Dosimetry/Validation Study of 131Iodine-Anti B1 (Murine) Radioimmunotherapy for Chemotherapy Refractory Low Grade B Cell Lymphomas and Low Grade Lymphomas That Have Transformed to Higher Grade Histologies

Study Overview
=================
Brief Summary
-----------------
Study RIT-II-001 is a phase II, multicenter study of the safety, tumor and organ dosimetry, dosimetry methods, and efficacy of Iodine-131 Anti-B1 Antibody for the treatment of patients with low-grade or transformed low-grade non-Hodgkin's lymphoma (NHL). The primary objective of this study is to demonstrate that each site could accurately conduct the whole body dosimetry required for the safe and effective dosing of Iodine-131 Anti-B1 Antibody. Additional objectives of this study are to evaluate the efficacy, dosimetry, and safety of Iodine-131 Anti-B1 Antibody.

Official Title
-----------------
Multicenter, Phase II Dosimetry/Validation Study of 131Iodine-Anti B1 (Murine) Radioimmunotherapy for Chemotherapy Refractory Low Grade B Cell Lymphomas and Low Grade Lymphomas That Have Transformed to Higher Grade Histologies

Conditions
-----------------
Lymphoma, Non-Hodgkin

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Patients must have a histologically confirmed diagnosis of low-grade non-Hodgkin's B-cell lymphoma or low-grade lymphoma that has transformed to intermediate-, or high-grade lymphoma (transformed lymphoma) according to the Working Formulation for Clinical Usage (IWF A, B, and C). Patients must have evidence that their tumor tissue expresses the CD20 antigen. Patients must have progressive disease of either low-grade or transformed lymphoma within one year of completion of the last chemotherapy regimen administered. Patients must have been previously treated with at least one chemotherapy regimen that included an anthracycline or anthracenedione. Patients must have a performance status of at least 60% on the Karnofsky Scale and anticipated survival of at least three months. Patients must have an absolute granulocyte count of over 1,500 /mm3 and a platelet count above 100,000 /mm3 within seven days of study entry. These blood counts must be sustained without support of hematopoietic cytokines or transfusion of blood products. Patients must have normal renal function (creatinine less than 2.0 mg/dL) and hepatic function (bilirubin less than 2.0 mg/dL) within seven days of study entry. Patients must have bi-dimensionally measurable or evaluable progressive lymphoma disease (at least a 25% increase in tumor size or new sites of disease when compared to the last best disease response). Progression must have occurred within 12 months of the preceding response. Patients must be at least 18 years of age. Patients must give written informed consent and sign an approved informed consent form prior to study entry. Exclusion Criteria Patients with more than an average of 25% of the intertrabecular marrow space involved by lymphoma in bone marrow biopsy specimens as assessed microscopically at study entry. Patients who have received cytotoxic chemotherapy, radiation therapy, immunosuppressants, or cytokine treatment within FOUR weeks prior to study entry (six weeks for nitrosourea compounds) or who exhibit persistent clinical evidence of toxicity. The use of steroids must have been discontinued (except maintenance-dose steroids) at least one week prior to study entry and patients must then show evidence of stable or progressive disease. Patients with prior hematologic stem cell transplant following high-dose chemotherapy or chemo/radiotherapy . Patients with obstructive hydronephrosis. Patients with evidence of active infection requiring intravenous antibiotics at the time of study entry. Patients with New York Heart Association class 3 or 4 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 patient has been disease-free for five years. Patients with known HIV infection. Patients with known brain or leptomeningeal metastases. Patients who are pregnant. Patients of child-bearing potential must undergo a pregnancy test within seven days of study entry. Males and females must agree to use effective contraception during the study. Patients with previous allergic reactions to iodine. This does not include IV contrast materials. Patients who were previously given any monoclonal or polyclonal antibodies of any foreign species for either diagnostic or therapeutic purposes. This includes engineered chimeric and humanized antibodies. Patients who previously received radioimmunotherapy. Patients with progressive disease in a field that has been previously irradiated with more than 3500 cGy. Patients who are on another protocol involving non-approved drugs or biologics.

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: Tositumomab and Iodine I-131 Tositumomab<br>Patients receive a dosimetric dose consisting of 450 milligrams (mg) of unlabeled tositumomab (TST, Anti-B1 Antibody) intravenously (IV) followed by 5 milliCurie (mCi) of Iodine I 131 TST IV. Serial whole body sodium iodide probe scintillation counts and whole body conjugate view gamma camera scans obtained approximately 1 hour after administration and then daily for the next 7 days were used to determine the radioactive clearance and the dose of iodine I 131 TST required to deliver a 75 centigray (cGy) therapeutic dose. The therapeutic dose was administered 7-14 days after the dosimetric dose and consisted of TST 450 mg and an activity of Iodine 131 calculated to deliver 75 cGy or 65 cGy of total body irradiation, depending on platelet count, and 35 mg TST. | Biological: Tositumomab (Anti-B1 Antibody) and Iodine-131 Tositumomab<br>* Patients receive a dosimetric dose consisting of 450 milligrams (mg) of unlabeled tositumomab (TST, Anti-B1 Antibody) intravenously (IV) followed by 5 milliCurie (mCi) of Iodine I 131 TST IV. Serial whole body sodium iodide probe scintillation counts and whole body conjugate view gamma camera scans obtained approximately 1 hour after administration and then daily for the next 7 days were used to determine the radioactive clearance and the dose of iodine I 131 TST required to deliver a 75 centigray (cGy) therapeutic dose. The therapeutic dose was administered 7-14 days after the dosimetric dose and consisted of TST 450 mg and an activity of Iodine 131 calculated to deliver 75 cGy or 65 cGy of total body irradiation, depending on platelet count, and 35 mg TST.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Received the Therapeutic Dose at the Seven Clinical Research Sites | The dosimetry methods were validated for seven different clinical research sites. | Day 1 within one hour of infusion (I) and prior to urination (U); Days 2, 3, and 4 after dosimetric dose (DD) I, following U; Days 6 and 7 after DD I, following U | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Therapeutic Doses (TD) (Total Body Dose) | Based on their platelet count and body weight. Participants received different TDs of TST. For obese participants (weighing more than 137% of their calculated lean body weight), the calculation to determine the administered activity (mCi) was performed using the maximum effective mass (i.e., the minimum of the participant's mass and 137% of their calculated lean body weight). The administered activity (mCi) for participants with a Baseline platelet count of 100001-149999 cells/millimeter cubed (mm^3) was reduced to a 65 cGy total body dose, after any adjustment for obesity. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Number of Participants (Par.) With Response (CR, CCR, or PR), as Assessed by the Investigator | Par. with 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 for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Number of Participants With Confirmed Response (CR, CCR, or PR), 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 for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Number of Participants With CR and CCR, as Assessed by the Investigator | The total number of participants with CR and CCR was reported. CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. Clinical Complete Response: complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Number of Participants With Confirmed CR and CCR, as Assessed by the Investigator | The total number of participants with CR and CCR was reported. Responses had to be confirmed by 2 separate evaluations occurring >=4 weeks apart. CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. Clinical Complete Response: complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Duration of Response for All Confirmed Responders (CR, CCR, or PR), as Assessed by the Investigator | Responses had to be confirmed by 2 separate evaluations occurring >=4 weeks apart. Duration of response 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 measurable lesions or the appearance of any new lesion. Individual lesions must be >2 cm in diameter by radiographic evaluation or >1 cm in diameter by physical examination. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Duration of Response for All Unconfirmed Responders (CR, CCR, or PR), as Assessed by the Investigator | Duration of response 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 measurable lesions or the appearance of any new lesion. Individual lesions must be >2 cm in diameter by radiographic evaluation or >1 cm in diameter by physical examination. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Duration of Response for All Confirmed Complete Responders, as Assessed by the Investigator | Responses had to be confirmed by 2 separate evaluations occurring >=4 weeks apart. Duration of response 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 measurable lesions or the appearance of any new lesion. Individual lesions must be >2 cm in diameter by radiographic evaluation or >1 cm in diameter by physical examination. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Duration of Response for All Unconfirmed Complete Responders, as Assessed by the Investigator | Duration of response 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 measurable lesions or the appearance of any new lesion. Individual lesions must be >2 cm in diameter by radiographic evaluation or >1 cm in diameter by physical examination. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Duration of Response for All Confirmed Clinical Complete Responders, as Assessed by the Investigator | Responses had to be confirmed by 2 separate evaluations occurring >=4 weeks apart. Duration of response 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 measurable lesions or the appearance of any new lesion. Individual lesions must be >2 cm in diameter by radiographic evaluation or >1 cm in diameter by physical examination. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Duration of Response for All Unconfirmed Clinical Complete Responders, as Assessed by the Investigator | Duration of response 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 measurable lesions or the appearance of any new lesion. Individual lesions must be >2 cm in diameter by radiographic evaluation or >1 cm in diameter by physical examination. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Median Time to Treatment Failure for All Participants | Time to treatment failure is defined as the length of time from the date of enrollment to the first incidence of treatment withdrawal, study removal, progression, and/or alternative therapy for the participant's lymphoma, or death. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Overall Survival | Overall survival is defined as the time from the treatment start date to the date of death from any cause. Time to death is the time from the dosimetric dose to the date of death. | Participants were evaluated for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Time to Disease Progression or Death for Responders, 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 for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 
| Time to Disease Progression or Death for All Participants, 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 for up to 142 months in Study 104731 or were followed in the long-term follow-up study (Study 104526) for up to 136.3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
iodine I 131 tositumomab, anti-B1 Antibody, Bexxar, radioimmunotherapy, tositumomab