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.: BEX104505 (formerly CP-97-011) Title: Phase II study of Iodine-131 anti-b1 antibody for 1st or 2nd relapsed indolent B-cell lymphomas or B-cell lymphomas that have transformed to a more aggressive histology Rationale: The rationale for this clinical trial was based on results of previous trials indicating that chemotherapyrefractory patients with few or no options for therapy responded well to Iodine-131 Anti B1 Antibody (hereafter referred to as tositumomab and iodine I 131 tositumomab). This study was designed to establish the safety and efficacy profile of tositumomab and iodine I 131 tositumomab in patients with 1st or 2nd relapsed indolent B cell lymphomas or B cell lymphomas that had transformed to a more aggressive histology. Phase: II Study Period: 02 July 1998 to 21 April 2011 Study Design: Study BEX104505 was designed as a single-arm, open label study that evaluated subjects treated with tositumomab and iodine I 131 tositumomab for safety and efficacy until the subject s disease progressed, the subject died, or the subject was on study for 2 years, whichever occurred first. Subjects who completed 2 years of Study BEX104505 were eligible to enter Study BEX104528 for long-term follow-up (LTFU) evaluations. All surviving subjects were assessed for survival and disease status, including subsequent therapy for NHL, and for long-term safety, including the use of thyroid medication, development of hypothyroidism, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and all other secondary malignancies. Additionally, these subjects were assessed for the development of any adverse event(s) deemed by the Principal Investigator as being possibly or probably related to the subject s previous treatment with tositumomab and iodine I 131 tositumomab. Laboratory evaluations consisted of thyroid stimulating hormone (TSH) levels and complete blood cell (CBC) counts with differential and platelet count. Subjects were followed for continued response and safety every six months for years 3 through 5 post treatment. Beginning at year six, all subjects were assessed annually through year 10 inclusive. Centres: St. Bartholomew s Hospital, United Kingdom and Christie Hospital NHS Trust, United Kingdom Indication: non-hodgkin s B Cell Lymphoma (NHL) Treatment: Subjects underwent 2 phases of study. In the first phase (dosimetric dose), subjects received an infusion of unlabeled tositumomab (450 mg) followed by tositumomab (35 mg) labeled with 5 mci of Iodine 131. Using the total body residence time derived from gamma counts obtained at the 3 imaging timepoints, a subject-specific dose of iodine 131 tositumomab was calculated to deliver the desired total body dose of radiotherapy. In the second phase, (therapeutic dose), subjects received tositumomab (450 mg) followed 35 mg tositumomab labeled with the subjectspecific dose of Iodine 131 to deliver a total body dose of 75 cgy. Subjects with platelet counts of 100,001 149,999 cells/mm 3 received 65 cgy, and obese subjects were dosed based upon 137% of their lean body mass. For thyroid protection, subjects were treated with either saturated solution potassium iodide (SSKI), Lugol s solution, or potassium iodide tablets starting at least 24 hours prior to the dosimetric dose and continuing for 14 days following the therapeutic dose. Objectives: To establish the response rate, duration of response, time to progression, time to treatment failure, and survival after treatment with tositumomab and iodine I 131 tositumomab in patients with 1st or 2nd relapsed indolent or transformed non-hodgkin's B-cell lymphoma. Primary Outcome/Efficacy Variable: The primary efficacy endpoint of the study was the response rate (CR+CCR+PR). Secondary Outcome/Efficacy Variables: The secondary efficacy endpoints were the duration of response, time to progression, time-to-treatment failure, safety, and survival. Statistical Methods: Analyses were performed using data from all enrolled subjects (intent-to-treat [ITT]). The response rate was estimated from objective evidence of tumor response or progression. Measurable lesions were defined as any lesion >2 cm in both perpendicular diameters at baseline, and response to therapy was assessed by the following criteria. Complete Response (CR): Complete resolution of all disease-related radiological abnormalities and disappearance of all signs and symptoms related to the disease. Clinical Complete Response (CCR): Complete resolution of all disease-related symptoms but residual focal abnormality which was thought to be residual scar tissue. Partial Response (PR): Greater than or equal to a 50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions. Stable Disease (SD): Less than a 25% increase and less than a 50% decrease in the sum of the products of the 1
longest perpendicular diameters of all measurable lesions with no new lesions. Progressive Disease (PD): Greater than or equal to a 25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measurable lesions. Two-sided 95% confidence intervals (95% CIs) were calculated. Long-term efficacy analyses included analyses of duration of response, time to progression or death (i.e., progression-free survival) and Kaplan-Meier analysis of overall survival. Long-term safety analyses included analyses of the cumulative incidence of HAMA positivity, the cumulative incidence of hypothyroidism, the cumulative incidence of MDS/AML, tabulation of deaths and analyses of other longterm adverse events including secondary malignancies. Study Population: Male or female subjects at least 18 years of age with a histologically confirmed diagnosis of B-cell CLL/PLL/SLL; lymphoplasmacytic - immunocytoma; follicle center, follicular, Grade I; follicle center, follicular, Grade II NHL; or one of these B-cell lymphomas which had transformed to a more aggressive histology were eligible for enrollment. Evidence of CD20 expression by tumor tissue was required. Subjects must have received 1 or 2 prior chemotherapy regimens and progressed following their last regimen. A performance status of at least 60% on the Karnofsky Scale and an anticipated survival of at least 3 months were also required, as was an absolute granulocyte count of >1500x10 9 /L and a platelet count of >100,000x10 9 /L within 14 days of study entry. Subjects were excluded if they had more than an average of 25% of the intratrabecular marrow space involved by lymphoma in bone marrow biopsy specimens as assessed microscopically within 42 days of study entry. Subjects who received cytotoxic chemotherapy, radiation therapy, or cytokine treatment within 4 weeks prior to study entry (6 weeks for nitrosourea compounds), or who exhibited persistent clinical evidence of toxicity were also excluded as were subjects with prior malignancies (other than lymphoma) except for adequately-treated skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 years. Number of Subjects BEX104505: Planned, N 40 Randomized, N 41 Completed, n (%) 38 (93%) a Total Number Subjects Withdrawn from BEX104505, N (%) 41 (100) Lost to follow-up 3(7) Received alternative therapy 1 (2) Progressive disease 27 (66) Died 1 (2) Other 9 (22) Number of Subjects BEX104528: Enrolled in BEX104528 from BEX104505 18 Total Subjects Withdrawn from BEX104528 18 (100) Lost to follow-up 1 (6) Died 8 (44) Other (completed 10 years follow-up) 9 (50) Demographics N (ITT population) 41 Females:Males 21:20 Mean age, years (SD) 58.2 (11.4) White, n (%) 41 (100) Dosing Summary Tositumomab: Therapeutic Dose Received dosimetric and therapeutic dose, n 40 Days from dosimetric dose to therapeutic dose, median 8.0 Iodine I 131 tositumomab dose (mg): Therapeutic (hot dose), 35.0 median Administered iodine I-131 tositumomab activity (mci), median 95.1 (49 145) (range) Was infusion rate adjusted? n (%) Yes 0 No 40 (100) Whole Body Dose 2
N 40 45 0 65 6 (15) 66 1 (3) 75 33 (83) Primary Efficacy Results: Investigator-assessed determination of the response rate (CR+CCR+PR), n (%) 31 (76%) Summary of Response Data, by ITT n (%) [95% CI] Unconfirmed Responses Unconfirmed response (CRu+CCRu+PRu) 31 (76) [62, 89] Unconfirmed complete response (CRu) 16 (39) [24, 54] Unconfirmed complete clinical response (CCRu) 4 (10) [1, 19] Unconfirmed partial response (PRu) 11 (27) [13, 40] Not evaluable for response 1 Confirmed Responses, n (%) [95% CI] Confirmed response (CR+CCR+PR) 22 (54) [38, 69] Complete response (CR) 14 (34) [20, 49] Confirmed complete response (CCR) 3 (7) [0, 15] Confirmed partial response (PR) 4 (10) [1, 19] Not evaluable for response 6 Secondary Outcome Variables: Duration of confirmed response (CR+CCR+PR), responders, 46.4 (15.2, Not Reached) months, median (95% CI) Time to progression, all subjects, months, median (95% CI) 12.6 (6.1, 29.9) Time-to-treatment failure, all subjects, months, median (95% CI) 9.5 (6.0, 26.9) Overall survival, all subjects, months, median (95% CI) 74.5 (34.9, 121.5) Most Frequent Adverse Events On-Therapy ANY EVENT 40 (98%) [37] ANC <1000 cells/mm 3 18 (44%) [18] Platelets <50,000 cells/mm 3 15 (37%) [15] WBC <2000 cells/mm 3 14 (34%) [14] Nausea 13 (32%) [12] Thrombocytopenia 11 (27%) [11] Fatigue 8 (20%) [6] Anemia 7 (17%) [7] Cough 7 (17%) [4] Headache 7 (17%) [4] Lethargy 7 (17%) [6] Pyrexia 7 (17%) [6] Upper respiratory tract Infection 6 (15%) [3] Back pain 5 (12%) [2] Chills 5 (12%) [5] Constipation 5 (12%) [3] Hypothyroidism b 5 (12%) [4] Vomiting 5 (12%) [3] Edema peripheral 4 (10%) [0] Oropharyngeal pain 4 (10%) [4] Pain 4 (10%) [3] 3
Pain in extremity 4 (10%) [1] Rash 4 (10%) [4] All Serious Adverse Events (fatal and non-fatal) - On-Therapy ANY EVENT 13 (32) [13] Anemia 6 (15) [6] Thrombocytopenia 6 (15) [6] Myelodysplastic syndrome 3 (7) [3] Lower respiratory tract infection 2 (5) [ 2] Pancytopenia 2 (5) [ 2] Pneumonia 2 (5) [ 2] Pyrexia 2 (5) [ 2] Febrile neutropenia 1 (2) [ 1] Haematuria 1 (2) [ 1] Haemophilus infection 1 (2) [ 1] Hepatic failure 1 (2) [ 1] Herpes simplex 1 (2) [ 1] Herpes zoster 1 (2) [ 1] Hypercalcaemia 1 (2) [ 1] Neutropenia 1 (2) [ 1] Neutropenic sepsis 1 (2) [ 1] Pleural effusion 1 (2) Radiculitis brachial 1 (2) [ 1] Renal failure chronic 1 (2) [ 1] Respiratory tract infection 1 (2) [ 1] Fatal Serious AEs ANY FATAL EVENT 5 (12%) [5] Myelodysplastic syndrome 2 (5) [2] Hepatic failure 1 (2) [1] Hypercalcemia 1 (2) [1] Pneumonia 1 (2) [1] Renal failure chronic 1 (2) [1] Human Anti-Murine Antibody (HAMA) n (%) Number evaluable for HAMA 41 (100) Number not evaluable 0 Positive at baseline 0 No baseline or follow-up 0 Conversion to HAMA positivity Positive 4 (10) Negative 37 (90) Time to HAMA positivity from dosimetric dose, median days 112 (12 264) (range) Thyroid function b Number evaluable for thyroid evaluations, n (%) 36 (88) Elevated TSH post therapy, n (%) 9 (25) c Hypothyroidism, n (%) 3 (8) Time to hypothyroidism from dosimetric dose, days 192, 475, 671 4
a. Nine subjects completed the 10 years of follow-up in Study BEX104528. b. Four subjects had elevated TSH levels or hypothyroidism at baseline. c. Three of 9 subjects with elevated TSH also developed hypothyroidism. Conclusions: Tositumomab and iodine I-131 tositumomab resulted in a 54% confirmed overall response rate, including a complete response rate (CR+CCR) of 41%, in subjects with 1st or 2nd relapsed indolent or transformed non-hodgkin's B-cell lymphoma. At the conclusion of 10 year follow up, the median duration of response for all confirmed responders was 46.4 months. The median overall survival was 74.5 months for all subjects. Hematologic toxicity included reduced neutrophil count (44%), platelet count (37%), white blood cell count (34%), and anemia (17%). Four subjects developed HAMA positivity within 12-264 days after receiving the dosimetric dose. Myelodysplastic syndrome was observed in 3 (7%) subjects, and no other second cancers were observed. Three subjects developed hypothyroidism, and 6 additional subjects had elevated TSH levels after treatment but were not reported to have hypothyroidism due primarily to an elevated TSH level or known hypothyroidism at baseline. Thus, tositumomab and iodine I-131 tositumomab achieved durable responses, including complete responses, in patients with 1st or 2nd relapsed indolent or transformed B-cell NHL. 5