Study of Radiolabeled Monoclonal Antibody Anti-B1 for the... | NCT01536561

Description Module

Brief Summary

Phase I/II, single-center, dose-escalation study of the safety, pharmacokinetics, dosimetry, and efficacy of TST/I-131 TST for the treatment of patients with chemotherapy-refractory or resistant low-grade, intermediate-grade, or high-grade B-cell lymphoma. Subjects received 1 to 3 dosimetric doses followed by a therapeutic dose of TST/I-131 TST. Study BEX104526 was a follow-up study of the long-term safety and efficacy data from the surviving patients who completed at least 2 years of follow-up following administration of TST/I 131 TST on Study BEX104728.

Dosimetric dose: Subjects received 1 to 3 dosimetric doses of TST/I-131 TST, followed by a therapeutic dose of TST/I-131 TST. Subjects received various doses of unlabeled TST (0, 95 or 475 mg) to determine the dose of unlabeled TST that optimized the radiation dose delivered to the tumor by TST/I-131 TST. The unlabeled TST was followed by 5 milliCurie (mCi) of I-131 TST. Serial whole body sodium iodide scintillation probe counts were obtained daily, for at least 5 days, in order to determine the rate of whole body clearance of radioactivity (residence time). The residence time was used to determine the radioactive clearance for the subject and the activity (in mCi) of I-131 required to deliver the desired TBD of radiation during the therapeutic dose. Because 475 mg was determined to be the optimal pre-dose of TST in the first subjects entered, the last 34 subjects received a single dosimetric dose that was preceded by an infusion of 475 mg of TST.

Therapeutic dose: Groups of 3-6 subjects were enrolled at successively higher whole-body radiation dose levels beginning at a total body dose (TBD) of 25 centiGray (cGy). The TBD of each subsequent dose level was escalated by 10 cGy. Subjects who had undergone bone marrow transplantation (BMT) underwent a separate dose escalation (10 cGy TBD increase per dose level) beginning at a TBD level of 65 cGy. The MTD was defined as the highest dose level at which 0/3 or 1/6 subjects experienced dose-limiting toxicity (DLT). DLT was defined as follows:

Any Grade 4 hematologic toxicity (National Cancer Institute [NCI] criteria) lasting greater than 7 days, or Any Grade 3 hematologic toxicity lasting greater than 2 weeks, or Any Grade 3 or 4 nonhematologic toxicity Redosing. Subjects who achieved tumor regression were considered for re-dosing, using the original therapeutic dose of TST/I-131 TST, at the time the tumor was no longer shrinking in an attempt to upgrade their response.

Retreatment. Subjects who achieved partial (PR) or complete response (CR) were considered for retreatment following relapse of their NHL, if progression occurred ≥6 weeks following the therapeutic dose. The original therapeutic dose of TST/I-131 TST was given unless a grade 2 or greater toxicity had been encountered, in which case a reduced dose was administered for the repeat therapeutic dose.

Detailed Description

DLT was defined as follows:

Any Grade 4 hematologic toxicity (National Cancer Institute [NCI] criteria) lasting greater than 7 days, or Any Grade 3 hematologic toxicity lasting greater than 2 weeks, or Any Grade 3 or 4 nonhematologic toxicity Redosing: Subjects who achieved tumor regression were considered for re-dosing, using the original therapeutic dose of TST/I-131 TST, at the time the tumor was no longer shrinking in an attempt to upgrade their response.

Retreatment: Subjects who achieved a partial response (PR) or complete response (CR) were considered for retreatment following relapse of their NHL, if progression occurred ≥6 weeks following the therapeutic dose. The original therapeutic dose of TST/I-131 TST was given unless a grade 2 or greater toxicity had been encountered, in which case a reduced dose was administered for the repeat therapeutic dose.

Subjects who completed at least 2 years of follow-up in BEX104728 were enrolled in LTFU Study BEX104526 for continued radiographic response evaluations and safety evaluations every 6 months for years 3 through 5 post-treatment and annually for years 6 through 10 post-treatment. Subjects in BEX104526 were assessed for survival and disease status, including subsequent therapy for NHL, and for long-term safety, including the development of hypothyroidism, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and any other secondary malignancies. Additionally, subjects were followed for the development of any adverse event(s) (AEs) deemed by the Principal Investigator as being possibly or probably related to a subject's treatment with TST/I-131 TST. Laboratory evaluations, consisting of thyroid stimulating hormone (TSH) level and complete blood cell count with a differential and platelet count, were obtained annually through year 10 post-treatment.

Study assessments included demographic and baseline characteristics; tumor response, duration of response, survival (progression-free survival [PFS] and overall survival [OS]), adverse events (AEs), incidence of human anti-murine antibody (HAMA), incidence of hypothyroidism, and serious (fatal and non-fatal) adverse events (SAEs).

Dosing;"Dosimetric Doses", Intravenous (IV) administration of unlabeled TST (0, 95 or 475 mg) was administered to determine the dose of unlabeled TST that optimized the radiation dose to the tumor. This was followed by 5 mCi of I-131 TST. Serial whole body sodium iodide scintillation probe counts were obtained daily, for at least 5 days, in order to determine the rate of whole body clearance of radioactivity (residence time). The residence time was used to determine the radioactive clearance from the subject and subsequently the activity (in mCi) of Iodine-131 required to deliver the desired TBD of radiation during the therapeutic dose of TST/I-131 TST. Because 475 mg was determined to be the optimal pre-dose of tositumomab in the first subjects entered, the last 34 subjects received a single dosimetric dose that was preceded by an infusion of 475 mg of tositumomab (Source Data: Listing 13).

"Therapeutic Dose", Groups of 3-6 subjects were treated at successively higher therapeutic whole body radiation doses, beginning at a TBD of 25 cGy. The TBD was escalated in 10 cGy increments in subsequent dose level cohorts until the MTD was achieved. A separate determination of MTD was conducted for subjects who had undergone prior BMT. This was initiated at a TBD of 65 cGy TBD and increased in 10 cGy increments until determination of the MTD. The MTD was defined as the dose at which fewer than 1/3 or 2/6 subjects experienced DLT, i.e. any Grade 4 hematologic toxicity (absolute neutrophil count [ANC], platelets, hemoglobin, white blood count [WBC] lasting > 7 days or any Grade 3 hematologic toxicity lasting > 14 days, as defined in Section 4.1.

Re-Dosing; Subjects who achieved tumor regression were considered for re-dosing, using the original therapeutic dose of TST/I-131 TST, at the time the tumor was no longer shrinking in an attempt to upgrade their response. Patients were not redosed sooner than 6 weeks following a therapeutic dose.

Retreatment (≥6 weeks following therapeutic dose); Subjects who achieved a PR or CR were considered for retreatment following relapse of their NHL. The original therapeutic dose of TST/I-131 TST was given unless a Grade 2 or greater toxicity had been encountered, in which case the dose level immediately below the original dose was administered.

Label	Type	Description	Intervention Names
open-label, dose escalation	Experimental	Each subject will undergo two phases of study. The first phase, termed "tracer Study", involves the injection of low-radioactivity doses (about 5 mCi) of 131-I anti-B1 for the purposes of determining the rate of whole body clearance of radiation so that a whole body radiation can be calculated. The calculated whole-body radiation dose per mCi administered can then be used to determined how many mCi will be required to deliver a specified whole-body radiation dose in the second phase of the study for each patient, termed radio-immunotherapy dose in a tracer-projected whole-body radiation dose will be used for dose escalation with a minimum of three subjects per dose level.	Biological: Radiolabeled Monoclonal Antibody Anti-B1 for the Treatment of B-Cell Lymphomas (Tositumomab and Iodine I 131 Tositumomab)

Name	Type	Description	Arm Group Labels	Other Names
Radiolabeled Monoclonal Antibody Anti-B1 for the Treatment of B-Cell Lymphomas (Tositumomab and Iodine I 131 Tositumomab)	Biological	131-I anti-B1 is the product of 131-I labeling of the anti-CD20 murine monoclonal antibody and the anti-B1 antibody itself is an intact IgG2a murine monoclonal antibody which has specificity far the CD20 antigen on human B cells. Anti-B1 is a clear, colorless liquid. 131-I labeling of the anti-B1 antibody will be carried out by iodogen technique. Trace labeling of the antibody will involve the labeling of approximately 1 to 3 mg of antibody with 5 mCi of 131-I.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants (Par.) During Initial Treatment Exposed to the Indicated Dose Levels of the Therapeutic Dose (TD), Re-dose, and Total Dose (TD + Re-dose)	Par. (groups of 3-6) received the TD at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (par. who had bone marrow transplantation), increasing by 10 cGy increments at each dose level, until the maximum tolerated dose (MTD) was achieved. The MTD was defined as the highest dose level at which 0/3 or 1/6 par. experienced dose-limiting toxicity (DLT): any Grade 4 hematologic toxicity (National Cancer Institute criteria) lasting >7 days, any Grade 3 hematologic toxicity lasting >2 weeks, or any Grade 3/4 nonhematologic toxicity. Not Applicable (NA) indicates that no par. were re-dosed.	Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
Number of Participants During Retreatment Exposed to the Indicated Dose Levels of the TD, Re-dose, and Total Dose (TD + Re-dose)	Retreatment was administered to participants either at the initial TD of TST/I 131 TST or at a reduced dose if a >=Grade 2 toxicity had occurred after initial treatment, until the MTD was achieved. The MTD was defined as the highest dose level at which 0/3 or 1/6 participants experienced DLT: any Grade 4 hematologic toxicity (National Cancer Institute criteria) lasting >7 days, any Grade 3 hematologic toxicity lasting >2 weeks, or any Grade 3/4 nonhematologic toxicity. Not Applicable (NA) indicates that no participants were re-dosed.	Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
Maximum Tolerated Dose (MTD) of TST/I 131 TST Evaluated in the Study	Participants who had prior bone marrow transplantation (BMT) initiated TD at 65 cGy TBD, whereas those who had no prior BMT initiated TD at 25 cGy TBD. The MTD was defined as the highest dose level at which 0/3 or 1/6 par. experienced DLT: any Grade 4 hematologic toxicity (National Cancer Institute criteria) lasting >7 days, any Grade 3 hematologic toxicity lasting >2 weeks, or any Grade 3/4 nonhematologic toxicity. Not Applicable (NA) indicates that no par. were re-dosed.

Secondary Outcomes

Measure	Description	Time Frame
Tumor/Organ Dosimetry at the Indicated Predoses of 475 mg, 95 mg, and 0 mg (Initial Treatment)	The effect of unlabeled TST pre-treatment on targeting of radioactive TST was evaluated. Serial whole body sodium iodide scintillation probe counts were obtained from participants approximately 1 hour after the administration of the dosimetric dose (DD) and then daily for at least 5 days. Initially, participants received either two or three DDs, each of which was preceded by a pre-dose of unlabeled tositumomab (0, 95, or 475 mg) to determine the dose of unlabeled tositumomab that optimized the radiation dose to tumor. The tumor radiation absorbed dose was determined using gamma camera images.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

PubMed Identifier	Type	Citation	Retractions
10942366	Background	Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M, Regan D, Fisher S, Gutierrez J, Kroll S, Stagg R, Tidmarsh G, Wahl RL. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood. 2000 Aug 15;96(4):1259-66.

Label	URL
Results for study 104728 can be found on the GSK Clinical Study Register.	View source

ID	Type	URL	Comment
104728	Clinical Study Report	View IPD

ID	Title	Description
FG000	TST and Iodine I 131 TST	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

ID	Title	Description
BG000	TST and Iodine I 131 TST	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Units	Counts
Participants	BG00059

Type

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Description

Population Description

Reporting Status

Anticipated Posting Date

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Dispersion Type

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Calculate Percentage

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Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants (Par.) During Initial Treatment Exposed to the Indicated Dose Levels of the Therapeutic Dose (TD), Re-dose, and Total Dose (TD + Re-dose)

Par. (groups of 3-6) received the TD at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (par. who had bone marrow transplantation), increasing by 10 cGy increments at each dose level, until the maximum tolerated dose (MTD) was achieved. The MTD was defined as the highest dose level at which 0/3 or 1/6 par. experienced dose-limiting toxicity (DLT): any Grade 4 hematologic toxicity (National Cancer Institute criteria) lasting >7 days, any Grade 3 hematologic toxicity lasting >2 weeks, or any Grade 3/4 nonhematologic toxicity. Not Applicable (NA) indicates that no par. were re-dosed.

Intent-to-Treat (ITT) Exposed Population: all participants who were enrolled into the study and received at least one dose of study drug.

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Number

participants

Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Units	Counts
Participants	OG00059

Title

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TD=0cGy+Re-dose=NA; Total=0cGy

Title	Measurements
	OG0006

TD=25cGy+Re-dose=NA; Total=25cGy

Title	Measurements
	OG0001

TD=25cGy+Re-dose=25cGy; Total=50cGy

Primary

Number of Participants During Retreatment Exposed to the Indicated Dose Levels of the TD, Re-dose, and Total Dose (TD + Re-dose)

Retreatment was administered to participants either at the initial TD of TST/I 131 TST or at a reduced dose if a >=Grade 2 toxicity had occurred after initial treatment, until the MTD was achieved. The MTD was defined as the highest dose level at which 0/3 or 1/6 participants experienced DLT: any Grade 4 hematologic toxicity (National Cancer Institute criteria) lasting >7 days, any Grade 3 hematologic toxicity lasting >2 weeks, or any Grade 3/4 nonhematologic toxicity. Not Applicable (NA) indicates that no participants were re-dosed.

ITT Exposed Population

Posted

Number

participants

ID	Title	Description
OG000	TST and Iodine I 131 TST: Retreatment	After the "Initial Treatment" (DD of TST and Iodine I 131 TST, followed by TD), participants who achieved a partial response (PR:>=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions) or complete response (CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease) and subsequently developed progressive disease were retreated at the time of disease progression. Retreatment was administered either at the initial TD of TST/I 131 TST or at a reduced dose if a Grade 2 or greater toxicity had occurred after the "Initial Treatment." Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the LTFU study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Primary

Maximum Tolerated Dose (MTD) of TST/I 131 TST Evaluated in the Study

Participants who had prior bone marrow transplantation (BMT) initiated TD at 65 cGy TBD, whereas those who had no prior BMT initiated TD at 25 cGy TBD. The MTD was defined as the highest dose level at which 0/3 or 1/6 par. experienced DLT: any Grade 4 hematologic toxicity (National Cancer Institute criteria) lasting >7 days, any Grade 3 hematologic toxicity lasting >2 weeks, or any Grade 3/4 nonhematologic toxicity. Not Applicable (NA) indicates that no par. were re-dosed.

ITT Exposed Population

Posted

Number

Total body radiation dose in cGy

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Primary

Tumor/Organ Dosimetry of TST/I 131 TST for All Predoses (Initial Treatment)

Serial whole body sodium iodide scintillation probe counts were obtained from participants approximately 1 hour after the administration of the dosimetric dose and then daily for at least 5 days. 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). Spleen volume may vary based on disease status, and volume correction allows for a comparison of spleen dose across participants.

ITT Exposed Population. Of the 59 participants analyzed, 23 received 2 or 3 dosimetric doses (DD); tumor/organ dosimetry was calculated for all 86 DD. The "n" in the category title reflects the number of DD, which will differ for each target organ depending on whether adequate gamma camera images were available for analysis after each of the 86 DD.

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Mean

Standard Deviation

cGy/75 cGy TBD

Serial anterior and posterior gamma whole body scans were obtained 1 hour after the administration of the dosimetric dose (on Day 0), and then daily for at least 5 days until Day 7

dosimetric doses

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Tumor/Organ Dosimetry at the Indicated Predoses of 475 mg, 95 mg, and 0 mg (Initial Treatment)

The effect of unlabeled TST pre-treatment on targeting of radioactive TST was evaluated. Serial whole body sodium iodide scintillation probe counts were obtained from participants approximately 1 hour after the administration of the dosimetric dose (DD) and then daily for at least 5 days. Initially, participants received either two or three DDs, each of which was preceded by a pre-dose of unlabeled tositumomab (0, 95, or 475 mg) to determine the dose of unlabeled tositumomab that optimized the radiation dose to tumor. The tumor radiation absorbed dose was determined using gamma camera images.

ITT Exposed Population. Participants who received unlabelled doses of 0 mg, 95 mg, or 475 mg were analyzed. Of the 59 participants analyzed, 23 received 2 or 3 dosimetric doses (DD); tumor/organ dosimetry was calculated for all 86 DD. The "n" in the category title reflects the number of DD, which will differ for each target organ.

Posted

Mean

Standard Deviation

cGy/75 cGy TBD

Serial anterior and posterior gamma whole body scans were obtained 1 hour after the administration of the dosimetric dose (on Day 0), and then daily for at least 5 days until Day 7

dosimetric doses

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Number of Participants (Par.) With the Indicated 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).

ITT Exposed Population. Only those participants evaluable for response were analyzed.

Posted

Number

participants

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

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).

ITT Exposed Population. Only those participants evaluable for confirmed response were analyzed.

Posted

Number

participants

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

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.

ITT Exposed Population. Only those participants with unconfirmed response (CR, CCR, or PR) and those who experienced progressive disease were analyzed.

Posted

Median

95% Confidence Interval

months

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Time to Progression of Disease or Death

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.

ITT Exposed Population. Only those participants who experienced progression were evaluated.

Posted

Median

95% Confidence Interval

months

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.
OG001

Secondary

Overall Survival

Overall survival is defined as the time from the treatment start date to the date of death from any cause.

ITT Exposed Population. Only those participants who died during the study and during the follow-up period were analyzed.

Posted

Median

95% Confidence Interval

months

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.
OG001	TST and Iodine I 131 TST: Retreatment

Secondary

Half-life: Initial Half-life (t1/2 Alpha) and Terminal Half-life (t1/2 Beta) of I 131 TST for the Antibody Predose Levels of 0 mg, 95 mg, and 475 mg

t1/2 alpha is the estimated initial or alpha phase half-life in a two-compartmental pharmacokinetic model . t1/2 beta is the estimated terminal or beta phase half-life in a two-compartmental pharmacokinetic model; also denoted as t1/2. Half-life measures how long it takes for the concentration of drug in the blood to decrease by half.

ITT Exposed Population. The sample size ("n") in the category titles is the number of infusions (dosing occasions) with parameter results.

Posted

Mean

Standard Deviation

hours (hr)

Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion.

infusions

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Clearance (CL) of I 131 TST for the Indicated Antibody Predose Levels

Clearance is defined as the volume of blood from which drug is removed per unit time and is a measure of the rate at which drug is removed from the body after the dose.

ITT Exposed Population. The sample size ("n") in the category titles is the number of infusions (dosing occasions) with parameter results.

Posted

Mean

Standard Deviation

Milliliters per hour (mL/hr)

Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion.

infusions

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Area Under the Concentration Time Curve (AUC) of I 131 TST for the Indicated Antibody Predose Levels

Area under the concentration-time curve from the end of the infusion extrapolated to infinite time. AUC measures how much drug is in the system over time after infusion. ID, injected dose.

ITT Exposed Population. The sample size ("n") in the category titles is the number of infusions (dosing occasions) with parameter results.

Posted

Mean

Standard Deviation

%ID * hours per milliliter (%ID.hr/mL)

Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion.

infusions

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Maximum Blood Concentration (Cmax) of I 131 TST for the Indicated Antibody Predose Levels

Cmax is defined as the maximum observed concentration of the drug in blood.

ITT Exposed Population. The sample size ("n") in the category titles is the number of infusions (dosing occasions) with parameter results.

Posted

Mean

Standard Deviation

% Injected Dose per milliliter (%ID/mL)

Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion

infusions

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Volume of Distribution at Steady State (Vss) of I 131 TST for the Indicated Antibody Predose Levels

Vss is defined as the volume of distribution of the drug at steady state.

ITT Exposed Population. The sample size ("n") in the category titles is the number of infusions (dosing occasions) with parameter results.

Posted

Mean

Standard Deviation

liters

Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion

infusions

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Number of Participants Who Developed Human Anti-mouse Antibodies (HAMA Postivitiy) After Receiving Tositumomab

Tositumomab is a murine (mouse) antibody (immunoglobulin) of the IgG2a subclass. Participants in this study 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 human anti-mouse antibodies above the HAMA assay threshold, and a negative HAMA value indicates either the absence or a below threshold level of human anti-mouse antibodies.

ITT Exposed Population. Only those participants evaluable for HAMA were analyzed.

Posted

Number

participants

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Time to HAMA Positivity From the First Dosimetric Dose (Time From Baseline [Dosimetric Dose] to the First Reported Presence of HAMA)

ITT Exposed Population. Participants who converted to HAMA positivity were analyzed.

Posted

Median

Full Range

days

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

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.

ITT Exposed Population

Posted

Number

participants

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Time to Nadir for the Indicated Hematologic Laboratory Parameters

Nadir is defined as the lowest laboratory value recorded following the administration of the study medication.

ITT Exposed Population. Only those participants for which nadir could be calculated were analyzed. Some participants did not have post-baseline data available.

Posted

Median

Full Range

days

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Time to Recovery to Baseline for the Indicated Hematologic Laboratory Parameters

Time to recovery to baseline is the time required for recovery from nadir values to baseline values.

ITT Exposed Population. Only those participants for which nadir could be calculated were analyzed. Some participants did not have post-baseline data available.

Posted

Median

95% Confidence Interval

days

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

Nadir Values for the 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.

ITT Exposed Population. Only those participants for which nadir could be calculated were analyzed. Some participants did not have post-baseline data available.

Posted

Median

Full Range

1000 cells/millimeters cubed (mm^3)

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.

Secondary

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.

ITT Exposed Population

Posted

Median

Full Range

G/dL

ID	Title	Description
OG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.
OG001

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Myelodysplastic Syndrome	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0005 affected59 at risk EG0015 affected14 at risk
Acute Myeloid Leukemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0003 affected59 at risk EG0010 affected14 at risk
Bladder Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0011 affected14 at risk
Squamous Cell Carcinoma of Skin	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0011 affected14 at risk
Anal Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0011 affected14 at risk
Carcinoid Tumour Pulmonary	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Hemangioma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Lip and/or Oral Cavity Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Renal Cell Carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Serum Sickness	Immune system disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Anaphylactic Reaction	Immune system disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Anaphylactoid Reaction	Immune system disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Anemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0003 affected59 at risk EG0010 affected14 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0003 affected59 at risk EG0010 affected14 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Febrile Neutropenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Hemophilus Infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Sepsis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0011 affected14 at risk
Pneumonia Streptococcal	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Staphylococcal Sepsis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Pyrexia	General disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Fatigue	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Necrotising Panniculitis	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Pyrexia	General disorders	MedDRA	Systematic Assessment	EG00031 affected59 at risk EG0015 affected14 at risk
Fatigue	General disorders	MedDRA	Systematic Assessment	EG00020 affected59 at risk EG0013 affected14 at risk
Chills	General disorders	MedDRA	Systematic Assessment	EG00017 affected59 at risk EG0014 affected14 at risk
Pain	General disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Asthenia	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0011 affected14 at risk
Axillary Pain	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Catheter Site Rash	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Chest Pain	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Ill-Defined Disorder	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Infusion Site Inflammation	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Infusion Site Phlebitis	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Medical Device Complication	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Mucous Membrane Disorder	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Oedema Peripheral	General disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Nausea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00020 affected59 at risk EG0017 affected14 at risk
Vomiting	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0008 affected59 at risk EG0011 affected14 at risk
Diarrhea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0006 affected59 at risk EG0011 affected14 at risk
Constipation	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0003 affected59 at risk EG0010 affected14 at risk
Gastritis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0003 affected59 at risk EG0010 affected14 at risk
Abdominal Discomfort	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0011 affected14 at risk
Abdominal Pain	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Abdominal Pain Upper	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Diarrhea Hemorrhagic	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Fecal Incontinence	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Paraesthesia Oral	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
White Blood Cells < 2000 cells/cm^3	Investigations	MedDRA	Systematic Assessment	EG00022 affected59 at risk EG0014 affected14 at risk
Absolute Neutrophil Count <1000 cells/cm^3	Investigations	MedDRA	Systematic Assessment	EG00021 affected59 at risk EG0016 affected14 at risk
Platelets <50000 cells/cm^3	Investigations	MedDRA	Systematic Assessment	EG00018 affected59 at risk EG0013 affected14 at risk
Hemoglobin <8.0 g/dL	Investigations	MedDRA	Systematic Assessment	EG00011 affected59 at risk EG0012 affected14 at risk
Upper Respiratory Tract Infection	Infections and infestations	MedDRA	Systematic Assessment	EG0006 affected59 at risk EG0011 affected14 at risk
Urinary Tract Infection	Infections and infestations	MedDRA	Systematic Assessment	EG0005 affected59 at risk EG0011 affected14 at risk
Nasopharyngitis	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Respiratory Tract Infection	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Sinusitis	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Device related infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Eye infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Herpes Virus Infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Herpes Zoster	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Infusion Site Cellulitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Pneumonia	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Postoperative Wound Infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Vestibular Neuronitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Viral infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Viral Upper Respiratory Tract Infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Urticaria	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0008 affected59 at risk EG0011 affected14 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0006 affected59 at risk EG0011 affected14 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0005 affected59 at risk EG0010 affected14 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0005 affected59 at risk EG0012 affected14 at risk
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Night sweats	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Skin Irritation	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00010 affected59 at risk EG0012 affected14 at risk
Muscle Spasms	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0012 affected14 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0007 affected59 at risk EG0011 affected14 at risk
Pain in Extremity	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0004 affected59 at risk EG0011 affected14 at risk
Musculoskeletal Discomfort	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Musculoskeletal Pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Arthropathy	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Flank Pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Muscular Weakness	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Musculoskeletal Stiffness	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Headache	Nervous system disorders	MedDRA	Systematic Assessment	EG0006 affected59 at risk EG0013 affected14 at risk
Dizziness	Nervous system disorders	MedDRA	Systematic Assessment	EG0005 affected59 at risk EG0010 affected14 at risk
Hypoaesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Sciatica	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Oropharyngeal Pain	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0005 affected59 at risk EG0011 affected14 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0003 affected59 at risk EG0010 affected14 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0011 affected14 at risk
Dyspnea	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Dyspnoea Exertional	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Nasal Congestion	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Nasal Dryness	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Nasal Ulcer	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Tachypnea	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Throat Irritation	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Hypothyroidism	Endocrine disorders	MedDRA	Systematic Assessment	EG0007 affected59 at risk EG0013 affected14 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0003 affected59 at risk EG0010 affected14 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Pancytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Conjunctivitis	Eye disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Diplopia	Eye disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Eye Irritation	Eye disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Photophobia	Eye disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Decreased Appetite	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0004 affected59 at risk EG0011 affected14 at risk
Oliguria	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Ureteric Obstruction	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Urinary Incontinence	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Urinary Retention	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0011 affected14 at risk
Bladder Pain	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0011 affected14 at risk
Flushing	Vascular disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Hypotension	Vascular disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Serum Sickness	Immune system disorders	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Weight Decreased	Investigations	MedDRA	Systematic Assessment	EG0002 affected59 at risk EG0010 affected14 at risk
Disorientation	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Nightmare	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Sinus Tachycardia	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0011 affected14 at risk
Angina Pectoris	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0010 affected14 at risk
Vertigo	Ear and labyrinth disorders	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Laceration	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected59 at risk EG0010 affected14 at risk
Ear Discomfort	Ear and labyrinth disorders	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0011 affected14 at risk
Ear Injury	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0011 affected14 at risk
Liver Function Test Abnormal	Investigations	MedDRA	Systematic Assessment	EG0000 affected59 at risk EG0011 affected14 at risk

ID	Term
D008228	Lymphoma, Non-Hodgkin
D016393	Lymphoma, B-Cell

ID	Term
D008223	Lymphoma
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D008232	Lymphoproliferative Disorders
D008206	Lymphatic Diseases
D006425	Hemic and Lymphatic Diseases
D007160	Immunoproliferative Disorders
D007154	Immune System Diseases

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	TST and Iodine I 131 TST: Initial Treatment	Participants received 1 to 3 dosimetric doses (DD) consisting of 0, 95, or 475 milligrams (mg) of tositumomab (TST) intravenously (IV) followed by 5.0 millicurie (mCi) of Iodine (I 131) TST IV. This was followed by a therapeutic dose (TD) administered 7-14 days after the DD, starting at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (only for participants who had undergone bone marrow transplantation) with increments of 10 cGy at each dose level (DL) until the maximum tolerated dose (MTD) was achieved. Participants were re-dosed with a second TD when their tumor stopped regressing (was no longer shrinking). Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the Long-Term Follow-Up (LTFU) study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.			17	59	55	59
EG001	TST and Iodine I 131 TST: Retreatment	After the "Initial Treatment" (DD of TST and Iodine I 131 TST, followed by TD), participants who achieved a partial response (PR:>=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions) or complete response (CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease) and subsequently developed progressive disease were retreated at the time of disease progression. Retreatment was administered either at the initial TD of TST/I 131 TST or at a reduced dose if a Grade 2 or greater toxicity had occurred after the "Initial Treatment." Participants who had completed at least 2 years of follow-up after administration of TST/I 131 TST during the TD phase and had signed the informed consent to participate in the LTFU study (BEX104526) were followed for up to 10 years. Participants did not receive any study medication during the LTFU study.			7	14	12	14