Radiopharmaceuticals in Bone Metastasis: Clinical Trials, Imaging and Dosimetry. John L. Humm & Neeta Pandit-Taskar Memorial Sloan-Kettering

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1 Radiopharmaceuticals in Bone Metastasis: Clinical Trials, Imaging and Dosimetry John L. Humm & Neeta Pandit-Taskar Memorial Sloan-Kettering

2 Disclosures John L Humm Served on the Scientific Advisory Board of Algeta

3 Objectives of this Presentation To assess pharmacokinetics, biodistribution and dosimetry of Ra-223 in patients with prostate cancer

4 Protocol Design Ra-223 dose escalation: 50, 100 kbq/kg & 200 kbq/kg Serial gamma camera images immediately, post first void (0-6 h of treatment), and 24 6 h, h, h and h Serial whole body counts (NaI probe) Pre-void, post 1st void (0-6 h of treatment), and 24 6 h, h, h and h Serial blood and serum counts 1m, 5 m, 15m, 30 m, 45m, 1 h, 24 6 h, h, h and h

5 Radium-223 Decay Radium-223 decay chain Radium-223 in Alpharadin is an alpha-emitter t 1/2 = days Of the total decay energy 93.5% emitted as 4 particles < 4% emitted as particles < 2% emitted as γ or X-rays 223 Ra d α 219 Rn 3.96 s α 215 Po 1.78 ms α β Decays via a series of α, β, and emitting daughters 211 Bi 2.17 m β (0.27%) 211 Po 516 ms α 211 Pb 36.1 m α (99.73%) β 207 Pb stable 5 Henriksen G, et al. Cancer Res. 2002;62: TI 4.77 m

6 The Ra-223 Spectrum Ra-223 Rn-219 Po-215 Pb / Bi-211 Pb days 4 s 1.8 ms 36m * 2.2 m 84 kev X-rays ~41% 154 kev (9%), 269 kev (14%) 271 kev 10% Nothing imageable 351 kev + higher 13% 5 energy windows used: 84 kev, 154, 269, 351 and 403 kev

7 Serial WB Images from Royal Marsden Posterior Images from Day 0 through 7

8 Imaging Organs Since other centers had focused on acquiring serial whole body scans, our philosophy was to try to get early organ data. Relevant organs would be vertebrae, kidney, liver, G.I. tract. Serial ant & post spot views of the abdomen and pelvis following upon the imaging trial design of an earlier trial with 213 Bi-M195 antibodies. Images are much more noisy on account of the low administered activity.

9 Patient at the 50kBq/kg FDG D27 Lt fem tu 1.4 Tc-99m MDP D20 ant & post Ra-223 ant & post

10 Patient at the 200 kbq/kg dose level MIP FDG -7 Rt hum 1.74 Tc-99m MDP D 10 Ant & Post Ra-223 Ant & Post

11 0-10 m m m m m m 232 min post 1 d 2 d 6 d Bone scan D13

12 Bone Retention is very long Posterior View Pelvis Ra d Bone scan 200kBq/kg (240 Ci) Ra d Bone scan

13 %WB Activity (ndc) Whole Body Clearance Time (hr)

14 Blood (%ID/l) Blood Clearance T1/2 fast (h) T1/2 slow (h)

15 Whole Body Excretion Urinary Excretion First void (%) Amount in bowel at 1d (%) Amount Excreted from Whole Body at 7d (range 6-8) %ID 4% (range %) 51% (range 43-59%) 68% (range 44-78%)

16 Where does the administered activity go? Fraction of injected activity in the intestine over time Time Uptake in intestine % mean injected dose + standard deviation 10 min min min min h h

17 What happens to the Daughters?

18 Parent and Daughter Sequence Day 0 Pre-void All Counts Parents Final Daughter

19 Parent and Daughter Sequence Day 0 Post-void All Counts Parents Final Daughter

20 Radium Activity dominated by gut activity Day 1 Ant Post Parent Daughter We do not see Pb or Bi daughters leaving gut contents and re-locating in kidney

21 Parent and Daughter Sequence Day 1 All Counts Parents Final Daughter

22 Parent and Daughter Sequence Day 3 All Counts Parents Final Daughter

23 Parent and Daughter Sequence Day 6 All Counts Parents Final Daughter

24 Ratio of counts from daughter to parents Ratio of counts within identical ROI drawn over the final Bi-211 daughter to the summed parental emission G.I. tract Kidney Liver Bone lesion n min 0.162± ± ± ± min 0.152± ± ± ± min 0.147± ± ± ± h (n=1) Ra-223 standard 4 h 0.151± ± ± day 0.155± ± days ± or 7 days ±0.006

25 Absorbed doses (Gy/MBq) to different organs From George Sgouros Individual emission contributions (Gy/MBq) Total Total SD Target organ Alpha Beta Photon (Gy/MBq) (rad/mci) (%) Organ Dose in a 73- kg Adult given 50 kbq/kg Gy rad Adrenals 0.00E E E Brain 0.00E E E Breasts 0.00E E E Gallbladder wall 0.00E E E LLI Wall 0.00E E E Small intestine wall 3.19E E E Stomach wall 0.00E E E ULI wall 0.00E E E Heart wall 1.61E E E Kidneys 2.99E E E Liver 2.79E E E Lungs 0.00E E E Muscle 0.00E E E Ovaries 0.00E E E Pancreas 0.00E E E Red marrow 1.32E E E Osteogenic cells 1.14E E E Skin 0.00E E E Spleen 0.00E E E Testes 0.00E E E Thymus 0.00E E E Thyroid 0.00E E E U. bladder wall 3.71E E E Uterus 0.00E E E Whole body 2.22E E E

26 Organs that matter Individual emission contributions (Gy/MBq) Dose to an Adult given 50 kbq/kg Target organ Alpha Beta Photon Gy rad Red marrow 1.3E E E Osteogenic cells 1.1E E E Remember - Most of this is α-dose

27 223 Ra Bone Marrow dosimetry Less than 1% of 292 patients treated in phase I & II trials receiving between 5 and 250 kbq of 223 Ra had CTC grade 4 hematological toxicity; 2%-4% had grade 3 toxicity. Cheetham & Petrylak, Alpha Particles as Radiopharmaceuticals in the Treatment of Bone Metastases: Mechanism of Action of Radium-223 Chloride (Alpharadin) and Radiation, ONCOLOGY. Vol. 26 No. 4, Yet individual red marrow absorbed doses based on standard MIRD estimates were often above 3 Gy.

28 Marrow Dosimetry Bone Bone R Trabecular marrow cavity Trabecular marrow cavity α-emitters deposit energy uniformly in the marrow space. Target marrow cells also assumed uniformly distributed α-emitters mostly on bone surface and more concentrated at diseased sites Mean to marrow cavity won t predict effect From Hobbs, et al. Phys Med Bio 12

29 Autoradiograph of 223 Ra in dog Normal bone Tumor Bone marrow Courtesy of Oyvind Bruland Low dose to bone marrow

30 Spatial profile of hematopoietic progenitor cells Bourke et al, Blood, 114: 4077, 2009

31 Dose-response for toxicity bone r Marrow cavity R 400 micron Hobbs, et al. Phys Med Bio 12

32 Lesion Dosimetry Radiation dose requires an estimate of the activity AND knowledge of the tumor mass (or volume of distribution of the radionuclide) #107 Ratio of counts in bone lesions : normal bone (uncorrected for partial volume effects) Subject Number Hot spot #1 Hot spot # L humerus 1.55 L femur R humeral 1.19 L iliac head L femur 1.42 R humerus R distal 1.36 L humeral head femur Sacrum 2.04 Degenerative disease R hip Upper spine 1.14 L acetabulum R scapula 1.23 Thoracic spine Pubic 1.72 L iliac R humerus

33 What can we say about tumor dose? Unable to determine tumor doses by gamma camera imaging. Estimates will need to rely on accurate bone modeling and microdosimetric calculation. Autoradiographs will help but will be difficult to obtain Tumor cells close to bone surface will get significant doses of α-radiation. Hobbs, et al. Phys Med Bio 12

34 Dose Rates to the Public from Alpharadin The administered activities in Alpharadin therapies are extremely low (50 kbq or 1.35 μci per kilogram body weight). Therefore the exposure rates to staff and the public resulting from patients undergoing this therapy are very small. Contrast this to the dose rates in µsv/hr to 90 µsv/hr (contact) after a bone scan Time after administration ~0 h ~24 h T~48 h T~1 week Activity Contact 1 m Contact 1 m Contact 1 m Contact 1 m Mean 50kBq

35 CONCLUSIONS PK analysis: rapid blood clearance with little or no binding to blood elements Little urinary excretion based on imaging and wb counts Imaging demonstrated bone targeting, and excretion through small bowel (rapid) with transit through large bowel. No significant redistribution of daughters to dose limiting organs such as the kidney. Imaging data can result in mis-leading radiation dose information to dose limiting tissues such as marrow and G.I. tract. Imaging data unable to estimate radiation dose to metastatic lesions.

36 Acknowledgements Jorge Carrasquillo, Joseph O Donoghue, MSKCC, New York George Sgouros, Johns Hopkins University School of Medicine, Baltimore Wesley Bolch, University of Florida, Gainesville Øyvind Bruland, The Norwegian Radium Hospital, Oslo

37 Question 1 Which organ has the highest amount of 223 Ra at 24 hr post injection? A. Bone B. Liver C. Kidney D. Large intestine E. Muscle

38 Answer 1 A. Bone B. Liver C. Kidney D.Large intestine E. Muscle About 50% of the administered activity is in the large intestine at 24hr

39 Question 2 The radiation dose to the bone marrow from 223 Ra? A. Uniform and largely a consequence of activity in the bone B. Uniform and largely a consequence of activity in blood C. Uniform and largely a consequence of longer range β- emissions D. Is extremely non-uniform due to the short range of α- emissions E. Is negligible because of the short range of α-particles

40 Answer 2 A. Uniform and largely a consequence of activity in the bone B. Uniform and largely a consequence of activity in blood C. Uniform and largely a consequence of longer range β-emissions D.Is extremely non-uniform due to the short range of α-emissions E. Is negligible because of the short range of α-particles

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