Nuclear

Physics Enterprises

Radium-223 Therapy:

Handling & Radiation Safety

Issues

Jeffry A. Siegel, Ph.D.

President & CEO

2014 Meeting Mid-Atlantic States

Radiation Control Programs

Malvern, PA

NRC’s Licensing Decision on 223Ra Dichloride

January 10, 2013 (FSME-13-002)

NRC staff carefully reviewed radiation safety aspects of medical use of 223Ra dichloride to determine if radiopharmaceutical should be licensed under 10 CFR Part 35, Subpart E (§ 35.300) or 10 CFR Part 35, Subpart K (§ 35.1000)

ACMUI evaluated medical use & submitted report recommending regulation under § 35.300

NRC staff agreed with ACMUI recommendation licensing under § 35.300 appropriate because medical use similar to other commonly used beta and photon-emitting therapeutic radiopharmaceuticals

In addition, physicians who are approved for use of any beta emitter or any photon-emitting radionuclide with a photon energy < 150 keV under §§ 35.390 or 35.396 can be authorized for the medical use of 223Ra dichloride

NOTES: Depending on type of license (broad or limited scope) and location (NRC or Agreement State), many licensees may need to apply for and receive a license amendment (e.g., Ra has Z=88) before being able to use Ra-223 dichloride

NRC does not require use of dose calibrator for medical use of radium-223 dichloride as it is licensed under § 35.300. However, some Agreement States and importantly, FDA prescribing information do require dose calibrator measurement

NRC Regulations & Agreement State Compatibility

10 CFR 35.300 Use of unsealed byproduct material for which a written directive is required

Compatibility Category Health and Safety (H&S) designation Not required for compatibility; has particular health and safety significance

10 CFR 35.390 Training for use of unsealed byproduct material for which a written directive is required

10 CFR 35.396 Training for the parenteral administration of unsealed byproduct material requiring a written directive

§§ 35.390 and 35.396 carry Compatibility Category B designation Must be adopted as written; if not, significant transboundary implications

10 CFR 35.1000 Other medical uses of byproduct material or radiation from byproduct material Licensing new medical use/emerging technology

Some confusion & compatibility concerns unintended regulatory “hole” NRC licenses under 300, can Agreement State license under 1000?

Xofigo Treatment Regimen

Administered on a patient-specific basis

Treatment activity is based on patient body weight

1.35 Ci/kg (50 kBq/kg)

70-kg patient would receive 95 Ci (3.5 MBq)

Supplied as unit dosage in syringe (contamination and activity intake highly unlikely for members of public and radiation workers)

Ra-223 mimics Ca selectively targets bone, specifically areas of bone mets by forming complexes with the bone mineral hydroxyapatite

Ra & Ca in same column of periodic table Group 2 (II A)

Treatment given every 4 weeks for 6 cycles (6 total administrations)

Common Radionuclide Therapy Procedures

(licensed under § 35.300)

Radionuclide Agent Indication AA (MBq)

32P Phosphate Polycythemia Vera 148

Chromic Phosphate Neoplastic Effusions and

Radiation Synovectomy 111-185

89Sr Chloride Bone pain 148

90Y Ibritumomab Tiuxetan NHL 1184(max)

131I Sodium iodide Hyperthyroidism 370-1110

Sodium iodide Thyroid Cancer 3700-14800

Tositumomab NHL 3108(av)

153Sm EDTMP Bone pain 2590

223Ra Xofigo Bone mets 3.5 (av)

Radium-223: Decay Properties

4 particles emitted per decay

• 223Ra dichloride is a

radiopharmaceutical; t½ = 11.4 days1

• Total decay energy is 28 MeV2

• Of the total energy emitted during

decay of 223Ra and its progeny2

95.2% emitted as particles

3.7% emitted as particles

1.1% emitted as γ or X-rays

• Principal photon emissions (>5%):

X: 81 keV, 84 keV

γ: 154 keV, 269 keV, 271 keV,

351 keV, 402 keV

Decays via a series of α-, β-, and γ-emitting daughters

223Ra

11.43 d

219Rn

3.96 s

α

α

α

β−

β−

β−

α

215Po

1.78 ms

211Pb

36.1 m 207TI

4.77 m

211Bi

2.17 m

211Po

516 ms

207Pb

stable

6

Radium-223 decay chain1

References: 1. Henriksen G, et al. Can Res. 2002;62:3120-3125. 2. ENSDF decay data in the MIRD format for 223Ra, 219Rn, 215Po, 211Pb, 211Bi, 207Tl and 211Po.

α

223Ra Production

223Ra occurs naturally 235U

But insufficient quantity for medical use

223Ra for medical use is byproduct material

226Ra irradiated by neutrons in reactor 227Ac

227Ac 227Th 223Ra

227Ac: ; t½ = 22 y

227Th: ; t½ = 18.7 d

Range of α-emitting Radiopharmaceuticals

Compared to β-emitters

References: 1. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.

Bone marrow

Tumor

Range of α-particle (short range – 2 to 10 cell diameters2) Optimize radiation dose to bone mets; minimize dose to bone marrow (minimize toxicity)

Range of β-particle (long range – 10 to 1000 cell diameters2)

Bone

Bone Mineral (Hydroxyapatite) Radionuclide

Short range of α-particles reduces bone marrow exposure1

µSv/h per MBq

µSv/h per patient dose

Distance from vial Ra-223 Tc-99m Ra-223 3.5 MBq (95µCi)

Tc-99m 740 MBq

(20000µCi)

one meter 0.0469 0.0215 0.16 15.9

one centimeter 469 215 ~27* 2652*

* Estimated finger dose per minute,

assuming handling of unshielded source

9

Xofigo: External Radiation Exposure Associated

with Handling is Low

Dose rates as calculated values* (All data presented are unshielded values)

*Exposure rate constants published by David S. Smith & Michael G. Stabin (Health Physics 2012; 102:271-291). Value for 223Ra

represents derived value for 223Ra + all its radioactive progeny in equilibrium.

Xofigo Pharmacokinetics

Distribution

After iv injection, rapidly cleared from blood and incorporated primarily into bone/bone mets or is excreted into the intestine

Organ activity uptake: At 10 minutes post injection, activity uptake observed in bone and intestine. At 4 h, 44 - 77% of administered activity in bone. No significant uptake in other organs at 4 h

Blood: At 15 minutes post injection, 20% of administered activity remains in blood, decreasing to 4% at 4 h and <1% at 24 h

Elimination

Fecal excretion is major route of elimination from body, 5% excreted in urine (no evidence of hepato-biliary excretion). A median of 76% of administered activity excreted from the body at 7 days

Median biological half-time in body 3.5 days (teff 2.7 days)

Measurement of Radium-223

Radium-223 primarily emitter, but s & photons also

emitted during decay of 223Ra and its radioactive progeny

enabling detection with conventional routinely available

instrumentation:

• Standard dose calibrators for determining patient dosages

• Survey meters for external radiation level surveys (e.g.,

routine area surveys, material receipt, after spills &

monitoring of waste held for decay-in-storage prior to

disposal)

Due to short physical half-life of 223Ra, disposable as non-radioactive

waste after appropriate amount of time (decay-in-storage) pursuant to

10 CFR 35.92 (radioactive progeny have much shorter half-lives

ranging from 1.8 msec to 36 min)

• Well counters for removable contamination (wipe) surveys

NIST and Measurement Accuracy of Dose

Calibrator for Ra-223

NIST* performed activity measurements in variety of dose calibrators for Ra-223 in various dose vials and syringes containing range of volumes and activities

Single calibrated dial setting found to result in accurate measurements

Dose calibrator measurement accuracies for Ra-223 were shown to be within +/-5% for all geometries

*Bergeron DE, Zimmerman BE, Cessna JT. Development of secondary standards for 223Ra. Appl Radiat Isot 2010; 68:1367-1370

Dose Calibrator Measurements of

Ra-223 activity

Licensees to calibrate their own dose calibrator with NIST traceable 223Ra standard

Capintec CRC-25R used; calibrated using NIST traceable activity source - dial

setting determined to be 264. Each syringe contained 2 MBq in 3.5 cc volume

Elapsed Expected Activity Measured Activity % Deviation

Time (days) 10 cc 5 cc 10 cc 5 cc 10 cc 5 cc

0 2.14 MBq 2.08 MBq 2.14 MBq 2.08 MBq 0% 0% 7 1.40 MBq 1.36 MBq 1.39 MBq 1.35 MBq -0.6% -0.4% 14 0.91 MBq 0.89 MBq 0.90 MBq 0.89 MBq -1.5% 0.2% 21 0.60 MBq 0.58 MBq 0.60 MBq 0.59 MBq 0.2% 1.6% 28 0.39 MBq 0.38 MBq 0.39 MBq 0.38 MBq -0.8% 1.3% 35 0.26 MBq 0.25 MBq 0.26 MBq 0.25 MBq 0% 1.7% 42 0.17 MBq 0.16 MBq 0.17 MBq 0.16 MBq 0% 0.6% 49 0.11 MBq 0.11 MBq 0.11 MBq 0.11 MBq 0.9% 0.3% 56 0.071 MBq 0.069 MBq 0.072 MBq 0.070 MBq 1.3% 1.3% 63 0.046 MBq 0.045 MBq 0.043 MBq 0.043 MBq -6.5% -4.4% 70 0.030 MBq 0.030 MBq 0.030 MBq 0.030 MBq -1.3% 1.7% 77 0.020 MBq 0.019 MBq 0.020 MBq 0.019 MBq 1.0% -3.2%

Xofigo: Radiation Surveys Associated with

Medical Use

Measurements made at two separate locations using 4 different GM survey meters, which all consisted of Ludlum Model 14C ratemeters connected to Model 44-9 GM pancake probes

Activity present in one drop of Ra-223 dichloride solution, a volume corresponding to 0.05 ml, 50 kBq. Ra-223 activities from 50 kBq down to 0.3 kBq were prepared.

The survey meters, all placed at a distance of 2 cm from the activity, indicated that all radium-223 activities were distinguishable from background and could be detected; the MDA was estimated to be at least 5 Bq for all 4 survey meters studied.

Conventional pancake detector can easily measure presence of radium-223 dichloride, if a spill or contamination event should occur, or as necessary for permissible waste disposal after on-site decay-in-storage.

Survey meter exposure and count rate

measurements of Ra-223 activity

Syringe/Volume Activity Ludlum mR/h

1 2 bkg bkg

Ludlum cpm 1 2

Background (cpm) 1 2

1 cc syringe + 0.05 cc

50 kBq (1.35 Ci)

50 / .03 --- 120K --- 160 ---

0.3 cc syringe + 0.25 cc

28.4 kBq (0.77 Ci)

20 / .03 --- 60,000 --- 0 ---

0.3cc syringe + 0.25 cc

26.75 kBq (0.72 Ci)

20 / .05 25 / .05 50,000 80,000 160 160

3 cc syringe + 1 cc 5.98 kBq (0.16 Ci)

2.5 / .05 3.0 / .05 8,000 10,000 150 150

3 cc syringe + 1 cc

5.63 kBq (0.15 Ci)

2.0 / .05 3.0 / .05 6,000 10000 100 100

0.3 cc syringe + 0.1 cc

0.598 kBq (0.016 Ci)

0.6 / .05 0.7 / .05 2000 2400 150 150

0.3 cc syringe + 0.1 cc

0.563 kBq (0.015 Ci)

0.7 / .05 0.6/ .05 2200 2000 100 100

0.3 cc syringe + 0.05 cc

0.299 kBq (0.0081 Ci)

0.3 / .05 0.4 / .05 1000 1150 150 150

0.3 cc syringe + 0.05 cc

0.2815 kBq (0.0076 Ci)

0.4 / .05 0.4/ .05 1100 1100 100 100

Patient Release: Xofigo is an Outpatient

Treatment

• Xofigo treatment involves low administered activity

95 µCi / 3.5 MBq for a 70 kg patient Estimated maximum likely external dose to others, D() = 34.6 Q0 Tp (0.25)

= 34.6 x (0.0469 μSv/MBq h) x (3.5 MBq) x (11.4 d) x (0.25)

= 16 μSv = 1.6 mrem (= dose to total decay; conservative by factor 8) Specific gamma ray constant of 0.0469 (at 1 m) is for 223Ra + all its progeny in

radioactive equilibrium (Smith & Stabin. Health Phys 2012; 102:271-291)

• Xofigo patients immediately releasable pursuant to 10 CFR 35.75

Negligible external radiation dose & risk to others (activity intake/internal

radiation dose highly unlikely). 5 mSv 1081 MBq (av = 3.5 MBq)

1.6 mrem equivalent to exposure to 2 days of background radiation (300

mrem/y or 0.8 mrem/day) or 1/5 that received from a chest x-ray (10

mrem). Given most conservative LNT risk model, fatal cancer risk

0.00008%. Given that normal incidence of cancer in US 40%, the

additional risk due to this exposure is a factor of 500K less