeutic dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants (Par.) With Confirmed Response as Assessed by the Investigator | Responses had to be confirmed by 2 separate evaluations occurring >=4 weeks apart. Par. with confirmed response include those with Complete Response (CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease), Clinical Complete Response (CCR: complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present), or Partial Response (PR: >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions). | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Number of Participants With Confirmed Complete Response (CR) as Assessed by the Investigator | CR is defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Number of Participants With Confirmed Complete Response Plus Clinical Complete Response (CR + CCR) as Assessed by the Investigator | CCR is defined as the complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present. Generally, an unchanging lesion =<2 centimeters (cm) in diameter by radiographic evaluation or =<1 cm in diameter by physical examination can be considered scar tissue. The extent of disease must be unchanged or decreased upon follow-up evaluations. If the extent of disease was unchanged or if further decreases occurred for 6 months or longer, the participant was reclassified as having a CR. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Number of Participants With Confirmed Partial Response (PR) as Assessed by the Investigator | Confirmed PR is defined as a >=50 percent reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, with no new lesions. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Duration of Response for All Confirmed Responders (CR, CCR, or PR) as Assessed by the Investigator | Response duration is defined as the time from the first documented response until disease progression. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Duration of Response for Confirmed CR as Assessed by the Investigator | Response duration is defined as the time from the first documented response until disease progression. Disease progression is defined as a >=25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measureable lesions or the appearance of any new lesion. Individual lesions must be >2 centimeters (cm) in diameter by radiographic evaluation or >1 cm in diameter by physical examination. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Duration of Response for CR and CCR as Assessed by the Investigator | Response duration is defined as the time from the first documented response until disease progression. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Duration of Response for All Confirmed Partial Responders as Assessed by the Investigator | Response duration is defined as the time from the first documented response until progressive disease. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Number of Participants With or Without (w/o) a Prior Response to Rituximab (Before Entry Into This Study) Who Were Classified as Responders in This Study | Response corresponds to the best response evaluation (ordered by CR, CCR, and PR) and does not require subsequent confirmation. Participants with CR, CCR, or PR are considered to be responders. A prior response to rituximab refers to a CR, CCR, or PR after rituximab treatment before enrollment into Study BEX104507. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Duration of Response for All Participants Classified as Responders With or Without a Prior Response to Rituximab | Duration of response is defined as the time from the first documented response to disease progression. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Number of Participants With or Without (w/o) a Prior Response to Rituximab (Before Entry Into This Study) Who Were Classified as Having a Complete Response (CR) in This Study | CR is defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Duration of Response for All Participants With CR With or Without a Prior Response to Rituximab | Duration of response is defined as the time from the first documented response to disease progression. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Progression-free Survival for Participants With or Without a Prior Response to Rituximab | Progression-free survival is defined as the time from treatment start to the first documented occurrence of disease progression or death. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Time to Progression of Disease or Death in All Responders, Participants With CR + CCR, and Participants With PR as Assessed by the Investigator | Progression-free survival or time to progression is defined as the time from the dosimetric dose to the first documented occurrence of disease progression or death. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Overall Survival | Overall survival is defined as the time from the treatment start date to the date of death from any cause. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Adverse Events (AE) Possibly or Probably Related to Study Drug and Experienced by at Least 5% of Participants | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The Investigator assessed whether the adverse event was possibly or probably related to study drug. In addition, all laboratory-derived hematologic toxicities were assumed to be possibly or probably related to study drug. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Number of Participants With the Indicated Type of Infection | An infection is the colonization of a host organism by a parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease. Specimen samples of the body fluid are cultured for testing whether the infectious organism is present and grown in the culture media to assess the growth pattern of the organisms present in the specimen. The culture results could be positive or negative. The positive culture results indicate that the tested participant has the infection under investigation, in which case therapeutic treatment with anti-infective is required. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Number of Participants With an Infection for Which Anti-infectives Were Administered | Anti-infectives are capable of acting against infection, by inhibiting the spread of an infectious agent or by killing the infectious agent outright. Anti-infective is a general term that encompasses antibacterials, antibiotics, antifungals, antiprotozoans, and antivirals. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Number of Participants With Serious Adverse Events (SAE) Related to Study Drug | 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. Medical events that may not result in death, be life-threatening, or require hospitalization may be considered to be a serious ADEs when based upon appropriate medical judgment. Relatedness was based on the investigator's medical judgement. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Time to Nadir and Time to Recovery to Baseline in Hematologic Laboratory Evaluations | Nadir is defined as the lowest laboratory value recorded following the administration of the study medication. Time to recovery to baseline in hematologic laboratory evaluations is the time required for recovery from nadir values to baseline values. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Nadir Values for ANC, a Hematologic Parameter | Nadir is defined as the lowest laboratory value recorded following the administration of study medication. ANC is a measure of the number of neutrophil granulocytes present in the blood. Neutrophils are a type of white blood cell that fights against infection. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Nadir Values for Hemoglobin, a Hematologic Parameter | Nadir is defined as the lowest laboratory value recorded following the administration of study medication. Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Nadir Values for Hematologic Parameters Platelets and WBC Count | Nadir is defined as the lowest laboratory value recorded following the administration of study medication. Platelets and WBCs are types of blood cells. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Number of Participants With the Indicated Grade 3 or Grade 4 Hematologic Toxicities | Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No adverse event or within normal limits; 1 = Mild adverse event; 2 = Moderate adverse event; 3 = Severe and undesirable adverse event; 4 = Life-threatening or disabling adverse event; 5 = Death related to adverse event. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 
| Duration of the Indicated Grade 3 or Grade 4 Hematologic Toxicities | Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No adverse event or within normal limits; 1 = Mild adverse event; 2 = Moderate adverse event; 3 = Severe and undesirable adverse event; 4 = Life-threatening or disabling adverse event; 5 = Death related to adverse event. | Participants were evaluated until death (up to 80.2 months in Study BEX104507) or were followed in the long-term follow-up study for up to 10.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tositumomab, radioimmunotherapy, rituximab, anti-B1, I 131, Bexxar, iodine, non-Hodgkin's lymphoma