try George Sgouros, Ph.D. Russell H. Morgan Dept of Radiology & Radiological Science Baltimore MD

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1 Bexxar Dosimet try George Sgouros, Ph.D. Russell H. Morgan Dept of Radiology & Radiological Science Johns Hopkins University, School of Medicine Baltimore MD

2 Clinical i l Experi ience with anti- CD-20 Targeted Radioimmu unotherapy Richard L. Wahl, M.D. Johns Hopkin ns University Division of Nu uclear Medicine Departments of Radi iology and Oncology

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4 Immunotherapy Targets on B Cells DR slg CD19 CD20 B lymphocyte CD22 2 Surface proteins targeted by immunotherapy Unlabeled monoclonal antibodies (MAbs) Conjugated MAbs Radioisotopes Drugs Toxins Adapted from Press O, et al. Cancer J Sci Am. 1998:4(suppl 2):s19 s26.

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7 Czuczman et al, J Clin Oncol 22:23, , 2004 Rituximab + CHOP

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9 I-131 Tositumom mab Treatment Regi imen Thyroid protective agent: Day 1 continuing th hrough 14 days post-therapeutic dose Day 0 Dosimetric Dose 450 mg unlabeled tositumomab, 35 mg tositumomab radiolabeled I 131 (5 mci) Unlabeled dose infused over 1 hour Radiolabeled tracer dose infused over 20 minutes Total Body Counts x 3 Day 0 Day 2, 3, or 4 Day 6or7 Day 7 14 Therapeutic Dose 450 mg unlabeled tositumomab, 35 mg tositumomab radiolabeled I 131 to deliver specific cgy TBD (variable mci) Unlabeled dose infused over 1 hour Radiolabeled therapeutic dose infused over 20 minutes

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13 Normal Biodistribution ib i Scan 1 Scan 2 Scan 3 Da ay 0/Visit 1 Day 3/Visit 2 Day 6/Visit 3 Total body residence time hours First Image (shortly after dosimetric dose) Most activity in the blood pool (heart and major blood vessels) Uptake in liver and spleen is < in heart Anterior Anterior Anterior

14 Range of mci Required to Deliver Targeted Total Body Radiation Dose* Numb ber of Patients (n=225) mci Activity to Deliver 75 cgy TBD (mci) * Patients were prescribed either 65 5cGy or 75 cgy depending on their platelet count. Data were standardized to 75 cgy. Data on File, GlaxoSmithKline.

15 Dosimetry for I-131 Tositumomab

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18 Activity Hours to Deliver 75 cgy TBD Mass Activity Hours Mass Activity Hours Mass Activity Hours

19 The Equation Used to Calculate the Therap peutic Dose Therapeutic Dose (mci) = Activity Hours (mci h) Residence Time (h) Desired TBD (cgy) X 75 cgy* * 65 cgy for platelet count > 100,000 and < 150,000/mm 3.

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21 Summary: I Tositumomab Effective treatment for relapsed follicular NHL As first line Rx, has 95% response rate Complete responses are quite durable Major toxicity is hematopoietic Explored for retreatment with success in HAMA neg pts. High dose RIT is possible with stem cell support and very active Recent data suggest I-131 Rituximab has similar anti- tumor activity

22 Study Design Randomization Arm A Tositumomab and Iodine I 131 Tositumomab Arm B Tositumomab Arm B Crossover after reenrollment Patients with Progressive NHL and HAMA negative

23 Slide 22 s3 increased size of arrows stewarts, 11/2/2004

24 MIRROR Panel Assessed Time to Progression or Death Arm A vs. Arm B Proportio on Progression n-free Iodine I-131 Tositumomab (n=42) Tositumomab (n=36) Time from Treatment (years)

25 Conclusions This study documents that the radionuclide contributes significantly to the action of th he radioimmunoconjugate in the BEXXAR therapeutic regimen The radionuclide contributes durability of response to both the frequency and Toxicity associated with the radionuclide was primarily predictable and manageable myelosuppression Low term safety risks: thyroid insufficiency, HAMA seroconversion,,possibly MDS are acceptable in light of efficacy results

26 Effect of Chemotherapy: NHL # Variable Characteristics 1 AGE Age at RIT 2 NPC Number of prior chemotherapy regimen 14 Zevalin; 18Bexxar ( 9 ns 0 at RIT 3 TLC Elapsed time since last chemotherapy (m 3.1 ± 1.7 (1-8) Y-; 131 I-anti-CD20) 4 BMD Bone marrow dose (Gy) Treated 5 BSL Baseline as per at time of dosing RIT guidelines Platelets ( 10 3 /mm 3 ) 206 ± 100 Absolute neutrophil count (1/mm BM dose ~ constant 3 ) ± SEX Male sex 23 (72%) 7 TYP Type of RIT 90 Y-ibritumomab tiuxetan 14 (44%) Identify best 131 I-tositumomab predictor of Hematologic 18 (56%) toxicity 8 DST Disease stage at RIT I-II 14 variables consideredd III-IV 9 PTR Prior treatment with Rituximab Alone With chemotherapy 10 RTR Refractory to Rituximab 11 BMI Bone marrow involvement at RIT 12 PMT Prior bone marrow transplant 13 PRT Prior radiation therapy 14 PTF Prior treatment with fludarabine Mean ± SD or N (%) 63 ±10 (40-80) months) 8.9 ± 6.4 (1-26) 1.6 ± 0.4 ( ) * 2.1 ± 0.4 ( ) 5 (16%) 27 (84%) 8 (25%) Multiple linear regression analysis 23 (72%) 14 (44%) 7 (22%) 4 (13%) 7 (22%) 9 (28%) Baechler, et al SNM 09

27 Effect of Chemotherapy: NHL Dose regimen Patient # Actual Proposed 3* H L 6 H 10 L 11 L 12 H 15 L 18 H 20 H 21 H 23 L 25* L 28 L 29 L H + L - L - H + L - H + * Patient with bone marrow involvement L H + L - H L - H Baechler, et al SNM 09

28 SPECT/CT Imaging Radionuclide Therapy Yuni Dewaraja based Dosimetry in In collaboration with Pete Roberson, Jeffrey Fessler, Scott Wilderman, Matthew Schipper, Ken Koral, Anca Avram, Mark Kaminski University of Michigan Departments of Radiology, Radiation Oncology, Electrical Engineering g & Internal Medicine This work is supported through grant EB awarded by the National Institute of Health

29 3D Dosimetry coupling SPECT/CT with Monte Carlo CT data Integrated imaging CT-based attenuation corr, scatter corr, VOI definition Monte Carlo Dosimetry: DPM Code Dose map SPECT projection Dose-rate map Dead time Reconstruction & quantification Dewaraja, et al. JNM 2010

30 Patient Results: Init tial tumor regression Day 0 post-tracertracer Day 0 post-tracer Day 5 post-therapy Dewaraja, et al. JNM 2010

31 Patient results: SPECT/CT images Day 0 post-tracer Day 5 post-therapy Day 8 post-therapy Dewaraja, et al. JNM 2010

32 Tracer-therapy correlation: whole-body (SPECT FOV) Dewaraja, et al. JNM 2010

33 Tracer-therapy correlation: tumor High correlation between tracer predicted and therapy delivered mean tumor absorbed dose R = tracer predicted dose (cgy) Dewaraja, et al. JNM 2010

34 Tumor dose-response Dewaraja, et al. JNM 2010