Study of Iodine 131 Anti B1 Antibody for 1st or 2nd Relapsed Indolent B-Cell Lymphomas or B-Cell Lymphomas That Have Transformed to a More Aggressive Histology

Study Overview
=================
Brief Summary
-----------------
This is a single-arm, open-label study of Iodine 131 Anti B1 Antibody for the treatment of 1st or 2nd relapsed indolent B cell lymphomas or B cell lymphomas that have transformed to a more aggressive histology. The primary endpoint of the study is to determine the response rate. Secondary endpoints of the study is to determine the duration of response, time to progression, time-to-treatment failure, safety, and survival. Forty patients will receive therapy on this study at the 2 clinical sites. Patients will undergo 2 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 on 1) Day 0; 2) Day 2, 3, or 4; and 3) Day 6 or 7 following the dosimetric dose. Using the dosimetric data from the 3 imaging timepoints, a patient-specific dose of Iodine 131 Anti B1 Antibody to deliver the desired total body dose of radiotherapy will be calculated. In the second phase, termed the radioimmunotherapeutic 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 35 mg Anti B1 Antibody labeled with the 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 (see Appendix A). 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 and continuing for 14 days following the last infusion of Iodine 131 Anti B1 Antibody (i.e., therapeutic dose).

Official Title
-----------------
Phase II Study of Iodine 131 Anti B1 Antibody for 1st or 2nd Relapsed Indolent B-Cell Lymphomas or B-Cell Lymphomas That Have Transformed to a More Aggressive Histology

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

Intervention / Treatment
-----------------
* Biological: tositumomab and Iodine I 131 tositumomab (anti-B1 antibody)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have a histologically-confirmed diagnosis of B-cell CLL/PLL/SLL; lymphoplasmacytic - immunocytoma; follicle center, follicular, grade I; or follicle center, follicular, grade II NHLs or one of these B-cell lymphomas which has transformed to a more aggressive histology (37). 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 (>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 received 1 or 2 prior chemotherapy regimens and have progressed following their last regimen. Patients who have received >2 prior chemotherapy regimens are excluded. Prior therapy with radiation, immunosuppressants, or steroids are not counted as chemotherapy regimens. Patients must have a performance status of at least 60% on the Karnofsky Scale (see Appendix B) and an anticipated survival of at least 3 months. Patients must have an absolute granulocyte count >1,500 x 109/l and a platelet count >100,000 x 109/l 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 upper limit of normal) and hepatic function (defined as total bilirubin <1.5 upper limit of normal and hepatic transaminases [AST + ALT] <5 x upper limit of normal) within 14 days of study entry. Patients must have bi-dimensionally measurable disease. At least one lesion must be >/=2cm x 2 cm (by CT scan). Patients must be at least 18 years of age. Patients must give written informed consent and sign an 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%. The procedure for bilateral bone marrow biopsy analysis of marrow involvement is included in Appendix C. Patients who have received cytotoxic chemotherapy, radiation therapy, or cytokine treatment within 4 weeks prior to study entry (6 weeks for nitrosourea compounds) or who exhibit persistent clinical evidence of toxicity. The use of systemic steroids must be discontinued one 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 IV antibiotics at the time of study entry. Patients with New York Heart Association class III or IV heart disease (see Appendix D) 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 who have been disease-free of another cancer for greater than 5 years must be carefully assessed at the time of study entry to rule out recurrent disease. Patients with known HIV infection. Patients with known brain or leptomeningeal metastases. Patients who are pregnant or breast-feeding. Patients of child-bearing potential must undergo a serum pregnancy test within 7 days prior to 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 treatment. 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 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 concurrently receiving either approved or non-approved (through another protocol) anti-cancer drugs or biologics. Patients who have received more than 2 prior chemotherapy regimens. Prior therapy with radiation, immunosuppressants, or steroids are not counted as chemotherapy regimens.

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 (anti-B1 antibody)<br>In the first phase (dosimetric dose) patients will receive an infusion of unlabeled Anti B1 Antibody (450 mg) followed by an infusion 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 following the dosimetric dose. Using the dosimetric data, a patient-specific dose of Iodine 131 Anti B1 Antibody to deliver the desired total body dose of radiotherapy will be calculated. In the second phase, (radioimmunotherapeutic dose), patients will receive an infusion of unlabeled Anti B1 Antibody (450 mg) followed by an infusion of 35 mg Anti B1 Antibody labeled with the patient-specific dose of Iodine 131 to deliver a whole body dose of 75 cGy. Patients will be treated with saturated solution potassium iodide, Lugol's solution, or potassium iodide tablets starting at least 24 hours prior to the first infusion and continuing for 14 days following the last infusion of Iodine 131 Anti B1 Antibody. | Biological: tositumomab and Iodine I 131 tositumomab (anti-B1 antibody)<br>* For the treatment of 1st or 2nd relapsed indolent B cell lymphomas or B cell lymphomas that have transformed to a more aggressive histology<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants (Par.) With Response 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). | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Number of Participants 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). | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Number of Participants With Confirmed Complete Response (CR) as Assessed by the Investigator | Responses had to be confirmed by 2 separate evaluations occurring >=4 weeks apart. 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Number of Participants With Confirmed Complete Response Plus Clinical Complete Response (CR + CCR) as Assessed by the Investigator | Responses had to be confirmed by 2 separate evaluations occurring >4 weeks apart. 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 (EOD) must be unchanged or decreased upon follow-up evaluations. If the EOD was unchanged or if further decreases occurred for >=6 months, the participant was reclassified as having a CR. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Number of Participants With Confirmed Partial Response (PR) as Assessed by the Investigator | Responses had to be confirmed by 2 separate evaluations occurring >=4 weeks apart. Confirmed PR is defined as a >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, with no new lesions. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Time to Progression of Disease or Death as Assessed by the Investigator | Time to progression or progression-free survival is defined as the time from the dosimetric dose to the first documented occurrence of disease progression or death. 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. New lesions must be greater than 2 x 2 centimeters (cm) in diameter by radiographic evaluation or greater than 1 cm in diameter by physical examination. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Time to Treatment Failure as Assessed by the Investigator | 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Overall Survival | Overall survival is defined as the time from the treatment start date to the date of death from any cause. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| 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 AE 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Number of Participants With the Indicated 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Nadir Values for Hematologic Parameters ANC, Platelets, and WBC Count | 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 WBC that fights against infection. Platelets and WBCs are types of blood cells. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| 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. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Number of Participants Who Became Positive or Negative for Human Anti-murine Antibody (HAMA) After Study Treatment | Tositumomab is a murine (mouse) antibody. Participants in this study were evaluated to determine if they developed a human anti-murine antibody (HAMA) immune response after administration of tositumomab and iodine I 131 tositumomab. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Time to HAMA Positivity From First Dosimetric Dose | Time to HAMA positivity is defined as the time from the first dosimetric dose to the first reported HAMA-positive result for the participant. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Number of Participants in the Indicated Categories of Thyroid Function Assessment | Hypothyroidism, a condition in which the thyroid gland does not produce enough thyroid hormone (resulting in the elevation of thyroid stimulating hormone [TSH] in the blood), may result from treatment with radioactive iodine I 131. A thyroid blockade medication was given prior to administration of the study drug and up to 2 weeks after the therapeutic dose to prevent the uptake of I 131 in the thyroid gland. Thyroid function was determined periodically, including during follow-up, in order to assess if there was any effect of the I 131 on thyroid function, such as hypothyroidism. | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. | 
| Number of Days Each Participant Took to Reach Hypothyroidism After the First Dosimetric Dose | Hypothyroidism is a condition in which the thyroid gland does not produce enough thyroid hormone (resulting in the elevation of thyroid stimulating hormone [TSH] in the blood). | Par. were evaluated until death/disease progression or 2 years in Study BEX104505. Par. who completed 2 years in BEX104505 were followed in study BEX104528 for up to 125 months. Data are included from both Study BEX104505 and Study BEX104528. |