Study No.: Title: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: SB393229/023 (formerly CP ) Title: Fludarabine Monophosphate Followed by Tositumomab and Iodine I 131 Tositumomab for Untreated Low-grade and Follicular Non-Hodgkin s Lymphoma Phase: II Study Period: 01 August 1998 to 05 August 2010 Data cut-off date in the long term follow-up study was 05 August Data cut-off for original study was 14 August Study Design: Single-group, open label, non-randomized, multicenter, interventional treatment, active control without placebo, safety/efficacy study Centres: One center in the USA Indication: Previously untreated, advanced-stage (stage III or IV) low-grade, transformed low-grade and follicular non- Hodgkin s B-cell lymphoma Treatment: Subjects received 3 cycles of intravenous (IV) fludarabine (25 mg/m 2 /day) for 5 days every 5 to 6 weeks. If subjects met the inclusion/exclusion criteria for radioimmunotherapy (RIT) with tositumomab (TST) and iodine I 131 tositumomab (I-131 TST), they began the first of two phases of RIT. The first phase was the dosimetric dose administered 6 weeks after Day 1 of the third cycle of fludarabine. The second phase, the therapeutic dose, was administered 7 to 14 days after the dosimetric dose. Subjects were treated with saturated solution potassium iodide (SSKI), Lugol s solution, or potassium iodide tablets at least 24 hours prior to the first phase of RIT treatment. The dosimetric dose was an IV infusion of unlabeled TST (450 mg) administered over one hour, followed by a 10 minute flush of 0.9% sodium chloride solution prior to a 30 minute infusion of 35 mg TST trace-labeled with 5 mci of iodine I 131 (I-131 TST). Anterior whole body counts were obtained before urination and within one hour of completion of the I-131 TST infusion. These counts were used to determine the rate of whole body clearance of radioactivity (total body residence time) and calculate the total body radiation dose (TBD) for each subject. The dose in mci of I-131 TST required to deliver a TBD of 45, 65 or 75 cgy (the therapeutic dose) was then determined for each subject. The TBD administered was dependent on the baseline platelet count and bone marrow involvement at restaging 5 to 6 weeks after Day 1 of the third cycle of fludarabine. The therapeutic dose was administered as an IV infusion of 450 mg unlabeled TST delivered over one hour, followed by infusion of the appropriate activity (75, 45 or 65 cgy) of I-131 TST delivered over 20 minutes.. Objectives: The objectives of this study were to evaluate the safety and efficacy of sequential administration of fludarabine followed by TST and I-131 TST in subjects with previously untreated low-grade, transformed low-grade and follicular NHL. Primary Outcome/Efficacy Variable: Efficacy variables were secondary to the safety outcomes for this study which were exposure, adverse events, and toxicities. Secondary Outcome/Efficacy Variable(s): Response rate, complete response rate, duration of response, time to disease progression, time to treatment failure, human anti-mouse antibody (HAMA) incidence and time to HAMA incidence, overall survival and molecular remission rates. Statistical Methods: All subjects enrolled in the study (the intent to treat [ITT]-Exposed population) were assessed for safety. Adverse events (AEs), hematologic toxicities, and blood chemistry and hematology results were summarized. For subjects who converted to HAMA positivity, Kaplan-Meier estimates of incidence and time to development of HAMA were produced. Responses were classified as complete response (CR), clinical complete response (CCR), partial response (PR), stable disease (SD) or progressive disease (PD) for subjects exposed to both fludarabine and TST and I-131 TST. Responses were reported by demographics, disease, and dosing subgroups. Duration of response, progression free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Ninety-five percent confidence intervals (CIs) were calculated for response rates and time to progression. Molecular remission rates were reported for subjects with remission at the molecular level. Study Population: Male or female adults with previously untreated, histologically-confirmed, advanced-stage (stage III or IV), low-grade, transformed low-grade and follicular non-hodgkin s B-cell lymphoma; evidenced CD20 antigen, adequate renal function, adequate kidney function, Karnofsky performance status of at least 60%, and an absolute granulocyte count of 1500 cells/mm 3 and a platelet count of 100,000 cells/mm 3. Subjects were excluded if they had CNS involvement, HIV or an active infection requiring intravenous antibiotics, prior malignancy or lymphoma within 5 years, were HAMA positive at baseline, or had NYHA class III or IV heart disease. 1

2 Enrolled () Received <3 Cycles of Fludarabine Received 3 Cycles of Fludarabine Received Number of Subjects: Planned, N Between 30 and 40 Entered, N Completed, n (%) 20 (53) 0 20 (56) 20 (57) Total Number Subjects Withdrawn, N (%) 18 (47) 2 (100) 16 (44) 15 (43) Lost to Follow-up, n (%) 4 (11) 1 (50) 3 (8) 3 (9) Subject Wish 1 (3) 0 1(3) 1 (3) Withdrawn due to Progressive disease, n (%) 11 (29) 0 11 (31) 11 (31) Failed to meet inclusion/exclusion criteria, n 1 (3) 0 1 (3) 0 (%) Other, n (%) 1 (3) 1 (50) 0 0 Demographics N (ITT) 38 Females: Males 17:21 1:1 16:20 16:19 Mean Age, years (SD) 51.7 (13.4) 61.0 (11.3) 51.2 (13.4) 50.9 (13.5) White, n (%) 36 (95) 2 (100) 34 (94) 33 (94) Stage III lymphoma at diagnosis, n (%) 13 (34) 0 13 (36) 13 (37) Stage IV lymphoma at diagnosis, n (%) 22 (58) 2 (100) 20 (56) 19 (54) Primary Efficacy Results: After 3 cycles of Fludarabine, prior to N=36 Combined Regimen After Period Response Rates n (%) 95% CI n (%) 95% CI n (%) 95% CI Complete response, clinical complete response or partial response (CR, CCR or PR) 32 (89) 79,99 32 (91) 82, (95) 88,100 Complete response (CR) 3 (8) 0, (77) 63, (71) 57, 85 Confirmed complete response (confirmed CR) NA NA 24 (69) 53, (63) 48, 78 Secondary Outcome Variable(s): After Combined Regimen Period Duration of Response (CR, CCR or PR) Subjects with a response and progressed, n (%) 12 (34) 15 (39) Subjects censored, n (%) 20 (57) 21 (35) Median (months) Not Reached Not Reached Time to Progression Subjects with progression, n (%) 17 (49) 19 (50) Subjects censored, n (%) 18 (51) 19 (50) Median (months) Time to Treatment Failure Subjects with treatment failure, n (%) 18 (51) 21 (55) Subjects censored, n (%) 17 (49) 17 (45) Median (months) Overall Survival 2

3 Subjects who died, n (%) 7 (20) 9 (24) Subjects censored, n (%) 28 (80) 29 (76) Median (months) Not reached Not reached After HAMA n (%) n (%) Evaluable for HAMA 32 (84) 32 (91) Conversion to HAMA positivity 2 (5) 2 (6) Subjects censored 30 (79) 30 (86) Time to HAMA positivity (days) for the 2 subjects with conversion 184, , 195 Safety Results: Reported over the period 01 August 1998 to 05 August 2010 (data cut-off date in the long term followup study. Data cut-off for original study was 14 August 2007) Adverse Events: All AEs (serious and non-serious), regardless of relationship to study drug, were recorded on the AE CRF from the time of enrolment to 12 weeks following the therapeutic dose of TST and iodine, or until administration of alternative therapy for the subject s NHL, whichever occurred first. Subsequent to this time frame, only AEs that were considered by the Investigator to be possibly or probably associated with the administration of study drug were to be reported. Subjects with Most Frequent On-therapy AEs that occurred in more than one subject Body System Preferred Term Fludarabine, prior to N= 35 n (%) n (%) n (%) Subjects with any AE(s), n (%) 31 (82) 34 (97) 37 (97) General disorders and administration site conditions 18 (47) 22 (63) 27 (71) Fatigue 7 (18) 11 (31) 16 (42) Pyrexia 9 (24) 10 (29) 15 (39) Asthenia 5 (13) 5 (14) 9 (24) Chills 3 (8) 3 (9) 6 (16) Malaise 1 (3) 1 (3) 2 (5) Pain 1 (3) 1 (3) 2 (5) Gastrointestinal disorders 18 (47) 16 (46) 25 (66) Nausea 13 (34) 10 (29) 18 (47) Vomiting 3 (8) 5 (14) 7 (18) Constipation 2 (5) 2 (6) 3 (8) Abdominal distension 1 (3) 2 (6) 3 (8) Diarrhoea 0 2 (6) 3 (8) Mouth Ulceration 0 1 (3) 2 (5) Skin and subcutaneous tissue disorders 17 (45) 10 (29) 22 (58) Rash 7 (18) 2 (6) 8 (21) Ecchymosis 1 (3) 4 (11) 5 (13) Drug eruption 3 (8) 1 (3) 4 (11) Night sweats 1 (3) 2 (6) 3 (8) Erythema 2 (5) 0 2 (5) Hyperhidrosis 1 (3) 1 (3) 2 (5) Pruritus 1 (3) 1 (3) 2 (5) Rash macular 2 (5) 0 2 (5) Urticaria 1 (3) 1 (3) 2 (5) Nervous system disorders 5 (13) 19 (54) 21 (55) Headache 4 (11) 6 (17) 9 (24) Somnolence 1 (3) 7 (20) 8 (21) Dizziness 0 6 (17) 6 (16) Sinus Headache 0 2 (6) 2 (5) Combined Regimen Period 3

4 Blood and lymphatic system 12 (32) 11 (31) 19 (50) Neutropenia 11 (29) 2 (6) 12 (32) Anaemia 2 ( 5) 9 (26) 10 (26) Leukopenia 3 (8) 3 (9) 5 (13) Febrile neutropenia 1 (3) 2 (6) 3 (8) Thrombocytopenia 1 (3) 2 (6) 3 (8) Pancytopenia 1 (3) 1 (3) 2 (5) Musculoskeletal and connective tissue disorders 8 (21) 13 (37) 19 (50) Back pain 1 (3) 4 (11) 5 (13) Myalgia 1 (3) 4 (11) 5 (13) Arthralgia 1 (3) 4 (11) 4 (11) Pain in extremity 3(8) 1 (3) 4 (11) Muscle spasms 0 3 (9) 3 (8) Neck pain 0 2 (6) 2 (5) Respiratory, thoracic and mediastinal disorders 8 (21) 14 (40) 17 (45) Cough 6 (16) 10 (29) 14 (37) Nasal congestion 5 (13) 6 (17) 8 (21) Oropharyngeal pain 2 (5) 5 (14) 7 (18) Dyspnoea 2 (5) 5 (14) 6 (16) Rhinorrhoea 2 (5) 2 (6) 4 (11) Rales 2 (5) 1 (3) 3 (8) Sinus congestion 1 (3) 2 (6) 3 (8) Wheezing 3 (8) 0 3 (8) Dyspnoea exertional 0 2 (6) 2 (5) Paranasal sinus hypersecretion 1 (3) 1 (3) 2 (5) Productive cough 0 2 (6) 2 (5) Infections and infestations 6 (16) 11 (31) 16 (42) Sinusitis 2 (5) 3 (9) 5 (13) Nasopharyngitis 1 (3) 3 (9) 4 (11) Upper respiratory tract infection 1 (3) 2 (6) 3 (8) Herpes zoster 0 2 (6) 2 (5) Oral herpes 1 (3) 1 (3) 2 (5) Metabolism and nutrition disorders 6 (16) 4 (11) 10 (26) Decreased appetite 6 (16) 4 (11) 10 (26) Hypokalaemia 2 (5) 0 2 (5) Psychiatric disorders 4 (11) 5 (14) 8 (21) Insomnia 2 (5) 2 (6) 4 (11) Anxiety 1 (3) 3 (9) 3 (8) Cardiac disorders 2 (5) 4 (11) 5 (13) Palpitations 1 (3) 3 (9) 4 (11) Tachycardia 1 (3) 1 (3) 2 (5) Reproductive system and breast disorders 4 (11) 1 (3) 5 (13) Vascular disorders 3 (8) 2 (6) 5 (13) Hypotension 2 (5) 1 (3) 3 (8) Hot flush 1 (3) 1 (3) 2 (5) Endocrine disorders 0 4 (11) 4 (11) Hypothyroidism 0 3 (9) 3 (8) Renal and urinary disorders 4 (11) 0 4 (11) Micturition urgency 2 (5) 0 2 (5) Ear and labyrinth disorders 0 3 (9) 3 (8) Immune system disorders 3 (8) 0 3 (8) Drug hypersensitivity 3 (8) 0 3 (8) Injury, poisoning and procedural complications 0 3 (9) 3 (8) Contusion 0 3 (9) 3 (8) Investigations 1 (3) 2 (6) 3 (8) 4

5 Neoplasms begnign, malignant and unspecified 0 3 (9) 3 (8) (including cysts and polyps) Eye disorders 1 (3) 1 (3) 2 (5) Surgical and medical procedures 1 (3) 1 (3) 2 (5) Sinus operation 1 (3) 1 (3) 2 (5) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Includes both fatal and non-fatal events Fludarabine prior to N= 35 Combined Regimen Period Subjects with non-fatal SAEs, n (%) [related] n (%) [related] n (%) [related] n (%) [related] Any Event 1 (3) [0] 5 (14) [5] 6 (16) [5] Febrile neutropenia 1 (3) [0] 2 (6) [2] 3 (8) [2] Acute myeloid leukaemia 0 1 (3) [1] 1 (3) [1] Chronic myelomonocytic leukemia 0 1 (3) [1] 1 (3) [1] Myelodysplasic syndrome 0 1 (3) [1] 1 (3) [1] Squamous cell carcinoma of skin 0 1 (3) [1] 1 (3) [1] Cardiac failure congestive 1 (3) [0] 0 1 (3) [0] Subjects with fatal SAEs, n (%) [related] n (%) [related] n (%) [related] n (%) [related] Arrhythmia 1 (3) [0] 0 1 (3) [0] Conclusion: See Citations. 5