An Open-Label, Single Institution, Phase II Study Using Radioactive Yttrium90 Microsphere (SIR-Sphere®) in Uveal Melanoma Patients With Hepatic Metastasis
Phase: PHASE2
Conditions: Stage IV Uveal Melanoma
Sponsor: Thomas Jefferson University

CLINICAL PROTOCOL 
 
Date of Version: 1/16/2012  
Protocol Title: An open-label, single institution phase II study using radioactive yttrium90 
microsphere (SIR-Spheres® microspheres) in uveal melanoma patients with hepatic metastasis 
 
Study Medication: Radioactive yttrium90 microsphere (SIR-Spheres®) 
 
IRB Number: 
 
 
 
Principal Investigator: 
Takami Sato M.D., Ph.D. 
Co-Principal Investigator:  
Carin F. Gonsalves, M.D. 
 
Co-Investigators:  
Pramila R. Anne, M.D., David J. Eschelman, M.D., Daniel Brown, M.D., Michael J. Mastrangelo, 
Voichita BarAd, M.D., Laura Pino, PA-C, Linda Ferguson, CRNP  
 
Clinical Research Nurse/Coordinator: 
MaryAnn Laudadio, R.N. 
 
Medical Physicist: 
Laura A. Doyle, M.S., Jun Li, Ph.D., Yan Yu, Ph.D. 
 
Radiation Safety Officer: 
Mr. John Keklak, Larry Martino  
 
Statistician: 
Inna Chervoneva, Ph.D. 
 
 

 
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[Table of Contents] 
Protocol Summary 
 
 
 
 
 
- 5 - 
 
Schedule of Study Activity 
 
 
 
 
- 7 - 
 
1.0 Background  
 
 
 
 
 
- 8 - 
 
 
1.1 Uveal Melanoma 
1.2 Systemic Treatment for Metastatic Uveal Melanoma  
1.3 Surgical Treatment for Liver Metastases 
1.4 Hepatic Intra-arterial Chemotherapy for Liver Metastases 
1.5 Chemoembolization of Liver Metastases 
1.6 Immunoembolization of Liver Metastases 
1.7 Selective internal radiation therapy (SIRT, radioactive microspheres) for cancer 
1.8 SIRT for metastatic uveal melanoma  
 
2.0 Study Objectives and Endpoints 
 
 
 
- 13 - 
 
 
2.1 Study Objectives 
2.11 Primary Objectives 
2.12 Secondary Objectives 
2.2 Study Endpoints 
2.3 Other Parameters 
 
3.0 Study Design  
 
 
 
 
 
-14 - 
 
 
 
 
 
  
4.0 Selection of Patients   
 
 
 
 
- 15 - 
4.1 Inclusion criteria  
4.2 Exclusion criteria 
 
5.0 Treatment Schedule   
 
 
 
 
– 17 - 
5.1 Pre-study Evaluation  
5.2 Flow study and pretreatment assessment 

 
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5.3 Biopsy of hepatic metastasis 
5.4 Radioactive microsphere treatment 
5.5   One-month post-procedure visit 
5.6  3-month post-procedure visits 
5.7   Subsequent follow-up visits 
5.8 End of study visit 
5.9 Withdrawal of subjects 
5.10 Follow-up after withdrawal from study 
 
6.0 Supportive Care Guidelines    
 
 
 
 
 
- 21 - 
6.1 Post-Treatment Care  
6.2 Pre- and Post-treatment Supportive Therapies 
 
7.0 Evaluation of Response 
 
 
 
 
- 22 -  
 
 
7.1 Evaluation of clinical response 
7.11 Definition of Measurable Disease 
7.12 Baseline Documentation of "Target" and "Non-Target" Lesions  
7.13 Evaluation of overall response in the liver metastases 
7.14 Response criteria for liver metastases 
7.2 Progression free survival in hepatic metastases (PFS-L) 
7.3 Overall survival  
7.4  Molecular characteristics of tumor and response to treatments 
 
8.0 Drug Information  
 
 
 
 
 
– 27 - 
8.1  Product Description 
8.2  Calibration of Radioactivity 
8.3  Biological Properties and Action 
8.4  Expected Adverse Reactions 
 
8.5 Exposure in Utero 
 

 
3
9.0 Dose calculation   
 
 
 
 
 
- 30 - 
9.1  Dose calculation methods 
9.1.1 Body Surface Area (BSA) Method  
9.1.2 Partition Model for Calculation of Dose/Activity of SIR-Spheres microspheres  
 
9.2 Dose Modification 
9.21 Previous embolization treatment 
9.22 Shunting to the lung 
9.23 External Beam Radiation  
9.24 Other chemotherapy  
 
10.0 Radiation Safety  
 
 
 
 
 
– 33 - 
11.0 Safety Assessment   
 
 
 
 
– 34 - 
11.1  Definitions 
11.11 Adverse Event (AE) 
11.12 Preexisting Conditions 
11.13 Adverse Event Reporting Period 
11.14 Seriousness 
11.2  Evaluation of Adverse Events 
11.3  Attribution of Causality of Adverse Events 
11.4  Reporting Adverse Events 
11.5 Thomas Jefferson University Data and Safety Monitoring Plan 
11.6 Follow-Up of Adverse Event 
 
12.0 Statistical Considerations   
 
 
 
– 38 - 

 
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13.0 Data Disclosure and Patient Confidentiality   
 
– 40 - 
14.0 Ethical Considerations  
 
 
 
 
– 40 -  
14.1 Protection of Human Subjects from Research Risks 
14.2 Institutional Review Board 
14.3  Informed Consent 
 
References 
 
 
 
 
 
 
- 42 - 
 
 
 
 
 
 
 

 
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PROTOCOL SUMMARY 
 
 
Protocol Number: 
 
 
 
 
Protocol Title: 
An open-label, single institution phase II study using radioactive 
yttrium90 microsphere (SIR-Spheres®) in uveal melanoma patients 
with hepatic metastasis 
 
Study Objectives:  
Primary objectives 
(1) Investigate the potential efficacy (clinical response) of 
radioactive yttrium90 microsphere in hepatic metastasis from uveal 
melanoma. 
 
(2) Investigate the safety of radioactive yttrium90 microsphere in 
patients with metastatic uveal melanoma.   
Investigate correlation between molecular characteristics of 
metastatic uveal melanoma and treatment outcomes. 
 
 
Secondary objectives:  
 
 
Investigate overall survival, progression free survival, and duration 
of response 
 
Study Population: 
Patients with stage IV uveal melanoma with hepatic metastasis 
 
Study Design: 
Single institution phase II study.   
 
Investigational Product: Radioactive yttrium90 microsphere (SIR-Spheres® microspheres) 
 
Dosage Form: 
Liquid suspension 
 

 
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Route of Administration: 
Intrahepatic arterial infusion 
 
Dosage and Treatment:      Up to 3.0 Giga-Becquerels (GBq) for two treatments 
 
 
Endpoints: 
Response Rate: 60% stabilization rate (CR+ PR+SD) warrants 
future study. 
Adverse Events: Treatment-emergent and related serious adverse 
events, and Grade 3 and 4 laboratory abnormalities for safety 
assessments 
 
Other Parameters: 
Overall survival (OS), progression free survival (PFS) and duration 
of response in the liver  
 
Duration of Subject  
 
Participation in Study: 
Maximum of 2 years after the last radiosphere treatment or death, 
  
or study closure 
 
Duration of Follow-up: 
Safety data will be collected for three months after the last 
radiosphere treatment, or initiation of a different type of 
locoregional or systemic treatment for progression of disease, or 
death, whichever comes first. Survival information will be collected 
via phone or visit on a quarterly basis up to 2 years after the last 
radiosphere treatment or death.   
 
Number of Subjects: 
48 
Required 
 
 

 
7
 
 

 
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1.0Background 
1.1 Uveal Melanoma 
Uveal melanoma is the most common adult primary intraocular malignant tumor (1, 2). The 
incidence of uveal melanoma is 4.3 cases per million population, with a slightly higher rate in 
males (4.9 cases per million) when compared with females (3.7 cases per million). Uveal 
melanoma is more commonly seen in an older age group, with a progressively rising age-specific 
incidence rate that peaks at the age of 70 years (24.5 cases per million in males and 17.8 cases per 
million in females) (3). 
 
Up to 50% of patients with posterior uveal melanoma subsequently develop systemic metastasis 
after the initial diagnosis and treatment (4), however, clinically evident metastatic disease at the 
time of initial presentation is uncommon, indicating that there is early subclinical metastasis in 
most cases (5).  The liver is the predominant organ involved in 70% to 90% of cases with 
metastatic uveal melanoma (6-8) and tends to be the first manifestation of metastatic disease  (8, 
9).  Lungs (20%), bone (16%), and skin (12%) are other sites that may be affected (9). The 
metastatic pattern of uveal melanoma is often distinct from that of the cutaneous form of the 
disease. Approximately 90% of uveal melanoma patients die with liver metastases (7). Despite 
achieving great accuracy in correctly diagnosing uveal melanoma in the United States (2), 
mortality owing to this tumor has remained unchanged over the past 3 decades (5). In general, the 
survival with metastatic uveal melanoma is poor, with a median survival of less than 6 months (6, 
8). 
 
Many cytogenetic investigations of primary uveal melanoma have revealed that the majority of 
choroidal and ciliary body melanomas are characterized by non-random alternations in 
chromosomes 1, 3, 6 and 8 (10).  Monosomy 3 (either true or functional) and trisomy 8, partial 
duplication of 8q, or iso-chromosome 8q are the most frequent karyotypic abnormalities present in 
approximately 50% of cases (10). Recent investigation has indicated that monosomy 3 is a 
significant predictor of poor prognosis (11).  Approximately 70% of patients with monosomy 3 in 
their primary tumor have died of metastases within 4 years after the initial diagnosis; whereas 
tumors with normal chromosome 3 status (disomy 3) rarely gave rise to metastatic disease (11).  
Existence of chromosome 3 abnormality in hepatic metastasis might be correlated to the outcome 

 
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of trans-arterial embolization of metastases (12). 
 
1.2 Systemic Treatment for Metastatic Uveal Melanoma 
Systemic chemotherapy has failed to show significant efficacy against metastatic uveal melanoma. 
Retrospective reviews from the M. D. Anderson Cancer Center and ECOG indicated that the 
response rates to chemotherapeutic drugs commonly used for the treatment of metastatic 
cutaneous/mucosal melanoma rarely induced responses in patients with uveal melanoma, 
especially when the liver was involved with metastatic disease (9, 13).  Dacarbazine-based 
chemotherapies that have been used for the treatment of metastatic cutaneous melanoma are 
ineffective in the treatment of metastatic uveal melanoma (9, 13, 14).  
 
Pyrhonen et al. reported superior results in a pilot study using the combination of bleomycin, 
Oncovin, lomustine, DTIC (BOLD) plus interferon in a small group of patients with metastatic 
uveal melanoma (15). This combination has been evaluated in several other clinical trials and was 
reported to give markedly variable response rates (15-18).  The average response rate is 14%, 
hardly an improvement over other regimens. Neurotoxicity was observed in 13% of the patients. 
Severe and unpredictable pulmonary toxicity was observed occasionally (16).  
 
The combinations of treosulfan with gemcitabine or cytosine arabinoside were shown to be active 
in over 70% of uveal melanoma cells tested with ex vivo sensitivity test (19). Based on these 
results, clinical trials using the treosulfan-gemcitabine combination were conducted with modest 
clinical benefit (20). 
 
Dorval et al. failed to discern any objective responses to high dose IL-2 in their study of patients 
with metastatic uveal melanoma (21). 
 
1.3 Surgical Treatment for Liver Metastases 
Since the liver is the first and in many cases the only site of metastases in patients with uveal 
melanoma, local treatment aimed at controlling liver metastases holds promise in managing this 
otherwise highly chemo-resistant tumor. Total resection of the solitary metastasis in the liver or 
other sites (22, 23) offers a distinct survival advantage. We reported protracted survival with 
surgery for visceral metastases from uveal melanoma.  However, only 9% of patients with 

 
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metastases were eligible for surgical intervention (22). The longest median survival of 22 months 
was observed when a complete surgical excision of the hepatic metastasis was followed by 
intra-arterial hepatic fotemustine or dacarbazine plus cisplatin (24). 
 
1.4 Hepatic Intraarterial Chemotherapy for Liver Metastases 
Hepatic intra-arterial chemoinfusion with an agent that has a rapid systemic clearance rate and a 
high hepatic extraction rate allows maximum local drug exposure.  Leyvraz, et al. reported that 
intrahepatic chemoinfusion of Fotemustine resulted in a response rate of 40% for patients with 
liver metastases from uveal melanoma (25).  Hepatic intra-arterial chemoinfusion with carboplatin 
was also used for liver metastases from uveal melanoma (26).  
 
Isolated hepatic perfusion (IHP) has been used for liver metastases from uveal melanoma (27).  A 
series of 22 patients with metastatic uveal melanoma confined to liver was treated at the National 
Cancer Institute using IHP with melphalan and TNF- (n=11) or melphalan alone (n=11) (27). 
There was one treatment-related death.  Among the 21 evaluable patients, there were two 
radiographic complete responses (9.5%) and 11 partial responses (52%).  The overall median 
duration of response was 9 months (range 5-50 months).  Recently, a special catheter system has 
been developed to isolate the hepatic circulation from the systemic circulation.  This allows 
multiple cycles of chemotherapy to be delivered directly to the liver without a major operation 
(peripheral hepatic perfusion, PHP). A randomized phase III trial comparing PHP and the best 
available treatment is ongoing. 
 
1.5 Chemoembolization of Liver Metastases 
 
Mavligit et al. reported that hepatic artery chemoembolization with cisplatin and polyvinyl sponge 
achieved a 46% response rate with a median survival of 11 months (28). We subsequently 
conducted a phase II trial of hepatic artery chemoembolization using 1,3-bis 
(2-chloroethyl)-1-nitrosourea (BCNU) in combination with ethiodized oil followed by infusion of 
a transiently occlusive agent, gelatin sponge particles (29). A total of 29 patients were treated with 
chemoembolization with BCNU.  Among 23 evaluable patients, one patient achieved complete 
response (CR), 3 patients achieved partial response (PR) and 12 patients achieved stable disease 
(SD). Median overall survival (OS) of the entire intent-to-treat group of patients was 5.1 months 
(range 0.1-27.6); for patients with CR or PR, 23.5 months (range 7.4-27.6); SD, 8.7 months (range 

 
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2.9-14.4); and progressive disease (PD), 3.3 months (range 1.6-5.6).  Importantly, while control of 
hepatic metastases was obtained, progression was seen in extra-hepatic sites such as spine, lung, 
lymph nodes, and brain in more than two thirds of patients (29).  
 
1.6 Immunoembolization of Liver Metastases 
Since local chemotherapies for metastatic uveal melanoma are not uniformly successful and since 
even successful local chemotherapies frequently fail at extrahepatic sites, a local immunotherapy 
is theoretically a reasonable approach to control the liver metastases and to potentially induce a 
systemic antitumor immune response to prevent distant failure.  Based on the above scientific 
rationale, our group developed a novel approach to the treatment of liver malignancy using 
embolization of the liver metastases with granulocyte-macrophage colony stimulating factor 
(GM-CSF) (immunoembolization).  
In our phase I clinical study, 34 uveal melanoma patients with less than 50% involvement of the 
liver were treated with immunoembolization of hepatic metastases with various doses of GM-CSF 
(30). There were no treatment-related deaths or life-threatening events observed up to and 
including the 2,000 µg dose level of GM-CSF. Among 31 evaluable patients, there were 2 
complete responses (CR), 8 partial responses (PR), and 10 cases of stable disease (SD) in their 
hepatic metastases. The median overall survival (OS) of intent-to-treat patients was 14.4 months. 
Multivariate analyses indicated that female gender, high doses of GM-CSF ( 1,500 µg) and 
regression of hepatic metastases (CR and PR) were correlated to longer OS (30). 
 
The result of the phase I trial with immunoembolization was also compared to our institutional 
historical control of patients who were treated with chemoembolization using BCNU (less than 
50% involvement of the liver with metastases). Compared with 19 patients who received 
chemoembolization, 16 patients who received high dose immunoembolization had significantly 
better OS (20.4 vs. 9.8 months, P = .005) and progression free survival in systemic (extra-hepatic) 
sites (PFS-S) (12.4 vs. 4.8 months, P = .001) (31). 
 
1.7 Selective internal radiation therapy (SIRT, radioactive microspheres) for cancer 
Selective internal radiation therapy (SIRT) has been used to deliver high dose of radiation to 
tumor, while minimizing damage to surrounding normal tissues.  Various radioactive particles 
have been used.  In this study, we will use Yttrium-90 (90Y-) microspheres (SIR-Spheres 

 
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microspheres).   
Due to the size of microsphere (20-60µm), yttrium-90 microspheres (SIR-Spheres) become 
trapped within arteries supplying liver tumors exposing them to high dose radiation. 
 
Hypervascular hepatic tumors such as hepatocellular carcinoma obtain their blood supply almost 
exclusively from the hepatic artery whereas normal liver parenchyma receives 75% of its blood 
supply from the portal vein.  There are three times more arterial vessels supplying hepatic tumors 
than normal liver parenchyma.  Therefore, the microspheres lodge preferentially within the 
vasculature of liver tumors, with minimal amounts lodging in the normal liver parenchyma and, 
ideally, no amounts distributing to other organs, particularly to the lung.  
 
Over 14,000 people have been treated with SIR-Spheres microspheres at more than 200 
locations in >25 countries across the globe. SIR-Spheres® microspheresare currently being used 
to treat primary and secondary tumors of the liver such as hepatocellular carcinoma and colorectal, 
breast and neuroendocrine tumors, respectively.  There are significant numbers of reports in the 
literature supporting the efficacy and safety of the use of yttrium-90 for treatment of such tumors.  
The largest treating countries are the USA, Australia, Germany, Spain, Italy, New Zealand, and 
Hong Kong, with treatment experience rapidly growing in other EU countries, Turkey and other 
countries. Treatment has been predominantly for liver metastases derived from colorectal cancer 
and other solid tumors in western countries and for hepatocellular carcinoma in the Asian 
countries and Southern Europe.   
 
1.8 SIRT for metastatic uveal melanoma  
Radioactive plaque and proton beam radiation have been used for treatment of primary uveal 
melanoma.  Although melanoma cells are generally resistant to radiation, treatment of metastatic 
uveal melanoma with high-dose local radiation might have therapeutic benefits. In our institution, 
a total of 12 uveal melanoma patients, five men and 7 women, ages 48-81 (median 65) with hepatic 
metastases were treated with SIRT due to tumor progression after trans-arterial embolization 
(n=9), complications of trans-arterial embolization (n=1) or patient preference (n=2) (32). Patients 
had both hepatic lobes treated on separate occasions (n=7), one lobe (n=3) or whole liver (n=2) 
therapy. Treatment dose per patient was reduced by 25% due to prior trans-arterial embolization 
procedures. The mean total SIRT dose delivered was 1.0 GBq (0.62-1.47 GBq). Five patients had 

 
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an increase in hepatic enzymes (Grade1-4) at 1-month follow-up. No procedure related deaths or 
serious adverse events were experienced. Best tumor response was as follows: CR (n=0), PR 
(n=0), SD (n=8), PD (n=4), with a median follow-up of 7.8 months (1.0-16.0). The median time to 
liver progression was 7.0 months (1.0-15.5). Nine of the 12 patients, including 2 patients with 
>25% pretreatment tumor burden, died due to progression of liver disease (n=6), extrahepatic 
disease (n=1) or both (n=2). Post-SIRT, median overall patient survival was 10.8 months 
(1.0-19.0). Three patients (ECOG 0 performance status) are still alive at 13.5-19.0 months (median 
16.2 months) following SIRT. Although this is a small retrospective study at a single institution 
conducted in heavily pre-treated patients, the potential efficacy of radiosphere treatment in 
metastatic uveal melanoma was suggested. Our observation is supported by a report from other 
institutions (33) and warrants further investigation in a prospective clinical study.   In this clinical 
trial, we will prospectively investigate the safety and efficacy of SIRT using yttrium-90 
SIR-Spheres® microspheres in uveal melanoma patients with hepatic metastases.  Patients will be 
stratified based on their history of previous transarterial embolization of the hepatic artery.  The 
safety and efficacy of treatments will be separately analyzed in these two patient cohorts.   
 
2.0 Study Objectives and Endpoints 
2.1 Study Objectives 
2.11 Primary Objectives 
(1) Investigate the potential efficacy (clinical response) of radioactive yttrium90 
microspheres in hepatic metastasis from uveal melanoma. 
(2) Investigate the safety of radioactive yttrium90 microsphere in patients with 
metastatic uveal melanoma.   
 
2.12 Secondary Objectives 
(1) Survivals: Investigate overall survival (OS), progression free survival without 
progression of hepatic metastasis (PFS-L), and duration of response. 
(2) Correlation between molecular characteristics of metastatic uveal melanoma and 
treatment outcomes.  
 
2.2 Study Endpoints 
(1) Response Rate: 60% stabilization rate (CR+ PR+SD) warrants future study. 

 
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(2) Adverse Events: Treatment-emergent and related serious adverse events, and 
Grade 3 and 4 laboratory abnormalities for safety assessments. 
 
2.3 Other Parameters 
Overall survival (OS), progression free survival (PFS) and duration of response 
 
3.0  Study Design  
This is an open-label, uncontrolled single institution phase II study for metastatic uveal melanoma.  
Uveal melanoma patients who received one or less prior trans-arterial embolization treatment of 
hepatic metastasis are eligible.  Patients will be stratified into two groups: Group A, no prior 
intra-hepatic arterial treatment, n=24; Group B, one prior hepatic trans-arterial embolization 
treatment, n=24.  They will be treated with intra-hepatic arterial infusion of Yttrium-90 radioactive 
microspheres (SIR-Spheres microspheres).  
 
Within 4 weeks prior to radiosphere treatment, patients undergo the pre-assessment angiogram and 
technetium-99m-labelled macroaggregated albumin (99m Tc -MAA) nuclear scan to block the 
collateral flow to non-target organs and to calculate the shunting rate to the lung.  Once patients 
meet the eligibility criteria of the study, the radiosphere treatment will be given.  The Yttrium-90 
radioactive microsphere treatment generally consists of two sequential uni-lobar treatments, 
approximately 4 weeks (3 to 5 weeks) apart.  In selected patients, if clinically feasible, a biopsy of 
hepatic metastasis will be obtained prior to radiosphere treatment to investigate the correlation 
between efficacy of treatments and molecular characteristics of metastatic uveal melanoma.  
 
The side effects of Yttrium-90 radioactive microspheres will be monitored every 2 weeks for one 
month following each treatment and then every month for three months after the last radiosphere 
treatment.  The efficacy of radiosphere treatment will be evaluated every 3 months from the last 
treatment for 2 years until disease progression or death.   
 
If patients experience grade 3 toxicity after the first treatment with Yttrium-90 radioactive 
microspheres, the second radiosphere treatment will be held until the resolution of toxicity to grade 
1 or less or for a maximum of 6 weeks.  The dose of the second radiosphere treatment will be 
decreased by 50% for liver-related grade 3 toxicity.  A dose reduction will not be considered for 

 
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grade 3 GI toxicity unless the next treatment is repeated to the same hepatic lobe. The study 
treatment will be discontinued for grade 4 toxicity or if patients do not recover from the grade 3 
toxicity to at least a grade 1 within 6 weeks.  
 
The study will require two years of accrual with an additional two years of follow-up for survival 
analysis. 
 
4.0 Selection of Patients 
4.1 Inclusion criteria 
4.11 
Histologically confirmed metastatic uveal melanoma in the liver.  Patients must 
have at least one untreated, or progressed liver metastasis that is  10 mm in longest 
diameter by spiral CT scan or MRI.  The total volume of the tumors must be less 
than 50% of the liver volume. 
 
 
 
4.12 
Either no previous trans-hepatic arterial treatment or progressive hepatic metastasis 
after prior regional treatment with trans-arterial embolization.  Embolization of 
hepatic artery with different types of medication will be considered to be one 
regional treatment.   
 
4.13 
Willingness and ability to give informed consent. 
 
4.14 
ECOG performance status of 0, or 1. 
 
4.14 
Adequate renal and bone marrow functions:  
 
Serum creatinine  2.0 mg/dl, granulocyte count  1000/mm3, and platelet count  
100,000/mm3. 
 
4.15 
Adequate liver function: total bilirubin <1.6 mg/ml and albumin > 3.0 g/dl,  
 
4.2 Exclusion criteria 
4.201 Failure to meet any of the criteria set forth in section 4.1. 
 
 

 
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4.202 Significant shunting to the lung (>20%) identified on MAA scan. 
 
4.203 Unsuccessful closure of major collateral blood flows from the hepatic artery to 
non-targeted organs such as the GI tract. Small collaterals that are considered to be 
safe for Sir-Sphere® treatment by interventional radiologists and radiation 
oncologists are eligible. 
 
 
 
4.204 A solitary liver metastasis that is amenable to surgical removal for potential cure.  
 
4.205 Presence of symptomatic liver failure including ascites and hepatic 
encephalopathy. 
 
4.206 Presence of life-limiting extra-hepatic metastasis that requires a systemic treatment 
within 3 months.  Patients with extra-hepatic metastasis that can be controlled with 
a loco-regional treatment are eligible.  
 
4.207 Presence of untreated brain metastases.  If patients have had previous treatment for 
brain metastasis, an MRI or CT scan of the brain must confirm the stabilization of 
the brain metastasis for more than 4 weeks.   
 
4.208 Occlusion of the main portal vein, or inadequate collateral flow around an 
 
occluded branch of the portal vein as determined by angiography.   
 
4.209 Presence of uncontrolled hypertension or congestive heart failure, or acute 
myocardial infarction within 6 months of entry. 
 
4.210 Presence of any other medical complications that imply a survival of less than six 
months.   
 
4.211 Uncontrolled severe bleeding tendency or active GI bleeding.  
 
4.212 Significant allergic reaction to iodinated contrast. 

 
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4.213 Systemic chemotherapy within 2 weeks prior to study entry (signing consent form). 
 
4.214 Previous radiation treatment that includes the liver in the main radiation field. 
 
4.215 Pregnancy or breast-feeding women. 
 
4.216 Biliary obstruction, biliary stent, or prior biliary surgery including sphincterotomy 
but excluding cholecystectomy. 
 
4.217 Previous treatment with isolated hepatic perfusion 
 
4.218 Children under the age of 18 
 
 
5.0 Treatment Schedule 
5.1 Pre-study Evaluation  
MRI of the abdomen (with and without gadolinium) and CT of the chest, abdomen and pelvis 
(with and without intravenous contrast).  Both imaging exams should be performed prior to 
enrolling patients to evaluate for extrahepatic disease and tumor burden within the liver. 
Comprehensive examination including history, physical examination, and laboratory tests to 
confirm eligibility of patients for the study will also be done (Schedule table). These tests should 
be done within 4 weeks prior to enrollment of patients to confirm their eligibility. Once their 
eligibility is confirmed, flow study and radiosphere treatment will be scheduled. 
 
5.2 Flow study (therapy-planning angiography) and pretreatment assessment 
Within 4 weeks of radiosphere treatment, therapy planning arteriography of the superior 
mesenteric and celiac arteries will be performed.   
The major purpose of the flow study is as follows: 
1) Confirm the ability to selectively catheterize the hepatic arterial vasculature. 
2) Assess the flow characteristics in the hepatic arteries. 
3) Determine the hepatic arterial supply to the tumor, i.e., right, left or both hepatic arteries. 

 
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4) Determine the influence of hepatic arterial anatomy relative to the intrahepatic distribution of 
tumor on the ability to treat the diseased portion of the liver as a single unilobar treatment, or two 
sequential unilobar treatments, or 2 fractionated whole liver treatments. 
5) Confirm the absence of significant, uncorrectable blood shunting from the liver to the 
gastrointestinal tract or other abdominal organs (e.g., pancreas). 
6) Perform a technetium-99m macro-aggregated albumin (99m Tc-MAA) study to assess the 
presence and degree of lung shunting of the microspheres from the liver. 
 
During the therapy planning angiography, selective arteriography of the proper, right and left 
hepatic arteries will be obtained in at least two projections (i.e. PA, RAO) to look for extrahepatic 
arterial blood supply arising from the hepatic arteries.  Coil embolization of extrahepatic arteries 
(i.e. right gastric, gastroduodenal artery) will be performed as deemed necessary by the 
interventional radiologist performing the study.  Following coil embolization of extrahepatic 
arteries, 99mTc-MAA particles will be injected into the proper hepatic artery or injected separately 
into right and left hepatic arteries by splitting the 99mTc-MAA dose.  The injection location of 
99mTc-MAA will also be at the discretion of the interventional radiologist performing the 
procedure. The patient will be transported to nuclear medicine for a single photon emission CT 
(SPECT) scan to assess for shunting to the lungs and extrahepatic activity. CT scan of chest, 
abdomen, and pelvis with and without contrast, MRI of the abdomen with and without gadolinium, 
and PET scan will be performed as baseline imaging tests for radiosphere treatment.  These tests 
will be done within 4 weeks of radiosphere treatment. 
The dose for treatment will be determined by the radiation oncology attending using the MRI 
and/or CT scan imaging and the results of flow study using the equations described in Section 9.  
The determined dose will be ordered. 
 
5.3 Biopsy of hepatic metastasis 
Within 4 weeks of radiosphere treatment, tumor specimens will be obtained by core biopsy of a 
representative hepatic metastasis.  DNA as well as RNA will be extracted from the core biopsy 
specimens after confirming diagnosis of metastatic melanoma by histology and will be used for 
molecular studies including DNA array analysis and genome-wide SNP analysis.  If patients have 
established diagnosis of metastatic uveal melanoma to the liver, they could decline this biopsy.  

 
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The tumor biopsy will also be exempt if the tumor tissue specimen can not be obtained by a 
conventional technique such as US-guided or CT-guided biopsy.  
 
5.4 Radioactive microsphere treatment 
Within 4 weeks after the flow study, selective internal radiation therapy (SIRT) using yttrium-90 
SIR-Spheres® microspheres (radiosphere treatment) will be performed. Due to multiple, bilobar 
metastases, both right and left hepatic lobes need to be treated in the majority of patients. The goal 
of therapy is to treat the tumor bearing liver in 2 sessions. Treatments are preferentially done in a 
lobar fashion. In the setting of complex anatomy, fractionated whole liver therapy is used as an 
alternative. In general, the delivery of radioactive microspheres will require two sequential 
unilobar treatments separated by a period of 4 ± 1 weeks.  The lobe to be treated first will be 
determined by the treating physicians.  The radiosphere dose for each hepatic lobe will be 
determined based on the tumor volume in individual lobes.   
 
In patients whose hepatic artery does not allow two separate sequential unilobar treatments, whole 
liver treatment via the proper hepatic artery may be performed if no extrahepatic arteries are 
identified distal to the catheter site intended for radioactive microsphere delivery.  The dose will be 
delivered in two fractionated doses separated by 4 ± 1 weeks (fractionated whole liver).  
 
If a prior hepatectomy has been performed leaving a single lobe for treatment, or if metastatic 
disease is confined to a single lobe, the entire dose will be delivered in a single session to the 
affected lobe.   
 
Treatment will be administered on an outpatient basis with overnight, 23-hour observation 
permitted at the investigator’s discretion.  Patients will receive the supportive care as described in 
Section 7.   
 
Approximately 100ml of blood specimens will be obtained for Peripheral Blood Mononuclear Cell 
(PBMC) collection prior to radiosphere treatment.  Additionally, 10 ml of blood specimens will be 
obtained for serum collection prior to, and 1 hour after radiosphere treatment. 
 
Blood tests including CBC with differential, comprehensive metabolic panel including total 

 
20
bilirubin, SGOT (AST), SGPT (ALT), LDH, alkaline phosphatase, albumin, creatinine, BUN, 
glucose, calcium, and LDH will be ordered every 2 weeks for one month, then every month for 
three months to monitor treatment-related toxicity.   
 
5.5 One-month post-procedure visit 
In 4 weeks (± 1 week) after the last radiosphere treatment (usually after the second radiosphere 
treatment), patients will be evaluated for treatment-related acute toxicity.  Patient will also have a 
1-month follow-up CT scan of the chest, abdomen and pelvis (with and without contrast) to assess 
extrahepatic disease. 
 
Approximately 100ml of blood specimens will be obtained for PBMC collection.  Additionally, 10 
ml of blood specimens will be obtained for serum collection. 
 
5.6   3-month post-procedure visit 
Three months (± 2 weeks) after the last radiosphere treatment (usually after the second radiosphere 
treatment), patients will be evaluated for response to treatment and late toxicity.  CT scan of the 
chest, abdomen and pelvis (with and without contrast); MRI of the abdomen (with and without 
gadolinium) and PET scan will be obtained.  
 
Approximately 100ml of blood specimens will be obtained for PBMC collection.  Additionally, 10 
ml of blood specimens will be obtained for serum collection. 
 
5.7   Subsequent follow-up visits 
After the 3-month office visit, patients will be followed every three months for the maximum of 
two years. CT scan of the chest, abdomen and pelvis (with and without contrast); MRI of the 
abdomen (with and without gadolinium), PET scan, and blood test including CBC with 
differential, comprehensive metabolic panel including total bilirubin, SGOT (AST), SGPT (ALT), 
LDH, alkaline phosphatase, albumin, creatinine, BUN, glucose, and calcium will be obtained prior 
to the individual follow-up visits.  
 
5.8  End of study visit 

 
21
At the conclusion of two-year follow-up or upon withdrawal of patients from the study, patients 
will be evaluated by a study physician. CT scan of the chest, abdomen and pelvis (with and without 
contrast); MRI of the abdomen (with and without gadolinium), PET scan, and blood test including 
CBC with differential, comprehensive metabolic panel including total bilirubin, SGOT (AST), 
SGPT (ALT), LDH, alkaline phosphatase, albumin, creatinine, BUN, glucose, and calcium will be 
ordered.  If patients are evaluated with the above tests within 1 month prior to the conclusion of 
study, this visit will be substituted for the end of study visit.  
 
5.9 Withdrawal of subjects 
The following criteria will be used to withdraw patients from the study. 
1. Progressive disease (PD) by RECIST criteria or at the end of 2 years following treatment 
initiation. Patients will be withdrawn from the study if significant extra-hepatic disease develops 
and systemic therapy is required.  In addition, if patients demonstrate significant intra-hepatic 
tumor progression and require additional percutaneous or catheter-directed therapy, they will be 
withdrawn from the study. 
2. Unacceptable toxicity. This is defined as greater than or equal to grade 4 toxicity.   
3. The patient may withdraw from the study at any time for any reason with written notification to 
the investigator. 
4. Investigator’s decision that it is in the patient’s best interest to come off study. 
5. A major protocol violation, or if requested by the sponsor or regulatory agency.  
6. The withdrawal of a subject from the trial may also occur if the subject is noncompliant.  This 
will not affect the standard of the patient’s future medical care. 
7. Death of a subject. If a subject dies while participating in this study, regardless of the cause, 
an SAE form must be completed. 
 
5.10  Follow-up after withdrawal from study 
All patients, including patients who discontinue protocol therapy because of toxicity or 
progressive disease must be followed every three months up to a minimum of 2 years to determine 
clinical status and to document time to progression and duration of survival.  Telephone contact 
and record review is allowed for this purpose.  If patients are removed from study due to grade 4 
toxicity, patients must be followed until toxicity level decreases to ≤ grade 1 or considered 
resolved with sequelae.  

 
22
For patients who achieved PR, CR, or SD in the liver metastases after radiosphere treatment, tumor 
measurements should be continued every 3 months for up to 2 years after initiation of protocol 
therapy or until PD in the liver metastases is confirmed. 
 
6.0 Supportive Care Guidelines  
6.1 Post-Treatment Care  
 Following treatment, the patient will remain under observation according to standard care 
guidelines for the aftercare of procedures involving femoral artery catheterization. This typically 
involves at least 6-hour monitoring. After 6 hours of observation, the patient will be sent home 
when the interventional radiology (IR) attending physician determines that the patient is stable and 
that there is no risk of bleeding from the catheter site.  Patients could be kept over night for further 
observation at the discretion of IR attending or study physicians.  At the time of discharge, patients 
will be instructed regarding aftercare and will be provided with a 24-hour telephone number that 
they may use to contact the IR attending or study physician if they develop a problem.  
 
6.2 Pre- and Post-treatment Supportive Therapies 
 The following supportive therapy will be administered at the discretion of investigator,  
unless otherwise contraindicated:  
(1) Pre- and post-therapy intravenous hydration.  
(2) Gastrointestinal prophylaxis to prevent GI inflammation and ulceration: a proton  
pump inhibitor (e.g. Pantoprazole 40mg orally once daily) continuing for 4 weeks post treatment.  
(3) Anti-nausea prophylaxis: e.g., anti-emetics (e.g. Ondansetron 8mg orally or i.v., every 8 hours, 
PRN) for post-treatment nausea. 
(4) Post-embolization syndrome prophylaxis: Provided the patient is not diabetic – and oral 
steroids are not otherwise contraindicated – a tapering dose of oral corticosteroids (e.g., 
Methylprednisolone 24mg, 20mg, 16mg, 12mg, 8mg, 4mg orally on days 0, 1, 2, 3, 4 & 5 
respectively, or dexamethazone 4 mg, bid for 3 days, then once a day for 3 days) commencing on 
the day of treatment will be administered.  
(5) Pain control:  Oral analgesia (e.g., Ketorolac 10mg orally  every 6 hours PRN, or oxycodone 5 
mg, orally every 4 hours PRN) may be required for 1 week following treatment to relieve pain 
from radiation injury and embolic effects related to SIR-Spheres microspheres, and liver 
capsular pain from tumor edema.  

 
23
 
7.0 Evaluation of Response 
7.1 Evaluation of clinical response 
7.1.1  Definition of Measurable Disease 
Measurable disease 
Measurable disease is defined by the presence of at least one measurable lesion as defined below 
and adapted from the RECIST criteria version 1.1 (34).  All measurements must be recorded in 
metric notation.  If measurable disease is restricted to a solitary lesion, its malignant nature should 
previously have been confirmed by cytology/histology.  
 
Since some melanoma metastases contain melanin pigment and since successfully treated liver 
metastases may develop significant necrosis, evaluation of radiological response after 
embolization treatments is generally difficult.  Therefore, we will obtain CT scan and MRI of the 
liver, and PET scan of the body for the precise evaluation of radiological responses.  However, the 
same modality will be used for measurement of the liver metastases and assessment of the 
response.  We prefer to use MRI for response assessment due to its superiority in measurement of 
tumor size and assessment of tumor necrosis compared to traditional spiral CT scans.  
 
The longest diameter (LD) of the largest liver lesion should be  10 mm by spiral CT scan or MRI 
in order to become eligible for the study.   
Non-measurable disease 
All other lesions including small lesions (<10 mm on spiral CT scans or MRI) are considered 
“non-measurable”.  The following lesions are also considered as “non-measurable”: Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, abdominal masses that are not 
confirmed and followed by imaging techniques, tumors treated by irradiation or by intra-tumor 
injection therapy.   
 
7.1.2  Baseline Documentation of "Target" and "Non-Target" Lesions 
Target Lesions (Indicator Lesions) 

 
24
The target lesions are defined as measurable lesions that will be used for evaluation of response. For 
this protocol, target liver lesions require serial measurement of a longest diameter and should be 
≥10 mm by spiral CT scan or MRI at the time of study entry.  
 
Target lesions (up to a maximum number of 5 for the liver metastases) must be identified and 
measured at baseline prior to the initiation of radiosphere treatment.  Target lesions must be 
selected on the basis of their size (LD) and suitability for repetitive measurements. 
 
 
 
 
 
 
 
 
Non-Target Lesions 
All other lesions (or sites of melanoma) must be identified as “non-target” and their location and 
characteristics must be recorded at baseline.  During follow-up evaluations, these lesions must be 
followed as “present” or “absent”.  
 
7.1.3 Evaluation of overall response in the liver metastases 
Clinical response in the liver metastases will be evaluated 3 months after the last radiosphere 
treatment using CT scans or MRI of the abdomen.  The same modality must be used for serial 
measurements of target lesions.  The sum of the longest diameter (LD) of up to 5 target liver 
lesions will be used to determine response.  The investigators must identify target indicator lesions 
and measure them within 4 weeks prior to the first radiosphere treatment as baseline. The 
investigators will then measure the same target lesions 3 months after the last radiosphere 
treatment.   
 
The sum of the baseline LDs will be compared to the sum of LDs after radiosphere treatments.  
New lesions will be defined as lesions that appear in the treated lobe(s) of the liver after the 
baseline evaluation and should be  10 mm in longest diameter. Development of new lesion(s) in 
an untreated lobe (area) of the liver will not be considered as “Progressive Disease” for evaluation 
of liver response.  
 
7.1.4 Response criteria for liver metastases 
The response of liver metastases will be evaluated by MRI or CT scans using the criteria adapted 
from the international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee. The same imaging modality must be used for the serial measurements of 

 
25
tumor diameter.  The response must be confirmed by two consecutive imaging tests performed not 
less than 4 weeks apart. The definition of response of liver metastases in the treated lobe(s) is 
shown in Table 1.  Evaluation of target and non-target lesions in the treated liver lobe(s) to 
determine response of liver metastases is shown in Table 2.  
In terms of PET scan assessment, up to 6 metabolically active metastases with SUV of 2 or greater 
will be recorded prior to the radiosphere treatment.  If more than 50% of these lesions show SUV 
of 2 or less at 3 month PET assessment, the radiosphere treatment will be considered to be 
“effective” (35).   
 
Table 1. The definition of response of liver metastases in the treated lobe(s) 
 
 
 
 
 
 
 
 
 
 
 
To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by the 
follow-up assessment using the same imaging test at a minimum interval of 4 weeks.  The patients 
who have a CR or PR without confirmatory assessment will be categorized as SD.  In the case of 
SD, follow-up measurements must have met the SD criteria at least once at a minimum interval of 
4 weeks. The patients who have a SD without confirmatory assessment will be categorized as PD.     
 
 
 
 
Table 2. Evaluation of target and non-target lesions in the treated liver lobe(s) 
Complete Response (CR) Disappearance of all target and non-target liver lesions  
Partial Response (PR) 
> 30% decrease in the sum of the longest diameters (“sum 
LD”) relative to baseline sum LD with at least stable 
non-target liver lesions 
Stable Disease (SD) 
Absence of change which would qualify as response or 
progression 
Progression (PD) 
> 20% increase in the sum LD in target liver lesions or 
unequivocal progression of non-target liver lesions in the 
treated lobe(s)   
Appearance of one or more new liver lesions >10 mm in 
the treated lobe(s) 

 
26
 
 
 
 
 
 
7.2 Progression free survival in hepatic metastases (PFS-L) 
PFS-L is measured from the start of the treatment to confirmation of progression of hepatic 
metastasis by either imaging tests or physical examination, or death of patient, whichever comes 
first.  
 
7.3 Overall survival  
 
Overall survival (OS) is measured from the start of the treatment to patient death. Date and cause 
of death will be recorded. The cause of death will be categorized as either cancer-related or 
cancer-unrelated.   
 
7.4 Molecular characteristics of tumor and response to treatments 
It has been reported that DNA arrays using tumor specimens could predict the survival of patients 
with primary uveal melanoma (36).  We also reported that presence of monosomy 3 in liver biopsy 
specimens is correlated to poor prognosis in patients who received embolization of hepatic 
metastasis (37).  We will investigate whether the above observations are also seen in patients who 
receive radiosphere treatments.  We hypothesized that the presence of monosomy 3 in hepatic 
metastasis is correlated to resistance to radiosphere treatment.  Furthermore, correlation between 
specific gene expression patterns and clinical response will be investigated.  We will investigate 
whether the same gene profile reported in the literature (36) predicts the outcome of radiosphere 
treatment.  Hepatic tumor specimens will be obtained by core biopsy prior to radiosphere 
treatment.  DNA as well as RNA will be extracted from the tumor specimens after confirming 
diagnosis of metastatic melanoma.  RNA specimens will be reverse-transcribed to cDNA and 
Target Liver 
Lesions 
Non-Target Liver 
Lesions 
New Liver Lesions 
in the treated lobes 
Overall Liver 
Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 

 
27
tested with DNA microarray analysis. Furthermore, extracted DNA specimens will be tested with 
a genome-wide SNP analysis and the correlation between genomic abnormality such as 
monosomy 3 and/or excess copies of chromosome 8, and response to radiosphere treatment will be 
investigated (38). Peripheral blood mononuclear cells will be used as a control for 
molecular/genetic analysis of tumor specimens.  
 
7.5 Immunological and cytokine response to radiosphere treatment 
It has been reported that local liver treatments induce inflammatory cytokines and also change the 
levels of angiogeneic cytokines (39)(40), which might contributes to a clinical response to the 
treatment.  We have also reported that a patter of productions of IL-6, IL-8, and TNF-alpha is 
different between uveal melanoma patients who received immunoembolization with GM-CSF for 
their hepatic metastases and those treated with plain embolization without GM-CSF (41).  It is 
speculated that radiation treatment to established tumors would result in destruction of 
tumor-induce immunosuppressive microenvironment and might induce an anti-tumor immune 
response.  To investigate this hypothesis, blood specimens will be collected prior to, and after 
radiosphere treatments and changes in serum cytokines and T cell subpopulation including 
regulatory T cells and memory T cells will be investigated.  We hypothesized that patients with a 
good clinical response have decrease in circulating regulatory T cells and increase in a subset of 
memory T cells as seen in immunoembolization studies (unpublished data).  
 
Approximately 100ml of blood specimens will be obtained for PBMC collection prior to 
radiosphere treatment and then at 1-month and 3-month office visits.  Additionally, 10 ml of blood 
specimens will be obtained for serum collection prior to, and 1 hour after radiosphere treatment, 
and then at 1-month and 3-month office visits. 
 
8.0 Drug Information 
8.1 Product Description 
SIR-Spheres microspheres consist of biocompatible microspheres containing yttrium-90 with a 
size range of 30 to 40 microns in diameter. Yttrium-90 is a high energy pure beta radiation emitting 
isotope with no primary gamma emission. The maximum energy of the beta particles is 2.27MeV 
with a mean of 0.93MeV. The maximum range of these emissions in tissue is 11mm with a mean 
range of 2.5mm. The half-life of yttrium-90 is 64.1 hours. In use requiring the isotope to decay to 

 
28
infinity, 94% of the radiation is delivered in 11 days, leaving only background level radiation, 
which has no therapeutic value. SIR-Spheres microspheres themselves are a permanent implant. 
Each device is for single patient use. 
 
SIR-Spheres microspheres are commercially available from:  
Sirtex Medical Inc.  
16 Upton Drive, #2-4  
Wilmington, MA 01887  
Fax: (978) 229-9585  
Email: csusa@sirtex.com  
 
8.2 Calibration of Radioactivity 
Yttrium-90 is a pure beta emitter with a half-life of 64.1 hours. The activity of SIR-Spheres 
microspheres is calibrated to 09:00 hours Sydney time for Australia, which is 18:00 USA Eastern 
Standard Time for the United States and 23:00 Greenwich Mean Time for Europe and is supplied 
with an activity of 3 Giga-Becquerels (GBq) ± 10% at time of calibration.. 
After 14 days, only 2.5% of the original activity remains. 
 
8.3 Biological Properties and Action 
Following implantation via a hepatic artery catheter, SIR-Spheres microspheres become 
embolized in the microvasculature of liver tumors, where they have a local radiotherapeutic effect. 
Some limited concurrent damage to healthy hepatic parenchyma is caused by radiation that 
escapes tumor boundaries and from SIR-Spheres microspheres that fail to become embedded in 
tumors. Following decay of the yttrium-90 to stable zirconium-90, the inert microspheres remain 
implanted in the tumor tissue. The device is not phagocytosed, nor does it dissolve or degrade after 
implantation. High dose radiation emitted from the device is cytocidal to cells within the range of 
the radiation. Treatment with SIR-Spheres microspheres exploits a normal physiological process 
to selectively target the cancerous tissue. Healthy liver tissue receives the overwhelming majority 
of its blood supply via the portal vein and much less from the hepatic artery. However, when 
tumors develop in the liver, the overwhelming majority of tumor blood supply is via branches of 
the hepatic artery and much less from the portal vein. The consequence of this is that 

 
29
catheterization and administration of agents via the hepatic artery permits the preferential targeting 
of therapeutic material to liver tumors. 
 
8.4 Expected Adverse Reactions  
Common adverse effects 
When the patient is treated with the proper technique, without excessive radiation to any organ, the 
common adverse events after receiving SIR-Spheres® microspheres are fever, transient decrease in 
hemoglobin, mild to moderate abnormality of liver function tests – specifically a mild increase in 
SGOT, alkaline phosphatase and bilirubin, abdominal pain, nausea, vomiting, and diarrhea. The 
majority of adverse events are grade 1 and 2 toxicity.  
Most patients develop a post-operative fever that starts immediately after implantation of SIR- 
Spheres microspheres® and can last from a few days to a week.  The fever does not necessarily 
indicate sepsis but may be related to the embolic effect of the microspheres and the acute toxic 
effects on the tumor.  If there is any suspicion of bacterial infection, blood culture will be 
performed and appropriate antibiotics will be given.  
 
Many patients experience nausea that may last up to several weeks and this may occasionally be 
severe enough to require anti-emetic medication that should be continued until the symptoms 
subside.  
 
Serious Abdominal Pain  
Many patients experience abdominal pain immediately after administration of SIR- 
Spheres® microspheres and may need pain relief with narcotic analgesia. The pain generally 
subsides within an hour or so, but patients may require oral analgesia for up to several days.  
 
Immediate, excessive abdominal pain after implantation of SIR-Spheres® microspheres may 
indicate that microspheres have been inadvertently delivered to other organs such as the pancreas, 
stomach or duodenum. This will result in acute pancreatitis or peptic or duodenal ulceration.  A 
post-implantation nuclear scan will verify the placement of the microspheres.  This is performed 
with a gamma camera, which will pick up the secondary radiation from the yttrium-90. The 
introduction of microspheres into the vasculature of the stomach, duodenum or other organs of the 
gastrointestinal tract can cause chronic pain, ulceration and bleeding. Additional tests such as 

 
30
serum amylase are also indicated if pancreatitis is suspected. If this were to occur the patient 
should be treated using best standard practice, including pain relief, and intravenous fluids.  
 
The development of acute peptic ulceration is suggested by the recognized symptoms of ulcer 
disease and diagnosed by endoscopy.  If this were to occur, the patient should be treated using best 
standard practice, including pain relief, gastric acid blocking drugs and intravenous fluids. 
Treatment is the same as for any cause of acute peptic ulceration.  
 
Delayed Serious Events  
Radiation Pneumonitis  
Microsphere shunting to the lungs can cause edema and fibrosis that may not be reversible. 
Extrahepatic shunting may be identified through the injection of 99mTc-MAA into the hepatic 
artery (20, 21). High levels of implanted radiation and/or excessive shunting to the lung may lead 
to radiation pneumonitis. This may be suspected if patients develop a non-productive cough 
several days or weeks after the implantation of SIR-Spheres® microspheres and is diagnosed by 
chest X-ray.  Patients should be treated with systemic corticosteroids and supportive care until 
symptoms have subsided.  
 
Radiation Hepatitis  
The use of radiosphere leads to irradiation of both tumor and normal liver parenchyma. As a result, 
patients with diseases which compromise the functioning of the liver parenchyma or with very 
small lesions scattered throughout the normal parenchyma may be at greater risk of liver function 
impairment. Excessive radiation to the normal liver parenchyma may result in radiation hepatitis. 
This can be difficult to diagnose, and may appear many weeks after the implantation of 
SIR-Spheres® microspheres.  It is suspected if there is unexplained progressive deterioration in 
liver function. The diagnosis can be confirmed by histological examination of core liver biopsy.  If 
the diagnosis is suspected or proven then patients should be treated with systemic corticosteroids 
and supportive care until the inflammation settles.  
 
8.5 Exposure in Utero 
There are no studies on the safety and effectiveness of SIR-Spheres® microspheres in pregnant 
women, nursing mothers or children. Women of childbearing age requiring SIR-Spheres® 

 
31
microspheres should be treated when non-pregnancy can be ascertained.  Safety in pregnancy and 
childhood has not been established and SIR-Spheres® microspheres should not be implanted into 
these patients.  
 
The patient may emit low levels of radiation for several weeks, therefore care must be taken with 
pregnant women and children in close proximity to the patient.  
 
9.0  Dose calculation 
9.1 Dose calculation methods 
The detail method to calculate the dose of SIR-Spheres microspheres is described in the 
Appendix 1 (SIR-Spheres User Manual).  
 
There are two methods for calculating the activity of SIR-Spheres® microspheres to implant –BSA 
method and Partition model.  In this study, two methods will be combined to give the maximum 
dose to tumors and to avoid serious radiation injury to the normal liver and lung. The final dose for 
treatment will be determined by radiation physicist and radiation oncologist.  
However, the radiation dose to the normal liver parenchyma should not exceed 35 Gray in 
patients with normal liver and 30 Gray in patients with cirrhosis.  The dose to the lung 
should not exceed 20 Gray. The dose received by the tumor has no upper limit. 
 
9.1.1 Body Surface Area (BSA) Method  
(1) Tumor involvement: 
(calculated by CT scan) 
 
(2) Body Surface Area:  BSA(m2) = 0.20247 × H0.725 × W0.425 
 
(3) Total Activity of SIR-Spheres (GBq):  A =  BSA - 0.2 + TI 
 
It should be noted that the calculated activity of yttrium-90 may have to be further reduced if  
the percentage lung shunting is greater than 10% as demonstrated by the a technetium-99m scan 
(nuclear medicine break-through scan) (See Section 9.2, Dose Modification) .  
 
L
T
V
V
TI =

 
32
9.1.2 Partition Model for Calculation of Dose/Activity of SIR-Spheres microspheres  
This method involves implanting the highest possible activity to the tumor while maintaining    
radiation dose to sensitive tissues such as the lung and the normal liver.  Therefore this method    
provides the highest radiation dose to the tumor that is associated with protection of normal tissue 
from radiation damage.  
 
The following equation is used to calculate the radiation dose received by an organ after 
SIR-Spheres® microspheres have been delivered to that organ:  
 
(1) Lung shunt fraction: F= Total lung counts/(Total lung counts + Total liver counts) 
 
(2) Tumor to normal liver uptake ratio: R=Tumor counts/normal liver counts, using a sample 
region in tumor and normal liver of the same size (If more than one region is sampled, the an 
average value is calculated) 
 
(3) NOMINAL INFUSED TREATMENT DOSE PER GBq TOTAL ACTIVITY 
 
 
 
 
 
 
 
(4) NOMINAL DOSE TO TUMOR PER GBq TOTAL ACTIVITY 
 
 
 
 
 
 
 
 
(5) NOMINAL DOSE TO LIVER PER GBq TOTAL ACTIVITY 
 
 
 
 
 
 
 
 
(6) NOMINAL DOSE TO LUNG PER GBq TOTAL ACTIVITY 
(Lung volume is estimated as 1000cc, 1,000g) 
 
 
 
 
 
 
 
L
1
)
1(
67
.
49
/
M
F
A
D

−
=
Dtumor /A = 49.67 (1−F)
R
[ML + MT (R −1)]
Dliver /A = 49.67 (1−F)
1
[ML + MT (R −1)]
F
A
D

=
67
.
49
/
lung

 
33
Where: 
A = prescribed activity 
Dtumor = dose to tumor 
F = lung shunt fraction 
ML = mass of liver including tumor 
MT = mass of tumor 
R = tumor:normal liver uptake ratio 
Dliver = dose to normal liver 
Dlung = dose to lung 
 
Note:  All activities are in GBq and masses in g (grams). For the purpose of calculating tissue 
mass, all tissue densities are estimated at 1g/cc.  
Tumor and liver volumes can generally be determined using the diagnostic package associated 
with the CT scanner.  The tumor and normal liver volumes in individual hepatic lobes (i.e., right 
and left lobe) will be calculated separately and the radiosphere dose to each lobe will be decided 
independently.  If dose estimation for individual lobes is not feasible, the radiosphere dose will be 
split to 70% (right lobe) and 30% (left lobe). If an older scanner is used, the CT scan of the liver is 
performed using 10 mm slices.  The tumor and total liver areas are traced out for each slice of the 
MRI and/or CT scan. This is traced using a graphics tablet and the total areas multiplied by 10 mm 
to give the volume of tumor and normal liver.   
 
 
 
 
9.2 Dose Modification 
9.2.1 Previous embolization treatment 
The calculated protocol dose of SIR-Spheres microspheres can be modified. If patients have had 
prior trans-arterial embolization, then the calculated protocol dose will be decreased by 25%. The 
dose may also be decreased to limit the total radiation dose to the liver to 30 Gy.  
 
9.2.2 Shunting to the lung 
The percent lung shunting may alter the activity that can be safely implanted commensurate with 
an acceptable risk of radiation pneumonitis.  The following recommendations apply:  
 
Percent Lung Shunting Activity of SIR-Spheres® microspheres  

 
34
<10%: Deliver full amount of SIR-Spheres microspheres 
10% to 15%: Reduce amount of SIR-Spheres microspheres by 20%  
15% to 20%: Reduce amount of SIR-Spheres microspheres by 40%  
>20%: Do not give SIR-Spheres microspheres 
 
The reduction in the activity implanted should be considered in light of the radiation dose that may 
be received by the tumor.  In some patients, a reduction in activity of 20% may ensure the safety of 
the lung, but no longer provide sufficient radiation to the tumor.  This will depend on the bulk of 
tumor being treated and the tumor to normal ratio of SIR-Spheres microspheres deposition.  This 
can be determined from the nuclear medicine breakthrough scan, in which the amount of MAA in 
the liver can be quantified into that in the tumor and that in the normal liver.   
The final dose of individual treatment will be determined by a radiation oncologist based on the 
information describe above.  
 
10.0 Radiation Safety   
Personnel involved in any aspect of handling SIR-Spheres microspheres must be suitably 
qualified and be appropriately trained to deal specifically with this device. This includes nuclear 
medicine staff, staff involved in the implantation procedure and in post-implant care of the patient. 
Such staff requires the support of a radiation safety officer or expert in radiation physics, and 
licenses for the facility will normally require that such expertise is available to ensure safe use of 
isotopes within the facility. Complete information will be found in the Radiation section in the 
Sirtex Medical User Manual (Appendix 1).  
 
Radiation exposure to the treatment team and to either nursing staff or visitors following the 
implantation is presented in depth in the Sirtex Medical User Manual.  The representative exposure 
levels for the technician or pharmacist preparing a typical patient dose, and for the physician 
implanting that prepared dose of SIR-Spheres microspheres are also included in this manual. 

 
35
11.0  Safety Assessment 
11.1 Definitions 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence that happens during the specified medical 
event reporting period regardless of whether or not it is considered related to treatment. 
 
AEs include the following: 
• All suspected adverse medication reactions. 
• All reactions from medication, overdose, abuse, withdrawal, sensitivity, or toxicity. 
• Apparently unrelated illnesses, including the worsening of a preexisting illness (see 
Preexisting Conditions below). 
• Injury or accidents.  Note that if a medical condition is known to have caused the injury 
or accident (e.g., a fall secondary to dizziness), the medical condition (dizziness) and 
the accident (fall) should be reported as two separate adverse events.   
• Abnormalities in physiological testing or physical examination (findings that require 
clinical intervention or further investigation beyond ordering a repeat [confirmatory] 
test). 
• Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an 
already reported clinical event.  
 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should 
not be reported as adverse events.  However, the medical condition for which the procedure 
was performed should be reported if it meets the definition of an adverse event.   
 
11.1.2 Preexisting Conditions 
In this trial, a preexisting condition (i.e., a disorder present before the adverse event 
reporting) should not be reported as an adverse event unless the condition worsens or 
episodes increase in frequency during the adverse event reporting period.  Recurrence or 
progression of tumor will not be regarded as an adverse event, but will be recorded for 
patient follow-up. 

 
36
 
11.1.3 Adverse Event Reporting Period 
The adverse event reporting period for this trial begins when the patient receives the first 
radiosphere treatment and ends 3 months after the last radiosphere treatment.  All adverse 
events that occur in trial subjects during the adverse event reporting period specified in the 
protocol will be reported, whether or not the event is considered treatment-related. 
In addition, even after the completion of adverse event reporting period, if investigators 
consider that patients develop a serious adverse event that would be possibly related to the 
study treatment, such SAE will be reported. 
11.1.4 Seriousness 
Each adverse event is to be classified by the investigator as SERIOUS (including 
life-threatening) or NON-SERIOUS.  This classification of the gravity of the event 
determines the reporting procedures to be followed. 
An adverse event that meets one or more of the following criteria/outcomes is classified as 
SERIOUS: 
• Death 
• Life-threatening (i.e., immediate risk of death) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject 
• An event not included in the list above, but one that jeopardizes the subject or may require 
intervention to prevent one of the outcome listed above 
 
A NON-SERIOUS event is one that does not meet the criteria described for a serious or 
life-threatening event. 
 
11.2 Evaluation of Adverse Events 
The Common Terminology Criteria for Adverse Events (CTCAE version 4.0) 
(http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev4.pdf) will 
be used to grade the maximum intensity of the event. 

 
37
The acute toxicity assessment will be performed 1 month after the last radiosphere treatment.  
The patient will be re-evaluated for late toxicity at 3-month follow-up visit. After completion 
of the 3-month visit, patients will be followed every three months for 2 years for survival.  
Follow-up over the telephone will be allowed for this purpose.  During this follow-up period, if 
investigators consider that patients develop a serious adverse event that would be possibly 
related to the study treatment, such SAE will be reported.   
 
11.3 Attribution of Causality of Adverse Events 
One of the investigators will assign an attribution to each AE that occurs.  Attribution will be 
determined according to the criteria specified in CTCAE v4.0, which are summarized below: 
5-Definite – The AE is clearly related to the treatment. 
4-Probable – The AE is likely related to the treatment. 
3-Possible – The AE may be related to the treatment. 
2-Unlikely – The AE is doubtfully related to the treatment. 
1-Unrelated – The AE is clearly not related to the treatment. 
 
11.4 Reporting Adverse Events 
Any adverse event that is associated with treatment and that is both serious and unexpected 
will be reported to FDA by telephone or FAX within 7 days.  All of the investigators and the 
Thomas Jefferson University IRB will be notified as well.  A follow-up safety report will be 
submitted within 15 days of initial notification.   
 
In addition, the Sirtex Medical Inc. is to be notified within 24 hours of becoming aware of any 
serious adverse event.  
 
 
 
 
 
Medical Director  
 
 
 
Sirtex Technology Pty. Ltd.  
 
 
 
Email: qa@sirtex.com 
 
 
 
Fax: +61 2 9936 1404 
 

 
38
AE’s will be reported to the Thomas Jefferson University IRB and the Clinical Research 
Management Office (CRMO) as specified in the TJU Data Safety and Monitoring Plan. 
Unexpected fatal adverse events associated with treatment will be reported within 24 
hours to the TJU IRB, to the Data Safety Management Board (DSMB) and to Sirtex.   
Fatal adverse events not related to treatment will be reported to the TJU IRB and to the DSMB 
within 5 days.   
 
 AE will be reported according the table below. 
Unexpected Event 
Grade 1-3  
Attribution of Possible, 
Probable or Definite  
Grade 4 
Regardless of Attribution  
Grade 5 
Death  
Report to CRMO via website 
within 48 hours.  Report to 
TJU IRB within 48 hours. 
CRMO reports to DSMB 
immediately following 
receipt. 
Report to CRMO via 
website and TJU IRB 
within 48 hours. CRMO 
reports to DSMB 
immediately following 
receipt. 
 Report to CRMO 
via website and TJU 
IRB within 24 
hours. Report to 
Sirtex within 24 
hours. 
 
Expected Event 
Grades 1-3  
Grade 4 
Regardless of Attribution  
Grade 5 
Death 
Report to CRMO via website 
within 10 working days.   
 
Summary of all adverse 
events submitted quarterly to 
DSMB. 
Report to CRMO via 
website and TJU IRB 
within 48 hours. CRMO 
reports to DSMB 
immediately following 
receipt. 
 
Summary of all adverse 
events submitted quarterly 
to DSMB. 
Report to CRMO 
via website and TJU 
IRB within 24 
hours. 
 
Summary of all 
adverse events 
submitted quarterly 
to DSMB.  
 
11.5 Thomas Jefferson University Data and Safety Monitoring Plan 
The study will be conducted in accordance with the Thomas Jefferson University Data and 
Safety Monitoring Plan.  Adverse events will be recorded and graded based on CTCAE v4.0.  
All adverse events will be reported to the Kimmel Cancer Center Clinical Research 
Management Office (CRMO) using a password-protected web-site. Unexpected fatal 
adverse events associated with radiosphere treatment will be reported within 24 hours to 

 
39
the TJU IRB.  Fatal adverse events not related to radiosphere treatment will be reported to the 
TJU IRB and to the DSMB within 5 days.  None-fatal events will be reported according to the 
table in Section 11.4. 
 
11.6 Follow-Up of Adverse Event 
All AE’s will be followed until they are resolved or the subject’s participation in the trials 
ends.  In addition, all SAE’s will be followed by one of the investigators at Thomas Jefferson 
University even after the subject’s participation in the trial is completed until they resolve or 
until one of the investigators assesses them as “chronic” or stable”. 
 
12.0 Statistical Considerations 
This is a phase II clinical trial to investigate safety and efficacy of radioactive microsphere 
(SIR-Spheres® microspheres).  Uveal melanoma patients with progressing hepatic metastases who 
received no more than one intra-hepatic arterial treatment will be enrolled. Patients will be first 
stratified into two groups: Group A, no prior intra-hepatic arterial treatment; Group B, one prior 
intra-hepatic arterial treatment). 
 
A total of 24 uveal melanoma patients will be enrolled into each group.  The primary endpoint of 
this study is the clinical benefit rate (CR+PR+SD).  A Simon’s two-stage optimal design 
(alpha=0.05, beta=0.20) will be applied to each group of patients (42, 43). The 60% of clinical 
benefit rate will be considered effective enough for the future investigation of this treatment.  The 
radiosphere treatment will be considered to be ineffective if clinical benefit rate is 30% or less. 
 
Choice of design is guided by a desire to stop the trial early if the actual stabilization rate is 30% or 
less.  If the stabilization rate is 60% or greater, we would like to have a low probability of failing to 
conclude effective.  Based on the optimal design, we will: 
 
 
    
Look after this 
 
   
Stop if number of 
 
 
number of patients 
  
successes is less than or equal to 
Stage I:  
 
8 
 
 
 
 
3 
Stage II:  
 
24 
 
 
 
 
10 
 

 
40
With this design, we have no more than a 5% chance of concluding effective (60% success rate) 
when the success rate is at most 30%.  Similarly, we have no more than a 20% chance of 
concluding ineffective (30% stabilization rate) when it is effective.  If the actual response rate is 
30% or worse, we have at least a 0.81 probability that the trial will stop after the first 8 subjects.  If 
the response rate is 60%, the probability that the trial will be stopped in stage I is 0.17.  The 
overall power of this design is 80.6%. 
 
The first stage of study requires 8 patients in each cohort.  If 3 or fewer patients achieve 
stabilization or regression of hepatic metastases, further enrollment of patients into that group will 
be stopped with the conclusion that clinical benefit rate can not be 60% or greater. If at least 4 
patients show response (CR, PR, or SD) in at least one of these two groups, the study will be 
continued to accrue 16 more patients in that group(s).  If 10 or fewer patients among 24 patients in 
the group(s) show stabilization or regression of hepatic metastases, the study will be concluded 
that clinical benefit rate will not be 60% or more and no further study will be considered for the 
patients from the corresponding group(s). 
 
We are currently treating 50-100 new uveal melanoma patients with hepatic metastases at Thomas 
Jefferson University Hospital.  Approximately 1-2 patients would be accrued to this study every 
months and the accrual to this study will be completed within 2 years. 
 
The estimated median survival of patients who receive this treatment is 6-12 months.  We will 
follow the patients until their death or for 2 years.  A maximum of 4 years including accrual of 
patients will be required to complete this study. 
 
The overall survival (OS), progression free survival without progression of hepatic metastasis 
(PFS-L), and duration of response will be evaluated using the Kaplan-Meier method.  All 
estimates of rates (e.g., clinical benefit rate and toxicity) will be presented with corresponding 
confidence intervals.  For clinical benefit rates, the method of Atkinson and Brown will be used to 
adjust for the two-stage design (44). 
 
All molecular and immunological studies are exploratory and the results will be reported in a 
descriptive manner.  The genome-wide SNP analysis will be done at the KCC core facility.  Paired 

 
41
t-test or paired Wilcoxon test will be used to compare the serum cytokines and T cell 
subpopulations before and after radiosphere treatment. 
 
13.0 Data Disclosure and Patient Confidentiality 
Patient medical information obtained as a result of this study is considered confidential. Disclosure 
to third parties other than to the patient’s primary physician and to those noted below is prohibited.  
All reports and communications relating to subjects in this study will identify each patient only by 
his/her number (and initials if allowed by local regulations).  Data generated as a result of this 
study must be available for inspection upon request by the FDA (or other Health Authority or 
government agency), and the IRB. In addition, Sirtex Medical Inc. that provides the funding for 
this clinical study has a right to investigate the data obtained from this study.  
Patient confidentiality will be maintained at all times unless government regulation or applicable 
law requires disclosure.  If local or national regulations are modified to require additional 
consent(s) or documentation for release of source documents or other medical information, 
required for the study, it is the responsibility of the investigator to obtain such consent and 
documentation with relevant approvals by the local IRB. 
 
14.0  Ethical Considerations 
14.1  Protection of Human Subjects from Research Risks 
The study will be conducted in accordance with the Declaration of Helsinki and with rules and 
regulations in accord with the U.S. Office of Protection from Research Risks (OPRR). 
 
14.2  Institutional Review Board 
The study will be reviewed and approved by a duly constituted IRB before patients are screened 
for entry.  The investigator will ensure that all aspects of the IRB review are conducted in 
accordance with current institutional, local, and national regulations.  Amendments to the protocol 
will be subject to the same requirements as the original protocol.  The Investigator will submit all 
periodic reports and updates that the IRB may require, including any final close out reports.  The 
Investigator will inform the IRB of any reportable adverse events as required by local regulations. 
 

 
42
14.3  Informed Consent 
Each patient will be provided with oral and written information that describes the nature and 
duration of the study in a language he/she can understand.  The required schedule for treatment 
and interval safety evaluations (irrespective of holidays), plus the planned follow-up schedule, 
should be carefully reviewed and possibly reinforced with a calendar.  The patient must 
consent in writing to participate before undergoing therapy on the protocol.  The original 
signed consent form will be retained.  Each patient will be given a copy of his/her consent 
form. 
 
 

 
43
 
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