Comparison Of Rituximab Versus Tositumomab and Iodine I 131 Tositumomab (BEXXAR® Therapeutic Regimen) For Patients With Relapsed Follicular Non-Hodgkins Lymphoma

Study Overview
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Brief Summary
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Comparison of rituximab versus Iodine I 131 Tositumomab Therapeutic Regimen (Tositumomab and Iodine I 131 Tositumomab or the Bexxar Therapeutic Regimen, formerly called Iodine-131 Anti-B1 Antibody) in subjects with follicular non Hodgkins B cell lymphoma. 506 subjects will be enrolled at 30 to 40 sites in the US, Canada, and Europe. Subjects will be randomly assigned to one of two treatment arms. In Arm A, subjects will receive 375 milligrams/meter2 (mg/m2 )of rituximab, given as an intravenous (IV) infusion once weekly for 4 weeks. In Arm B, subjects will undergo a two-phase treatment. In the first phase, termed the dosimetric dose, subjects will receive an infusion of unlabeled Tositumomab (450 mg) immediately followed by an infusion of 5 millicuries (mCi) (0.18 gigabecquerel [GBq]) of Iodine 131 Tositumomab (35 mg). Whole body gamma camera scans will be obtained three times (Day 0; Day 2, 3, or 4; and Day 6 or 7) following the dosimetric dose. The information derived from the scans will enable a patient specific dose to be calculated to deliver the desired total body dose of radiation (65 or 75 centigray [cGy]). In the second phase, termed the therapeutic dose, subjects in Arm B will receive an infusion of unlabeled Tositumomab (450 mg) immediately followed by an infusion of the subject specific activity of Iodine 131-conjugated Tositumomab (35 mg). Thyroid blockade will be implemented 24 hours prior to the dosimetric dose and continued for 14 days following the therapeutic dose. Subjects on study will be followed for response and safety at Week 7, Week 13, and every three months for the first and second year, every six months for the third year, and then annually for the forth and fifth years; and then for vital status, additional therapy, and long term safety events through year ten. Follow Up after subsequent NHL therapy will be carried out to assess tolerance of next anti-lymphoma therapy, development of myelodysplasia (MDS)/acute myelogenous leukemia (AML), HAMA or hypothyroidism, unexpected safety issues, and death.

Official Title
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A Multi-Center, Randomized, Phase 3 Study of Rituximab Versus Iodine I 131 Tositumomab Therapeutic Regimen For Patients With Relapsed Follicular Non-Hodgkins Lymphoma

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Biological: Tositumomab and Iodine I 131 Tositumomab
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically confirmed diagnosis of follicular lymphoma Recurrent lymphoma after one or two qualifying therapy regimen(s) Patients must not have progressed within 4 weeks of their last chemotherapy dose Rituximab may have been used once as a single agent, in one continuous course of 4-8 weekly infusions (10-week period), or in combination with chemotherapy in a single prior treatment Patients whose prior therapy includes rituximab must have had a 6 month or greater response duration following the rituximab-containing regimen. Performance status of at least 70% on the Karnofsky Scale and an anticipated survival of at least three months Adequate absolute neutrophil count and platelet count within 21 days of study entry without support of blood products/growth factors Adequate renal function and adequate hepatic within 21 days of study entry Measurable disease, with at least one lesion measuring >/=2.0 cm x 2.0 cm by CT scan Human Anti Mouse Antigen negative Written informed consent prior to study entry Exclusion criteria: Histologic transformation to diffuse, large cell lymphoma. History of more than one course of Rituximab Disease limited to single lymph node or single group of nodes Involvement of 25% of the intratrabecular marrow by bone marrow biopsy specimen. Active infection requiring IV antibiotics at the time of study entry New York Heart Association Class III/IV heart disease Prior chemotherapy, biologic, radiation or steroid therapy for NHL within 8 weeks Any prior radioimmunotherapy Prior history of malignancy other than lymphoma (except for treated basal cell, squamous cell skin cancer, in situ cervical cancer, or other cancer that is disease-free for 5 years) Known HIV infection Hepatitis B positive Known central nervous system involvement

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tositumomab and Iodine I 131 Tositumomab<br>Dosimetric dose: 450 mg Tositumomab infused over 1 hour followed by 5 mCi I 131 Tositumomab infused over 20 minutes Therapeutic dose: 450 mg Tositumomab infused over 1 hour followed by Individualized mCi activity of I 131 Tositumomab (35 mg) infused over 20 minutes. | Biological: Tositumomab and Iodine I 131 Tositumomab<br>* Dosimetric dose: 450 mg Tositumomab infused over 1 hour followed by 5 mCi I 131 Tositumomab infused over 20 minutes Therapeutic dose: 450 mg Tositumomab infused over 1 hour followed by Individualized mCi activity of I 131 Tositumomab (35 mg) infused over 20 minutes.<br>* Other names: Iodine I 131 Tositumomab;|
| Active Comparator: Rituximab<br>Rituximab 375 mg/m2 given as an IV infusion once weekly for four weeks. | Biological: Rituximab<br>* Rituximab 375 mg/m2 given as an IV infusion once weekly for four weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | Event-free survival is defined as the time from the date of randomization to the first occurrence of (whichever came first) progressive disease, death, or additional Non-Hodgkins Lymphoma (NHL) therapy due to disease-related symptoms, threatened end-organ function, cytopenias secondary to NHL, massive bulk disease, or steady progression over at least 6 months. Progressive disease is defined as at least a 50% increase in the sum of the perpendicular diameters of all measurable lesions and the appearance of new lesions at least 1.4 centimeters (cm) x 1.4 cm (i.e., 2.0 cm^2) by radiographic evaluation or greater than 1.0 cm by palpation upon physical examination. | From the date of randomization to the first occurrence of progressive disease, death, or additional Non-Hodgkins Lymphoma (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively) | 
| Progression-free Survival | Progression-free survival is defined as the time from the initial date of dosing to the first documented disease progression or death. Disease assessment was based on the International Workshop to Standardize Response Criteria (IWSRC) for Non-Hodgkin's Lymphoma (NHL). Progression is defined as at least a 50% increase in the sum of the perpendicular diameters of all measurable lesions and the appearance of new lesions at least 1.4 centimeters (cm) x 1.4 cm (i.e., 2.0 cm^2) by radiographic evaluation or greater than 1.0 cm by palpation upon physical examination. | From first dose of treatment until disease progression or death, whichever came first (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Response | Complete response (CR) is defined as the complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms (by the IWSRC) if present before therapy, and normalization of those biochemical abnormalities definitely assignable to NHL. Confirmation of response was carried out by an independent reviewer | Participants were followed for response at Week 7, Week 13, every 3 months for the first and second year, every 6 months for the third year, and then annually | 
| Duration of Response | Response duration is defined as the time from the first documented response (complete response, complete response unconfirmed, or partial response) until disease progression. Partial response is defined as at least a 50% decrease in the product of two perpendicular diameters of all measurable lesions; no increase in the size of other nodes, liver, or spleen; and no new disease sites. | Participants were followed for response at Week 7, Week 13, every 3 months for the first and second year, every 6 months for the third year, and then annually | 
| Time to Death | Time to death is defined as the time from treatment start to the date of death. As a median time to death is not presented for either group, see the outcome measure entitled Number of Participants Who Had Died by the Month Indicated for data regarding time to death. | From first dose of treatment until disease progression or death, whichever came first (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively) | 
| Number of Participants Who Had Died by the Month Indicated | The median time to death could not be calculated for participants in either treatment group; thus, data are shown as the number of participants who had died by the month indicated. | From first dose of treatment until disease progression or death, whichever came first (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively) | 
| Time to Next Treatment | Time to next treatment is defined as time from the date of randomization until the new treatment is needed for NHL. Because too few evaluable participants were enrolled/treated, analysis of the time to next treatment was not conducted as planned. | Time from study randomization to 120 days after study drug administration | 
| Hematologic Nadir for Absolute Neutrophil Count | Hematologic toxicity includes the analysis of hematologic nadir, which is defined as the lowest hematology value within 120 days of study drug administration. | Time from study randomization to 120 days after study drug administration | 
| Hematologic Nadir for Hemoglobin | Hematologic nadir is defined as the lowest hematology value within 120 days of study drug administration. | Time from study randomization to 120 days after study drug administration | 
| Hematologic Nadir for Platelet Count and White Blood Cell (WBC) Count | Hematologic nadir is defined as the lowest hematology value within 120 days of study drug administration. | Time from study randomization to 120 days after study drug administration | 
| Time to Nadir Values for the Indicated Hematological Parameters | Hematologic nadir is defined as the lowest hematology value within 120 days of study drug administration. Time to nadir is defined as the number of days from the last administration of study drug to nadir. | Time from study randomization to 120 days after study drug administration | 
| Time to Recovery to Baseline Grade for the Indicated Hematological Parameters | Hematologic nadir is defined as the lowest hematology value within 120 days of study drug administration. Time to recovery to Baseline grade is defined as the number of days from the last administration of study drug to a post-nadir hematology value of unmaintained Baseline grade or lower. | Time from study randomization to 120 days after study drug administration | 
| Duration of Grade 3/4 Toxicity for the Indicated Hematological Parameters | Duration of Grade 3/4 toxicity is defined as the time between the date of the first Grade 3/4 lab result to the first lab date with a Grade of 0, 1, or 2 result. Laboratory abnormalities will be recorded as AEs using NCI CTCAE, Version 3, if they are associated with clinical squeal and/or require an intervention. Specific AEs not listed in the NCI criteria will be graded as follows: 1. Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities, 2. Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities, 3. Severe: An event that prevents normal everyday activities, 4. Life-threatening or debilitating, and 5. Death | Time from study randomization to 120 days after study drug administration | 
| Number of Participants That Developed Hypothyroidism | Hypothyroidism is defined as elevated Thyroid-Stimulating Hormone (TSH) or current history of using thyroid medication. The frequency of hypothyroidism at study enrollment will be determined, and participants with hypothyroidism at Baseline were excluded from analysis. | From the date of randomization to the first occurrence of progressive disease, death, or additional Non-Hodgkins Lymphoma (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively) | 
| Number of Participants With an Infusion Reaction | An infusion reaction is defined as any adverse event that occured within 24 hours of an infusion. An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product | First 24 hours of study drug administration. | 
| Number of Hospitalizations | The frequency of hospitalizations within 90 days of treatment was summarized. Because too few evaluable participants were enrolled/treated, analysis of the number of hospitalizations was not conducted as planned. | Time of treatment until 90 days post-treatment | 
| Number of Participants With Myelodysplasia/Leukemia | The cumulative incidence of myelodysplasia/leukemia was estimated. | From the date of randomization to the first occurrence of progressive disease, death, or additional Non-Hodgkins Lymphoma (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively) | 
| Number of Participants With Any Serious Adverse Event (SAE) and Non-serious Adverse Event (AE) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant temporally associated with the use of a medicinal product, whether or not it is considered related to the medicinal product. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is a Grade 4 (life threatening or disabling) non-hematologic laboratory abnormality assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. | From randomization through Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rituximab, tositumomab and iodine I 131 tositumomab, non-Hodgkins lymphoma, radioimmunotherapy, anti-B1 antibody, Bexxar, NHL, Tositumomab