# Presentation: 040717

## Targeted Therapy with Rhenium-188 An Attractive Radioisotope for Broad Clinical Applications

- F. F. (Russ) Knapp, Jr.
***Nuclear Medicine Program***
***Nuclear Science and Technology Division***
***Oak Ridge National Laboratory (ORNL)***
***Oak Ridge, Tennessee***

**Annual Congress**
**European Association of Nuclear Medicine**
**Amsterdam, The Netherlands**
**August 25, 2003**

## Goals of Presentation 

- Goals of Presentation

**Describe attractive properties and benefits for using rhenium-188 as a high energy beta-emitter**
**properties of generator**
**ease of use**
**short half-life, high ********-**** energy**
**Systemic administration of rhenium-188-labeled agents for targeted therapy**
**bone pain palliation**
**tumor therapy**
**marrow ablation**
**Radiation synovectomy**
**Invasive therapy with rhenium-188**
**coronary restenosis therapy**
**liver cancer therapy**

## Augers

- Alphas

**Notes:**
Based on the application required, the beta-emitting radioisotope is chosen based on the depth of penetration required.  

## Production of Medical Radioisotopes

**Accelerators/Cyclotrons – usually “Proton-Rich”**
**Reactors – Fission products**
***Reactors – Direct Production  -  usually “Neutron-Rich”***
**Radionuclide Generators – Reactor or****accelerator-produced parent radioisotopes**

- ORNL 98-5790a/rra

## Why Rhenium-188?

**High beta energy – 2.12 MeV – maximum****155 KeV gamma photon for imaging**
**16.9 hour half-life**
***Available from generator – long shelf-life of several months – low cost and routine availability***
**Carrier-free as Re-188-perrhenate – saline elution**
**Perrhenate chemistry similar to Tc-99m**
***Multiple therapeutic applications***

- ORNL 2002-03847/rra

## Rhenium-188 is Formed by Decay

- of the Tungsten-188 Parent

- Production and Decay Scheme for Tungsten-188

- ORNL 2003-02191/rra

## Tungsten-188 is Loaded on the Alumina

- Generator as Tungstic Acid

- ORNL 2000-05336/rra

## Slide 8

## Sufficient Levels of Re-188Can Be Obtained by Daily Elution

- Sufficient Levels of Re-188Can Be Obtained by Daily Elution

- ORNL 99-03755a/rra

## Generator Set-up atRoyal Perth Hospital, Australia

- ORNL PHOTO 1017-98

- Generator Set-up atRoyal Perth Hospital, Australia

## High Yields and Low Breakthrough are Maintained for Over Two Months

- 100

- 80

- 60

- 40

- 20

- 0

- Percent Re-188 Yield/Bolus

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 10

- 8

- 6

- 4

- 2

- 0

- Percent Re-188 Breakthrough
- X 10-4/Bolus

- Elution Number

## Widespread International Use

- of the ORNL W-188/Re-188 Generator

## Slide 13

## Clinical Trials with Re-188 

- Clinical Trials with Re-188

**Systemic administration of rhenium-188-labeled agents for targeted therapy**
- bone pain palliation
**tumor therapy**
**marrow ablation**

## Examples of Radioisotopes for Bone Pain Palliation

- Radioisotope

- Agent

- Company/
- Institution

**Phosphorus-32**
**Rhenium-186 **
**Samarium-153**
**Strontium-89**
*Rhenium-188*

**Phosphate**
**HEDP**
**EDTMP**
**Chloride**
*HEDP/DMSA*

**Mallinckrodt**
**DuPont**
**Amersham**
*ORNL, et al.*

## Examples of Clinical Trials Evaluating Rhenium-188 HEDPfor Bone Pain Palliation

- Examples of Clinical Trials Evaluating Rhenium-188 HEDPfor Bone Pain Palliation

**Bonn, Germany**
- Prof. H.-J. Biersack, M.D.
- H. Palmedo, M.D., et al.

**Dresden, Germany**
- Prof. J. Kropp, M.D.
- K. Liepe, M.D., et al.

**Montevideo, Uruguay**
- J. Gaudiano, M.D., et al.

**Athens, Greece**
- Prof. G. Limouris, M.D., et al.

**Shanxi Hospital, PRC**
- H. Zhang, D.M.Sc., et al.

- Status

- Institution

- 22 pts – single treatment
- Dose escalation – 1.3-4.4 GBq
- 75% pain relief – 4.4 GBq group
**64 pts – randomized/two treatments**
**Repeated   Therapy = improved   Progession-free**
**And overall survival**

- 15 pts -1600-3459 MBq
- 80% pain relief/12-week followup

- 21 pts – 12 = single dose - 35 mCi
- 9 pts = scaled dose to 60 mCi     78% pain relief

- 6 pts. – 1.5 Gy marrow dose
- 80% pain relief – 2.4 months

- 61 pts. – uncontrolled trial
- 1 year follow-up     80% pain relief

## Study Design

**Randomization: **
**	****Group A****	****	****1 **x** injection ****	****Group B****	****	****2 **x** injection    ****(interval of 8 w)**
**Follow-up until death**

**(H. Palmedo, et al., J. Clin. Oncol., 21, 2869, 2003)**

## Results

**Patients**

- 30 patients
- 1 x injection

- 28 patients
- 2 x injection

**2 excluded**

**4 excluded**

**64 patients randomized**

**(H. Palmedo, et al., J. Clin. Oncol., 21, 2869, 2003)**

## Results

- GROUP B

- GROUP A

**0**
**27**
**25**

- Toxicity

**Grade**
**Thrombo.**
**Leuko.**

- Pain

**1**
**2**
**4**

**II**
**1**
**1**

**0**
**23**
**25**

**1**
**3**
**5**

**II**
**2**
**1**

**Response**
**Duration (mon)**

- 60%
- 2.55 (1.2-9.4)

- 92%
- 5.66 (2.0-12.5)

**(H. Palmedo, et al., J. Clin. Oncol., 21, 2869, 2003)**

## Multiple Re-188-HEDP TherapyHas a Dramatic Effect onProgression-Free Survival

**Group B**

**Group A**

**Progression-free Survival Time (months)**

**0.2**

**0.4**

**0.6**

**0.8**

**1**

**5**

**10**

**15**

**20**

**25**

- Multiple Re-188-HEDP TherapyHas a Dramatic Effect onProgression-Free Survival

**Proportion of Patients**

**(H. Palmedo, et al., J. Clin. Oncol., 21, 2869, 2003)**

## Tc-99m-MDP Imaging Demonstrates Significant Change in Metastatic Foci After 5 Months

- ANT

- POST

**(S. Li, et al., Clinical Nuclear Medicine, 26, 919, 2001) **

- 52-year-old female, breast cancer

## Cell Counts Beginning at Pre-therapy Baseline After Injection of Re-188-HEDP

**12**
**10**
**8**
**6**
**4**
**2**
**0**

**300**
**250**
**200**
**150**
**100**
**50**
**0**

**1000/qmm**

**Weeks After Therapy (n =61)**

**1000/qmm**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**PLT**

**WBC**

- Platelets

- Leukocytes

**(S. Li, et al., Clinical Nuclear Medicine, 26, 919, 2001) **

## Clinical Trials with Re-188 

- Clinical Trials with Re-188

**Systemic administration of rhenium-188-labeled agents for targeted therapy**
**bone pain palliation**
- tumor therapy
**marrow ablation**

## NS3 Ligand Group Replacement of Lys with Ar
Renal retention reducedby 50%
30% increased tumor uptake

- The Re-188-Labeled Pre-engineered Re-188 (Arg11) CCMSH Peptide is a Metal-Cyclized -MSH Analogue Which Shows Good Melanoma Targeting

- Peptide Incorporates Direct Labeling Moiety

**NS3 Ligand Group Replacement of Lys with Ar**
**Renal retention reduced****by 50%**
**30% increased tumor uptake**

**(Courtesy of T. P. Quinn, University of Missouri)**

- ORNL 2003-01956/rra

## Slide 25

## Slide 26

## Clinical Trials with Re-188 

- Clinical Trials with Re-188

- Radionuclide synovectomy

## Rhenium-188-Labeled Agents for Synovectomy

**Re-188 hydroxy apatite**
**animal studies show promise**
**Re-188 sulfur colloid**
**easy to prepare but may be difficult to handle**
**Re-188 tin colloid**
**Jeong, et al., Seoul National University Hospital**
**Easy to prepare – stable**
**>70% in 1-10 micron size range**
**First clinical studies recently reported**

## Rhenium-188-Tin-Colloid for Treatment of Rheumatoid Arthritis

**Efficacy and safety study in 22 knees/21 enrolled patients refractory to corticosteroid injection**
**370-1110 MBq- evaluation at 1, 3, 6, 9, and 12 months**
**Improvement in all outcome variables**
**Pain – decreased in 19 cases (86.3%)**
**Joint tenderness – improved in 14 cases (63.6%)**
**Joint swelling – decreased in all cases**
**No clinical side effects**
**Improvement in arthritis and well tolerated**

**(Lee, et al., Nucl. Med. Commun., 24, 689, 2003)**

## Homogeneous Distributionof Re-188-Tin-Colloid One Hour After Intra-articulation

**Anterior-****Planar**

- Homogeneous Distributionof Re-188-Tin-Colloid One Hour After Intra-articulation

**Coronal**
**SPECT**

**Sagittal**
**SPECT**

**Lee, et al., Nucl. Med. Commun., 24, 689 (2003)**

## Efficacy of Re-188-Tin-Colloid in Reducing Pain Intensity

**80**

**60**

**40**

**20**

**VAS (mm)**

**0**

**1**

**3**

**6**

**9**

**12**

**Months**

**VAS (mm)**

**0**

**1**

**3**

**6**

**9**

**12 m**

**Mean**
**SD**

**68.0**
**26.1**

**44.0**
**31.1**

**50.7**
**34.7**

**31.4**
**26.9**

**23.6**
**24.4**

**25.1**
**23.4**

**188****Re-tin colloid injection**

**Lee, et al., Nucl. Med. Commun., 24, 689 (2003)**

## Clinical Trials with Re-188 

- Clinical Trials with Re-188

**Systemic administration of rhenium-188-labeled agents for targeted therapy**
**bone pain palliation**
**tumor therapy**
- marrow ablation

## Examples of Radioisotopes for Targeted Bone Marrow Ablation

- Radioisotope

- Agent

- Company/
- Institution

**Holmium-166**

**DOTMP**

**NEORX, Inc. Melanoma****Patients**
**Multiple Myeloma**
**Animal Studies**
*Ulm/Hannover, Germany**Leukemia Patients*

**Yttrium-90**

**EDTMP**

*Rhenium-188*

*Anti-CD 66*

**Samarium-153**

**EDTMP**

## Re-188-Labeled-BW 250/183 Shows Good Targeting to Marrow and Low Soft Tissue Uptake

- ORNL 99-06615/rra

- Posterior View
- 24 Hours Post Therapy

**(Reske, et al.,****Eur. J. Nucl. Med., October 1999)**

## 
Invasive therapy with rhenium-188
coronary restenosis therapy
liver cancer therapy

**Invasive therapy with rhenium-188**
- coronary restenosis therapy
**liver cancer therapy**

- Clinical Trials with Re-188

## Restenosis After Coronary Balloon Angioplasty is a Major Clinical Problem

**(reprinted with permission from Schwartz, et al****Science and Medicine,****March-April, 1996)**

- ORNL PHOTO 101088-97/rra

## >500,000 coronary angioplasty procedures in U.S./year
30-50% rate of restenosis
Re-treatment cost$1-2 billion/year
Radiation doseof 20-25 Gy/0.5 mm depth can significantly reduce restenosis

- Coronary Restenosis After Angioplastyis a Major Clinical Problem Which Can be Inhibited by Irradiation of the Vessel Wall

- ORNL 99-06003c/rra

**>500,000 coronary angioplasty procedures in U.S./year**
**30-50% rate of restenosis**
**Re-treatment cost****$1-2 billion/year**
**Radiation dose****of 20-25 Gy/0.5 mm depth can significantly reduce restenosis**

**Stenosis**

**Normal Coronary**
**Artery**

**Angioplasty**

**Post-Angioplasty**

**Restenosis 30-50%**

**Restenosis Reduced to 5-10%**

**Irradiation**

## Uniform Dose Delivery to the Vessel Wall is Very Importantfor Beta Emitters

- Uniform Dose Delivery to the Vessel Wall is Very Importantfor Beta Emitters

- ORNL 98-6723a/rra

## Coronary Irradiation with Rhenium-188 Liquid-Filled Balloons Successfully Reduces Restenosis Following PTCA

- Results

- Trial

- Approx. Dose/Depth

- Dresden

- ULM

- IAEA

- Korea

- Columbia University

- Cedars Sinai, LA

- Taiwan

- Munich

- Sydney

- 30 Gy/0.5 mm

- 22.5 Gy/0.5 mm

- 30 Gy/1 mm

- 15 Gy/1 mm

- 26 Gy/media13 Gy/Adventia

- 48 Gy/1 mm

- 14 Gy/0.5 mm

- 28 Gy/0.5 mm

- 25 Gy/0.5 mm

- 28 Pts/12% - 6 m edge restenosis “Candy Wrapper Effect”

- Rotoblator   50 Pts/10.4% - 6 m

- De Novo Lesions    25 Pts

- Ineffective   40 Pts/40%

- Recurrent in Stent21 Pts/18%

- 25 Pts

## Inhibition of Restenosis with Rhenium-188 Has Been Demonstrated in a Swine Coronary Balloon Overstretch Injury Model

**(Data from Judah Weinberger, M.D., Ph.D., Columbia University, New York)**

**Control artery 30 days after**
**balloon overstretch injury**

**Injured artery 30 days following**
**25 Gray Dose from Rhenium-188**

**Hyperplasia**

**Normal Wall**
**Thickness**

- ORNL 97-1281808b/rra

## Slide 41

## Before PTCA and IRT

- During IRT

- After PTCA and IRT

- 6 Months Follow-upafter PTCA and IRT

**(J. Kropp, M.D. and K. Reyhen, M.D., University Hospital, Dresden, Germany)**

## 
Invasive therapy with rhenium-188
coronary restenosis therapy
liver cancer therapy

**Invasive therapy with rhenium-188**
**coronary restenosis therapy**
- liver cancer therapy

- Clinical Trials with Re-188

## Re-188 Labeling of B20 Particles

**2.5 mg of the****B20**** ****microspheres**
**20 μmol of gentisic acid****per ml reaction suspension**
**Reaction time of 90 min**
**Particle size = 20-30 microns**** **

**Effect of SnCl****2****-2H****2****O concentration on particle****bound radioactivity**

**100**

**80**

**60**

**40**

**20**

**0**

**10**

**20**

**30**

**40**

**0**

**Sn(II) chloride (********mol/ml)**

**Particle Bound Radioactivity**
**(%)**

**(from J. Kropp, et al., Dresden, Germany)**

**17**

## Re-188-B20 Treatment of Liver Metastases from Colorectal Carcinoma

**99m****Tc**
**Pre-Therapy**

**188****Re-B20****9.1 MBq**
**Post Therapy**

**22 h**

**(from J. Kropp, et al.,**
**Dresden, Germany)**

**1 h**

**44 h**

## 18F-FDG PET Demonstrates Effectsof Re-188-B20 Particles for LiverCancer Therapy

**SUV = 8.2**

**SUV = 4.1**

**Before therapy**

**Two weeks****after therapy**

**(from J. Kropp,****et al., Dresden,****Germany)**

- 18F-FDG PET Demonstrates Effectsof Re-188-B20 Particles for LiverCancer Therapy

**(Coronal view)**

## 188Re-B20 Particles Have Also Been Used for Treatment of an Aesthesioneuroblastoma

**188****Re-****microspheres**** 30 min p.i.**

**99m****Tc-microspheres, ****30**** min p.i.**

**Rare malignant tumor****of the olfactory nerve **
**Inoperable**

- 188Re-B20 Particles Have Also Been Used for Treatment of an Aesthesioneuroblastoma

**(from J. Kropp, et al., Dresden, Germany)**

## Re-188 Oxo Core N2S2 Chelate

- Re-188 Oxo Core N2S2 Chelate

- ORNL 2003-02202/rra

## Stable, Neutral Re-188-Complexfor Lipiodol Extraction

- Stable, Neutral Re-188-Complexfor Lipiodol Extraction

- ORNL 2003-02193/rra

## Re-188-Lipiodol for Treatment of HCC

- ORNL 2003-02185/rra

## Excellent in vivo stability – minimal kidney activity
No changes in WBC, ANC or platelets – 24h; 1, 2and 3m
AFP levels generally decreased – bilirubin unchanged
CT showed tumor size decrease in most patients
Good performance status – resumed work in 1 week
MTD often not achieved – PT’s with 165, 168and 206 mCi tolerated
Higher dose limitation seems to be liver MTD

- ORNL 2003-02186/rra

- ResultsPhase I with Rhenium-188 LIpiodol

**Excellent *****in vivo***** stability – minimal kidney activity**
**No changes in WBC, ANC or platelets – 24h; 1, 2****and 3m**
**AFP levels generally decreased – bilirubin unchanged**
**CT showed tumor size decrease in most patients**
**Good performance status – resumed work in 1 week**
**MTD often not achieved – PT’s with 165, 168****and 206 mCi tolerated**
**Higher dose limitation seems to be liver MTD**

**16 patients – scout dose (200 MBq)/therapy dose (4 GBq)**

## Slide 52

## Summary and Conclusions

**Rhenium-188 is an attractive candidate for a wide variety of therapeutic applications**
**Physician-sponsored trials are in progress at over****60 centers world-wide**
**These trials demonstrate ease of generator use****and effectiveness of using rhenium-188 for multiple therapeutic applications**
**Major applications expected to continue in oncology**
**Installation in a central radiopharmacy would be expected to cost effectively provide unit doses****for a variety of applications **

## Acknowledgments

***U.S. Department of Energy***
***ORNL*****Saed Mirzadeh, Ph.D.****Arnold Beets**
***Cedars Sinai, LA*****N. Eigler, M.D.****J. Whiting, Ph.D.**
***Columbia University*****J. Weinberger, M.D., Ph.D.**
***IAEA*****A. K. Padhy, M.D. - colleagues****at 23 participating clinical sites***** ***
***Montevideo*****J. Gaudiano, M.D.**
***Athens*****G. Limouris, M.D.**

***Bonn*****Prof. H.-J. Biersack, M.D.****H. Palmedo, M.D.****S. Guhlke, Ph.D.**
***Canterbury*****P. J. Blower, Ph.D.****M. O’Doherty, M.D.**
***Dresden*****J. Kropp, M.D.****K. Liepe, M.D.****Wunderlich, Ph.D.**
***Seoul*****Prof. J.-K. Chung, M.D.****J.-M. Jeong, Ph.D**
***ULM*****Prof. S. N. Reske, M.D.****J. Kotzerke, M.D.**

## The A Team