GSK Clinical Study Register

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1 In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register. The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all named persons associated with the study Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered

2 CONFIDENTIAL UM2009/00281/00 The GlaxoSmithKline group of companies BEX (RIT-II-001) Division: Worldwide Development Information Type: Clinical Study Report Control: Dose-response-without-placebo Title: Phase: Multicenter, Phase II Dosimetry/Validation Study of 131 Iodine Anti-B1 (Murine) Radioimmunotherapy for Chemotherapy- Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas That Have Transformed to Higher Grade Histologies II Compound Number: SB Effective Date: 17 September 2010 Subject: Dosimetry methodology, efficacy, patient-specific radiation doses and safety. Author(s): Indication Studied: Follicular or transformed follicular non-hodgkin s lymphoma Initiation Date: 5 December 1995 Completion Date: 29 May 2008 Date of Report: 18 July 2010 Earlier CSRs 24 December March 2000 Sponsor Signatory: (and Medical Officer) M.D., Ph.D. Director Clinical Development Oncology Research and Development GlaxoSmithKline 1250 South Collegeville Road Collegeville, PA This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents. Copyright 2010 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1

3 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) TABLE OF CONTENTS PAGE ABBREVIATIONS... 6 ETHICS AND GOOD CLINICAL PRACTICE INTRODUCTION Tositumomab BEXXAR Therapeutic Regimen Dosimetric Dose Therapeutic Dose Pharmacokinetics Maximum Tolerated Dose Maximum tolerated non-myeloablative dose No Prior Bone Marrow Transplant Bone Marrow Transplant Maximum tolerated myeloablative dose Total Body Residence Time Scintillation probe and gamma camera STUDY OBJECTIVE(S) INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE INVESTIGATIONAL PLAN Study Design Discussion of Study Design Protocol Amendment(s) Selection of Study Population Inclusion/Exclusion Criteria Inclusion Criteria Exclusion Criteria Treatments Investigational Products Study Assessments and Procedures Safety Assessments Data Management Dosimetry Analysis Original Dosimetry Analysis Current Dosimetry Analysis Prescribed Activity Statistical Analyses Biodistribution Assessments Management of gamma camera scans Biodistribution assessments (Days 0 to 7) Biodistribution criteria STUDY POPULATION RESULTS Disposition of Subjects

4 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 5.2. Populations Analyzed Demographics and Baseline Characteristics Exposure and Treatment Compliance TOTAL BODY DOSIMETRY, PRESCRIBED ACTIVITY, AND BIODISTRIBUTION RESULTS (DAYS 0 TO 7) Comparison of Probe and Camera Total Body Residence Times Comparison of Probe and Camera Prescribed Activities Administered Activity Independent Assessment of Biodistribution SAFETY RESULTS Adverse Events Serious Adverse Events Other Significant Adverse Events Second Cancers Deaths DISCUSSION AND CONCLUSIONS Discussion Residence Times Determined from Probe and Gamma Camera Original Analysis: Comparison of Probe and Gamma Camera with 6 to 8 Time Points Current Analysis: Comparison of Probe and Gamma Camera 3 Time Points Dosimetry Prescribed Activity of Therapeutic Dose Safety Conclusions REFERENCES CASE NARRATIVES Non-Fatal Serious Adverse Events

5 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) LIST OF TABLES PAGE Table 1 Studies in Relapsed/Refractory Non-Hodgkin s Lymphoma Table 2 Total Body Residence Times Determined by Scintillation Probe and Gamma Camera Table 3 Disposition of Subjects Table 4 Subject Demographics and Baseline Characteristics Table 5 Dosing Summary for Iodine I 131 Tositumomab Table 6 Table 7 Table 8 Table 9 Table 10 Comparison Total Body Residence Times Derived from Probe and Camera - Three Time Points Point Estimate and 90% Confidence Interval for Ratio of Total Body Residence Times Using Camera to Total Body Residence Times Using Probe Comparison of Total Body Residence Times Derived from Probe and Gamma Camera Counts at Six to Eight Time Points Comparison Prescribed Activities Derived from Probe and Camera Total Body Residence Times - Three Time Points Point Estimate and 90% Confidence Interval for Ratio of Camera and Probe Prescribed Activities Table 11 Criteria for an Expected an Altered Biodistribution Table 12 Table 13 Additional Observations of Subjects with an Expected Biodistribution Subject Specific Observed Uptake with an Expected Biodistribution Table 14 Summary of Adverse Events (Overall >= 3 Subjects) Table 15 Second Cancers and MDS/AML

6 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) LIST OF FIGURES PAGE Figure 1 Figure 2 Figure 3 Correlation of Total Body Residence Times Derived from Gamma Camera and Probe Anterior Counts Correlation of Total Body Residence Times Derived from Gamma Camera and Probe Counts (geometric mean) Correlation of Prescribed Activities Derived from Gamma Camera and Probe Total Body Residence Times

7 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Abbreviations AE Adverse event AML Acute myelogenous leukemia AST Aspartate transaminase Anti-B1 Antibody Tositumomab CD20 Cluster of differentiation 20 (antigen) cgy Centigray CHOP Cyclophosphamide, doxorubicin, vincristine, prednisolone CI Confidence interval cm Centimeter CRF Case report form CRO Contract research organization CVP Cyclophosphamide, etoposide, prednisone FDA Food and Drug Administration GCP Good clinical practice GSK GlaxoSmithKline HAMA Human anti-murine antibody ICH International Conference on Harmonisation IEC Independent Ethics Committee IgG Immunoglobulin G IRB Institutional Review Board ITT Intent-to-treat IV Intravenous LDH Lactate dehydrogenase mci Millicurie MDS Myelodysplastic syndrome MedDRA Medical Dictionary for Regulatory Activities mg Milligram ml Milliliter mm Millimeter NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events NHL Non-Hodgkin s lymphoma NRC Nuclear Regulatory Commission OCEANS GlaxoSmithKline s Worldwide Clinical Safety Database QC Quality control SAE Serious adverse event SD Standard deviation SOC System Order Class reporting of adverse events SSKI Saturated solution of potassium iodide TSH Thyroid-stimulating hormone U-235 Uranium-235 US United States USP United States Pharmacopeia 6

8 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Trademark Information Trademarks of the GlaxoSmithKline group of companies BEXXAR Trademarks not owned by the GlaxoSmithKline group of companies ClinTrial Iodogen MedDRA SAS 7

9 ETHICS AND GOOD CLINICAL PRACTICE CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) The protocol was approved by each institution s Institutional Review Board or Ethics Committee. The protocol was originally issued on 28 Sep 1995 and amended on 01 Nov 1995, 04 Dec 1995, and 06 Aug This study was conducted in accordance with the guiding principles of the Declaration of Helsinki. The therapy was verbally explained to subjects and written informed consent was obtained from all subjects. 8

10 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 1. INTRODUCTION 1.1. Tositumomab Tositumomab is a monoclonal antibody that binds specifically to the CD20 (human B- lymphocyte restricted differentiation antigen, Bp 35 or B1) antigen. CD20, a transmembrane phosphoprotein expressed on pre-b lymphocytes and at higher density on mature B lymphocytes [Tedder, 1985], is expressed on >90% of B-cell non-hodgkin s lymphomas (B-NHL) [Anderson, 1984] BEXXAR Therapeutic Regimen The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) is indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low grade, follicular, or transformed non-hodgkin's lymphoma, including patients with rituximab-refractory non-hodgkin s lymphoma. Possible mechanisms of action of the BEXXAR therapeutic regimen include induction of apoptosis [Cardarelli, 2002], complement-dependent cytotoxicity (CDC) [Stashenko, 1980], and antibody-dependent cellular cytotoxicity (ADCC) [Cardarelli, 2002] mediated by the antibody. In addition, cell death is associated with ionizing radiation from the radioisotope. CD20 does not shed from the cell surface and does not internalize following antibody binding [Press, 1994]. The BEXXAR therapeutic regimen is administered in two discrete steps consisting of the dosimetric dose and the therapeutic dose. Each dose consists of a sequential infusion of tositumomab followed by iodine I 131 tositumomab Dosimetric Dose The dosimetric dose consists of Tositumomab (450 mg) followed by Iodine I 131 Tositumomab (containing 5.0 mci Iodine-131 and 35 mg Tositumomab). Following the dosimetric dose, total body gamma camera counts and whole body images are obtained at the following timepoints. a. Within one hour of infusion and prior to urination b. 2-4 days after infusion of the dosimetric dose, following urination c. 6-7 days after infusion of the dosimetric dose, following urination Therapeutic Dose The total body residence time, derived from total body gamma camera counts obtained at the three time points, is used to calculate the Iodine-131 activity (mci) to be administered to deliver the therapeutic dose of 65 or 75 cgy. The therapeutic step is administered 7-14 days after the dosimetric step and consists of Tositumomab 450 mg and an activity of Iodine-131 calculated to deliver 75 cgy or 65 cgy of total body irradiation, depending on platelet count, and 35 mg Tositumomab. 9

11 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) For subjects with 150,000 platelets/mm 3, the recommended dose is the activity of Iodine-131 calculated to deliver 75 cgy total body irradiation; for subjects with NCI Grade 1 thrombocytopenia (platelet counts 100,000 but <150,000 platelets/mm 3 ), the recommended dose is the activity of Iodine-131 calculated to deliver 65 cgy total body irradiation. The BEXXAR therapeutic regimen is not indicated for patients with platelet counts < 100,000. The therapeutic dose is not administered if there is an altered biodistribution determined by either the total body residence time or by visual examination of whole body camera images. An altered biodistribution is determined by total body residence times of less than 50 hours and more than 150 hours or by visual examination of any of the three gamma camera scans Pharmacokinetics Dose-dependent blood pharmacokinetics were observed in a phase I study (RIT-I-000) following total protein doses of 10, 105, or 485 mg of antibody (tositumomab and iodine I 131 tositumomab). The median blood clearance following administration of 485 mg of Tositumomab (450 mg predose of tositumomab followed by a 35-mg dose of antibody containing 5 mci of iodine I 131 tositumomab) in 110 subjects with NHL was 68.2 mg/hr (range: mg/hr). Subjects with high tumor burden (>500 g), splenomegaly (spleen mass >400 g), or bone marrow involvement had faster clearance, a shorter terminal half-life, and a larger volume of distribution. A predose of 475 mg tositumomab (administered prior to both the dosimetric dose and therapeutic dose) was selected for use in the phase II and III studies based on increased tumor targeting, higher response rate, reduced pharmacokinetic variability, decreased splenic targeting and increased the terminal half-life of the radiolabeled antibody. Elimination of Iodine-131 occurred by decay and excretion in the urine. Urine was collected for 49 dosimetric doses. After 5 days, the whole body clearance was 67% of the injected dose. Ninety-eight percent of the clearance was accounted for in the urine Maximum Tolerated Dose Maximum tolerated non-myeloablative dose The maximum tolerated dose (MTD) of iodine I 131 tositumomab was determined in both a non-myeloablative dose finding study and a myeloablative dose finding study. The maximum tolerated non-myeloablative dose was determined in Study RIT-I-000 [Kaminski, 1993; Kaminski, 1996]. Groups of 3 subjects were treated at successively higher therapeutic whole body radiation doses, beginning at a total body dose (TBD) of 25 cgy. The cgy TBD was adjusted in 10 cgy increments until the MTD was achieved No Prior Bone Marrow Transplant The optimal predose of unlabeled tositumomab was determined to be 475 mg. The MTD of iodine I 131 tositumomab was determined to be 75 cgy TBD for subjects who had not undergone a prior bone marrow transplant. None of the subjects with baseline platelets 10

12 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) above 100,000 cells/mm 3 who were initially treated with 25, 35, 45, 55, 65, or 75 cgy developed protocol-defined dose-limiting hematologic toxicity. Two of three subjects treated with 85 cgy developed dose-limiting toxicity (DLT), and 1 of 3 subjects subsequently treated with 75 cgy developed dose-limiting hematologic toxicity Bone Marrow Transplant A separate determination of MTD was conducted in Study RIT-I-000 with subjects who had undergone prior bone marrow transplantation (BMT). The initial 2 subjects who received 65 cgy and 1 subject who subsequently received 55 cgy developed hematologic toxicity. Only 1 of 6 subjects dosed at 45 cgy developed hematologic toxicity. Therefore, the MTD for subjects who had undergone prior BMT was determined to be 45 cgy Maximum tolerated myeloablative dose The maximum tolerated myeloablative dose of tositumomab and iodine I 131 tositumomab was established to be 2725 cgy in a Phase I/II trial investigating the use of tositumomab and iodine I 131 tositumomab as a single agent prior to autologous stem cell transplant in subjects with NHL [Press, 1993] Total Body Residence Time The therapeutic dose of the BEXXAR Therapeutic Regimen is based on subject-specific total body clearance. Therefore, individual subjects receive a precisely adjusted total body dose that maximizes the therapeutic effect and minimizes organ and bone marrow toxicity. Although the total body residence time and the total body effective half-life are both measures of total body clearance, total body residence time is used for determining the therapeutic dose in accordance with the Medical Internal Radiation Dose (MIRD) schema [Siegel, 1999]. Total body residence time is the time at which the activity is 37% of that at time zero, whereas total body effective half-life is the time at which the activity is 50% of that at time zero. Total body clearance, as measured by total body counts derived from either a scintillation probe or a gamma camera, was dependent on the same factors noted for blood clearance (high tumor burden, splenomegaly, or bone marrow involvement). The mean total body effective half-life as measured by gamma camera counts in 980 subjects [US Prescribing Information for BEXXAR; Table 1] was 67 hours (range: hours) and the mean total body residence time was 96.7 hours (range: hours). 11

13 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Table 1 Studies in Relapsed/Refractory Non-Hodgkin s Lymphoma Original Study No. (GSK Study No.) RIT-I-000 [BEX104728] RIT-II-001 [BEX104731, 24 December 1997] RIT-II-002 Arm A & B [BEX104515] RIT-II-004 [BEX104504] CP [BEX104507] CP [BEX104545] Study Title RIT-I-000/RIT-I-000A: Phase I Study of Radiolabeled Monoclonal Antibody Anti-B1 for the Treatment of B-Cell Lymphomas & RIT-I-000B: Extended Phase I/II study to determine the safety and efficacy of Coulter Clone 131Iodine-B1 radioimmunotherapy of advanced non-hodgkin s Lymphoma Multicenter, Phase II Dosimetry/Validation Study of 131Iodine Anti-B1 (murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas that Have Transformed to Higher Grade Histologies. A Randomized Study of Iodine-131 Anti-B1 Antibody Versus Anti-B1 Antibody in Chemotherapy-Relapsed/Refractory Low-Grade or Transformed Low-Grade Non-Hodgkin s Lymphoma (NHL). Note: Arm A (Iodine-131 Anti-B1 Antibody arm) and Arm B (Anti-B1 Antibody arm) data are captured separately in Section m , Table 8.1). Multicenter, Pivotal Phase III Study of Iodine-131 Anti-B1 Antibody (Murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas that have Transformed to Higher Grade Histologies. Phase II Study of Iodine-131 Anti-B1 Antibody for Non-Hodgkin s Lymphoma Subjects who have Previously Received Rituximab. Expanded Access Study of Iodine I 131 Tositumomab for Relapsed/Refractory Low-Grade and Transformed Low-Grade Non-Hodgkin s Lymphoma Scintillation probe and gamma camera In clinical trials, total body residence times have been derived from counts obtained from either a sodium iodide scintillation probe or a gamma camera (Table 2). A scintillation probe was used to determine total body residence times in Study RIT-I-000. The equivalence of a scintillation probe and a gamma camera for determining total body residence time was subsequently demonstrated in Study RIT-II-001. In both studies, total body residence times were derived from greater than 6 time points. Subsequent studies, that include RIT-II-002, RIT-II-004 and CP , used residence times based on three time points since the total body elimination kinetics were monoexponential and three time points were shown to adequately characterize the total body activity-time curve and reliably determine total body residence time for iodine I 131 tositumomab. 1 The total body residence time, as described in the US Prescribing Information for BEXXAR, is derived from whole body gamma camera counts obtained at the three time points. 1 The mean percent difference between the three-data point scheme and the eight-data point scheme was 0.1%. 12

14 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Table 2 Total Body Residence Times Determined by Scintillation Probe and Gamma Camera Time Probe TBRT (hours) Gamma Camera TBRT (hours) points Study Days 0-7 median mean (SD) range median mean (SD) range RIT-I-000 (n=95) a (20.7) mg predose (16.1) (n= 21) 95 mg predose (19.1) (n= 25) 475 mg (15.6) predose (n=49) RIT-II-001 (n=45) b (18.0) (18.6) RIT-II-002 (n=61) 3 Arm A (n=42) (19.6) Cross over (14.0) (n=19) RIT-II-004 (n=60) (17.6) CP (n=40) (14.3) a. Fifty-nine subjects were enrolled and subjects received 1 3 dosimetric doses followed by a therapeutic dose. The initial 25 subjects (except 2 subjects) received either two or three dosimetric doses, each of which was preceded by a predose of unlabeled antibody (0, 95, or 475 mg) to determine the dose of unlabeled tositumomab that optimized the radiation dose to tumor. Because 475 mg was determined to be the optimal predose of antibody, the last 34 subjects received a single dosimetric dose that was preceded by an infusion of 475 mg of unlabeled antibody. b. Forty-seven subjects were enrolled and residence time data were determined for 45 subjects who had between 6 and 8 probe measurements and gamma camera scans collected. Data Source: BLA

15 2. STUDY OBJECTIVE(S) The objectives of phase II Study (RIT-II-001) were: CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 1. To validate the dosimetry methods for 7 to 10 clinical research sites by demonstrating concordance of dosimetry estimates to those at the 2. To determine the response rate, response duration, time to treatment failure, and survival after treatment with tositumomab and iodine I 131 tositumomab [previously referred to as Iodine-131 Anti-B1 Antibody]. 3. To assess patient-specific radiation doses and the dosimetry of iodine I 131 tositumomab. 4. To assess the safety of iodine I 131 tositumomab. 5. To test the feasibility of using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30+3 validated questionnaire for assessing the quality of life of treated patients 14

16 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 3. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE The study was conducted by investigators at 5 centers in the United States (US) and 2 centers in the United Kingdom: Site No. Investigator Contact Information M.D. M.D. USA M.D. USA M.D. M.D., Ph.D. USA M.D., Ph.D. USA M.D., Ph.D. M.D. M.D., FRCPath. M.D., FRCP USA UK MD, FRCP UK No data safety monitoring committee was convened. The study was administered by the sponsor. Whole body gamma camera scans were converted from BIT file format to DICOM file format by BioClinica, Inc., 826 Newtown-Yardley Road, Newtown, PA The independent assessment of biodistribution was performed at BioClinica by MD, Total body residence times were calculated by Ph.D. at Nuclear Physics Enterprises, a consultant for GlaxoSmithKline. 15

17 4. INVESTIGATIONAL PLAN 4.1. Study Design CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Study RIT-II-001 was a phase II, multicenter study to evaluate the safety, tumor and organ dosimetry, dosimetry methods, and efficacy of tositumomab and iodine I 131 tositumomab for the treatment of subjects with low-grade or transformed low-grade B- NHL. The primary objective of this study was to demonstrate that each site could accurately conduct the whole body dosimetry required for the safe and effective dosing of Iodine-131 Anti-B1 Antibody (iodine I 131 tositumomab). Additional objectives of this study were to evaluate the efficacy, dosimetry, and safety of iodine I 131 tositumomab. A total of 47 subjects were enrolled in this study from seven study centers between 5 December 1995 and 20 November Discussion of Study Design Subjects received a dosimetric dose of tositumomab and iodine I 131 tositumomab followed by a therapeutic dose of tositumomab and iodine I 131 tositumomab. The dosimetric dose involved the intravenous (IV) administration of 450 mg of unlabeled tositumomab followed by 5 mci of iodine I 131 tositumomab. Serial anterior and posterior whole body sodium iodide probe scintillation counts and whole body conjugate view gamma camera scans were obtained approximately 1 hour after the administration of the dosimetric dose and then daily for the next 7 days. The radiation counts from the probe measurements were used to determine the radioactive clearance from the subject and, subsequently, the dose (in mci) of iodine I 131 tositumomab required to deliver a 75 cgy whole body dose of radiation (the therapeutic dose). The radiolabeled portion of the therapeutic dose was also preceded by an infusion of 450 mg of unlabeled tositumomab. In Amendment 3 of the protocol, the method of determining the dose was changed from sodium iodide probe counts to gamma camera counts, and dosing was adjusted for subjects with a low platelet count (100, ,999 cells/mm3) and/or obesity. For obese subjects (subjects weighing more than 137% of their calculated lean body weight), the calculation to determine the administered activity (mci) was performed using the maximum effective mass (i.e., the minimum of the subject s mass and 137% of their calculated lean body weight). The administered activity (mci) for subjects with a baseline platelet count of 100, ,999 cells/mm 3 was reduced to a 65 cgy total body dose, after any adjustment for obesity. 16

18 4.3. Protocol Amendment(s) CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) The original protocol dated 28 September 1995 was amended four times as follows: Protocol Version Protocol Date IND 3323 Serial No. Original 28 Sep Amendment No Nov Amendment No Dec Amendment No Jun Amendment No Aug Selection of Study Population A total of 47 subjects were enrolled from seven institutions. Tumor biopsy material was tested for the expression of the CD20 antigen by immunohistopathology using Anti-B1 (frozen sections only) or anti-l26 antibodies. Low-grade lymphoma histologies were defined by the International Working Formulation: small lymphocytic, with or without plasmacytoid differentiation; follicular small cleaved, mixed small cleaved, and large cell histologies (<50% large cells); and related low-grade B-cell lymphoma histologies Inclusion/Exclusion Criteria Inclusion Criteria 1. Subjects must have a histologically confirmed diagnosis of low-grade non-hodgkin's B-cell lymphoma or low-grade lymphoma that has transformed to intermediate-, or high-grade lymphoma (transformed lymphoma) according to the Working Formulation for Clinical Usage (IWF A, B, and C). 2. Subjects must have evidence that their tumor tissue expresses the CD20 antigen. 3. Subjects must have progressive disease of either low-grade or transformed lymphoma within one year of completion of the last chemotherapy regimen administered. 4. Subjects must have been previously treated with at least one chemotherapy regimen that included an anthracycline or anthracenedione. 17

19 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 5. Subjects must have a performance status of at least 60% on the Karnofsky Scale and anticipated survival of at least three months. 6. Subjects must have an absolute granulocyte count of over 1,500 /mm 3 and a platelet count above 100,000 /mm 3 within seven days of study entry. These blood counts must be sustained without support of hematopoietic cytokines or transfusion of blood products. 7. Subjects must have normal renal function (creatinine less than 2.0 mg/dl) and hepatic function (bilirubin less than 2.0 mg/dl) within seven days of study entry. 8. Subjects must have bi-dimensionally measurable or evaluable progressive lymphoma disease (at least a 25% increase in tumor size or new sites of disease when compared to the last best disease response). Progression must have occurred within 12 months of the preceding response. 9. Subjects must be at least 18 years of age. 10. Subjects must give written informed consent and sign an approved informed consent form prior to study entry Exclusion Criteria 1. Subjects with more than an average of 25% of the intertrabecular marrow space involved by lymphoma in bone marrow biopsy specimens as assessed microscopically at study entry. 2. Subjects who have received cytotoxic chemotherapy, radiation therapy, immunosuppressants, or cytokine treatment within FOUR weeks prior to study entry (six weeks for nitrosourea compounds) or who exhibit persistent clinical evidence of toxicity. The use of steroids must have been discontinued (except maintenance-dose steroids) at least one week prior to study entry and subjects must then show evidence of stable or progressive disease. 3. Subjects with prior hematologic stem cell transplant following high-dose chemotherapy or chemo/radiotherapy. 4. Subjects with obstructive hydronephrosis. 5. Subjects with evidence of active infection requiring intravenous antibiotics at the time of study entry. 6. Subjects with New York Heart Association class 3 or 4 heart disease or other serious illness that would preclude evaluation. 7. Subjects with prior malignancy other than lymphoma, except for adequately treated skin cancer, in situ cervical cancer, or other cancer for which subject has been disease-free for five years. 8. Subjects with known HIV infection. 9. Subjects with known brain or leptomeningeal metastases. 18

20 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 10. Subjects who are pregnant. Subjects of child-bearing potential must undergo a pregnancy test within seven days of study entry. Males and females must agree to use effective contraception during the study. 11. Subjects with previous allergic reactions to iodine. This does not include IV contrast materials. 12. Subjects who were previously given any monoclonal or polyclonal antibodies of any foreign species for either diagnostic or therapeutic purposes. This includes engineered chimeric and humanized antibodies. 13. Subjects who previously received radioimmunotherapy. 14. Subjects with progressive disease in a field that has been previously irradiated with more than 3500 cgy. 15. Subjects who are on another protocol involving non-approved drugs or biologics Treatments Patients received a dosimetric dose followed by a therapeutic dose. The dosimetric dose involved the intravenous (IV) administration of 450 mg of unlabeled tositumomab followed by 5 mci of Iodine-131 tositumomab. Serial whole body sodium iodide probe scintillation counts and whole body conjugate gamma camera scans were obtained within approximately 1 hour after the administration of the dosimetric dose and then daily for the next 7 days. The radiation counts from the probe measurements were used to determine the radioactive clearance from the patient and, subsequently, the number of mci of Iodine-131 tositumomab required to deliver a 75 cgy whole body dose of radiation, the therapeutic dose. The radiolabeled portion of the therapeutic dose was also preceded by an infusion of 450 mg of tositumomab. In Amendment 3 of the protocol, the method of determining the dose was changed from sodium iodide probe counts to gamma camera counts and dosing was adjusted for patients with a low platelet count (100, ,999 cells/mm3) and/or obesity. For obese patients (patients weighing more than 137% of their lean body weight), the calculation to determine the administered activity (mci) was performed using the maximum effective mass (i.e., the minimum of the patient s mass and 137% of their calculated lean body weight) rather than their actual total body weight. The administered activity (mci) for patients with a baseline platelet count of 100, ,999 cells/mm3 was reduced to a 65 cgy total body dose, after any adjustment for obesity Investigational Products The unlabeled tositumomab and iodine I-131 tositumomab used in this study were previously described in Section 3.3 and Listing 15 of Final Study Report RIT-II-001 [24 December 1997]. Tositumomab used in this trial was manufactured by Coulter Corporation (Hialeah, FL, USA). Tositumomab was supplied in a single-use vial as 5 ml of a sterile, clear, colorless solution containing: Protein concentration: mg/ml Potassium phosphate: 1.0 ± 0.1 mg/ml 19

21 Sodium chloride: 8.5 ± 0.1 mg/ml Maltose: 0.1 ± 0.01 g/ml ph 7.2 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Tositumomab was radiolabeled using the Iodogen method and quality control-tested at each site. The antibody was radiolabeled at each site using a radiolabeling kit developed by Coulter Pharmaceutical, Inc., containing Iodogen for the antibody labeling, a column for purification, and the supplies needed for quality control testing Study Assessments and Procedures The protocol defined the study day as days from the therapeutic dose, however, this report used the study day as days from the dosimetric dose. The latter definition was used to provide consistent definitions with prior and subsequent reports. Patients were monitored for efficacy by physical examination and sequential radiographs (i.e., computerized tomography (CT) scans of chest, abdomen, and pelvis, and other appropriate radiographs for assessing the tumors), which were obtained at baseline, day 2 (PE only), week 7, week 13, then every 3 months for 2 years, and then every 6 months thereafter until disease progression or death. In addition, a bone marrow biopsy was performed at baseline and at the time of complete response (CR) in patients who had a positive baseline bone marrow biopsy Safety Assessments Subjects enrolled in Study RIT-II-001 were scheduled to be assessed for life by physical examination, laboratory evaluation, and assessment of human-anti-mouse antibodies (HAMA) as previously described [RIT-II-001, 24 December 1997]. Subjects participating in Study RIT-II-001 who completed at least two years of follow-up after treatment with tositumomab and/or Iodine I 131 tositumomab were invited to enroll in multi-center study BEX (formerly Corixa study CCBX ) for the long-term follow-up up to 10 years. Upon providing informed consent, subjects enrolled in Study BEX were followed for continued response (as applicable) and safety every 6 months for Years 3 through 5 status post treatment with tositumomab and/or iodine I 131 tositumomab. Beginning at Year 6, patients were assessed annually through Year 10 (inclusive). In addition to continued assessment for survival, disease status, and including subsequent therapy for NHL, subjects were evaluated for long term safety, including the use of thyroid medication, development of hypothyroidism, myelodysplasia (MDS), acute myelogenous leukemia (AML), and all other secondary malignancies. Additionally, these patients will be followed for the development of any adverse events deemed by the Principal Investigator as being possibly or probably related to the patient s previous treatment with Tositumomab and/or Iodine I 131 Tositumomab. Laboratory evaluations consisting of a TSH level (for all patients) and a complete blood cell (CBC) count with a differential and platelet count (for patients in continuing response only) were obtained annually through Year 10 post treatment with tositumomab and/or Iodine I 131 tositumomab. 20

22 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 4.8. Data Management At the clinical study sites, the investigator or their designee recorded all required subject data on clinical reporting forms (CRFs). The completed original CRFs were returned to GSK Clinical Data Management for processing. The investigator retained copies of the CRFs. Data entry applications were designed and validated using a data entry screen software system ClinTrial. ClinTrial is a registered trademark of Phase Forward, Waltham, MA. Data values recorded on the CRF were entered using double dependent data entry. Computerized data validation was performed on CRF data using generic, standard and study-specific data validation checks. Validation discrepancies, if not covered by a Standard Clarification Agreement (SCA), were queried using the documented data query process for review and resolution by investigators, and if appropriate, with reference to the clinical study team members. Any necessary changes were made to both the CRF and the database by data management staff. Quality Control (QC) tasks were conducted in accordance with existing data management standard operating procedures to ensure database accuracy against the data collected in the CRF. QC procedures are in alignment with the International Conference on Harmonization of Good Clinical Practice (ICH GCP). Adverse events, Adverse Infection and concomitant medications were coded by the autoencoder using industry standard dictionaries (MedDRA, version 11.0) and company standard GSK Drug based on WHO Drug for the concomitant medications. SAE data, consistent with the data collected for other adverse events, was entered onto the database and quality assured, including reconciliation with the Global Clinical Safety and Pharmacovigilance database at GlaxoSmithKline. After all data management QC/QA procedures were completed, the database was released. The database is not frozen since the subjects continue to be followed until death or the elapse of 10 years from initiation of protocol defined therapy (if subjects enrolled in long-term follow-up study BEX104526), whichever occurs first. The raw data (CRFs, etc.) will be archived at the end of the study according to GSK standard procedures. Since the study is ongoing, the CRFs are being processed by the CRO, Parexel. The original CRFs are being stored at the present time in the Lowell, MA offices of Parexel Dosimetry Analysis Original Dosimetry Analysis The dosimetry analysis compared total body residence times obtained by sodium iodide probe and gamma camera counts in the same subjects receiving the dosimetric dose of tositumomab and iodine I 131 tositumomab. Both serial total body anterior and posterior gamma camera scans and sodium iodide probe scintillation counts were obtained at 6 to 8 time points between Days 0 and 7, specifically within 1 hour after the administration of 21

23 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) the dosimetric dose of iodine I 131 tositumomab and then daily for the next 7 days. These data were used to establish an overall time-activity pattern to enable comparison of total body residence times Current Dosimetry Analysis The current dosimetry analysis of 41 subjects compares total body residence times obtained by sodium iodide probe and gamma camera counts collected on Day 0, Day 2 to 4, and Day 6 to 7, as described in the US Prescribing Information for BEXXAR. The dosimetry analysis was performed by Nuclear Physics Enterprises, a consultant of GSK. Total body residence times were calculated with anterior only counts and the geometric mean of anterior and posterior counts. Although 47 subjects were enrolled, the current analysis includes only the 41 subjects for whom counts were obtained using both a scintillation probe and a gamma camera and original dosimetry worksheets were provided. The dosimetry analysis was conducted as described below. 1. For each subject and timepoint, anterior and posterior total body probe and gamma camera counts and respective background counts were obtained. The backgroundcorrected total body count (anterior and posterior) was calculated by subtracting the background count from the total body count for each orientation at each timepoint. Geometric mean background-corrected counts were also determined from the anterior/posterior data for the both the probe and camera at each timepoint; 2. The time in hours from the start of the 131 I tositumomab dosimetric infusion to the acquisition of each total body count for each subject at each timepoint was then determined; 3. Next, the percent injected activities (%IAs) remaining at each timepoint were calculated for each subject by dividing the background-corrected total body count for that timepoint by the background-corrected total body count from the first timepoint and multiplying by 100 for both anterior-only and geometric mean counts (anterior and posterior); and 4. The times from the start of the dosimetric infusion and the percent injected activity values for all three timepoints represent the total body activity-time curve for each subject. Four activity-time curves were thus generated: two based on probe data and two based on gamma camera data, representing anterior-only and geometric mean (anterior and posterior) data for the probe and gamma camera. These activity-time curves were fit using nonlinear least squares. Actually, the natural logarithms of the %IAs were first determined to enable pseudo-linear curve fitting (this is because a curve-fit of these log-transformed data to a linear function is equivalent to a monoexponential fit to non-transformed data). The total body residence times were then calculated for each of the fitted lines for anterior-only and geometric mean (anterior and posterior) data for both the probe and camera in each subject. 22

24 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Anterior-only and geometric mean (anterior and posterior) counts for the total body at the various time points were referenced to the respective total body counts at the earliest imaging time, which represented 100% of the administered activity. This provided activity-time data such that the activity values represented the activity uptake as a percentage of the administered activity at each timepoint. These activity-time data were fit to a single exponential function and then integrated analytically to determine the total body residence times based on anterior-only and geometric mean (anterior and posterior) total body data for both the probe and gamma camera. Total body residence time,τ, rather than total body effective half-time, is used. Residence time is the cumulated activity divided by the administered activity. Total body effective half-time T eff, on the other hand, is the time at which 50% of the administered activity has cleared from the body. The total body residence time is mathematically equal to 1.44 times the total body effective half-time. The activity of 131 I in the 131 I tositumomab treatment in the total body as a function of time can be described using either T eff or τ : In terms of T eff : In terms of τ: A TB (t) = A 0 exp t/teff A TB (t) = A 0 exp - t/τ where A TB (t) is the total body activity at any time t and A 0 is the administered activity. Rearrangement of the above equations, leads to: When t = T eff When t = τ A TB A ( t) 0 = exp = 0.5 (or 50%) A TB A ( t) 0 = exp 1 = 0.37 (or 37%) where A TB (t)/a 0 is fractional injected activity at time t (multiplication by 100% yields the percent injected activity). As the above equations indicate, at the time post-injection equal to the total body residence time, the percent injected activity is 37% (the percent injected activity at the time equal to the effective half-time is 50%). 23

25 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Prescribed Activity The total body residence times of the 41 subjects, derived from gamma counts using either a probe or camera, were used to determine the prescribed activities (mci). The calculations were validated by Nuclear Physics Enterprises. The equation for deriving the prescribed activity (A) is described below: A (mci) = Activity Hours ( mci h) TBRT ( h) x Desired Total Body Dose ( cgy) 75 cgy where: A (mci) = I-131 activity required for therapeutic administration in mci; Activity Hours = patient-specific constant taking into account patient sex, actual weight, or maximum effective mass (if necessary); Total Body Residence Time: clearance of activity from body in hours; and Desired Total Body Dose = either 75 cgy or 65 cgy (if reduced platelet count) Statistical Analyses Data were summarized using SAS, version 8.2 and include retrospective dosimetry analysis which were performed on a subpopulation of 41 subjects for whom counts were obtained using both a scintillation probe and a gamma camera and original dosimetry worksheets were provided. Summary statistics (mean, median, standard deviation, minimum and maximum) were calculated for the total body residence times (Probe (A), Camera (A), Probe (GM) and Camera (GM) and prescribed activity (GM). Percent differences were also calculated for total body residence time [Probe (A) vs Camera (A) and for Probe (GM) vs Camera (GM)] and for prescribed activity [Probe (GM) vs Camera (GM)]. Summary statistics and 95% confidence intervals were calculated for the actual values as well as for the percent change between methods. The Pearson correlation coefficient was calculated as a measure of the linear relationship between the Probe and Camera methods. The intraclass correlation coefficient was also calculated as a measure of agreement or concordance between the total body residence times derived from probe counts and total body residence times derived from gamma camera counts. Following log e -transformation, total body residence time and prescribed activity values were analyzed to assess the comparability of values derived from gamma counts using the gamma camera or using the probe. Point estimates and associated 90% CIs were constructed using the residual variance. These point estimates and CIs were exponentially back-transformed to obtain point estimates and associated 90% CIs for the 24

26 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) ratios of the total body residence time and prescribed activity values for gamma camera to probe Biodistribution Assessments Management of gamma camera scans Whole body anterior and posterior gamma camera scans were converted to DICOM file format by an independent Contract Research Organization (CRO), BioClinica Inc., Newtown, PA. The images used for biodistribution assessments were obtained on the following 3 time points between Days 0 and 7: within 1 hour after the completion of the dosimetric dose, Day 3, and Day 7. The images of whole body subject scans were saved electronically for submission to GSK, its designee, and/or the FDA. Whole body scans were archived from the camera in the native camera file format or Dicom/Interfile format, and whole body image data were transferred to an acceptable digital media (i.e., CD ROM, DAT, or Optical Disc). All images were reviewed by BioClinica for quality control Biodistribution assessments (Days 0 to 7) The independent assessment of biodistribution was coordinated at BioClinica and performed by MD, The independent reviewer, a nuclear medicine physician, visually examined whole body images of subjects who received iodine I-131 tositumomab administered during the dosimetric phase of the study (Days 0-7). The independent reviewer determined whether the biodistribution at each time point for the 41 evaluable subjects was expected or altered according to the Read Rules developed by BioClinica [Biodistribution Review Sample Case Report Form], in accordance with the Charter [Charter for the Independent Review of Biodistribution], and based on the US Prescribing Information for BEXXAR. In addition, the overall biodistribution at all time points was assessed and the optimal time point for determining the biodistribution was recorded Biodistribution criteria Criteria for assessing biodistribution as described in the US Prescribing Information for BEXXAR: Expected biodisribution: At the first imaging time point, most of the radioactivity was in the blood pool (heart and major blood vessels) and the uptake in a normal liver and spleen was less than in the heart. At subsequent imaging time points, radioactivity in the blood pool decreased significantly, and accumulation of radioactivity in a normal liver and spleen decreased. Images might show uptake by the thyroid gland, kidneys, urinary bladder, and minimal uptake by the lungs. Tumor uptake in soft tissues and in normal organs was seen as areas of increased intensity. 25

27 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Altered biodistribution: At the first imaging time point, biodistribution was considered altered if the blood pool was not visualized or if there was diffuse, intense tracer uptake in the liver and/or spleen or uptake suggestive of urinary obstruction. Diffuse lung uptake greater than that of the blood pool on the first day represented altered biodistribution. At subsequent imaging time points, biodistribution was considered altered if uptake suggestive of urinary obstruction and diffuse lung uptake greater than that of the blood pool was observed. 5. STUDY POPULATION RESULTS 5.1. Disposition of Subjects Forty-seven subjects were enrolled from seven institutions in the United States and the United Kingdom between 5 December 1995 and 20 November 1996, and 46 subjects received both the dosimetric dose and the therapeutic dose. Although subjects in Study RIT-II-001 were followed until death, subjects who completed at least two years of evaluations were eligible to enroll in long-term follow-up Study BEX Subjects enrolled in Study BEX were assessed through Year 10 post treatment for survival, subsequent therapy, long-term safety (use of thyroid medication, development of hypothyroidism, myelodysplasia, acute myelogenous leukemia and other second malignancies), and adverse events. Among the 47 subjects evaluated in Study RIT-II- 001, 11 subjects enrolled in Study BEX for continued evaluation of safety and efficacy. All subjects completed long term follow-up either in the original Study RIT-II- 001 or Study BEX (Table 3). 26

28 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Table 3 Disposition of Subjects Number of Subjects Planned, N 48 Enrolled in RIT-II-001, N 47 Withdrawal from RIT-II-001, n (%) 47 (100) Reason for Withdrawal Adverse Events 1 (2) Lost to Follow-Up 2 (4) Subject Wish 1 (2) Progressive Disease 38 (81) Other 5 (11) Enrolled in BEX104526, n (%) a 11 (23) Withdrawal from BEX104526, n (%) b 7 (15) Reason for Withdrawal Patient died 2 (4) Other (completion of 10-Year follow up) 5 (11) a. Eleven of the 47 subjects who withdrew from Study RIT-II-001 enrolled in long term follow-up Study BEX for continued evaluation. Study BEX104526, titled A Multi-Centre Long-Term Follow-Up Study of Subjects with Low-Grade Non-Hodgkin's Lymphoma Previously Treated with Tositumomab and/or Iodine I 131 Tositumomab in Studies RIT-I-000, RIT-II-001, RIT-II-002, RIT-II-004, or CP , evaluated subjects for continued response (if applicable) and safety every 6 months for Years 3 through 5 post-treatment and beginning at Year 6, subjects are assessed annually through Year 10 inclusive. b. All subjects completed follow up in Study BEX but 4 of 11 subjects did not complete the withdrawal form at the time this report was completed. Data Source: Table 6.5, Table 6.6, and Listing Populations Analyzed The 47 subjects enrolled between 5 December 1995 and 20 November 1996 were originally described in the Intent to Treat (ITT) Population of the RIT-II-001 Final Report [RIT-II-001, 24 Dec 1997]. This original report included dosimetry analysis of 45 out of 47 enrolled subjects who completed 6 to 8 time points of both probe measurements and gamma camera scans after receiving the dosimetric dose. The current abbreviated study report presents retrospective dosimetry analysis assessments of 41 subjects (Dosimetry Population) who completed probe measurements and gamma camera scans on the following three time points: Day 0, Days 2 to 4, and Days 6 to 7. Original dosimetry worksheets were available for 41 evaluable subjects who received both probe measurements and gamma camera scans. In addition, the current report presents an independent assessment of biodistribution and dosimetry calculations based on three time points of the 41 subjects that was not performed in the original study report. 27

29 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 5.3. Demographics and Baseline Characteristics The demographics and baseline characteristics of the 41 subjects (Dosimetry Population) are presented in Table 4. The median time from the diagnosis of B-NHL to study entry was 44 months, and subjects had received a median of 5 prior therapies (range: 2 13). Thirty of 41 (73%) subjects had low-grade B-NHL at enrollment, and 37 subjects (90%) had stage III or IV disease at study entry. The majority of subjects (88%) had two or more high-risk factors as defined by the International Prognostic Index (IPI). Sixteen of 34 (47%) subjects evaluated for bulky disease had bulky disease (>500 g). Twenty of 41 subjects (49%) had no bone marrow involvement, and no subjects had greater than 25% bone marrow involvement. 28

30 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Table 4 Subject Demographics and Baseline Characteristics Subject Characteristics Dosimetry Population (n=41) Demographics Male, N (%) 22 (54) Female, N (%) 19 (46) Age, median years (range) 51 (23-74) Weight, median kg, (range) 76 (45-112) Ethnic origin White, N (%) 39 (95) Months from diagnosis to entry, median (range) 44 (8-263) Prior therapies, median (range) 5 (2-13) Prior chemotherapies 4 (1-8) Prior radiation therapies 1 (1-5) Grade at Enrollment, n (%) Low 30 (73) Intermediate 10 (24) High 1 (2) Stage at Entry, n (%) II 4 (10) III 4 (10) IV 33 (80) Cell type NHL at enrollment Small lymphocytic with plasmocytoid 1 (2) differentiation Monocytoid B-cell 1 (2) Small lymphocytic without plasmocytoid 2 (5) differentiation Follicular, small cleaved 16 (39) Follicular, mixed small cleaved and large cell 10 (24) Follicular, large cell lymphoma 2 (5) Diffuse mixed small cleaved and diffuse 3 (7) large cell Diffuse large cell lymphoma 3 (7) Stage at enrollment, N (%) II 4 (10) III 4 (10) IV 33 (80) Bone marrow involvement, N (%) < 0% 20 (49) > 0% 21 (51) > 25%, 0 Bulky disease, N (%) 16 (47) Spleen Involvement (Yes), N (%) 7 (17) Elevated baseline LDH > 200 IU/L, N (%) 15 (37) Modified IPI, International Prognostic Index (12) 2 18 (44) 3 15( 37) (7) a. Baseline spleen measurements were obtained for 9 subjects. Data Source: Table 6.1, Table 6.2, and Table

31 5.4. Exposure and Treatment Compliance CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) The dosing summary is presented for the 41 subjects in the Dosimetry Population (Table 5). All subjects received a single dosimetric dose of tositumomab (450 mg) and iodine I 131 tositumomab (35 mg). Three subjects required an infusion adjustment. All subjects received the therapeutic dose of tositumomab (450 mg) and iodine I 131 tositumomab (mean 35 mg, range 34 to 37 mg). Table 5 Dosing Summary for Iodine I 131 Tositumomab Dosimetric Dose (n=41) Therapeutic Dose (n=41) Administered activity, mci Mean, (SD) 5.2 (0.4) 86.1 (25.1) Median (range) 5.2 (3-6) 80.6 (45-177) Whole Body Dose, cgy Mean, (SD) Not Determined 73.0 (4.8) Median (range) Not Determined 75.0 (53-75) Administered activity was determined in millicurie (mci) and whole body dose determined in centigray (cgy) amount. Data Source: Table 8.1 and Table TOTAL BODY DOSIMETRY, PRESCRIBED ACTIVITY, AND BIODISTRIBUTION RESULTS (DAYS 0 TO 7) 6.1. Comparison of Probe and Camera Total Body Residence Times The original dosimetry analysis of subjects in Study RIT-II-001 compared counts obtained from a sodium iodide scintillation probe and gamma camera from between 6 to 8 time points after administration of the dosimetric dose [Section 4.7 Dosimetry of the Clinical Study Report RIT-II-001, 24 December 1997]. Since the total body elimination kinetics were monoexponential and three time points were shown to reliably determine total body residence time for iodine I 131 tositumomab, the US Prescribing Information for BEXXAR requires total body residence time calculations performed with gamma camera counts obtained on the following 3 imaging time points: Day 0, Day 2 to 4, and Day 6 to 7. Total body residence times calculated from the probe and gamma camera counts had high concordance regardless of whether anterior only counts or the geometric mean of anterior and posterior counts were used to the calculate total body residence time (Table 6). There was high concordance between total body residence times calculated from probe and gamma camera counts as demonstrated by the intraclass correlation coefficients that were close to When anterior-only counts were used to calculate the total body residence time, the intraclass correlation coefficient between probe and gamma camera 30

32 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) was Similarly, when the geometric mean of anterior and posterior counts was used, the intraclass correlation coefficient between probe and gamma camera was The mean total body residence times, calculated with both anterior and posterior counts (geometric mean) as described in the US Prescribing Information, were 94.5 ± 18.9 hours using probe counts and 95.0 ± 19.8 hours using gamma camera counts. Similarly, the mean total body residence times, calculated with anterior only counts, were 95.2 ± 19.4 hours using probe counts and 95.9 ± 19.9 hours using gamma camera counts. The 95% confidence intervals overlap for residence times derived from probe and gamma camera counts, suggesting that there was not a significant difference between total body residence times derived from probe and gamma camera counts. In addition, the mean percent differences of total body residence times derived from probe and gamma camera counts were small (Table 6) and probe and gamma camera total body residence times were highly correlated as depicted in Figure 1 and Figure 2. Table 6 Comparison Total Body Residence Times Derived from Probe and Camera - Three Time Points Total Body Residence Time, hours (n=41) Probe (A) Camera (A) Probe (AP) Camera (AP) Mean (SD) 95.2 (19.4) 95.9 (19.9) 94.5 (18.9) 95.0 (19.8) median % CI (89.3, 101.2) (89.8, 102.0) (88.7, 100.3) (88.9, 101.1) range 63.0 to to to to Percent Difference Total Body Residence Time (n=41) Probe (A) vs. Camera (A) Probe (AP) vs. Camera (AP) Probe (A) vs. Probe (AP) Camera (A) vs. Camera (AP) Mean (SD) -0.6 (4.39) -0.4 (4.23) 0.7 (2.21) 1.0 (1.90) Median % CI (-1.94, 0.75) (-1.69, 0.90) (0.06, 1.42) (0.37, 1.54) range to to to to 10.0 Intraclass Correlation Coefficient (n=41) Probe (A) vs. Camera (A) Probe (AP) vs. Camera (AP) Residence times were determined with anterior (A) counts or the geometric mean of anterior and posterior counts (AP). Data Source: Table 8.3, Figure 1 and Figure 2. 31

33 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Figure 1 Correlation of Total Body Residence Times Derived from Gamma Camera and Probe Anterior Counts Figure 2 Correlation of Total Body Residence Times Derived from Gamma Camera and Probe Counts (geometric mean) The total body residence times derived from gamma counts using probe or camera were also compared by constructing the 90% confidence interval of the ratio of total body residence times from camera to probe. The point estimate for the ratio (1.005) was close to 1.00, and the 90% confidence interval (0.99, 1.02) was narrow (Table 7). These results demonstrated that the total body residence time derived from probe counts was highly comparable to that derived from gamma camera counts. 32

34 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Table 7 Point Estimate and 90% Confidence Interval for Ratio of Total Body Residence Times Using Camera to Total Body Residence Times Using Probe Parameter Point Estimate of Ratio 90% Confidence Interval Total body residence time (h) , Data Source: Table 8.13 Original calculation of total body residence times The original analyses using 6 to 8 time points reported that the mean effective half-life from probe counts were similar to the mean effective half-life from gamma camera counts [RIT-II-001, 24 Dec 1997, Table and Table 5.2.2]. The results from the current analysis using 3 time points were similar to the original analysis using 6 to 8 time points when the originally reported effective half-lives was converted to residence times (Table 8). Table 8 Comparison of Total Body Residence Times Derived from Probe and Gamma Camera Counts at Six to Eight Time Points Total Body Residence Time, hours (n=45) a, b Probe Camera Mean (SD) 94.1 (13.6) 94.9 (18.6) Median Range 64.2 to to a. The total body residence time is equal to times the effective half-life that was originally reported in RIT-II-001, 24 Dec 1997, Table and Table b. The correlation between total body residence time obtaining from probe and gamma camera counts was previously reported as r=0.973 [RIT-II December 1997; Vose 2000] Forty of the 41 subjects evaluated had a residence time between 50 and 150 hours, the expected range described in the US Prescribing Information for BEXXAR. Although this subject had a residence time outside of the expected range by gamma camera determination, an independent visual inspection of the biodistribution concluded that the biodistribution was normal (Section 6.3). 33

35 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 6.2. Comparison of Probe and Camera Prescribed Activities The prescribed activity, defined as the millicurie (mci) amount of I-131 required to deliver a total body radiation absorbed dose of 75 cgy (or 65 cgy if platelet count of 100,000 to <150,000 platelets/mm 3 ), was determined using the total body residence time (derived from gamma counts obtained with a probe or a gamma camera), the desired total body dose (cgy), and the patient-specific activity hours as described in Section Similar to the comparison of total body residence times, the mean prescribed activities (mci) were comparable whether derived from probe total body residence times or camera total body residence times (Table 9). The mean prescribed activities derived from probe and gamma camera total body residence times were 85.8 mci and 85.3 mci, respectively. In addition, the mean percent differences of prescribed activities were small (Table 9) and there was high concordance (intraclass correlation coefficient = 0.984) between the prescribed activities derived from probe and gamma camera total body residence times as depicted in Figure 3. Table 9 Comparison Prescribed Activities Derived from Probe and Camera Total Body Residence Times - Three Time Points Prescribed Activity, mci (n=41) Probe (AP) Camera (AP) Mean (SD) 85.8 (24.5) 85.3 (23.9) Median % CI 78.3, , 92.6 Range 40.4 to to Percent Difference Prescribed Activity (n=41) Probe (AP) vs. Camera (AP) Mean (SD) 0.6 (4.3) Median % CI -0.7, 1.9 Range -7.7 to 11.9 Intraclass Correlation Coefficient (n=41) Probe (AP) vs. Camera (AP) Prescribed activities were determined with the geometric mean of anterior and posterior counts (AP) as required in the US Prescribing Information for BEXXAR and as described in Section Data Source: Table 8.12 and Figure 3. 34

36 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Figure 3 Correlation of Prescribed Activities Derived from Gamma Camera and Probe Total Body Residence Times The prescribed activities (mci) calculated from total body residence times derived from gamma counts using probe or camera were also compared by constructing the 90% confidence interval of the ratio of the prescribed activity from camera to probe. Since there is an inverse relationship between total body residence time and prescribed activity, the ratio of the prescribed activity is the inverse or reciprocal of the total body residence time ratio. The point estimate for the ratio of the prescribed activity was close to 1.00 (0.995) and the 90% confidence interval was narrow (Table 10). These results demonstrated that the prescribed activity calculated with the total body residence time derived from probe counts was highly comparable to that obtained with total body residence times derived from gamma camera counts. Table 10 Point Estimate and 90% Confidence Interval for Ratio of Camera and Probe Prescribed Activities Parameter Point Estimate of Ratio 90% Confidence Interval Prescribed activity (mci) , Data Source: Table Administered Activity The original activity estimates, first calculated using 6 to 8 time points using either probe or gamma camera total body residence times [RIT-II-001, 24 Dec 1997, Listing 21.2], were similar to the prescribed activities calculated with three time points in the current analysis. The mean administered activity of the therapeutic dose for 47 subjects was 87.6 mci (standard deviation 25.0) and the range across subjects was 45.2 to mci [RIT- II-001, 24 Dec 1997, Section 4.4 and Table 2.6]. 35

37 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 6.3. Independent Assessment of Biodistribution The biodistribution of iodine I 131 tositumomab after administration of the dosimetric dose has been previously described [US Prescribing Information for BEXXAR] and was used as a reference for defining the biodistribution in subjects after receiving the dosimetric dose (Table 11). Table 11 Criteria for an Expected an Altered Biodistribution Expected Biodistribution At the first imaging time point, most of the radioactivity was in the blood pool (heart and major blood vessels) and the uptake in a normal liver and spleen was less than in the heart. At subsequent imaging time points, radioactivity in the blood pool decreased significantly, and accumulation of radioactivity in a normal liver and spleen decreased. Images might show uptake by the thyroid gland, kidneys, urinary bladder, and minimal uptake by the lungs. Tumor uptake in soft tissues and in normal organs was seen as areas of increased intensity. Altered Biodistribution At the first imaging time point, biodistribution was considered altered if the blood pool was not visualized or if there was diffuse, intense tracer uptake in the liver and/or spleen or uptake suggestive of urinary obstruction. Diffuse lung uptake greater than that of the blood pool on the first day represented altered biodistribution. At subsequent imaging time points, biodistribution was considered altered if uptake suggestive of urinary obstruction and diffuse lung uptake greater than that of the blood pool was observed. The original study reports of RIT-II-001 did not include an assessment of biodistribution. For this report, gamma camera images of subjects were retrospectively evaluated by an Independent Reviewer to determine whether subjects had an expected or altered biodistribution after receiving the dosimetric dose of tositumomab and iodine I-131 tositumomab. The independent review of biodistribution was performed with the same time points described in US Prescribing Information for BEXXAR (Day 0, Day 2 to 4, and Day 6 to 7) after the dosimetric dose used to perform the total body residence time calculations (Section 6.1). The independent reviewer visually assessed the gamma camera images of the 41 subjects who received both gamma camera scans and scintillation probe scans so that the dosimetry calculations could be compared with results from the independent biodistribution assessments. The 41 subjects evaluated from Study RIT-II-001 all displayed expected organ distribution kinetics. Most of the radioactivity on the first time point resided in the blood pool (heart and major blood vessels) with secondary uptake in the liver and spleen. Additional subject-specific observations of an expected biodistribution are summarized in Table

38 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Table 12 Additional Observations of Subjects with an Expected Biodistribution Additional N (%) observations a Thyroid 10 (24) Stomach b 4 (9.7) Lung 2 (4.9) Skeleton c 1 (2.4) a. At subsequent imaging time points, such as Day 3 and Day 7 after the dosimetric dose, an expected biodistribution might show uptake by the thyroid gland, kidneys, urinary bladder, and minimal uptake by the lungs. b. Two subjects had observed uptake in both the stomach and lungs. c. One subject had observed uptake in both the thyroid and skeleton. Data Source: Biodistribution Review Completed Case Report Forms RIT-II-001. Thyroid uptake was observed in 10 subjects, lung uptake was observed in 2 subjects, stomach uptake was observed in 4 subjects, and skeletal uptake was observed in 1 subject (Table 13). The observed uptake was noted on either Day 3 or Day 7 after the dosimetric dose. Table 13 Subject Specific Observed Uptake with an Expected Biodistribution a. Day the uptake was observed after administration of the dosimetric dose. Total body residence times (TBRT) were determined with the geometric mean of anterior and posterior counts (AP). Data Source: Listing 7 and Biodistribution Review Case Report Forms RIT-II

39 7. SAFETY RESULTS CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) This abbreviated study report summarizes all adverse experiences of subjects enrolled in Study RIT-II-001 and long-term follow up study BEX (formerly Corixa study CCBX ). Whereas subjects who were enrolled in Study RIT-II-001 were to be followed for life, subjects who withdrew from Study RIT-II-001 and enrolled in Study BEX received safety assessments every 6 months for Years 3 through 5 status post treatment with tositumomab and/or Iodine I 131 tositumomab. Beginning at Year 6, patients were assessed annually through Year 10 (inclusive) Adverse Events The adverse experiences observed in the study were originally submitted in the Final Report on 24 December 1997 (reporting period 5 December 1995 to 15 November 1997) and the RIT-II-001 Final Report Amendment on 29 March 2000 (reporting period 5 December 1995 to 8 January 1999). This abbreviate study report summarizes all adverse events of subjects followed under the original protocol RIT-II-001 and the long term follow up protocol BEX from 5 December 1995 to 29 May This summary represents a safety update since 8 January A summary of all adverse events reported in the ITT Population are presented in Table 8.8 and a summary of all adverse events reported in the Dosimetry Population are presented in Table 8.4. A summary of common adverse events reported in at least 3 subjects of the Dosimetry Population overall is presented in Table 14. Table 14 Summary of Adverse Events (Overall >= 3 Subjects) Dosimetry Population System Organ Class Adverse event (Preferred Term) Overall (N=41) Grade 3/4 (N=41) General disorders and administration site conditions Pyrexia 14 (34%) 0 Oedema periphera 6 (15%) 0 Chills 4 (10%) 0 Vomiting 10 (24%) 0 Gastrointestinal disorders Abdominal pain 5 (12%) 0 Diarrhoea 3 (7%) 0 Infections and infestations Upper respiratory tract 5 (12%) 0 infection Herpes zoster 4 (10%) 0 Nasopharyngitis 3 (7%) 0 Sinusitis 3 (7%) 0 Nervous system disorders Headache 9 (22%) 0 Cough 5 (12%) 0 Dyspnoea 3 (7%) 0 Oropharyngeal pain 3 (7%) 0 38

40 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Dosimetry Population System Organ Class Adverse event (Preferred Term) Overall (N=41) Grade 3/4 (N=41) Skin and subcutaneous tissue disorders Pruritus 6 (15%) 0 Erythema 3 (7%) 0 Urticaria 3 (7%) 0 Musculoskeletal and connective tissue disorders Myalgia 7 (17%) 0 Back pain 4 (10%) 0 Arthralgia 3 (7%) 0 Musculoskeletal and connective tissue disorders Thrombocytopenia 9 (22%) 9 (22%) Anemia 8 (20%) 4 (10%) Neutropenia 5 (12%) 4 (10%) Neoplasms a Myelodysplastic syndrome 4 (10%) 4 (10%) Acute myeloid leukemia 3 (7%) 3 (7%) Endocrine disorders Hypothyroidism 8 (20%) 0 Decreased appetite 4 (10%) 0 Hypotension 3 (7%) 0 a. Neoplasms include benign, malignant, and unspecified (including cysts and polyps). All second cancers are described in Section Data Source: Table 8.4 and Table Serious Adverse Events As of 29 May 2008, the cut-off date for this report and the date of the last subject last visit, 19 of 41 (46%) subjects in the Dosimetry and Biodistribution Population and 23 of 47 (49%) subjects in the ITT Population experienced a serious adverse event. A listing of serious adverse events by patient number is provided in Listing 16 and summarized in Table 8.6 and Table Narratives for subjects with the non-fatal serious adverse events are provided in Section Other Significant Adverse Events As reported previously, human anti-murine antibody (HAMA) samples for 43 of 47 (91%) subjects were analyzed by the sites local lab and 46 of 47 (98%) subjects were analyzed using a centralized validated HAMA radioimmunoassay. Based on both the local HAMA assay results and central laboratory results, 1 of 46 (2%) subjects (the same subject in both assays) developed HAMA following treatment [Section 8, RIT-II-001 Final Report Amendment on 29 March 2000]. The one HAMA-positive subject had a total body effective half-life of 75.1 hours [Section 4.7.2, Final Report 24 December 1997] or a total body residence time of hours. The total body residence time of hours is within the expected total body residence time range (50 to 150 hours) described in the US Prescribing Information for BEXXAR. 39

41 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Second Cancers There were 11 (27%) subjects (14 cases) in the Dosimetry Population (Table 8.4 and Table 15) and 12 (26%) subjects (16 cases) in the ITT Population (Table 8.10) who were diagnosed with second cancers after receiving the therapeutic dose of tositumomab and iodine I 131 tositumomab. Three subjects in the Dosimetry Population were diagnosed with two consecutive second cancers (Table 15). A comprehensive description is reported in Listing 16; prior chemotherapies and radiation therapies are reported in Listing 3 and Listing 4, respectively. Table 15 Second Cancers and MDS/AML n (%) No. Prior therapies for NHL Study Day of Diagnosis Myelodysplastic syndrome a, b, c 4 (10) Acute myeloid leukemia a, b, c 3 (7) Basal cell carcinoma d 1 (2) Adenocarcinoma 1 (2) Bladder transitional cell carcinoma 1 (2) Breast cancer in situ 1 (2) Mucoepidermoid carcinoma of the parotid 1 (2) Lung cancer a 1 (2) Skin cancer 1 (2) a. b. c. d. Two subjects in the ITT Population were diagnosed with basal cell carcinoma. Data Source: Listing Deaths As of the cut-off for this abbreviated study report, 34 of the 47 subjects who enrolled in the study (ITT Population) died (Table 8.11). Thirty-three of the 34 (97%) deaths in the ITT Population occurred greater than thirty days after the therapeutic dose; 23 of the 34 (68%) deaths in the ITT Population were due to progression of lymphoma. Thirty of the deaths were in the Dosimetry Population and 21 of 30 (70%) deaths were due to progression of lymphoma that occurred greater than 30 days after receiving the therapeutic dose (Table 8.7). Three subjects died due to AML, 3 subjects died due to transplant complications, 1 subject died due to cerebral herniation, and 1 subject died due to adenocarcinoma. Ten of the 30 deaths in the Dosimetry Population occurred within 1 year of the dosimetric dose, 15 of the 30 deaths occurred within 5 years of the dosimetric dose, and 7 of the 30 deaths occurred greater than 5 years of the dosimetric dose. Narratives for subjects who died are provided in Section

42 8. DISCUSSION AND CONCLUSIONS 8.1. Discussion CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) This study report updates the original dosimetry analysis that demonstrated that each site could accurately conduct the whole body dosimetry required for the safe and effective dosing of tositumomab and iodine I 131 tositumomab. Whereas the original study report assessed dosimetry at 6 to 8 time points after the dosimetric dose, the current analysis presents dosimetry analysis from 3 time points as described in the US Prescribing Information for BEXXAR. In addition, an independent visual assessment of gamma camera images was performed to determine the biodistribution of iodine I 131 tositumomab. The objective of the present retrospective analysis was to compare total body residence time calculations derived from probe counts and gamma camera counts obtained on Day 0, Day 3, and Day 7 after the dosimetric dose and to summarize the biodistribution by visual inspection of gamma camera images on the same time points Residence Times Determined from Probe and Gamma Camera A probe was first used for the purpose of total body residence time determination [Study RIT-I-000] and probe data were later demonstrated to produce equivalent results to those obtained by gamma camera in Study RIT-II-001. Subsequent studies [RIT-II-002, RIT- II-004 and CP ] used residence times based on three time points since the total body elimination kinetics were monoexponential and three time points were shown to adequately characterize the total body activity-time curve and reliably determine total body residence time for iodine I 131 tositumomab Original Analysis: Comparison of Probe and Gamma Camera with 6 to 8 Time Points The original dosimetry analysis of 45 subjects in RIT-II-001 demonstrated that total body residence time calculations were comparable when determined with probe or gamma camera counts from 6 to 8 time points. The dosimetry analysis compared total body residence times derived from probe counts and gamma camera counts in the same subjects receiving the dosimetric dose of tositumomab and iodine I 131 tositumomab. Both serial total body anterior and posterior probe and gamma camera counts were obtained within 1 hour after the administration of the dosimetric dose of iodine I 131 tositumomab and then daily for the next 7 days. These data were used to establish an overall time-activity pattern to enable comparison, of total body residence times. Total body residence time estimates from the probe and gamma camera counts were highly correlated (r = 0.973) when determined with probe or gamma camera counts from 6 to 8 time points. Forty-three of the 45 (96%) estimates from gamma camera counts were within 10% of the residence times estimates from sodium iodide probe counts. The mean total body residence time derived from probe counts was 94.1 hours, and the mean gamma camera total body residence time derived from gamma camera counts was 94.9 hours. 41

43 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Current Analysis: Comparison of Probe and Gamma Camera 3 Time Points Dosimetry There was high concordance (intraclass correlation coefficient) between total body residence times calculated from probe and gamma camera counts when either anterior counts or the geometric mean of anterior and posterior counts were used to the calculate total body residence times. The mean total body residence time derived from probe counts (geometric mean) was 94.5 ± 18.9 hours, and the mean total body residence time derived from gamma camera counts (geometric mean) was 95.0 ± 19.8 hours. The total body residence times had overlapping 95% confidence intervals suggesting that there was not a significant difference between methods of gamma count acquisition. Lastly, the point estimate of the ratio (1.005) was close to 1.00 and the 90% confidence interval of the point estimate (0.99, 1.02) was very narrow. Similar to the original analysis using 6 to 8 time points, 40 of the 41 evaluable subjects had a total body residence time between 50 and 150 hours, the expected range described in the US Prescribing Information for BEXXAR. One subject had a residence time of 159 hours determined by gamma camera counts and a residence time of 150 hours determined by probe counts. Although this subject had a residence time outside of the expected range, an independent visual inspection of the biodistribution concluded that the biodistribution was normal. Lastly, the mean total body residence time from Study RIT- II-001 was similar to mean reported from 980 subjects (96.7 hours; range: hours) described in the US Prescribing Information for BEXXAR Prescribed Activity of Therapeutic Dose Since there is an inverse relationship between total body residence time and prescribed activity (the ratio of the prescribed activity is the inverse or reciprocal of the total body residence time ratio), there was also high concordance between the prescribed activities (mci) derived from probe and gamma camera total body residence times. Subjects were effectively administered the therapeutic dose using either method of determining the prescribed activity (administration of the therapeutic dose was based on either the probe or gamma camera prescribe activity) and the mean prescribed activity derived from probe and gamma camera total body residence times were 85.8 mci and 85.3 mci, respectively. The point estimate for the ratio of the prescribed activity were close to 1.00 (0.995) and the 90% confidence interval was very narrow (0.984, 1.006) and well within the typical range of 0.80 to 1.25 for demonstrating bioequivalence Safety BEXXAR therapy has been associated with the risk of secondary malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). In this trial, 4 (10%) and 3 (7%) subjects experienced MDS and AML, respectively. BEXXAR therapy has also been associated with hematological adverse events, hypothyroidism, and hypersensitivity. The most frequently reported adverse events ( 10%) reported in this trial are as follows: nausea, fatigue, fever, vomiting, headache, thrombocytopenia, anemia, hypothyroidism, myalgia, edema, pruritus, neutropenia, cough, upper respiratory 42

44 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) tract infections, abdominal pain, chills, herpes zoster, back pain, and decreased appetite. These adverse events were similar to those observed in BEXXAR pivotal trials. 43

45 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 8.2. Conclusions The therapeutic dose of tositumomab and iodine I 131 tositumomab is based on subjectspecific total body clearance of the dosimetric dose. This enables individual subjects to receive a precisely adjusted total body therapeutic dose (prescribed activity) that maximizes the therapeutic effect and minimizes organ and bone marrow toxicity. There was high concordance between the total body residence times calculated from probe and gamma camera counts obtained at three time points regardless of whether anterior only counts or the geometric mean of anterior and posterior counts were used to determine the total body residence time. The intraclass correlation coefficient of the total body residence time derived from probe and camera anterior counts was The intraclass correlation coefficient of the total body residence time derived from probe and camera anterior and posterior counts (geometric mean) was The mean total body residence time (geometric mean) was 94.5 hours using probe counts and 95.0 hours using gamma camera counts. The range of values and magnitude of the 95% confidence intervals were similar for probe and gamma camera-derived total body residence times. The point estimate for the ratio of total body residence time (1.005) was close to 1.00 and the 90% confidence interval (0.99, 1.02) was narrow, indicating that the two methods of obtaining gamma counts were highly comparable. The total body residence time may be determined with gamma camera counts obtained with either a probe or a gamma camera. The prescribed activity (mci) calculated with the total body residence time derived from probe counts was highly comparable to that obtained with total body residence times derived from gamma camera counts. The mean prescribed activity derived from probe and gamma camera total body residence times were 85.8 mci and 85.3 mci, respectively. There was high concordance of the prescribed activities derived from probe and gamma camera total body residence times (intraclass correlation coefficient = 0.984). The point estimate for the ratio of the prescribed activity (0.995) was close to 1.00 and the 90% confidence interval (0.984, 1.006) was narrow, indicating that the two methods of obtaining gamma counts were highly comparable. All subjects had an expected biodistribution by visual inspection of gamma camera images. One subject with a total body residence time greater than 150 hours had an expected biodistribution by visual inspection of gamma camera images. Adverse events were similar to those observed in BEXXAR clinical studies. The most frequently reported adverse events ( 10%) were nausea, fatigue, fever, vomiting, headache, thrombocytopenia, anemia, hypothyroidism, myalgia, 44

46 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) edema, pruritus, neutropenia, cough, upper respiratory tract infections, abdominal pain, chills, herpes zoster, back pain, and decreased appetite. 45

47 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) 9. REFERENCES Anderson, KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Nadler LM. Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation. Blood. 1984; 63: BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab), US Prescribing Information. October Cardarelli PM, Quinn M, Buckman D, Fang Y, Colcher D, King DJ, Bebbington C, et al. Binding to CD20 by anti-b1 antibody or F(ab')(2) is sufficient for induction of apoptosis in B-cell lines. Cancer Immunol Immunother. 2002; 1: Kaminski MS, Zasadny KR, Francis IR, Milik AW, Ross CW, Moon SD, Crawford SM, Burgess JM, Petry NA, Butchko GM, Glen SD, and Wahl, RL. Radioimmunotherapy of B-cell lymphoma with [131I] anti-b1 (anti-cd20) antibody. New England Journal of Medicine. 1993; 329: Kaminski MS, et al. A multicenter phase II study of iodine-131 anti-b1 antibody in patients with chemotherapy-relapsed/refractory low-grade or transformed low-grade B- cell non-hodgkin s lymphoma (NHL) Blood. 1997:90 (suppl, pt 1):509a. Abstract Kaminski MS, Zasadny KR, Francis IR, Fenner MC, Ross CW, Milik AW, Estes J, Tuck M, Regan D, Fisher S, Glenn SD, Wahl RL. Iodine-131-anti-B1 radioimmunotherapy for B-cell lymhoma. Journal of Clinical Oncology. 1996; 14: Press OW, Eary JF, Appelbaum FR, Martin PJ, Badger CC, Nelp WB, Glen S, Butchko G, Fisher D, Porter B, Matthews DC, Fisher LD, Bernstein ID. Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. New England Journal of Medicine. 1993;329: Press OW, Howell-Clark J, Anderson S, Bernstein I. Retention of B-cell-specific monoclonal antibodies by human lymphoma cells. Blood. 1994;83: Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, Robertson JS, Howell RW, Wessels BW, Fisher DR, Weber DA, Brill AB. MIRD Pamphlet No 16 Techniques for Quantitative Radiopharmaceutical Biodistribution Data Acquisition and Analysis for Use in Human Radiation Dose Estimates. Journal Nuclear Medicine. 1999;40:37S-61S. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. Journal of Immunology. 1980; 125: Tedder T, Boyd A, Freedman A, Nadler L, Schlossman S. The B cell surface molecule is functionally linked with B cell activation and differentiation. Journal of Immunology. 1985; 135(2): Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ, Radford JA, Zelenetz AD, Tidmarsh GF, Stagg RJ, Kaminski MS. Multicenter phase II study of iodine

48 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-hodgkin's lymphomas. Journal Clinical Oncology :

49 This section contained patient narratives which are textual descriptions of medical history, treatment and outcome for individual patients who experienced a clinically important adverse event including serious adverse events during the trial. They have been excluded to protect patient privacy. This data may be made available subject to an approved research proposal and a determination of the ability to provide information from the specific narratives whilst protecting the patient s privacy. For further information please see the Patient Level Data section of the GSK Clinical Study Register.

50 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.1 Summary of Patient Demographics and Baseline Characteristics Total (N=41) Age (yrs) n 41 <=60 yrs 32 (78%) >60 yrs 9 (22%) n 41 Mean(sd) 51.9(11.5) Median 51.0 Min-Max Gender n 41 Female 19 (46%) Male 22 (54%) Ethnic Origin n 41 White 39 (95%) Oriental 1 (2%) Black 1 (2%) Baseline Weight (kg) n 41 Mean(sd) 75.1(16.5) Median 75.8 Min-Max Baseline Height (cm) n 41 Mean(sd) 171.7(9.7) Median Min-Max Page 1 of 3 118

51 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.1 Summary of Patient Demographics and Baseline Characteristics Total (N=41) Baseline Karnofsky Performance Score n 41 Mean(sd) 89.5(8.4) Median 90.0 Min-Max Months from diagnosis to entry n 41 Mean(sd) 63.5(58.7) Median 44.1 Min-Max Baseline LDH n 41 Elevated 15 (37%) Low/Normal 26 (63%) n 41 Mean(sd) 336.0(266.8) Median Min-Max Bulky Disease n 34 Yes 16 (47%) No 18 (53%) Page 2 of 3 119

52 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.1 Summary of Patient Demographics and Baseline Characteristics Total (N=41) Modified IPI Score n (12%) 2 18 (44%) 3 15 (37%) (7%) n 41 Mean(sd) 2.3(0.9) Median 2.0 Min-Max 0-4 Page 3 of 3 120

53 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.2 Summary of Disease Characteristics at Diagnosis and Study Entry Total (N=41) Stage at Diagnosis n 41 I 2 (5%) II 2 (5%) III 8 (20%) IV 29 (71%) Stage at Entry n 41 II 4 (10%) III 4 (10%) IV 33 (80%) Grade at Diagnosis n 41 Low 40 (98%) Intermediate 1 (2%) Grade at Enrollment n 41 Low 30 (73%) Intermediate 10 (24%) High 1 (2%) Page 1 of 3 121

54 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.2 Summary of Disease Characteristics at Diagnosis and Study Entry Total (N=41) Cell Type at Diagnosis n 41 Small lymphocytic with plasmacytoid differentiation 3 (7%) monocytoid B-cell 1 (2%) Small lymphocytic without plasmacytoid differentiation 2 (5%) Follicular, Small Cleaved 19 (46%) Follicular, Mixed (<50% large cell) 14 (34%) Diffuse large cell 1 (2%) Other 1 (2%) Cell Type at Entry n 41 Small lymphocytic with plasmacytoid differentiation 1 (2%) monocytoid B-cell 1 (2%) Small lymphocytic without plasmacytoid differentiation 2 (5%) Follicular, Small Cleaved 16 (39%) Follicular, Mixed (<50% large cell) 10 (24%) Follicular large cell 2 (5%) Diffused mixes small-cleaved cell & large cell 3 (7%) Diffuse large cell 3 (7%) Other 3 (7%) Page 2 of 3 122

55 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.2 Summary of Disease Characteristics at Diagnosis and Study Entry Total (N=41) Bone Marrow Percent Involvement n 41 >0% 21 (51%) 0% 20 (49%) n 41 <25% 41(100%) n 41 Mean(sd) 4.7(6.5) Median 2.5 Min-Max 0-22 Spleen involvement n 41 NA 32 (78%) Yes 7 (17%) No 2 (5%) Page 3 of 3 123

56 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.3 Summary of Prior Chemotherapy and Radiation Therapies Total (N=41) All Therapy Types n 41 Mean(sd) 5.1(2.1) Median 5.0 Min-Max 2-13 All Chemotherapies n 41 Mean(sd) 3.8(1.8) Median 4.0 Min-Max 1-8 Radiation Therapies n 41 Mean(sd) 1.3(0.8) Median 1.0 Min-Max 1-5 Page 1 of 1 124

57 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.4 Summary of Baseline Physical Exam Total (N=41) HEENT n 35 Normal 27 (77%) Abnormal 8 (23%) Respiratory n 35 Normal 31 (89%) Abnormal 4 (11%) Cardiovascular n 35 Normal 33 (94%) Abnormal 2 (6%) Gastrointestinal n 35 Normal 28 (80%) Abnormal 7 (20%) Musculoskeletal n 35 Normal 33 (94%) Abnormal 2 (6%) Neurological n 35 Normal 34 (97%) Abnormal 1 (3%) Page 1 of 2 125

58 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.4 Summary of Baseline Physical Exam Total (N=41) Nodes n 35 Normal 5 (14%) Abnormal 30 (86%) Other n 35 Normal 30 (86%) Abnormal 5 (14%) Page 2 of 2 126

59 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.5 Summary of Disposition For Subjects with Residence Time Data Total (N=41) Study Status for Discontinued 41 (100%) Reason for Withdrawal from Lost to follow-up 1 ( 2%) Subject choice 1 ( 2%) Progressive disease 34 ( 83%) Other 5 ( 12%) Reason for Withdrawal from Patient died 2 ( 5%) Other 8 ( 20%) Page 1 of 1 127

60 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 6.6 Summary of Disposition For All Subjects Total (N=47) Study Status for Discontinued 47 (100%) Reason for Withdrawal from Adverse reaction or serious side effect 1 ( 2%) Lost to follow-up 2 ( 4%) Subject choice 1 ( 2%) Progressive disease 38 ( 81%) Other 5 ( 11%) Reason for Withdrawal from Patient died 2 ( 4%) Other 9 ( 19%) Page 1 of 1 128

61 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.1 Dosing Summary for Tositumomab: Dosimetric Dose Total (N=41) Tositumomab Unlabeled Dose (mg) n 41 Mean(sd) 450.0(0.0) Median Min-Max Iodine Tositumomab Labeled Dose (mg) n 41 Mean(sd) 35.0(0.0) Median 35.0 Min-Max Duration of Tositumomab Unlabeled Infusion (minutes) n 40 Mean(sd) 66.3(17.6) Median 60.0 Min-Max Duration of Iodine Tositumomab Labeled Infusion (minutes) n 41 Mean(sd) 31.6(5.3) Median 30.0 Min-Max Page 1 of 2 129

62 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.1 Dosing Summary for Tositumomab: Dosimetric Dose Total (N=41) Iodine Tositumomab Administered Activity (mci) n 41 Mean(sd) 5.2(0.4) Median 5.2 Min-Max 3-6 Infusion Rate Adjustment n 41 Yes 3 (7%) No 38 (93%) Type of Infusion Adjustment [a] n 3 Decreased by 1/2 3(100%) Reason for Infusion Adjustment [a] n 3 Decreased SBP 1 (33%) Rigors 1 (33%) Other 1 (33%) Page 2 of 2 130

63 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.2 Dosing Summary for Tositumomab: Therapeutic Dose Total (N=41) Tositumomab Unlabeled Dose (mg) n 41 Mean(sd) 450.0(0.0) Median Min-Max Tositumomab/Iodine Tositumomab Labeled Dose (mg) n 41 Mean(sd) 35.0(0.4) Median 35.0 Min-Max Duration of Unlabeled Infusion (minutes) n 38 Mean(sd) 63.6(10.7) Median 60.0 Min-Max Duration of Iodine Labeled Infusion (minutes) n 40 Mean(sd) 32.8(16.7) Median 30.0 Min-Max Page 1 of 2 131

64 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.2 Dosing Summary for Tositumomab: Therapeutic Dose Total (N=41) Tositumomab/Iodine Tositumomab Administered Activity (mci) n 41 Mean(sd) 86.1(25.1) Median 80.6 Min-Max Whole body cgy Dose (T) n 41 Mean(sd) 73.0(4.8) Median 75.0 Min-Max Infusion Rate Adjustment n 41 Yes 2 (5%) No 39 (95%) Type of Infusion Adjustment n 1 Decreased by 1/2 1(100%) Page 2 of 2 132

65 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.3 Summary of Total Body Residence Times Probe (A) Camera (A) Probe (GM) Camera (GM) (hours) (hours) (hours) (hours) (N=41) (N=41) (N=41) (N=41) N Mean STD Median Min Max COV % CI (89.3,101.19) (89.83, (88.72,100.3) (88.99,101.1) for Mean ) Page 1 of 2 133

66 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.3 Summary of Total Body Residence Times % % % % Difference Difference Difference Difference Probe (A) Probe (GM) Probe (A) Camera (A) Vs Vs Vs Vs Camera (A) Camera (GM) Probe (GM) Camera (GM) (N=41) (N=41) (N=41) (N=41) N Mean STD Median Min Max COV % CI (-1.94,0.75) (-1.69,0.9) (0.06,1.42) (0.37,1.54) for Mean Page 2 of 2 134

67 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.4 Summary of AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) ANY EVENT 38 (93%) General disorders and administration site conditions Any Event 30 (73%) Fatigue 17 (41%) Pyrexia 14 (34%) Oedema peripheral 6 (15%) Chills 4 (10%) Local swelling 2 (5%) Mucous membrane disorder 2 (5%) Asthenia 1 (2%) Catheter site erythema 1 (2%) Catheter site pain 1 (2%) Chest discomfort 1 (2%) Extravasation 1 (2%) Feeling abnormal 1 (2%) Gait disturbance 1 (2%) Hunger 1 (2%) Infusion site 1 (2%) extravasation Localised oedema 1 (2%) Malaise 1 (2%) Page 1 of 9 135

68 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.4 Summary of AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Gastrointestinal disorders Any Event 25 (61%) Nausea 18 (44%) Vomiting 10 (24%) Abdominal pain 5 (12%) Diarrhoea 3 (7%) Stomatitis 2 (5%) Abdominal discomfort 1 (2%) Abdominal pain upper 1 (2%) Abdominal strangulated 1 (2%) hernia Abdominal tenderness 1 (2%) Colitis ulcerative 1 (2%) Constipation 1 (2%) Dry mouth 1 (2%) Dyspepsia 1 (2%) Gastrooesophageal reflux 1 (2%) disease Haemorrhoids 1 (2%) Rectal fissure 1 (2%) Retching 1 (2%) Page 2 of 9 136

69 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.4 Summary of AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Infections and infestations Any Event 17 (41%) Upper respiratory tract 5 (12%) infection Herpes zoster 4 (10%) Nasopharyngitis 3 (7%) Sinusitis 3 (7%) Pharyngitis 2 (5%) Urinary tract infection 2 (5%) Bacteraemia 1 (2%) Device related infection 1 (2%) Device related sepsis 1 (2%) Herpes virus infection 1 (2%) Infusion site cellulitis 1 (2%) Labyrinthitis 1 (2%) Oral herpes 1 (2%) Pneumococcal sepsis 1 (2%) Pseudomonas infection 1 (2%) Respiratory tract 1 (2%) infection Staphylococcal sepsis 1 (2%) Urinary tract infection 1 (2%) enterococcal Viral infection 1 (2%) Viral upper respiratory 1 (2%) tract infection Page 3 of 9 137

70 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.4 Summary of AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Nervous system disorders Any Event 17 (41%) Headache 9 (22%) Dizziness 2 (5%) Neuropathy peripheral 2 (5%) Somnolence 2 (5%) Syncope 2 (5%) Ageusia 1 (2%) Ataxia 1 (2%) Lethargy 1 (2%) Migraine 1 (2%) Post herpetic neuralgia 1 (2%) Presyncope 1 (2%) Respiratory, thoracic and mediastinal disorders Any Event 17 (41%) Cough 5 (12%) Dyspnoea 3 (7%) Oropharyngeal pain 3 (7%) Epistaxis 2 (5%) Productive cough 2 (5%) Choking sensation 1 (2%) Lung disorder 1 (2%) Nasal congestion 1 (2%) Nasal discomfort 1 (2%) Oropharyngeal blistering 1 (2%) Pharyngeal erythema 1 (2%) Pleuritic pain 1 (2%) Pulmonary embolism 1 (2%) Page 4 of 9 138

71 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.4 Summary of AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Skin and subcutaneous tissue disorders Any Event 17 (41%) Pruritus 6 (15%) Erythema 3 (7%) Urticaria 3 (7%) Rash 2 (5%) Rash erythematous 2 (5%) Blood blister 1 (2%) Ecchymosis 1 (2%) Erythema nodosum 1 (2%) Petechiae 1 (2%) Rash maculo-papular 1 (2%) Rash pruritic 1 (2%) Skin lesion 1 (2%) Musculoskeletal and connective tissue disorders Any Event 14 (34%) Myalgia 7 (17%) Back pain 4 (10%) Arthralgia 3 (7%) Arthritis 1 (2%) Flank pain 1 (2%) Groin pain 1 (2%) Limb discomfort 1 (2%) Musculoskeletal chest pain 1 (2%) Musculoskeletal pain 1 (2%) Neck pain 1 (2%) Pain in extremity 1 (2%) Pain in jaw 1 (2%) Page 5 of 9 139

72 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.4 Summary of AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Blood and lymphatic system disorders Any Event 13 (32%) Thrombocytopenia 9 (22%) Anaemia 8 (20%) Neutropenia 5 (12%) Febrile neutropenia 2 (5%) Leukopenia 2 (5%) Lymphadenopathy 1 (2%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Any Event 11 (27%) Myelodysplastic syndrome 4 (10%) Acute myeloid leukaemia 3 (7%) Adenocarcinoma 1 (2%) Basal cell carcinoma 1 (2%) Bladder transitional cell 1 (2%) carcinoma Breast cancer in situ 1 (2%) Lip and/or oral cavity 1 (2%) cancer Lung squamous cell 1 (2%) carcinoma stage unspecified Skin cancer 1 (2%) Endocrine disorders Any Event 8 (20%) Hypothyroidism 8 (20%) Page 6 of 9 140

73 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.4 Summary of AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Metabolism and nutrition disorders Any Event 5 (12%) Decreased appetite 4 (10%) Dehydration 2 (5%) Vascular disorders Any Event 5 (12%) Hypotension 3 (7%) Flushing 1 (2%) Orthostatic hypotension 1 (2%) Pallor 1 (2%) Injury, poisoning and procedural complications Any Event 4 (10%) Contusion 1 (2%) Excoriation 1 (2%) Muscle strain 1 (2%) Skin laceration 1 (2%) Thermal burn 1 (2%) Ear and labyrinth disorders Any Event 3 (7%) Tinnitus 2 (5%) Ear discomfort 1 (2%) Immune system disorders Any Event 3 (7%) Serum sickness 2 (5%) Anaphylactic reaction 1 (2%) Page 7 of 9 141

74 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.4 Summary of AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Renal and urinary disorders Any Event 3 (7%) Oliguria 1 (2%) Ureteric obstruction 1 (2%) Urinary hesitation 1 (2%) Investigations Any Event 2 (5%) Blood thyroid stimulating 1 (2%) hormone increased Weight decreased 1 (2%) Psychiatric disorders Any Event 2 (5%) Confusional state 1 (2%) Insomnia 1 (2%) Reproductive system and breast disorders Any Event 2 (5%) Ovarian cyst 1 (2%) Vaginal lesion 1 (2%) Cardiac disorders Any Event 1 (2%) Tachycardia 1 (2%) Congenital, familial and genetic disorders Any Event 1 (2%) Spinocerebellar ataxia 1 (2%) Page 8 of 9 142

75 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.4 Summary of AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Eye disorders Any Event 1 (2%) Conjunctivitis 1 (2%) Page 9 of 9 143

76 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.5 Summary of Grade 3/4 AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) ANY EVENT 21 (51%) Blood and lymphatic system disorders Any Event 11 (27%) Thrombocytopenia 9 (22%) Anaemia 4 (10%) Neutropenia 4 (10%) Febrile neutropenia 2 (5%) Leukopenia 2 (5%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Any Event 5 (12%) Myelodysplastic syndrome 4 (10%) Acute myeloid leukaemia 3 (7%) Lung squamous cell 1 (2%) carcinoma stage unspecified Gastrointestinal disorders Any Event 4 (10%) Abdominal pain 1 (2%) Abdominal strangulated 1 (2%) hernia Colitis ulcerative 1 (2%) Dyspepsia 1 (2%) Nausea 1 (2%) Stomatitis 1 (2%) Page 1 of 3 144

77 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.5 Summary of Grade 3/4 AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) General disorders and administration site conditions Any Event 3 (7%) Chills 1 (2%) Feeling abnormal 1 (2%) Pyrexia 1 (2%) Infections and infestations Any Event 3 (7%) Device related sepsis 1 (2%) Pseudomonas infection 1 (2%) Staphylococcal sepsis 1 (2%) Renal and urinary disorders Any Event 2 (5%) Oliguria 1 (2%) Ureteric obstruction 1 (2%) Respiratory, thoracic and mediastinal disorders Any Event 2 (5%) Dyspnoea 1 (2%) Pleuritic pain 1 (2%) Pulmonary embolism 1 (2%) Immune system disorders Any Event 1 (2%) Serum sickness 1 (2%) Page 2 of 3 145

78 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.5 Summary of Grade 3/4 AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Injury, poisoning and procedural complications Any Event 1 (2%) Contusion 1 (2%) Musculoskeletal and connective tissue disorders Any Event 1 (2%) Arthritis 1 (2%) Nervous system disorders Any Event 1 (2%) Ataxia 1 (2%) Psychiatric disorders Any Event 1 (2%) Confusional state 1 (2%) Skin and subcutaneous tissue disorders Any Event 1 (2%) Erythema nodosum 1 (2%) Page 3 of 3 146

79 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.6 Summary of Serious AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) ANY EVENT 19 (46%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Any Event 11 (27%) Myelodysplastic syndrome 4 (10%) Acute myeloid leukaemia 3 (7%) Adenocarcinoma 1 (2%) Basal cell carcinoma 1 (2%) Bladder transitional cell 1 (2%) carcinoma Breast cancer in situ 1 (2%) Lip and/or oral cavity 1 (2%) cancer Lung squamous cell 1 (2%) carcinoma stage unspecified Skin cancer 1 (2%) Infections and infestations Any Event 5 (12%) Bacteraemia 1 (2%) Device related infection 1 (2%) Device related sepsis 1 (2%) Herpes zoster 1 (2%) Pneumococcal sepsis 1 (2%) Staphylococcal sepsis 1 (2%) Urinary tract infection 1 (2%) enterococcal Page 1 of 3 147

80 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.6 Summary of Serious AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Blood and lymphatic system disorders Any Event 3 (7%) Febrile neutropenia 2 (5%) Thrombocytopenia 2 (5%) Anaemia 1 (2%) Leukopenia 1 (2%) Neutropenia 1 (2%) General disorders and administration site conditions Any Event 3 (7%) Pyrexia 2 (5%) Asthenia 1 (2%) Chills 1 (2%) Vascular disorders Any Event 3 (7%) Hypotension 2 (5%) Orthostatic hypotension 1 (2%) Gastrointestinal disorders Any Event 2 (5%) Abdominal strangulated 1 (2%) hernia Colitis ulcerative 1 (2%) Immune system disorders Any Event 1 (2%) Serum sickness 1 (2%) Page 2 of 3 148

81 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.6 Summary of Serious AEs: Subjects with Residence Time Data System Organ Class Total Preferred Term (N=41) Nervous system disorders Any Event 1 (2%) Syncope 1 (2%) Renal and urinary disorders Any Event 1 (2%) Oliguria 1 (2%) Respiratory, thoracic and mediastinal disorders Any Event 1 (2%) Pleuritic pain 1 (2%) Skin and subcutaneous tissue disorders Any Event 1 (2%) Erythema nodosum 1 (2%) Page 3 of 3 149

82 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.7 Summary of Deaths: Subjects with Residence Time Data Total (N=41) Subject Status n 41 Dead 30 (73%) Alive at last contact, follow-up ended 11 (27%) Alive at last contact, follow-up ongoing 0 Primary Cause of Death n 30 Progression of lymphoma 21 (70%) Complications related to study drug 0 Other 9 (30%) Time to Death From Last Dose n 30 <=30 Days 0 >30 Days 30(100%) Unknown 0 Page 1 of 1 150

83 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.8 Summary of AEs: All Subjects System Organ Class Total Preferred Term (N=47) ANY EVENT 44 (94%) General disorders and administration site conditions Any Event 34 (72%) Fatigue 19 (40%) Pyrexia 16 (34%) Oedema peripheral 6 (13%) Chills 5 (11%) Local swelling 2 (4%) Mucous membrane disorder 2 (4%) Asthenia 1 (2%) Catheter site erythema 1 (2%) Catheter site pain 1 (2%) Chest discomfort 1 (2%) Extravasation 1 (2%) Feeling abnormal 1 (2%) Gait disturbance 1 (2%) Hunger 1 (2%) Infusion site 1 (2%) extravasation Localised oedema 1 (2%) Malaise 1 (2%) Multi-organ failure 1 (2%) Page 1 of 9 151

84 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.8 Summary of AEs: All Subjects System Organ Class Total Preferred Term (N=47) Gastrointestinal disorders Any Event 29 (62%) Nausea 21 (45%) Vomiting 12 (26%) Abdominal pain 6 (13%) Diarrhoea 4 (9%) Stomatitis 2 (4%) Abdominal discomfort 1 (2%) Abdominal pain upper 1 (2%) Abdominal strangulated 1 (2%) hernia Abdominal tenderness 1 (2%) Anal fissure 1 (2%) Colitis ulcerative 1 (2%) Constipation 1 (2%) Dry mouth 1 (2%) Dyspepsia 1 (2%) Gastrointestinal 1 (2%) haemorrhage Gastrooesophageal reflux 1 (2%) disease Haemorrhoids 1 (2%) Proctalgia 1 (2%) Rectal fissure 1 (2%) Retching 1 (2%) Page 2 of 9 152

85 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.8 Summary of AEs: All Subjects System Organ Class Total Preferred Term (N=47) Infections and infestations Any Event 19 (40%) Upper respiratory tract 5 (11%) infection Herpes zoster 4 (9%) Nasopharyngitis 3 (6%) Sinusitis 3 (6%) Pharyngitis 2 (4%) Urinary tract infection 2 (4%) Viral infection 2 (4%) Bacteraemia 1 (2%) Bacterial infection 1 (2%) Device related infection 1 (2%) Device related sepsis 1 (2%) Herpes virus infection 1 (2%) Infusion site cellulitis 1 (2%) Labyrinthitis 1 (2%) Oral herpes 1 (2%) Pneumococcal sepsis 1 (2%) Pseudomonas infection 1 (2%) Respiratory tract 1 (2%) infection Staphylococcal sepsis 1 (2%) Urinary tract infection 1 (2%) enterococcal Viral upper respiratory 1 (2%) tract infection Page 3 of 9 153

86 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.8 Summary of AEs: All Subjects System Organ Class Total Preferred Term (N=47) Nervous system disorders Any Event 18 (38%) Headache 10 (21%) Dizziness 2 (4%) Neuropathy peripheral 2 (4%) Presyncope 2 (4%) Somnolence 2 (4%) Syncope 2 (4%) Ageusia 1 (2%) Ataxia 1 (2%) Lethargy 1 (2%) Migraine 1 (2%) Post herpetic neuralgia 1 (2%) Sensory disturbance 1 (2%) Respiratory, thoracic and mediastinal disorders Any Event 18 (38%) Cough 5 (11%) Dyspnoea 3 (6%) Oropharyngeal pain 3 (6%) Productive cough 3 (6%) Epistaxis 2 (4%) Choking sensation 1 (2%) Lung disorder 1 (2%) Nasal congestion 1 (2%) Nasal discomfort 1 (2%) Oropharyngeal blistering 1 (2%) Pharyngeal erythema 1 (2%) Pleuritic pain 1 (2%) Pulmonary embolism 1 (2%) Page 4 of 9 154

87 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.8 Summary of AEs: All Subjects System Organ Class Total Preferred Term (N=47) Skin and subcutaneous tissue disorders Any Event 18 (38%) Pruritus 6 (13%) Erythema 4 (9%) Urticaria 3 (6%) Rash 2 (4%) Rash erythematous 2 (4%) Blood blister 1 (2%) Ecchymosis 1 (2%) Erythema nodosum 1 (2%) Periorbital oedema 1 (2%) Petechiae 1 (2%) Rash maculo-papular 1 (2%) Rash pruritic 1 (2%) Skin lesion 1 (2%) Blood and lymphatic system disorders Any Event 17 (36%) Thrombocytopenia 11 (23%) Anaemia 10 (21%) Neutropenia 5 (11%) Febrile neutropenia 3 (6%) Leukopenia 2 (4%) Disseminated intravascular 1 (2%) coagulation Lymphadenopathy 1 (2%) Page 5 of 9 155

88 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.8 Summary of AEs: All Subjects System Organ Class Total Preferred Term (N=47) Musculoskeletal and connective tissue disorders Any Event 15 (32%) Myalgia 7 (15%) Arthralgia 4 (9%) Back pain 4 (9%) Arthritis 1 (2%) Flank pain 1 (2%) Groin pain 1 (2%) Limb discomfort 1 (2%) Musculoskeletal chest pain 1 (2%) Musculoskeletal pain 1 (2%) Neck pain 1 (2%) Pain in extremity 1 (2%) Pain in jaw 1 (2%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Any Event 12 (26%) Myelodysplastic syndrome 4 (9%) Acute myeloid leukaemia 3 (6%) Basal cell carcinoma 2 (4%) Adenocarcinoma 1 (2%) Bladder transitional cell 1 (2%) carcinoma Breast cancer in situ 1 (2%) Lip and/or oral cavity 1 (2%) cancer Neoplasms benign, malignant and unspecified (incl cysts and polyps) continues... Page 6 of 9 156

89 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.8 Summary of AEs: All Subjects System Organ Class Total Preferred Term (N=47)... continuing Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung squamous cell 1 (2%) carcinoma stage unspecified Skin cancer 1 (2%) Tongue neoplasm malignant 1 (2%) stage unspecified Endocrine disorders Any Event 9 (19%) Hypothyroidism 9 (19%) Vascular disorders Any Event 7 (15%) Hypotension 4 (9%) Flushing 2 (4%) Orthostatic hypotension 1 (2%) Pallor 1 (2%) Metabolism and nutrition disorders Any Event 6 (13%) Decreased appetite 5 (11%) Dehydration 2 (4%) Page 7 of 9 157

90 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.8 Summary of AEs: All Subjects System Organ Class Total Preferred Term (N=47) Injury, poisoning and procedural complications Any Event 4 (9%) Contusion 1 (2%) Excoriation 1 (2%) Muscle strain 1 (2%) Skin laceration 1 (2%) Thermal burn 1 (2%) Ear and labyrinth disorders Any Event 3 (6%) Tinnitus 2 (4%) Ear discomfort 1 (2%) Immune system disorders Any Event 3 (6%) Serum sickness 2 (4%) Anaphylactic reaction 1 (2%) Investigations Any Event 3 (6%) Weight decreased 2 (4%) Blood thyroid stimulating 1 (2%) hormone increased Renal and urinary disorders Any Event 3 (6%) Oliguria 1 (2%) Ureteric obstruction 1 (2%) Urinary hesitation 1 (2%) Page 8 of 9 158

91 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.8 Summary of AEs: All Subjects System Organ Class Total Preferred Term (N=47) Psychiatric disorders Any Event 2 (4%) Confusional state 1 (2%) Insomnia 1 (2%) Reproductive system and breast disorders Any Event 2 (4%) Ovarian cyst 1 (2%) Vaginal lesion 1 (2%) Cardiac disorders Any Event 1 (2%) Tachycardia 1 (2%) Congenital, familial and genetic disorders Any Event 1 (2%) Spinocerebellar ataxia 1 (2%) Eye disorders Any Event 1 (2%) Conjunctivitis 1 (2%) Page 9 of 9 159

92 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.9 Summary of Grade 3/4 AEs: All Subjects System Organ Class Total Preferred Term (N=47) ANY EVENT 26 (55%) Blood and lymphatic system disorders Any Event 14 (30%) Thrombocytopenia 11 (23%) Anaemia 4 (9%) Neutropenia 4 (9%) Febrile neutropenia 3 (6%) Leukopenia 2 (4%) Disseminated intravascular 1 (2%) coagulation Neoplasms benign, malignant and unspecified (incl cysts and polyps) Any Event 6 (13%) Myelodysplastic syndrome 4 (9%) Acute myeloid leukaemia 3 (6%) Basal cell carcinoma 1 (2%) Lung squamous cell 1 (2%) carcinoma stage unspecified Tongue neoplasm malignant 1 (2%) stage unspecified Gastrointestinal disorders Any Event 5 (11%) Abdominal pain 1 (2%) Abdominal strangulated 1 (2%) hernia Gastrointestinal disorders continues... Page 1 of 4 160

93 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.9 Summary of Grade 3/4 AEs: All Subjects System Organ Class Total Preferred Term (N=47)... continuing Gastrointestinal disorders Colitis ulcerative 1 (2%) Dyspepsia 1 (2%) Nausea 1 (2%) Stomatitis 1 (2%) Vomiting 1 (2%) General disorders and administration site conditions Any Event 4 (9%) Chills 1 (2%) Feeling abnormal 1 (2%) Multi-organ failure 1 (2%) Pyrexia 1 (2%) Infections and infestations Any Event 3 (6%) Device related sepsis 1 (2%) Pseudomonas infection 1 (2%) Staphylococcal sepsis 1 (2%) Renal and urinary disorders Any Event 2 (4%) Oliguria 1 (2%) Ureteric obstruction 1 (2%) Page 2 of 4 161

94 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.9 Summary of Grade 3/4 AEs: All Subjects System Organ Class Total Preferred Term (N=47) Respiratory, thoracic and mediastinal disorders Any Event 2 (4%) Dyspnoea 1 (2%) Pleuritic pain 1 (2%) Pulmonary embolism 1 (2%) Immune system disorders Any Event 1 (2%) Serum sickness 1 (2%) Injury, poisoning and procedural complications Any Event 1 (2%) Contusion 1 (2%) Investigations Any Event 1 (2%) Weight decreased 1 (2%) Musculoskeletal and connective tissue disorders Any Event 1 (2%) Arthritis 1 (2%) Nervous system disorders Any Event 1 (2%) Ataxia 1 (2%) Page 3 of 4 162

95 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.9 Summary of Grade 3/4 AEs: All Subjects System Organ Class Total Preferred Term (N=47) Psychiatric disorders Any Event 1 (2%) Confusional state 1 (2%) Skin and subcutaneous tissue disorders Any Event 1 (2%) Erythema nodosum 1 (2%) Vascular disorders Any Event 1 (2%) Hypotension 1 (2%) Page 4 of 4 163

96 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.10 Summary of Serious AEs: All Subjects System Organ Class Total Preferred Term (N=47) ANY EVENT 23 (49%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Any Event 12 (26%) Myelodysplastic syndrome 4 (9%) Acute myeloid leukaemia 3 (6%) Basal cell carcinoma 2 (4%) Adenocarcinoma 1 (2%) Bladder transitional cell 1 (2%) carcinoma Breast cancer in situ 1 (2%) Lip and/or oral cavity 1 (2%) cancer Lung squamous cell 1 (2%) carcinoma stage unspecified Skin cancer 1 (2%) Tongue neoplasm malignant 1 (2%) stage unspecified Blood and lymphatic system disorders Any Event 5 (11%) Febrile neutropenia 3 (6%) Thrombocytopenia 2 (4%) Anaemia 1 (2%) Disseminated intravascular 1 (2%) coagulation Leukopenia 1 (2%) Blood and lymphatic system disorders continues... Page 1 of 3 164

97 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.10 Summary of Serious AEs: All Subjects System Organ Class Total Preferred Term (N=47)... continuing Blood and lymphatic system disorders Neutropenia 1 (2%) Gastrointestinal disorders Any Event 5 (11%) Abdominal strangulated 1 (2%) hernia Anal fissure 1 (2%) Colitis ulcerative 1 (2%) Gastrointestinal 1 (2%) haemorrhage Vomiting 1 (2%) Infections and infestations Any Event 5 (11%) Bacteraemia 1 (2%) Device related infection 1 (2%) Device related sepsis 1 (2%) Herpes zoster 1 (2%) Pneumococcal sepsis 1 (2%) Staphylococcal sepsis 1 (2%) Urinary tract infection 1 (2%) enterococcal General disorders and administration site conditions Any Event 4 (9%) Pyrexia 2 (4%) Asthenia 1 (2%) Chills 1 (2%) Multi-organ failure 1 (2%) Page 2 of 3 165

98 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.10 Summary of Serious AEs: All Subjects System Organ Class Total Preferred Term (N=47) Vascular disorders Any Event 4 (9%) Hypotension 3 (6%) Orthostatic hypotension 1 (2%) Immune system disorders Any Event 1 (2%) Serum sickness 1 (2%) Musculoskeletal and connective tissue disorders Any Event 1 (2%) Arthralgia 1 (2%) Nervous system disorders Any Event 1 (2%) Syncope 1 (2%) Renal and urinary disorders Any Event 1 (2%) Oliguria 1 (2%) Respiratory, thoracic and mediastinal disorders Any Event 1 (2%) Pleuritic pain 1 (2%) Skin and subcutaneous tissue disorders Any Event 1 (2%) Erythema nodosum 1 (2%) Page 3 of 3 166

99 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.11 Summary of Deaths: All Subjects Total (N=47) Subject Status n 47 Dead 34 (72%) Alive at last contact, follow-up ended 13 (28%) Alive at last contact, follow-up ongoing 0 Primary Cause of Death n 34 Progression of lymphoma 23 (68%) Complications related to study drug 0 Other 11 (32%) Time to Death From Last Dose n 34 <=30 Days 1 (3%) >30 Days 33 (97%) Unknown 0 Page 1 of 1 167

100 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.12 Summary of Prescribed Activity (mci) % Difference Prescribed Prescribed Activity Presecribed Activity Activity Probe (GM) Camera (GM) Probe (GM) (mci) (mci) Vs (N=41) (N=41) Camera (GM) (N=41) N Mean STD Median Min Max COV % CI (78.27,93.29) (78,92.64) (-0.73,1.87) for Mean Page 1 of 1 168

101 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Table 8.13 Summary of Dosimetry Analysis Geometric LS Mean 90% CI Parameter Comparison Probe Camera Ratio Lower Upper Prescribed activity Camera vs Probe (mci) Total Body Camera vs Probe Residence Time (h) Page 1 of 1 169

102 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Figure 1 Probe (A) vs Camera (A) Total Body Residence Time (hours) (Data as of: 20MAY10) Camera (A) Residence Time (hour) y = * x r = Intraclass Correlation Coefficient= Probe (A) Residence Time (hour) 170

103 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Figure 2 Probe (GM) vs Camera (GM) Total Body Residence Time (hours) (Data as of: 20MAY10) Camera (GM) Residence Time (hour) y = * x r = Intraclass Correlation Coefficient= Probe (GM) Residence Time (hour) 171

104 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Figure 3 Probe (A) vs Probe (GM) Total Body Residence Time (hours) (Data as of: 20MAY10) Probe (GM) Residence Time (hour) y = * x r = Intraclass Correlation Coefficient= Probe (A) Residence Time (hour) 172

105 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Figure 4 Camera (A) vs Camera (GM) Total Body Residence Time (hours) (Data as of: 20MAY10) Camera (GM) Residence Time (hour) y = * x r = Intraclass Correlation Coefficient= Camera (A) Residence Time (hour) 173

106 CONFIDENTIAL UM2009/00281/00 BEX RIT-II-001 Protocol: BEX Population: ITT-Exposed Figure 5 Probe (GM) vs Camera (GM) Prescribed Activity (mci) (Data as of: 20MAY10) Camera (GM) Prescribed Activity (mci) y = * x r = Intraclass Correlation Coefficient= Probe (GM) Prescribed Activity (mci) 174

107 CONFIDENTIAL UM2009/00281/00 BEX Synopsis Study Number: BEX (RIT-II-001) Title: Multicenter, Phase II Dosimetry/Validation Study of 131 Iodine Anti-B1 (Murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas That Have Transformed to Higher Grade Histologies Investigator(s): Multicenter Study center(s): 5 centers in the United States and 2 centers in the United Kingdom: Publication(s): Kaminski MS, et al. A multicenter phase II study of iodine-131 anti-b1 antibody in patients with chemotherapy-relapsed/refractory low-grade or transformed low-grade B- cell non-hodgkin s lymphoma (NHL) Blood. 1997:90 (suppl, pt 1):509a. Abstract Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ, Radford JA, Zelenetz AD, Tidmarsh GF, Stagg RJ, Kaminski MS. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-hodgkin's lymphomas. Journal Clinical Oncology : Study Period: 5 December May 2008 Phase of Development: II Objectives: 1. To validate the dosimetry methods for 7 to 10 clinical research sites by demonstrating concordance of dosimetry estimates to those at the 2. To determine the response rate, response duration, time to treatment failure, and survival after treatment with tositumomab and iodine I 131 tositumomab [previously refer to as Iodine-131 Anti-B1 Antibody]. 3. To assess patient-specific radiation doses and the dosimetry of iodine I 131 tositumomab. 4. To assess the safety of iodide I 131 tositumomab. 5. To test the feasibility of using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30+3 validated questionnaire for assessing the quality of life of treated patients. Methodology: In this multicenter, Phase II study, 47 subjects with low-grade or transformed low-grade B-NHL were enrolled from 5 December 1995 and 20 November Subjects received a dosimetric dose of tositumomab and iodine I 131 tositumomab followed by a therapeutic dose of tositumomab and iodine I 131 tositumomab. The dosimetric dose 1

108 CONFIDENTIAL UM2009/00281/00 BEX involved the intravenous (IV) administration of 450 mg of unlabeled tositumomab followed by 5 mci of iodine I 131 tositumomab. Serial anterior and posterior whole body sodium iodide probe scintillation counts and whole body conjugate view gamma camera scans were obtained approximately 1 hour after the administration of the dosimetric dose and then daily for the next 7 days. The radiation counts from the probe measurements were used to determine the radioactive clearance from the subject and, subsequently, the dose (in mci) of iodine I 131 tositumomab required to deliver a 75 cgy whole body dose of radiation (the therapeutic dose). The radiolabeled portion of the therapeutic dose was also preceded by an infusion of 450 mg of unlabeled tositumomab. In Amendment 3 of the protocol, the method of determining the dose was changed from sodium iodide probe counts to gamma camera counts, and dosing was adjusted for subjects with a low platelet count (100, ,999 cells/mm3) and/or obesity. For obese subjects (subjects weighing more than 137% of their calculated lean body weight), the calculation to determine the administered activity (mci) was performed using the maximum effective mass (i.e., the minimum of the subject s mass and 137% of their calculated lean body weight). The administered activity (mci) for subjects with a baseline platelet count of 100, ,999 cells/mm 3 was reduced to a 65 cgy total body dose, after any adjustment for obesity. Number of subjects: 47 Diagnosis and main criteria for inclusion: Male or non-pregnant, non-nursing female at least 18 years of age and diagnosed with follicular or transformed follicular NHL. Treatment administration: Subjects received a dosimetric dose of tositumomab and iodine I 131 tositumomab followed by a therapeutic dose of tositumomab and iodine I 131 tositumomab. The dosimetric dose involved the intravenous (IV) administration of 450 mg of unlabeled tositumomab followed by 5 mci of iodine I 131 tositumomab. Serial anterior and posterior whole body sodium iodide probe scintillation counts and whole body conjugate view gamma camera scans were obtained approximately 1 hour after the administration of the dosimetric dose and then daily for the next 7 days. The radiation counts from the probe measurements were used to determine the radioactive clearance from the subject and, subsequently, the dose (in mci) of iodine I 131 tositumomab required to deliver a 75 cgy whole body dose of radiation (the therapeutic dose). The radiolabeled portion of the therapeutic dose was also preceded by an infusion of 450 mg of unlabeled tositumomab. In Amendment 3 of the protocol, the method of determining the dose was changed from sodium iodide probe counts to gamma camera counts, and dosing was adjusted for subjects with a low platelet count (100, ,999 cells/mm3) and/or obesity. For obese subjects (subjects weighing more than 137% of their calculated lean body weight), the calculation to determine the administered activity (mci) was performed using the maximum effective mass (i.e., the minimum of the subject s mass and 137% of their calculated lean body weight). The administered activity (mci) for subjects with a baseline platelet count of 100, ,999 cells/mm 3 was reduced to a 65 cgy total body dose, after any adjustment for obesity. 2

109 CONFIDENTIAL UM2009/00281/00 BEX Criteria for evaluation: Subjects enrolled in Study RIT-II-001 were scheduled to be assessed for life by physical examination, laboratory evaluation, and assessment of human-anti-mouse antibodies (HAMA). Subjects participating in Study RIT-II-001 who completed at least two years of follow-up after treatment with tositumomab and/or Iodine I 131 tositumomab were invited to enroll in multi-center study BEX (formerly Corixa study CCBX ) for the long-term follow-up up to 10 years. Subjects enrolled in Study BEX were followed for continued response (as applicable) and safety every 6 months for Years 3 through 5 status post treatment with tositumomab and/or Iodine I 131 tositumomab. Beginning at Year 6, patients were assessed annually through Year 10 (inclusive). In addition to continued assessment for survival, disease status, and including subsequent therapy for NHL, subjects were evaluated for long term safety, including the use of thyroid medication, development of hypothyroidism, myelodysplasia (MDS), acute myelogenous leukemia (AML), and all other secondary malignancies. Additionally, these patients were followed for the development of any adverse events deemed by the Principal Investigator as being possibly or probably related to the patient s previous treatment with Tositumomab and/or Iodine I 131 Tositumomab. Laboratory evaluations consisting of a TSH level (for all patients) and a complete blood cell (CBC) count with a differential and platelet count (for patients in continuing response only) were obtained annually through Year 10 post treatment with tositumomab and/or Iodine I 131 tositumomab. Study Population: The current abbreviated study report presents retrospective dosimetry analysis assessments of 41 subjects (Dosimetry Population) who completed probe measurements and gamma camera scans on the following three time points: Day 0, Days 2 to 4, and Days 6 to 7. Original dosimetry worksheets were available for 41 evaluable subjects who received both probe measurements and gamma camera scans. In addition, the current report presents an independent assessment of biodistribution and dosimetry calculations based on three time points of the 41 subjects that was not performed in the original study report. Dosimetry: Both serial total body anterior and posterior gamma camera scans and sodium iodide probe scintillation counts were obtained at 6 to 8 time points between Days 0 and 7, within 1 hour after the administration of the dosimetric dose of iodine I 131 tositumomab and then daily for the next 7 days. Probe counts and gamma camera counts, collected on Day 0, Day 2 to 4, and Day 6 to 7, as described in the US Prescribing Information for BEXXAR, were used to establish an overall time-activity pattern to enable comparison of probe and gamma camera total body residence times. Anterioronly and anterior and posterior (geometric mean) derived total body residence times were calculated. Prescribed Activities: The prescribed activity, defined as the millicurie amount of I-131 required to deliver a total body radiation absorbed dose of 75 cgy (or 65 cgy if necessary if platelet count of 100,000 to <150,000 platelets/mm 3 ), was determined using the total body residence time (derived from gamma counts obtained with a probe or a gamma camera), the desired total body dose (cgy), and the patient-specific activity hours. 3

110 CONFIDENTIAL UM2009/00281/00 BEX Statistical methods: Data were summarized using SAS, version 8.2 and include retrospective dosimetry analysis which were performed on a subpopulation of 41 subjects for whom counts were obtained using both a scintillation probe and a gamma camera and original dosimetry worksheets were provided. Summary statistics (mean, median, standard deviation, minimum and maximum) were calculated for the total body residence times (Probe (A), Camera (A), Probe (GM) and Camera (GM) and prescribed activity (GM). Percent differences were also calculated for total body residence time [Probe (A) vs Camera (A) and for Probe (GM) vs Camera (GM)] and for prescribed activity [Probe (GM) vs Camera (GM)]. Summary statistics and 95% confidence intervals were calculated for the actual values as well as for the percent change between methods. The Pearson correlation coefficient was calculated as a measure of the linear relationship between the Probe and Camera methods. The intraclass correlation coefficient was also calculated as a measure of agreement or concordance between the total body residence times derived from probe counts and total body residence times derived from gamma camera counts. Following log e -transformation, total body residence time and prescribed activity values were analyzed to assess the comparability of values derived from gamma counts using the gamma camera or using the probe. Point estimates and associated 90% CIs were constructed using the residual variance. These point estimates and CIs were exponentially back-transformed to obtain point estimates and associated 90% CIs for the ratios of the total body residence time and prescribed activity values for gamma camera to probe. Biodistribution Assessments: The independent assessment of biodistribution was performed by a nuclear medicine physician who visually examined whole body images of subjects who received iodine I-131 tositumomab administered during the dosimetric phase of the study (Days 0-7). The independent reviewer determined whether the biodistribution at each time point for the 41 evaluable subjects was expected or altered according to the Read Rules Document developed by BioClinica (Charter for the Independent Review of Biodistribution), based on the US Prescribing Information for BEXXAR. Safety: Subjects enrolled in Study RIT-II-001 were scheduled to be assessed for life by physical examination, laboratory evaluation, and assessment of human-anti-mouse antibodies (HAMA) as previously described (RIT-II-001, 24 December 1997). Subjects participating in Study RIT-II-001 who completed at least two years of follow-up after treatment with tositumomab and/or Iodine I 131 tositumomab were invited to enroll in multi-center study BEX (formerly Corixa study CCBX ) for the long-term follow-up up to 10 years. Upon providing informed consent, subjects enrolled in Study BEX were followed for continued response (as applicable) and safety every 6 months for Years 3 through 5 status post treatment with tositumomab and/or Iodine I 131 tositumomab. Beginning at Year 6, patients were assessed annually through Year 10 (inclusive). In addition to continued assessment for survival, disease status, and including subsequent therapy for NHL, subjects were evaluated for long term safety, including the use of thyroid medication, development of hypothyroidism, myelodysplasia (MDS), acute myelogenous leukemia (AML), and all other secondary malignancies. 4

111 CONFIDENTIAL UM2009/00281/00 BEX Additionally, these patients will be followed for the development of any adverse events deemed by the Principal Investigator as being possibly or probably related to the patient s previous treatment with Tositumomab and/or Iodine I 131 Tositumomab. Laboratory evaluations consisting of a TSH level (for all patients) and a complete blood cell (CBC) count with a differential and platelet count (for patients in continuing response only) were obtained annually through Year 10 post treatment with tositumomab and/or Iodine I 131 tositumomab. Summary: Study Population Forty-seven subjects were enrolled between 5 December 1995 and 20 November 1996 and originally described in the Intent to Treat (ITT) Population of the RIT-II-001 Final Report (submitted to FDA on 24 Dec 1997). The original report included dosimetry analysis of 45 out of 47 enrolled subjects who completed 6 to 8 time points of both probe measurements and gamma camera scans after receiving the dosimetric dose. The current retrospective dosimetry and biodistribution analysis includes assessments of 41 subjects (Dosimetry Population) who completed probe measurements and gamma camera scans on the following three time points: Day 0, Days 2 to 4, and Days 6 to 7. The demographics and baseline characteristics of the 41 subjects (Dosimetry Population) are presented below. The median time from the diagnosis of B-NHL to study entry was 44 months, and subjects had received a median of 5 prior therapies (range: 2 13). Thirty of 41 (73%) subjects had low-grade B-NHL at enrollment, and 37 subjects (90%) had stage III or IV disease at study entry. The majority of subjects (88%) had two or more high-risk factors as defined by the International Prognostic Index (IPI). Sixteen of 34 (47%) subjects evaluated for bulky disease had bulky disease (>500 g). Twenty of 41 subjects (49%) had no bone marrow involvement, and no subjects had greater than 25% bone marrow involvement. 5

112 Subject Demographics and Baseline Characteristics CONFIDENTIAL UM2009/00281/00 BEX Subject Characteristics Dosimetry Population (n=41) Demographics Male, N (%) 22 (54) Female, N (%) 19 (46) Age, median years (range) 51 (23-74) Weight, median kg, (range) 76 (45-112) Ethnic origin White, N (%) 39 (95) Months from diagnosis to entry, median (range) 44 (8-263) Prior therapies, median (range) 5 (2-13) Prior chemotherapies 4 (1-8) Prior radiation therapies 1 (1-5) Grade at Enrollment, n (%) Low 30 (73) Intermediate 10 (24) High 1 (2) Stage at Entry, n (%) II 4 (10) III 4 (10) IV 33 (80) Cell type NHL at enrollment Small lymphocytic with plasmocytoid 1 (2) differentiation Monocytoid B-cell 1 (2) Small lymphocytic without plasmocytoid 2 (5) differentiation Follicular, small cleaved 16 (39) Follicular, mixed small cleaved and large cell 10 (24) Follicular, large cell lymphoma 2 (5) Diffused mixed small cleaved and diffuse 3 (7) large cell Diffuse large cell lymphoma 3 (7) Stage at enrollment, N (%) II 4 (10) III 4 (10) IV 33 (80) Bone marrow involvement, N (%) < 0% 20 (49) > 0% 21 (51) > 25%, 0 Bulky disease, N (%) 16 (47) Spleen Involvement (Yes), N (%) 7 (17) Elevated baseline LDH > 200 IU/L, N (%) 15 (37) Modified IPI, International Prognostic Index (12) 2 18 (44) 3 15( 37) (7) a. Baseline spleen measurements were obtained for 9 subjects. 6

113 CONFIDENTIAL UM2009/00281/00 BEX Total Body Residence Time Total body residence times calculated from the probe and gamma camera counts had high concordance regardless of whether anterior only counts or the geometric mean of anterior and posterior counts were used to the calculate total body residence time. There was high concordance between total body residence times calculated from probe and gamma camera counts as demonstrated by the intraclass correlation coefficients that were close to When anterior-only counts were used to calculate the total body residence time, the intraclass correlation coefficient between probe and gamma camera was Similarly, when the geometric mean of anterior and posterior counts was used, the intraclass correlation coefficient between probe and gamma camera was The mean total body residence times, calculated with the geometric mean of anterior and posterior counts as described in the US Prescribing Information, were 94.5 ± 18.9 hours using probe counts and 95.0 ± 19.8 hours using gamma camera counts. Similarly, the mean total body residence times, calculated with anterior only counts, were 95.2 ± 19.4 hours using probe counts and 95.9 ± 19.9 hours using gamma camera counts. The 95% confidence intervals overlap for residence times derived from probe and gamma camera counts, suggesting that there was not a significant difference between total body residence times derived from probe and gamma camera counts. In addition, the mean percent differences of total body residence times derived from probe and gamma camera counts were small and probe and gamma camera total body residence times were highly correlated. Furthermore, the results from the current analysis using 3 time points were similar to the original analysis using 6 to 8 time points. Comparison Total Body Residence Times Derived from Probe and Camera - Three Time Points Total Body Residence Time, hours (n=41) Probe (A) Camera (A) Probe (AP) Camera (AP) Mean (SD) 95.2 (19.4) 95.9 (19.9) 94.5 (18.9) 95.0 (19.8) Median % CI (89.3, 101.2) (89.8, 102.0) (88.7, 100.3) (88.9, 101.1) Range 63.0 to to to to Percent Difference Total Body Residence Time (n=41) Probe (A) vs. Camera (A) Probe (AP) vs. Camera (AP) Probe (A) vs. Probe (AP) Camera (A) vs. Camera (AP) Mean (SD) -0.6 (4.39) -0.4 (4.23) 0.7 (2.21) 1.0 (1.90) Median % CI (-1.94, 0.75) (-1.69, 0.90) (0.06, 1.42) (0.37, 1.54) range to to to to 10.0 Intraclass Correlation Coefficient (n=41) Probe (A) vs. Camera (A) Probe (AP) vs. Camera (AP) Residence times were determined with anterior (A) counts or the geometric mean of anterior and posterior counts (AP). 7

114 CONFIDENTIAL UM2009/00281/00 BEX Correlation of total body residence times from gamma camera and probe counts The total body residence times derived from gamma counts using probe or camera were also compared by constructing the 90% confidence interval of the ratio of total body residence times from camera to probe. The point estimate for the ratio was close to 1.00 (1.005), and the 90% confidence interval (0.99, 1.02) was narrow. These results demonstrated that the total body residence time derived from probe counts was highly comparable to that derived from gamma camera counts. Point Estimate and 90% Confidence Interval for Ratio of Total Body Residence Times Using Camera to Total Body Residence Times Using Probe Parameter Point Estimate of Ratio 90% Confidence Interval Total body residence time (h) , Prescribed Activity The prescribed activity, defined as the millicurie amount of I-131 required to deliver a total body radiation absorbed dose of 75 cgy (or 65 cgy if necessary if platelet count of 100,000 to <150,000 platelets/mm 3 ), was determined using the total body residence time (derived from gamma counts obtained with a probe or a gamma camera), the desired total body dose (cgy), and the patient-specific activity hours. Similar to the comparison of total body residence times, the mean prescribed activities (mci) were comparable whether derived from probe total body residence times or camera total body residence times. In addition, there was high concordance (intraclass correlation coefficient = 0.984) between the prescribed activities derived from probe and gamma camera total body residence times. 8

115 CONFIDENTIAL UM2009/00281/00 BEX Comparison Prescribed Activities Derived from Probe and Camera Total Body Residence Times - Three Time Points Probe (AP) Prescribed Activity, mci (n=41) Camera (AP) Mean (SD) 85.8 (24.5) 85.3 (23.9) Median % CI 78.3, , 92.6 Range 40.4 to to Percent Difference Prescribed Activity (n=41) Probe (AP) vs. Camera (AP) Mean (SD) 0.6 (4.3) Median % CI -0.7, 1.9 Range -7.7 to 11.9 Intraclass Correlation Coefficient (n=41) Probe (AP) vs. Camera (AP) Prescribed activities were determined with the geometric mean of anterior and posterior counts (AP) as required in the US Prescribing Information for BEXXAR. The prescribed activities (mci) calculated from total body residence times derived from gamma counts using probe or camera were also compared by constructing the 90% confidence interval of the ratio of the prescribed activity from camera to probe. The point estimate for the ratio of the prescribed activity was close to 1.00 (0.995) and the 90% confidence interval was narrow. These results demonstrated that the prescribed activity calculated with the total body residence time derived from probe counts was comparable to that obtained with total body residence times derived from gamma camera counts. Point Estimate and 90% Confidence Interval for Ratio of Camera and Probe Prescribed activities Parameter Point Estimate of Ratio 90% Confidence Interval Prescribed activity (mci) , Administered Activity The original activity estimates, first calculated using 6 to 8 time points using either probe or gamma camera total body residence times, were similar to the prescribed activities calculated with three time points in the current analysis (RIT-II-001, 24 Dec 1997, Listing 21.2). The mean administered activity of the therapeutic dose for 47 subjects was 87.6 mci (standard deviation 25.0) and the range across subjects was 45.2 to 177 mci (RIT-II-001, 24 Dec 1997, Section 4.4 and Table 2.6). 9

116 CONFIDENTIAL UM2009/00281/00 BEX Biodistribution Gamma camera images of subjects were retrospectively evaluated by an Independent Reviewer to determine whether subjects had an expected or altered biodistribution after receiving the dosimetric dose of tositumomab and iodine I-131 tositumomab. The independent review of biodistribution was performed with the same time points described in US Prescribing Information for BEXXAR (Day 0, Day 2 to 4, and Day 6 to 7) after the dosimetric dose. All 41 subjects evaluated from Study RIT-II-001 displayed expected organ distribution kinetics. Most of the radioactivity on the first time point resided in the blood pool (heart and major blood vessels) with secondary uptake in the liver and spleen. Among subjects with an expected biodistribution, thyroid uptake was observed in 10 subjects, lung uptake was observed in 2 subjects, stomach uptake was observed in 4 subjects, and skeletal uptake was observed in 1 subject. One subject with a total body residence time greater than 150 hours had an expected biodistribution despite being outside of the expected range of 50 to 150 hours according to the US Prescribing Information. Safety A summary of adverse events of subjects followed under the original protocol RIT-II-001 and the long term follow up protocol BEX from 5 December 1995 to 29 May 2008 is presented below. Nineteen of 41 (46%) subjects in the Dosimetry and Biodistribution Population and 23 of 47 (49%) subjects in the ITT Population experienced a serious adverse event. There were 11 (27%) subjects (14 cases) in the Dosimetry Population and 12 (26%) subjects (16 cases) in the ITT Population who were diagnosed with second cancers after receiving the therapeutic dose of tositumomab and iodine I 131 tositumomab. Four (10%) and 3 (7%) subjects experienced MDS and AML, respectively. 10

117 Summary of Adverse Events (Overall 3 Subjects) System Organ Class Adverse event (Preferred Term) CONFIDENTIAL UM2009/00281/00 BEX Dosimetry Population Overall (N=41) Grade 3/4 (N=41) General disorders and administration site conditions Pyrexia 14 (34%) 0 Oedema periphera 6 (15%) 0 Chills 4 (10%) 0 Vomiting 10 (24%) 0 Gastrointestinal disorders Abdominal pain 5 (12%) 0 Diarrhoea 3 (7%) 0 Infections and infestations Upper respiratory tract 5 (12%) 0 Infection Herpes zoster 4 (10%) 0 Nasopharyngitis 3 (7%) 0 Sinusitis 3 (7%) 0 Nervous system disorders Headache 9 (22%) 0 Cough 5 (12%) 0 Dyspnoea 3 (7%) 0 Oropharyngeal pain 3 (7%) 0 Skin and subcutaneous tissue disorders Pruritus 6 (15%) 0 Erythema 3 (7%) 0 Urticaria 3 (7%) 0 Musculoskeletal and connective tissue disorders Myalgia 7 (17%) 0 Back pain 4 (10%) 0 Arthralgia 3 (7%) 0 Musculoskeletal and connective tissue disorders Thrombocytopenia 9 (22%) 9 (22%) Anemia 8 (20%) 4 (10%) Neutropenia 5 (12%) 4 (10%) Neoplasms a Myelodysplastic syndrome 4 (10%) 4 (10%) Acute myeloid leukemia 3 (7%) 3 (7%) Endocrine disorders Hypothyroidism 8 (20%) 0 Decreased appetite 4 (10%) 0 Hypotension 3 (7%) 0 a. Neoplasms include benign, malignant, and unspecified (including cysts and polyps). Thirty-four of the 47 subjects who enrolled in the study (ITT Population) died. Twentythree of the 34 (68%) deaths in the ITT Population were due to progression of lymphoma. Thirty of the deaths were in the Dosimetry Population and 21 of 30 (70%) deaths were due to progression of lymphoma that occurred greater than 30 days after receiving the therapeutic dose. 11

118 CONFIDENTIAL UM2009/00281/00 BEX Conclusions: There was high concordance between the total body residence times calculated from probe and gamma camera counts obtained at three time points regardless of whether anterior only counts or the geometric mean of anterior and posterior counts were used to determine the total body residence time. The intraclass correlation coefficient of the total body residence time derived from probe and camera anterior counts was The intraclass correlation coefficient of the total body residence time derived from probe and camera anterior and posterior counts (geometric mean) was The mean total body residence time (geometric mean) was 94.5 hours using probe counts and 95.0 hours using gamma camera counts. The range of values and magnitude of the 95% confidence intervals were similar for probe and gamma camera-derived total body residence times. The point estimate for the ratio of total body residence time (1.005) was close to 1.00 and the 90% confidence interval (0.99, 1.02) was narrow, indicating that the two methods of obtaining gamma counts were highly comparable. The total body residence time may be determined with gamma camera counts obtained with either a probe or a gamma camera. The prescribed activity (mci) calculated with the total body residence time derived from probe counts was highly comparable to that obtained with total body residence times derived from gamma camera counts. The mean prescribed activity derived from probe and gamma camera total body residence times were 85.8 mci and 85.3 mci, respectively. There was high concordance of the prescribed activities derived from probe and gamma camera total body residence times (intraclass correlation coefficient = 0.984). The point estimate for the ratio of the prescribed activity (0.995) was close to 1.00 and the 90% confidence interval (0.984, 1.006) was narrow, indicating that the two methods of obtaining gamma counts were highly comparable. All subjects had an expected biodistribution by visual inspection of gamma camera images. One subject with a total body residence time greater than 150 hours had an expected biodistribution by visual inspection of gamma camera images. Adverse events were similar to those observed in BEXXAR clinical studies. The most frequently reported adverse events ( 10%) were nausea, fatigue, fever, vomiting, headache, thrombocytopenia, anemia, hypothyroidism, myalgia, edema, pruritus, neutropenia, cough, upper respiratory tract infections, abdominal pain, chills, herpes zoster, back pain, and decreased appetite. Date of Report: 17 September

119 CONFIDENTIAL The GlaxoSmithKline group of companies SB Division: World Wide Development Retention Category: GRS019 Information Type: Reporting and Analysis Plan Title: Core Reporting and Analysis Plan for Tositumomab and I-131 Tositumomab (BEXXAR Therapeutic Regimen) Clinical Studies Compound Number: SB Effective Date: 10-FEB-2012 Description: Core Reporting and Analysis Plan for BEXXAR Clinical Studies Subject: CORE Reporting and Analysis Plan for BEXXAR studies Author s Name, Title and Functional Area: Oncology Manager Statistics, Copyright 2012 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited 1

120 CONFIDENTIAL The GlaxoSmithKline group of companies SB Approved by: Approval via Director, Statistics and Programming Oncology Approval via Manager Oncology Clinical Development Approval via Director Oncology Clinical Development 09FEB2012 Date 08FEB2012 Date 09FEB2012 Date 1

121 CONFIDENTIAL SB TABLE OF CONTENTS PAGE ABBREVIATIONS INTRODUCTION STUDY OBJECTIVE(S) AND ENDPOINT(S) Study Objective(s) Study Endpoint(s) Statistical Hypotheses Pharmacokinetic (PK) and PK/Pharmacodynamic (PD) hypotheses STUDY DESIGN PLANNED ANALYSES Interim Analyses Final Analysis SAMPLE SIZE CONSIDERATIONS Sample Size Assumptions Sample Size Sensitivity Sample Size Re-estimation ANALYSIS POPULATIONS Analysis Datasets TREATMENT COMPARISONS Data Display Treatment and Other Sub-group Descriptors GENERAL CONSIDERATIONS FOR DATA ANALYSES Multicentre Studies Other Strata and Covariates Examination of Subgroups Multiple Comparisons and Multiplicity Genetic Markers DATA HANDLING CONVENTIONS Premature Withdrawal and Missing Data Derived and Transformed Data Assessment Windows Values of Potential Clinical Importance STUDY POPULATION Disposition of Subjects Protocol Deviations Demographic and Baseline Characteristics Treatment Compliance EFFICACY ANALYSES Primary Efficacy Analysis(es)

122 CONFIDENTIAL SB Secondary Efficacy Analysis(es) Other Efficacy Analysis(es) SAFETY ANALYSES Extent of Exposure Adverse Events Deaths and Serious Adverse Events Device Incidents and Near Incidents Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events Pregnancies (as applicable) Clinical Laboratory Evaluations Other Safety Measures HEALTH OUTCOMES ANALYSES Humanistic Measures Resource Utilisation Measures CLINICAL PHARMACOLOGY DATA ANALYSES Pharmacokinetic Analyses Pharmacodynamic Analyses Pharmacokinetic/Pharmacodynamic Analyses BIOMARKER DATA ANALYSIS PHARMACOGENETIC DATA ANALYSES Multiallelic Genetic Markers and Genotype Grouping Hardy-Weinberg Equilibrium Analysis Linkage Disequilibrium Analysis Endpoint Summary Statistics by Genotype Analysis Corresponding to the Primary Objective VIRAL GENOTYPING/PHENOTYPING REFERENCES ATTACHMENTS Table of Contents for Data Display Specifications Data Display Specifications

123 CONFIDENTIAL SB ABBREVIATIONS AE CR CRF CCR CTC HAMA ITT NHL OS PD PR PV RAP SAE SD SPD TSH ULN Adverse Event Complete Response Case Report Form Clinical Complete Response Common Toxicity Criteria Human Anti-Mouse Antibody Intent-to-Treat Non-Hodgkin s Lymphoma Overall Survival Progressive Disease Partial Response Protocol Violation Reporting and Analysis Plan Serious Adverse Event Stable Disease Sum of Products of Greatest Diameters Thyroid Stimulating Hormone Upper Limit of Normal Trademark Information Trademarks of the GlaxoSmithKline group of companies BEXXAR Trademarks not owned by the GlaxoSmithKline group of companies None 4

124 CONFIDENTIAL SB INTRODUCTION This Core Reporting and Analysis Plan (RAP) describes the standard analyses which will be completed for GlaxoSmithKline-sponsored studies of the BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) described in Table 1. Core analyses for the following sections are included: Study Population, Efficacy and Safety. The Core RAP will serve as the basis for analyses of each of the BEXXAR studies with the goal of maintaining consistent reporting methods across each of the studies. The study-specific objectives, endpoints, design, planned analysis, and sample size considerations are described in the study protocols. Table 1 Clinical Studies of Tositumomab and Iodine I 131 Tositumomab Study Identifier BEX (Formerly Corixa Study CP ) BEX (Formerly Corixa Study CP ) SB393229/027 (Formerly Corixa Study CCBX ) BEX (Formerly Corixa Study RIT-I-000) Title A Phase I, Dose-Escalation, Open-Label, Multicenter Study of Iodine-131 Anti-B1 Antibody for Intermediate- and High-Risk B-Cell Chronic Lymphocytic Leukemia. Phase I, Dose-Escalation Study of Iodine-131 Anti-B1 Antibody for Patients with Previously Treated Non-Hodgkin s Lymphoma With More Than 25% Bone Marrow Involvement. A multi-center, phase 1/2 study to examine the pharmacokinetics, whole body and organ dosimetry, and biodistribution of fissionderived Iodine I-131 tositumomab for subjects with previously untreated or relapsed follicular or transformed follicular non- Hodgkin s lymphoma RIT-I-000/RIT-I-000A: Phase I Study of Radiolabeled Monoclonal Antibody Anti-B1 for the Treatment of B-Cell Lymphomas & RIT-I-000B: Extended Phase I/II study to determine the safety and efficacy of Coulter Clone 131 Iodine-B1 radioimmunotherapy of advanced non-hodgkin s Lymphoma BEX (Formerly Corixa Study RIT-II-001) Multicenter, Phase II Dosimetry/Validation Study of 131 Iodine Anti-B1 (Murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas that have Transformed to Higher Grade Histologies. 5

125 CONFIDENTIAL SB Study Identifier BEX (Formerly Corixa Study RIT-II-002) (Arm A & B) BEX (Formerly Corixa Study RIT- II-004) BEX (Formerly Corixa Study CP ) SB393229/028 (Formerly Corixa Study CCBX ) BEX (Formerly Corixa Study EAP- CP ) SB393229/023 (Formerly Corixa Study CP ) BEX (Formerly Corixa Study CP ) BEX (Formerly Corixa Study RIT-II-003) SB393229/007 (Formerly Corixa Study CP ) BEX (Formerly Corixa Study CP ) SB393229/010 (Formerly Corixa Study CP ) Title A Randomized Study of Iodine-131 Anti-B1 Antibody Versus Anti-B1 Antibody in Chemotherapy-Relapsed/Refractory Low-Grade or Transformed Low-Grade Non-Hodgkin s Lymphoma (NHL). Note: Arm A (Iodine-131 Anti-B1 Antibody arm) and Arm B (Anti- B1 Antibody arm) data are captured separately in Section m1.13.3, 2.2, Table 4). Multicenter, Pivotal Phase III Study of Iodine-131 Anti-B1 Antibody (Murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas that have Transformed to Higher Grade Histologies. Phase II Study of Iodine-131 Anti-B1 Antibody for Non-Hodgkin s Lymphoma Patients who have Previously Received Rituximab. A Multi-Center, Randomized, Phase 3 Study of Rituximab Versus Iodine I 131 Tositumomab Therapeutic Regimen For Patients with Relapsed Follicular Non-Hodgkin s Lymphoma Expanded Access Study of Iodine I 131 Tositumomab for Relapsed/Refractory Low-Grade and Transformed Low-Grade Non-Hodgkin s Lymphoma. Fludarabine Monophosphate Followed by Iodine I 131 Tositumomab for Untreated Low-Grade and Follicular Non-Hodgkin s Lymphoma. 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. Phase II Trial of Iodine I 131 Tositumomab for Previously Untreated, Advanced-Stage, Low-Grade Non-Hodgkin s B-Cell Lymphoma. Phase II Multicenter Study of Iodine-131 Anti-B1 Antibody Consolidation for Patients with Diffuse Large B-Cell Non-Hodgkin s Lymphoma Following First-Line CHOP. Phase II Multicenter Study of CVP Followed by Iodine-131 Anti-B1 Antibody for Patients with Untreated Low-Grade Non-Hodgkin's Lymphoma. Retreatment Study of Patients with Non-Hodgkin s Lymphoma who have Previously Responded to Iodine-131 Anti-B1 Antibody. 6

126 CONFIDENTIAL SB Study Identifier SB393229/005 (formerly Corixa Study CP ) Title Phase II Study of Iodine I-131 Tositumomab Plus CHOP for Patients with Previously Untreated Mantle Cell Lymphoma The studies listed in Table 2 transitioned into two multi-center administrative studies BEX (formerly Corixa study CCBX ) and BEX (formerly Corixa study CCBX ). Long term follow-up data for these studies will be analyzed according to the original interventional protocols. Table 2 Clinical Studies Transitioned to Studies BEX and BEX Long-term Follow-up Protocols BEX (formerly Corixa study CCBX ) A Multi-Center Long-Term Follow-Up Study of Patients with Low-Grade Non-Hodgkin's Lymphoma Previously Treated with Tositumomab and/or Iodine I-131 Tositumomab in Studies RIT-I-000, RIT-II-001, RIT-II- 002, RIT-II-004, or CP Interventional Protocols BEX (formerly Corixa study RIT-I-000) BEX (formerly Corixa study RIT-II-001) BEX (formerly Corixa study RIT-II-002) BEX (formerly Corixa study RIT-II-004) BEX (formerly Corixa study CP ) BEX (formerly Corixa study CCBX ) A Multi-Center Long-Term Follow-Up Study of Patients with Low-Grade Non-Hodgkin's Lymphoma Previously Treated with Iodine I-131 Tositumomab in Studies CP , CP , CP , or CP SB /023 (formerly Corixa study CP ) SB /007 (formerly Corixa study CP BEX (formerly Corixa study CP ) BEX (formerly Corixa study CP ) SB393229/028 (formerly Corixa study CCBX ) 2. STUDY OBJECTIVE(S) AND ENDPOINT(S) Refer to the protocol for study objectives, endpoints and the hypotheses Study Objective(s) 7

127 CONFIDENTIAL SB Study Endpoint(s) 2.3. Statistical Hypotheses 2.4. Pharmacokinetic (PK) and PK/Pharmacodynamic (PD) hypotheses 3. STUDY DESIGN Refer to the protocol for study design. 4. PLANNED ANALYSES Refer to the statistical methods section of the protocol for planned analyses Interim Analyses Refer to the statistical methods section of the protocol for planned interim analyses Final Analysis 5. SAMPLE SIZE CONSIDERATIONS Refer to the protocol for the sample size calculations Sample Size Assumptions 5.2. Sample Size Sensitivity 5.3. Sample Size Re-estimation 8

128 CONFIDENTIAL SB ANALYSIS POPULATIONS The primary population for efficacy and safety analyses will be based on all subjects who were enrolled or randomized into the study and who received at least one dose of study drug (ITT-Exposed population) Analysis Datasets 7. TREATMENT COMPARISONS Refer to the statistical methods section of the protocol for planned treatment comparisons. No treatment comparisons will be done for one-arm studies Data Display Treatment and Other Sub-group Descriptors 8. GENERAL CONSIDERATIONS FOR DATA ANALYSES 8.1. Multicentre Studies No adjustment for multiple centers will be made Other Strata and Covariates 8.3. Examination of Subgroups 8.4. Multiple Comparisons and Multiplicity No adjustments will be made for multiple comparisons Genetic Markers 9

129 CONFIDENTIAL SB DATA HANDLING CONVENTIONS 9.1. Premature Withdrawal and Missing Data Subjects who drop out of the study (for any reason) will be included in analyses until the time of withdrawal. For event-time endpoints, the date of last known contact will be used for those subjects who have not reached the event (disease progression or death) at the time of the analysis; such subjects will be censored in the analysis Derived and Transformed Data Definition of Response Response classifications are defined as: Response corresponds to the best response ordered by CR, CCR, PR, SD, then PD and does not require subsequent confirmation. Confirmed responses require CR, CCR, or PR to be confirmed by two separate response evaluations at least 4 weeks apart. Definition of Duration Measures Duration measures are defined as follows: Time to progression or progression-free survival: time from treatment start date to the first documented disease progression or death. Duration of response: For all subjects with CR, CCR, or PR, duration of response is defined as the time from first documented response to the first documented disease progression. Time-to-treatment failure: time from treatment start date to the first occurrence of treatment withdrawal, decision to seek additional therapy, study removal, disease progression, alternative therapy for the patient s lymphoma, or death. Time-to-death or overall survival: time from treatment start date to the date of death from any cause. Baseline For all labs, the most recent value collected prior to treatment will be used as baseline. 10

130 CONFIDENTIAL SB Assessment Windows Assessment windows for programming will be summarized in a separate document. The windows will be used to assign assessments to the correct week or month Values of Potential Clinical Importance In order to identify records of clinical concern, NCI Common Toxicity Criteria (CTC) will be used to assign toxicity grades. 10. STUDY POPULATION Disposition of Subjects Summaries will be made to account for all subjects involved in the study. This will include the number of subjects enrolled or randomized and the number who received the dosimetric and therapeutic dose. The number of subjects discontinued from the study and the incidence of reasons for early discontinuation will also be reported along with the number of deaths. Summary statistics will also be provided for duration of follow-up from the dosimetric dose and also from the therapeutic dose Protocol Deviations The number and percentage of subjects with inclusion/exclusion criteria deviations will be summarized. Deviations to the inclusion and exclusion criteria will also be listed Demographic and Baseline Characteristics Demographic characteristics of age, sex, and ethnicity will be summarized. Age will be calculated from the date of screening relative to the date of birth as recorded in the CRF. These demographics will also be listed, with any other relevant details. Disease characteristics at diagnosis and at screening will also be summarized and listed. The number of subjects who received prior chemotherapies and radiation therapies will be summarized and listed if this data has been collected Treatment Compliance 11. EFFICACY ANALYSES Primary Efficacy Analysis(es) Response Classification: 11

131 CONFIDENTIAL SB Response corresponds to the best response evaluation (order by CR, CCR, PR, SD, and PD) and does not require subsequent confirmation. Confirmed response requires CR, CCR, or PR to be confirmed by two separate response evaluations at least 4 weeks apart. Response rate will be calculated as the proportion of subjects achieving CR, CCR or PR (confirmed and unconfirmed rates). A 95% confidence interval will be provided for the response rates. Definition of Duration Measures Duration measures are defined as follows: Time to progression or progression-free survival: time from treatment start date to the first documented disease progression or death. Duration of response: For all subjects with CR, CCR, or PR, duration of response is defined as the time from first documented response to the first documented disease progression. Time-to-treatment failure: time from treatment start date to the first occurrence of treatment withdrawal, decision to seek additional therapy, study removal, disease progression, alternative therapy for the patient s lymphoma, or death. Time-to-death or overall survival: time from treatment start date to the date of death from any cause Duration of response, time to progression, time to treatment failure and overall survival will be summarized by tabulating number of events, and number censored. Kaplan-Meier survival curves will be produced for these event-time endpoints. If applicable, treatment arms will be compared using a log-rank test Secondary Efficacy Analysis(es) Study-specific subgroup analyses consisting of univariate and multivariate analysis of efficacy endpoints and study-specific safety analyses may be performed as described in the study protocol. If additional analyses are performed, a description will be included in the clinical study report Other Efficacy Analysis(es) 12

132 CONFIDENTIAL SB SAFETY ANALYSES Extent of Exposure A summary of the dosing data will be completed for the dosimetric dose and for the therapeutic dose. Summary statistics will be calculated for the unlabeled dose received (mg), labeled dose received (mg), prescribed activity, administered activity, whole body dose, and infusion rate adjustments. Compliance with thyroid blockade medication will also be summarized with n and percentage of subjects who received the thyroid blockade medications Adverse Events For all adverse events, verbatim terms will be collected and coded using the preferred terms and grouped into system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA). The grouped system organ classes and preferred terms will be used in summaries. All adverse experiences from randomization until the last clinic visit associated with the study will be included in the summary tables. The worst toxicity grade per subject will be reported. Hematologic adverse events based on laboratory data (grade 3/4 lab toxicities) will also be included in the summary tables using the System Organ Class as Hematological AEs from Labs and are identified by the following preferred terms: Hemoglobin <8.0 g/dl, Platelets <50,000 cells/mm3, ANC<1000 cells/mm3, and WBC <2000 cells/mm3. All laboratory derived hematologic events will be considered as possibly related to study drug. For each table, the distribution (count and percent) of subjects experiencing an event will be given. The AE tables will summarize the events for all enrolled or randomized subjects. A list of the AE tables which will be provided is given in the attachment containing a table of contents of the tables, listings, and figures Deaths and Serious Adverse Events Total number of deaths will be summarized and the primary cause of death and date of death will be listed. Serious adverse events will also be summarized in the same manner as described for all adverse events Device Incidents and Near Incidents 13

133 CONFIDENTIAL SB Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events If applicable to a study, AEs leading to permanent discontinuation of study medication or leading to premature study conclusion will be summarized Pregnancies (as applicable) Clinical Laboratory Evaluations Clinical laboratory parameters (hematology and chemistry) will be summarized by visit using summary statistics. The assessment of qualitative hematological toxicities will examine four specific parameters: white blood cells (WBC), neutrophils, platelets and hemoglobin. The hematological toxicities will be summarized by worst grade after the baseline assessment. Onset of first Grade 3/4 toxicity and duration of Grade 3, 4, and 4+ toxicities will be summarized for each hematological parameter. Also, the nadir, time to nadir, and time to recovery to baseline grade will be summarized for the hematologic parameters Other Safety Measures The incidence and time to development of human anti-mouse antibody (HAMA) positivity will be summarized. Summaries will be provided of the percentage of subjects who convert to HAMA positivity. Kaplan-Meier estimates of the time to HAMA positivity will also be constructed. Thyroid stimulating hormone (TSH) levels will be listed for each subject along with flags to indicate low and high values based on the normal range. 13. HEALTH OUTCOMES ANALYSES Humanistic Measures Resource Utilisation Measures 14

134 CONFIDENTIAL SB CLINICAL PHARMACOLOGY DATA ANALYSES Pharmacokinetic Analyses Pharmacodynamic Analyses Pharmacokinetic/Pharmacodynamic Analyses 15. BIOMARKER DATA ANALYSIS 16. PHARMACOGENETIC DATA ANALYSES Multiallelic Genetic Markers and Genotype Grouping Hardy-Weinberg Equilibrium Analysis Linkage Disequilibrium Analysis Endpoint Summary Statistics by Genotype Analysis Corresponding to the Primary Objective 15

135 CONFIDENTIAL SB VIRAL GENOTYPING/PHENOTYPING 16

136 CONFIDENTIAL SB REFERENCES 17

137 CONFIDENTIAL SB ATTACHMENTS Table of Contents for Data Display Specifications TABLES Table No. Title Demographics and Baseline Characteristics 6.1 Summary of Enrollment 6.2 Summary of Disposition 6.3 Summary of Duration of Follow-up 6.4 Summary of Demographics 6.5 Summary of Disease Characteristics at Diagnosis and Study Entry 6.6 Summary of Number of Prior Chemotherapy and Radiation Therapies 6.7 Summary of Inclusion/Exclusion Criteria Deviations Efficacy 7.1 Summary of Response Evaluation by Visit 7.2 Summary of Response and Confirmed Response Rates 7.3 Summary Statistics for Kaplan-Meier Estimates for Duration of Response for all unconfirmed responders (unconfirmed CR+CCR+PR) 7.4 Summary Statistics for Kaplan-Meier Estimates for Progression Free Survival 7.5 Summary Statistics for Kaplan-Meier Estimates for Overall Survival 7.6 Summary statistics for Kaplan-Meier Estimates for Duration of Response for unconfirmed complete responders (unconfirmed CR) 7.7 Summary statistics for Kaplan-Meier Estimates for Duration of Response for unconfirmed clinical complete responders (unconfirmed CCR) 18

138 CONFIDENTIAL SB Table No. Title 7.8 Summary statistics for Kaplan-Meier Estimates for Duration of Response for unconfirmed CR + CCR 7.9 Summary statistics for Kaplan-Meier Estimates for Duration of Response for unconfirmed partial responders (unconfirmed PR) 7.10 Summary statistics for Kaplan-Meier Estimates for Duration of Response for confirmed responders (confirmed CR+CCR+PR) 7.11 Summary statistics for Kaplan-Meier Estimates for Duration of Response for confirmed complete responders (confirmed CR) 7.12 Summary statistics for Kaplan-Meier Estimates for Duration of Response for confirmed clinical complete responders (confirmed CCR) 7.13 Summary statistics for Kaplan-Meier Estimates for Duration of Response for confirmed CR + CCR 7.14 Summary statistics for Kaplan-Meier Estimates for Duration of Response for confirmed partial responders (confirmed PR) 7.15 Summary statistics for Kaplan-Meier Estimates for Progression Free Survival for Partial Responders (PR) 7.16 Summary statistics for Kaplan-Meier Estimates for Progression Free Survival for CR + CCR Safety 8.1 Dosing Summary for Tositumomab: Dosimetric Dose 8.2 Dosing Summary for Tositumomab: Therapeutic Dose 8.3 Summary of AEs 8.4 Summary of Drug-Related AEs 8.5 Summary of Grade 3/4 AEs 19

139 CONFIDENTIAL SB Table No. Title 8.6 Summary of Drug-Related Grade 3/4 AEs 8.7 Summary of AEs by Maximum Toxicity Grade 8.8 Summary of Drug-Related AEs by Maximum Toxicity Grade 8.9 Summary of Serious AEs 8.10 Summary of Drug-Related Serious AEs 8.11 Summary of Infections 8.12 Summary of HAMA Results 8.13 Summary Statistics for Kaplan-Meier Estimates for Time to HAMA Positivity 8.14 Summary of Chemistry Data Change from Baseline 8.15 Summary of Hematology Data Change from Baseline 8.16 Summary of Hematologic Toxicities by Maximum Toxicity Grade 8.17 Summary of Onset and Duration of Hematologic Toxicities (Grades 3 and 4) 8.18 Summary Statistics for Kaplan-Meier Estimates for Time to Recovery to Baseline Grade for Hematologic Parameters 8.19 Summary of Hematological Nadirs 8.20 Summary of Time to Nadir Values for Hematological Parameters 8.21 Summary of Deaths 8.22 Summary of Chemistry data Actual Values 8.23 Summary of Hematology Data Actual Values 8.24 Summary of Non-serious AEs 8.25 Summary of Drug-related Non-serious AEs 8.26 Summary of Frequent AEs (sorted in order of decreasing frequency) 8.27 Summary of Frequent SAEs 20

140 CONFIDENTIAL SB Table No. Title 8.28 Summary of Frequent Drug-related SAEs 8.29 Summary of Fatal SAEs 8.30 Summary of Fatal Drug-related SAEs LISTINGS Listing No. Title Demographics and Baseline Characteristics 1 Listing of Subject Enrollment by Investigative Site 2 Listing of Subject Disposition and Duration of Follow-up 3 Listing of Demographics 4 Listing of Disease Characteristics at Diagnosis and Study Entry 5 Listing of Inclusion/Exclusion Criteria Deviations Efficacy 5 Listing of Response Evaluations by Visit 6 Listing of Efficacy Endpoints : Duration of Response, Progression Free Survival, and Overall Survival Safety 7 Listing of Tositumomab Exposure Data 8 Listing of All AEs 9 Listing of Drug-related AEs 10 Listing of Grade 3/4 AEs 11 Listing of Drug-related Grade 3/4 AEs 12 Listing of Serious AEs 21

141 CONFIDENTIAL SB Listing No. Title 13 Listing of Drug-related Serious AEs 14 Listing of Infections 15 Listing of HAMA Results 16 Listing of Chemistry Data 17 Listing of Hematology Data 18 Listing of Deaths 19 Listing of Prior Chemotherapies 20 Listing of Prior Radiation Therapies 21 Listing of Subsequent Therapies 22 Listing of Fatal SAEs 23 Listing of TSH Data FIGURES 1 Kaplan-Meier Survival Curve of Duration of Response for Responders 2 Kaplan-Meier Survival Curve of Time to Progression 3 Kaplan-Meier Survival Curve of Time to Treatment Failure 4 Kaplan-Meier Survival Curve of Overall Survival (Time to Death) 5 Kaplan-Meier Survival Curve for Duration of Response for Confirmed Responders (CR, CCR, PR) Data Display Specifications 22

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195 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) LIST OF INVESTIGATORS AND IECS/IRBS FOR BEX (formerly RIT-II-001) Investigator Sub-Investigator Investigator no./center no. Description of Research Facility, Hospital/ Institution, and Address United Kingdom Prof. Name of IEC/IRB Committee, Address, Committee Chair United Kingdom United Kingdom Professor (Co-PI) United Kingdom Chairman: Dr. Chairman, Professor MD, FRCP, FRCPath - 1 -

196 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Investigator Sub-Investigator Investigator no./center no. Description of Research Facility, Hospital/ Institution, and Address United States MD Name of IEC/IRB Committee, Address, Committee Chair MD IRB Chairperson: MD MD Chairperson: IRB Chairman: MD - 2 -

197 CONFIDENTIAL UM2009/00281/00 BEX (RIT-II-001) Investigator Sub-Investigator Investigator no./center no. Description of Research Facility, Hospital/ Institution, and Address Name of IEC/IRB Committee, Address, Committee Chair IRB Chairman: MD, Professor of Medicine, All centres participated in the study under the US IND IRB Chairman: MD - 3 -

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