Clinical trial NCT01900002
Conditions: Advanced Adult Hepatocellular Carcinoma BCLC Stage C Hepatocellular Carcinoma Recurrent Adult Hepatocellular Carcinoma Stage III Hepatocellular Carcinoma AJCC v7 Stage IIIA Hepatocellular Carcinoma AJCC v7 Stage IIIB Hepatocellular Carcinoma AJCC v7 Stage IIIC Hepatocellular Carcinoma AJCC v7 Stage IV Hepatocellular Carcinoma AJCC v7 Stage IVA Hepatocellular Carcinoma AJCC v7 Stage IVB Hepatocellular Carcinoma AJCC v7 Unresectable Hepatocellular Carcinoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-09-13; Completion date: 2020-12-10
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well sorafenib tosylate and yttrium Y 90 glass microspheres work in treating patients with liver cancer that cannot be removed by surgery. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Yttrium Y 90 glass microspheres use glass beads to carry radiation directly to tumor cells without harming normal cells. Giving sorafenib tosylate with yttrium Y 90 glass microspheres may be an effective treatment for liver cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Median progression-free survival (PFS).

SECONDARY OBJECTIVES:

I. Overall survival (OS). II. Time to radiographic progression (TTRP). III. To evaluate the safety of the combination of sorafenib (sorafenib tosylate) and Yttrium-90; adverse events (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 \[NCI-CTAE v 4.0\]).

OTHER OBJECTIVES:

I. Predictive biomarkers of response to therapy and survival: will assess pre-treatment plasma level of insulin-like growth factor 1 (IGF-1) as above, and assess its predictive ability of time to progression (TTP) and OS.

OUTLINE:

Patients receive sorafenib tosylate orally (PO) twice daily (BID). After 4 weeks, patients receive yttrium Y 90 glass microspheres intra-arterially (IA). Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Arms: arm 1: Patients receive sorafenib tosylate PO BID. After 4 weeks, patients receive yttrium Y 90 glass microspheres IA. Courses of sorafenib tosylate repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Quality-of-Life Assessment intervention 3: Sorafenib intervention 4: Sorafenib Tosylate intervention 5: Yttrium Y 90 Glass Microspheres
Intervention descriptions: intervention 1: Correlative studies intervention 2: Ancillary studies intervention 3: Given PO intervention 4: Given PO intervention 5: Given IA

Protocol documents:
Prot_SAP_000.pdf: 
 
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Title page 
STUDY TITLE  
  
A Phase II study of Sorafenib and Yttrium-90 Glass Microspheres for Advanced  
Hepatocellular Carcinoma, BCLC Stage C  
 
 
Test drug (s): 
Test device: 
  
Sorafenib  
 Yttrium -90 glass microspheres (TheraSphere®, Nordion, 
Canada) 
Study purpose: 
To evaluate the safety of systemic therapy with Sorafenib 
(Nexavar®)  followed by liver directed therapy with Yttrium-90 
microspheres in patients with Child Pugh A and Barcelona 
Clinic Liver Cancer (BCLC)-stage C Hepatocellular cancer.   
 
Clinical study phase: 
Single Arm, Phase II 
Version no.: 
9 
Date: 
 June 19, 2015 
 
Amendment no.: 
 
Date: 
 
Onyx Study no.: 
 
Institution Study no.: 
 
 
 
Principal Investigator: 
 
Ahmed O. Kaseb, MD, Assistant Professor, 1515 Holcombe 
Blvd, Unit 426, Department of GI Medical Oncology,  
Houston, TX 77030, Phone: (713)792-2828. 
 


 
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  Collaborators:    
                                               Ravi Murthy, MD, Associate Professor,  1515 Holcombe Blvd,     
                                              Unit 1471, Department of Diagnostic Radiology, Houston, TX  
                                              77030, Phone: (713)745-0856.   
                                              Milind Javle, MD,  Associate Professor,  1515 Holcombe Blvd, 
Unit 426, Department of GI Medical oncology, Houston, TX  
77030,  Phone: (713)792-2828.  
                                              Armeen Mahvash, MD, Assistant Professor,  1515 Holcombe 
Blvd, Unit 1471, Department of Diagnostic Radiology, Houston, 
TX  77030, Phone: (713) 563-7340.                                               
                                                                    
                                              Rony Avritscher, MD, Assistant Professor,  1515 Holcombe 
Blvd, Unit 1471, Department of Diagnostic Radiology, Houston, 
TX  77030, Phone: (713) 563-7340.      
                                        
                                              Beth Chasen, MD, Assistant Professor,  1515 Holcombe Blvd, 
Unit 1471, Department of Nuclear Medicine, Houston, TX  
77030, Phone: (713) 563-3008.                                               
 
 
 
 
 
 
 
 
 
  


 
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Research Nurse:  Mary Brimer, RN, Department of GI Medical Oncology 
Data Manager:   Mary Brimer, RN, Department of GI Medical Oncology 
Statistician:                             Jeffrey S. Morris, PhD 
                                                 Professor, Department of Biostatistics 
                                                 MD Anderson Cancer Center      
                                                1400 Hermann Pressler Dr, Unit 1411,  
                                                 Houston, TX 77030,    
                                                Phone:713-563-4284 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Principal Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 


 
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Synopsis 
 
Title 
A Phase II study of Sorafenib and Yttrium-90 glass microspheres 
for Advanced Hepatocellular Carcinoma, BCLC Stage C 
Clinical study phase 
Phase II 
Study objective(s) 
The objective of this study is to evaluate the safety of continuous 
sorafenib 400 mg twice daily followed, after 4 (+/-1 week) 
weeks, by one Yttrium-90 treatment in patients with Child-Pugh 
A, BCLC-stage C HCC.   
          Primary objective: 
• Median progression-free survival (PFS) 
 
          Secondary objectives: 
• Overall Survival (OS) 
• Time to radiographic progression (TTRP) 
• To evaluate the safety of the combination of 
sorafenib and Yttrium-90; Adverse events (NCI-
CTAE v 4.0)  
Other objectives: 
 
Predictive Biomarkers of response to therapy and 
survival: will assess pre-treatment plasma level of IGF-1 as 
above, and assess its predictive ability of TTP and OS 
 
 
Indication 
Advanced HCC 
Study design 
This is a single-arm phase II clinical trial. The treatment period 
will be divided into 4 week cycles. During the study period, 
patients will undergo evaluation for safety every 4 weeks.  Tumor 
evaluations will be performed every 8 weeks.  
Type of control 
None 
Number of subjects 
20 
Primary Endpoint 
To evaluate the safety of the combination of sorafenib and 
Yttrium-90; Adverse events (NCI-CTAE v 4.0)  
 


 
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Diagnosis and main criteria 
for inclusion 
• Patients  >18 years of age 
• Patients with histological or cytologically documented HCC 
(Documentation of original biopsy for diagnosis is acceptable 
if tumor tissue is unavailable) or clinical diagnosis by 
AASLD criteria in cirrhotic subjects is required. For subjects 
without cirrhosis, histological confirmation is mandatory. 
• Patients must have at least one tumor lesion that can be 
accurately measured in at least one dimension according to 
RECIST  
• The target lesion has not been previously treated with local 
therapy (such as surgery, radiation therapy, hepatic arterial 
therapy, chemoembolization, radiofrequency ablation, 
percutaneous ethanol injection or cryoablation). 
• Patients who have received local therapy, such as surgery, 
radiation therapy, hepatic arterial embolization, 
chemoembolization, radiofrequency ablation, percutaneous 
ethanol injection or cryoablation are eligible if the previously 
treated lesions have progressed or recurred can be identified 
as target lesions.  Local therapy must have been completed at 
least 4 weeks prior to the baseline scan.  
• Patients who have received Yttrium-90 microspheres are not 
eligible. 
• Patients who have an ECOG PS ≤ 1  
• Patients who are categorized under BCLC-C stage 
• Cirrhotic status of Child-Pugh class A. Child-Pugh status 
should be calculated based on clinical findings and laboratory 
results during the screening period. 
• The following laboratory parameters: 
 
Platelet count ≥ 60 x 109/L  
 
Hemoglobin ≥ 8.5 g/dL 
 
Total bilirubin ≤ 2.5 mg/dl 
 
Alanine transaminase (ALT) and AST ≤ 5 x upper 
limit of normal 
 
Serum creatinine ≤ 1.5 x the upper limit of normal 
Prothrombin time (PT)-international normalized ratio (INR) 
≤ 2.3 or PT ≤ 6 seconds above control. 


 
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Plan for statistical analysis The primary analysis is to evaluate the toxicity profile, and the 
secondary analysis to assess the overall survival and progression-
free survival. The study will be monitored for toxicity.  Being 
descriptive in nature, this trial will not focus on hypothesis 
testing. Descriptive statistics will be computed for all continuous 
and categorical variables of interest.  All statistical analyses will 
be performed using SAS (version 9.3; SAS Institute, Inc., Cary, 
NC). For the primary analysis, all patients received treatment will 
be included the analysis for toxicity.  Continuous parameters will 
be summarized using descriptive statistics, such as number of 
patients, mean, standard deviation, median and range.  The 
toxicities will be summarized with frequency and 95% 
confidence interval (95% CI) by type, severity and their 
relationship to the treatment. Assuming a 30% of grade 3 or 4 
treatment related toxicity rate, with 20 patients, the 95% CI will 
be (9.9%, 50.1%). 
For the secondary analysis, the Kaplan-Meier method will be 
applied to estimate the probabilities of overall survival and 
progression-free survival as well as the median OS duration and 
PFS duration. The Log rank test will be used to compare the two 
time-to-event outcomes between patient subgroups. 
 


 
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Imaging Requirements 
 
• Triple Phase CT – To determine liver volume measurement, 
identify hepatic vascular anatomy to determine TheraSphere 
dosimetry  
 
• Spiral CT abdomen/pelvis –performed with cuts of 10 mm or 
less in slice thickness contiguously in the axial plane to assess 
hepatic and extra-hepatic lesions according to the RECIST 1.1 
criteria.  
 
• Spiral CT Chest –performed with cuts of 10 mm or less in 
slice thickness contiguously in the axial plane to assess extra-
hepatic lesions according to the RECIST 1.1 criteria.  
 
• MRI can replace CT scans; however, the same imaging 
modality should be used for all images in an individual 
patient throughout the study  
 
• Images for efficacy assessments will require a duplicate set of 
images in DICOM format  
 
• Hepatic angiography and 99mTc-MAA– selective celiac and 
superior mesenteric arteriograms are needed to evaluate the 
hepatic arterial anatomy for the whole liver, as well as 
evaluation of potential sources of extra-hepatic blood supply 
to tumors. Repeat 99mTc-MAA may be needed to estimate 
cumulative lung shunt or re-asses GI flow.  
 
 


 
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Biomarker Variables 
In addition to assessing the baseline plasma IGF-1 level, we will 
run exploratory biomarker studies utilizing available blood and 
plasma. A blood sample will be obtained from all patients at 
Screening. Plasma samples for biomarker evaluation will be 
obtained from all patients at six independent time points: (1) 
Screening; (2) Cycle 1/Day 1; (3) Cycle 2/Day 1; (4) Cycle 3/Day 
1; (5) Pre-Yttrium-90, on the same day; and (6) End of 
Treatment. Plasma from patients on treatment days will be 
obtained from blood samples harvested prior to drug 
administration. These biomarker studies are optional and 
donation of biomarker samples is not required for participation in 
the clinical trial. 
The planned biomarker study is designed to measure the 
correlation between plasma IGF-1 as a surrogate for the liver 
reserve, with TTRP, OS and PFS of patients, since the status of 
the underlying liver disease independently affect patients’ 
survival and outcome.  
Data from this biomarker analysis may be correlated with various 
other data obtained in this study (e.g., clinical activity, toxicity). 
 
 
 


 
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Table of contents 
Title page ........................................................................................................................................ 1 
Protocol Synopsis............................................................................................................................ 4 
Table of contents ............................................................................................................................. 9 
1.1 
Background and Rationale ............................................................................................. 13 
1.2 
Sorafenib ........................................................................................................................ 14 
1.2.1 
Preclinical ............................................................................................................... 14 
1.2.2 
Clinical experience ................................................................................................. 14 
2. 
TheraSphere ........................................................................................................................... 15 
2.1 
General Device Description ........................................................................................... 15 
2.3        Rationale for the Treatment of  Hepatocellular Carcinoma ......................................... 16 
3. 
Study objectives ..................................................................................................................... 18 
4. 
Study design ........................................................................................................................... 19 
5. 
Study population .................................................................................................................... 19 
5.1 
Eligibility ........................................................................................................................ 19 
5.1.1 
Inclusion criteria ..................................................................................................... 20 
5.1.2 
Exclusion criteria .................................................................................................... 21 
5.1.3 
Excluded therapies and medications, previous and concomitant ........................... 22 
5.2 
Withdrawal of subjects from study ................................................................................ 23 
6. 
Treatment[s] ........................................................................................................................... 24 
6.1 
Treatments to be administered ....................................................................................... 24 
6.2 
Sorafenib Dosage and administration ............................................................................ 24 
6.2.1.1 
Dose Reduction Levels ................................................................................... 25 
6.2.1.2 
Dose modification for hematologic toxicities ................................................. 25 
6.2.1.3 
Dose modification for non-hematologic toxicities .......................................... 26 
6.2.1.3.1 
Prevention/management strategies for diarrhea and fatigue .................... 26 
6.2.1.4 
Hand-foot-skin reaction .................................................................................. 27 
6.2.1.5 
Treatment-emergent hypertension .................................................................. 28 
6.3 
TheraSphere ................................................................................................................... 29 
6.4 
Procedures on Day of Treatment .................................................................................... 32 
6.5 
Radiation Safety in the Post-Treatment Period .............................................................. 33 
6.6 
Device Dosages .............................................................................................................. 33 
7. 
Procedures and variables ....................................................................................................... 33 
7.1 
Schedule of procedures .................................................................................................. 33 
7.1.1 
Tabulated overview ................................................................................................ 34 
7.1.2 
Timing of assessments ............................................................................................ 36 
7.1.3 
Medical history ....................................................................................................... 36 
7.2 
Efficacy .......................................................................................................................... 36 
7.3 
Pharmacokinetics / pharmacodynamics ......................................................................... 36 
7.4 
Safety .............................................................................................................................. 36 
7.4.1 
Adverse events ........................................................................................................ 37 
7.4.1.1 
Definitions ....................................................................................................... 37 
7.4.1.2 
Classifications for adverse event assessment .................................................. 38 
7.4.1.2.1 
Seriousness .............................................................................................. 39 
7.4.1.2.2 
Intensity ................................................................................................... 39 


 
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7.4.1.2.3 
Causal relationship .................................................................................. 40 
7.4.1.2.4 
Action taken with study treatment ........................................................... 41 
7.4.1.2.5 
Other specific treatment(s) of adverse events .......................................... 41 
7.4.1.2.6 
Outcome ................................................................................................... 41 
7.4.1.3 
Assessments and documentation of adverse events ........................................ 41 
7.4.1.4 
Reporting of serious adverse events ................................................................ 41 
7.4.1.5 
Expected adverse events ................................................................................. 42 
7.4.2 
Pregnancies ............................................................................................................. 43 
7.5 
Other procedures and variables ...................................................................................... 43 
7.6 
Appropriateness of procedures / measurements ............................................................. 43 
8. 
Statistical methods and determination of sample size ........................................................... 43 
8.1 
Statistical and analytical plans ....................................................................................... 43 
8.2 
Planned interim analyses ................................................................................................ 46 
8.3 
Determination of sample size ......................................................................................... 46 
9. 
Data handling and quality assurance ..................................................................................... 46 
9.1 
Archiving ........................................................................................................................ 46 
10. Premature termination of the study ........................................................................................ 46 
11. Ethical and legal aspects ........................................................................................................ 47 
11.1 Ethical and legal conduct of the study ........................................................................... 47 
11.2 Subject information and consent .................................................................................... 47 
11.3 Publication policy ........................................................................................................... 48 
11.4 Confidentiality ................................................................................................................ 48 
12. Reference list ......................................................................................................................... 49 
 
 
List of abbreviations 
 
AE 
                      
ADL                 
Adverse events 
Activities of daily living  
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BID 
bis in die, twice daily  
 
B-Raf 
B isoform of Rapidly Accelerated Fibrosarcoma protein 
BUN 
CBC                  
Blood Urea Nitrogen 
Complete Blood Count 
 
c-KIT 
Stem Cell Factor Receptor Tyrosine Kinase 
CR 
Complete Response 
C-RAF 
C isoform of Rapidly Accelerated Fibrosarcoma protein 


 
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CTCAE 
 
CT 
DSMB 
Common Terminology Criteria for Adverse Events 
Computed Tomography 
Data Safety Monitoring Board 
DHPD 
Dihydropyrimidine dehydrogenase 
ECOG 
eCRF 
 
Eastern Cooperative Oncology Group  
Electronic Case report Form 
EGFR 
Epidermal growth factor receptor 
ERK 
 
FACT-Hep 
FHSI8 
Extracellular Signal-regulated Kinases 
Functional Assessment of Cancer Therapy – Hepatobiliary Questionnaire 
Functional Assessment of Cancer Therapy – Hepatobiliary Symptom 
Index 8 
FDA 
Food and Drug Administration (US) 
FLT3 
GBq 
FMS-like tyrosine kinase 3 
Giga bBecquerel 
GCP 
 
GI 
 
Good Clinical Practice 
Gastrointestinal 
GMP 
 
Gy 
Good Manufacturing Practice 
Gray, a measure of irradiation dose 
HCC 
 
HDE 
Hepatocellular Carcinoma 
Humanitarian Device Exemption 
HFSR 
Hand foot skin reaction 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IDMC 
INR 
Independent Data Monitoring Committee  
International Normalized Ratio for prothrombin time 
IR 
Immediate release 
IRB 
LFT 
Institutional Review Board 
Liver function tests 
MAPK 
Mitogen Activated Protein Kinase 
MEK 
NCI 
MAP Kinase / ERK Kinase 1 
National Cancer Institute 
NM 
Nano molar 


 
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NYHA 
New York Heart Association 
PDGFR 
PE 
Platelet Derived Growth Factor Receptor 
Physical exam 
PFS 
PT 
Progression free survival 
Prothrombin Time 
PTT 
Partial thromboplastin time 
RCC 
RECIST 
Renal cell carcinoma 
Response Evaluation Criteria in Solid Tumor 
SAE 
99mTc-MAA 
TS 
TTP 
Serious adverse event 
Technetium-99m Macro-aggregated albumin 
TheraSphere 
Time-to-Progression 
SUSARs 
UADE 
Suspected unexpected serious adverse reactions 
Unanticipated Adverse Device Event 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
WBC 
Y-90(Y-88, 
Y-91) 
Vascular Endothelial Growth Factor Receptor 
White Blood Cells 
Ytrium-90 and isotopes 
 
 
1 Introduction  
 
More than 80% of hepatocellular carcinoma (HCC) patients are not candidates for 
curative treatments, such as resection or liver transplant, the outcome of HCC 
patients remained very poor. Recently, sorafenib—a multitarget tyrosine kinase 
inhibitor—was found to improve survival of patients with Child-Pugh A unresectable 
HCC. The median overall survival (OS) was 10.7 months for patients on sorafenib vs 
7.9 months for placebo, P = .0006, and median time-to-progression (TTP) was 5.5 
months for patients on sorafenib vs 2.8 months for placebo, (P <0.001). Notably, out 
of all patients under the SHARP trial, 421 patients had extrahepatic spread (EHS) 
and/or macrovascular invasion (MVI) (Sorafenib=209, placebo=212). For patients 
with EHS and/or MVI (Sorafenib vs placebo), OS was 8.9 vs 6.7 months (HR: 0.77; 
95% CI: 0.60, 0.99) and TTP was 4.1 vs 2.7 months (HR: 0.64; 95% CI: 0.48, 0.84). 
(Sherman M, et al. 44th  ASCO Annual Meeting). 
Considering that the cause of death of HCC patients with extrahepatic spread is 
mainly intrahepatic HCC progression or hepatic failure, rather than extrahepatic 
metastasis, the intentional addition of an intra-arterial local therapy modality, such as 


 
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Yttrium-90 microspheres, could offer added survival and quality of life benefit. 
Surprisingly, no data have been available on this approach until now. 
1.1 
Background and Rationale 
TheraSphere®, a localized, minimally embolic therapy, capitalizes on the 
hypervasculature nature of tumors delivering Yttrium-90 microspheres, a source of 
beta energy, via the hepatic artery to the tumor bed. The distribution of blood flow is 3 
to 7 times greater within the tumor than the surrounding noncancerous tissue. 
Consequently, there is preferential delivery of microspheres to the tumor capillary bed 
allowing for higher doses of radiation to be delivered to the tumor relative to the 
surrounding non-tumor parenchyma. The ability to concentrate radioactive 
microspheres within the tumor leads to an "inside-out" radiation, which in turn exerts 
a local tumoricidal effect. 
 
Preliminary data: Treatment details were retrospectively collected for a cohort of 
patients with advanced multifocal HCC at MD Anderson Cancer Center between 
January 2008 & May 2010 who received systemic sorafenib followed by liver directed 
therapy with Yttrium-90 microspheres. 19 patients met the criteria (BCLC stage B=3 
patients, and BCLC stage C=16 patients), (Child-Pugh A=16, and Child-Pugh B=3). 
Response rate was: PR 21% (n=4) and 79% (n=15) of these patients had SD by 
RECIST criteria. Median TTP per liver tumors was 7.3 months, and OS was 10.3 
months. Grade 3 /4 hepatic toxicities were absent within 30 days post Y90 
microsphere therapy. Significant adverse events were: GI ulcer (1), pancreatitis (1), 
lymphopenia (1), and mucositis (2) from which all patients recovered uneventfully. 
It will be also important in the future to determine how to most effectively integrate 
molecular assays that assess the likelihood of therapeutic benefit into clinical practice. 
Therefore, we plan to assess potential biological markers candidates to help predict 
response or survival benefit to this approach. Insulin like growth factor-1 (IGF-1) is 
produced predominantly in the liver, and our recent study showed that pre-treatment 
plasma IGF-1 may correlate with patients’ survival, and hence improve the prognostic 
ability of the Cancer of the Liver Italian Program (CLIP) score, and Barcelona Clinic 
Liver Cancer (BCLC) staging. IGF-1 significantly correlated with the 
clinicopathologic features. With an optimal IGF-1 cut point of 26 ng/mL, the overall 
survival for patients with IGF-1 >26 was 17.7 months (95% CI of 13.6, 22.8), and for 
IGF-1 ≤ 26 (60/288 patients) was 5.8 months (95% CI of 4.0, 12.5), p-value<0.0001. 
Additionally, we have accrued 20 patients on the current study with a primary aim to 
evaluate the safety of the combination of sorafenib and Yttrium-90; adverse events 
(NCI-CTAE v 4.0) and found no grade 4 or 5 reactions. A few grade 3 reactions 
occurred in the form of: liver enzymes increase (ALT=1 patient, AST=3 patients, and 
bilirubin = 1 patient), Fatigue (=2), and 1 patient for each of the following: 
encephalopathy, hypertension, hyponatremia, hypophosphatemia, thrombocytopenia, 
maculo-papular rash, weight loss and vomiting.  


 
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1.2 
Sorafenib 
1.2.1 Preclinical 
Sorafenib is a multikinase inhibitor which effects specific targets that are imperative for 
tumor cell proliferation including the serine/threonine kinases c-Raf and B-Raf (IC50 6 and 25 
nM respectively) and the receptor tyrosine kinase RET, Flt-3 and c-Kit (IC50 47, 33 and 68 
nM respectively) [1]. Sorafenib has potent activity against receptor tyrosine kinases important 
in tumor angiogenesis including the vascular endothelial growth factor receptor family 
(VEGFR1, -2, -3; IC50 26, 90 and 20 nM respectively ) and platelet derived growth factor-
beta (PDGFR-ί; IC50 57 nM). In cellular mechanistic (on target) assays, sorafenib was found 
to be a potent inhibitor of VEGFR-2, VEGFR-3, and PDGFR and Flt-3 receptor 
phosphorylation.  The anti-tumor activity of sorafenib in vivo is driven by its direct effects on 
tumor growth through its inhibition of the Raf/MEK/ERK pathway and on the anti-
angiogenic activity of the compound.  Sorafenib demonstrates broad anti-tumor activity in 
human tumor xenograft models of liver, kidney, lung, prostate, breast and leukemia. In 
human hepatocellular tumor cell lines, sorafenib potently inhibited cellular proliferations, 
Raf/MEK/ERK signaling and induced apoptosis. Sorafenib has potent activity against human 
tumor xenograft model of hepatocellular carcinoma with tumor stabilization seen at moderate 
doses and partial tumor regressions observed at higher doses.  
1.2.2 Clinical experience 
Sorafenib as a single agent has been evaluated globally in multiple Phase I and II trials in 
various malignancies. Two pivotal international multi-institutional, single agent, randomized, 
placebo-controlled trials led to sorafenib’s approval for renal cell carcinoma (RCC) (US 
2005, EU 2006) worldwide and hepatocellular carcinoma (HCC) (2007) worldwide. 
TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial) used a 
randomized, double-blind, placebo-controlled design to assess the efficacy of sorafenib in 
903 subjects with advanced RCC who received 1 prior systemic regimen.  The formal 
analysis of PFS using data available as of 28 Jan 2005 demonstrated a statistically significant 
doubling of PFS in subjects treated with sorafenib as well as a favorable safety profile of 
sorafenib in advanced RCC subjects. [2] This trial supported the US and European Union 
approvals of sorafenib in RCC, followed by regulatory approvals around the world, the first 
approved agent for this disease in over a decade. 
Clinical results in Phase I studies of sorafenib as a single agent were suggestive of a 
therapeutic effect in HCC and led to the design of a single arm  Phase II study (10874), in 
which 137 subjects with advanced, inoperable HCC Child-Pugh classes A and B were treated.  
The results of this study (median TTP of 5.5 months by independent assessment and median 
overall survival of 9.2 months), provided the basis for the randomized, placebo-controlled 
Phase III study in subjects with advanced HCC Child-Pugh class A (SHARP, Sorafenib HCC 
Assessment Randomized Protocol).  This large (602 subjects) Phase III study was the first 
international, randomized, double-blind, placebo-controlled study to demonstrate a 
statistically significant and clinically meaningful improvement in OS in advanced HCC 
subjects treated with sorafenib over placebo.[3]  Of the 299 sorafenib subjects valid for ITT 
analysis, the median OS was 10.7 months in the sorafenib group and 7.9 months in the 303 


 
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subjects randomized to the placebo group (hazard ratio in the sorafenib group, 0.69; 95% 
confidence interval, 0.55 to 0.87; p<0.001.  The nominal alpha for this analysis was 0.0077 
according to the pre-specified O'Brien-Fleming-type alpha spending function.  Therefore, 
sorafenib had a statistically significant effect on prolonging overall survival.  This significant 
survival benefit represented a 31% reduction in risk of death (or 44% improvement in OS) in 
subjects treated with sorafenib versus those treated with placebo. 
As of 31 December 2009, over 10,000 cancer patients with various malignancies have been 
exposed to sorafenib either as single agent or in combination with other chemotherapeutic 
agents in Phase I/II/III studies.  Sorafenib has been generally well tolerated at a dose of 400 
mg po twice daily (bid).  The most common drug related adverse events have included hand-
foot skin reaction, diarrhea, fatigue, hypertension, pain and rash.  Grade 3 and 4 drug-related 
adverse events are uncommon.  There was no evidence of cumulative toxicity and the 
majority of the adverse events were reversible.  
 
2.    TheraSphere 
2.1 
General Device Description 
 
TheraSphere® consists of insoluble glass microspheres in which yttrium-90 is an integral 
component of the glass. The sphere diameter ranges from 20 to 30 μm with 22,000 to 73,000 
microspheres per milligram. TheraSphere is available in six dose sizes (3 GBq, 5GBq, 7GBq, 
10GBq, 15GBq and 20 GBq) each supplied in 0.6 mL of sterile, pyrogen-free water contained 
in a 1.0 mL vial secured within a clear acrylic vial shield. A pre-assembled single-use 
TheraSphere Administration Set is provided for each dose. Each user site is provided with a 
re-useable TheraSphere Administration Accessory Kit that provides both radiation protection 
for the user and physical support of the dose vial and Administration Set during 
administration of the product.  
 
Yttrium-90 is a pure beta emitter which decays to stable zirconium-90 with a physical half-
life of 64.2 hours. The average energy of the beta emissions from yttrium-90 is 0.9367 MeV 
with mean tissue penetration of approximately 2.5 mm.  
TheraSphere is administered through the hepatic artery which supplies blood to tumor tissue 
(the portal vein supplies blood to the normal hepatic tissue). The microspheres are trapped in 
the vasculature of the tumor due to arteriolar capillary blockage where they exert a local 
radiotherapeutic effect. In clinical use, the glass microspheres remain permanently trapped in 
the vasculature where the isotope decays to infinity leaving background radiation with no 
therapeutic value.  
2.2        Global Regulatory Status of Therasphere 
 
TheraSphere received a Humanitarian Device Exemption (HDE) from the United States Food 
and Drug Administration (FDA) in 1999 (HDE H980006) and is currently approved for use in 
radiation treatment or as a neoadjuvant to surgery or transplantation in patients with 


 
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unresectable hepatocellular carcinoma (HCC) who can have placement of appropriately 
positioned hepatic arterial catheters. The device is also indicated for HCC patients with 
partial or branch portal vein thrombosis/occlusion, when clinical evaluation warrants the 
treatment. The current US package insert is provided in Appendix 1a.  
TheraSphere is approved for use in Europe for the treatment of hepatic neoplasia. 
TheraSphere is approved in Canada for the treatment of hepatic neoplasia in patients who 
have appropriately positioned arterial catheters. In addition, TheraSphere is available in 
Russia, India, South Africa and Kuwait for the treatment of hepatic neoplasia.  
2.3        Rationale for the Treatment of  Hepatocellular Carcinoma 
 
According to the American Cancer Society, primary liver cancer is a major health problem 
worldwide. [4]  Globally, it is the fifth most commonly diagnosed cancer in men and eighth 
most common in women, with more than 700,000 new cases in 2007. It is the third leading 
cause of cancer death in men and sixth among women. In North America and Western or 
Northern Europe, areas with historically low rates, the incidence of liver cancer is increasing, 
possibly due to increased prevalence of hepatitis C.  
In 2007, the US FDA approved sorafenib tosylate (Nexavar®), a small molecule Raf kinase 
and VEGF receptor kinase inhibitor, for the treatment of patients with unresectable 
hepatocellular carcinoma (HCC). [5] The approval was based on the results of an 
international, multicenter, randomized, double-blind, placebo-controlled trial (SHARP3 trial) 
in patients with unresectable, biopsy-proven hepatocellular carcinoma. [2]  Overall survival 
was the primary efficacy endpoint. A total of 602 patients were randomized; 299 to sorafenib 
400 mg twice daily and 303 to matching placebo. 
Demographics and baseline disease characteristics were similar between the sorafenib and 
placebo groups. Prior treatments included surgical resections (20 %), locoregional therapies 
(including radiofrequency ablation, percutaneous ethanol injection and transarterial 
chemoembolization in 40 percent), radiotherapy (5 %), and systemic therapy (4 %).  
The trial was stopped following a pre-specified second interim analysis for survival 
disclosing a statistically significant advantage for sorafenib [median 10.7 vs. 7.9 months; HR: 
0.69 (95 percent CI: 0.55, 0.87), p= 0.00058]. The final analysis of time-to-tumor progression 
(TTP) by independent radiological review was based on data from an earlier time point and 
demonstrated a statistically significant improvement in TTP in the sorafenib group [median 
5.5 vs. 2.8 months; HR: 0.58 (95 % CI: 0.45, 0.74), p=0.000007]. 
Sorafenib is now suggested as the standard-of-care (SOC) therapy for patients with advanced 
HCC, the patients classified as BCLC C according to the Barcelona Clinic Liver Cancer 
(BCLC) classification system. [6]  Sorafenib is included in the NCCN Clinical Practice 
Guidelines in Oncology (NCCN– Hepatobiliary cancers V.1.2010 – HCC5) as one of the 
possible treatments for patients with unresectable HCC and extensive liver disease who are 
not candidates for transplantation. [7] 
 
 
Although sorafenib is a standard-of-care in the treatment of patients with HCC, it is 
associated with only a modest improvement in median survival as compared to best 


 
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supportive care. Further, sorafenib treatment is associated with significant toxicity. The most 
common adverse reactions3 (≥20 percent) considered related to sorafenib were fatigue, 
weight loss, rash/ desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea 
and abdominal pain. [2]  Diarrhea was reported in 55 percent of sorafenib patients (grade 3 in 
10 %). Hand-foot syndrome (21 percent overall; grade 3 in 8 %) and rash (19 % overall; 
grade 3 in 1 %) were the most common dermatologic adverse reactions to sorafenib. 
Sorafenib dose reductions and drug holidays are often required to manage these toxicities.  
 
Adhoc subset analysis of the SHARP trial data indicated that the efficacy of sorafenib is 
reduced in an important subset of patients with advanced HCC.  [8] In patients with 
extrahepatic spread or macroscopic vascular invasion, the median survival was 8.9 months in 
patients treated with sorafenib as compared to 6.7 months in patients treated with placebo. 
 
The long-term experience of TheraSphere in the treatment in 291 patients with HCC as part 
of a single-center, prospective, longitudinal cohort study were recently reported. [9] A total of 
526 treatments were administered (mean, 1.8; range, 1-5). Toxicities included fatigue (57%), 
pain (23%), and nausea/vomiting (20%); 19% exhibited grade 3/4 bilirubin toxicity. The 30-
day mortality rate was 3%. Response rates were 42% and 57% based on WHO and EASL 
criteria, respectively. The overall TTP was 7.9 months (95% confidence interval, 6-10.3). 
Survival times differed between patients with Child-Pugh A and B disease (A, 17.2 months; 
B, 7.7 months; P = .002). Patients with Child-Pugh B disease who had portal vein thrombosis 
(PVT) survived 5.6 months (95% confidence interval, 4.5-6.7). Baseline age; gender; 
performance status; presence of portal hypertension; tumor distribution; levels of bilirubin, 
albumin, and alpha-fetoprotein; and WHO/EASL response rate predicted survival. These 
investigators concluded that patients with Child-Pugh A disease, with or without PVT, 
benefited most from treatment. Patients with Child-Pugh B disease who had PVT had poor 
outcomes. Therefore, TTP and overall survival varied by patient stage at baseline.  
Results from a separate cohort of 108 consecutive patients with advanced HCC using 
TheraSphere demonstrated a median overall survival from treatment of 16.4 months, with 
median time to progression of 10.0 months. [10] Tumor response at 90 days evaluated by 
RECIST in 62 patients were complete or partial response 10 (16%), stable disease 46 (74%) 
and progressive disease 6 (10%). Toxicities were generally mild to moderate. The most 
common being transient fatigue during the week following administration (61%) and 
abdominal pain (56%).  For patients with normal bilirubin at enrollment, 32% experienced 
Grade 1 or 2 elevations and three patients developed Grade 3 elevations. For patients with 
elevated bilirubin at enrollment, 17% experienced Grade 2 elevations and 30% experienced 
Grade 3 or 4 elevations. In the majority of patients, bilirubin returned to baseline values 
within 4-6 weeks. The conclusion was that Therasphere is safe and effective, even in patients 
with compromised liver function. 
Preliminary results of a Phase II investigation of the safety, tolerability and efficacy of 
administering TheraSphere and Nexavar (sorafenib) treatment in 26 patients with HCC 
indicate that the combination is safe. [11] In this trial, all patients  began sorafenib 400 mg 
BID at least 7 weeks in advance of TheraSphere treatment.Most patients (65%) required 
sorafenib dosage adjustment. The most common toxicities were diarrhea, fatigue and hand 
foot syndrome with most being self-limiting and responsive to sorafenib dose adjustment. 


 
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One single grade 4 toxicity of worsening cirrhosis was observed. Median survival is 15.5 
months which exceeds that reported in the sorafenib or placebo arms of the SHARP study 
(10.7 and 7.9 months respectively). The reported toxicities are consistent with the toxicity 
profile of both TheraSphere and sorafenib with no apparent increase in severity or frequency.  
  
Sorafenib will be given at a dose of 400 mg, orally, twice a day. Possible adverse events 
related to sorafenib include: cardiovascular: hypertension (9% to 17%); central nervous 
system: fatigue (37% to 46%), sensory neuropathy (≤13%), pain (11%); dermatologic: 
rash/desquamation (19% to 40%; grade 3: ≤1%), hand-foot syndrome (21% to 30%; grade 3: 
6% to 8%), alopecia (14% to 27%), pruritus (14% to 19%), dry skin (10% to 11%), erythema; 
endocrine & metabolic: hypoalbuminemia (≤59%), hypophosphatemia (35% to 45%; grade 3: 
11% to 13%; grade 4: <1%); gastrointestinal: diarrhea (43% to 55%; grade 3: 2% to 10%; 
grade 4: <1%), lipase increased (40% to 41% [usually transient]), amylase increased (30% to 
34% [usually transient]), abdominal pain (11% to 31%), weight loss (10% to 30%), anorexia 
(16% to 29%), nausea (23% to 24%), vomiting (15% to 16%), constipation (14% to 15%); 
hematologic: lymphopenia (23% to 47%; grades 3/4: ≤13%), thrombocytopenia (12% to 
46%; grades 3/4: 1% to 4%), INR increased (≤42%), neutropenia (≤18%; grades 3/4: ≤5%), 
hemorrhage (15% to 18%; grade 3: 2% to 3%; grade 4: ≤2%), leukopenia; hepatic: liver 
dysfunction (≤11%; grade 3: 2%; grade 4: 1%); neuromuscular & skeletal: muscle pain, 
weakness, respiratory: dyspnea (≤14%), and cough (≤13%). 
The early reports of serious adverse events possibly associated with the use of TheraSphere 
included death, hepatorenal failure, liver abscess, hepatic encephalopathy, hepatic 
decompensation, radiation hepatitis, radiation pneumonitis, duodenal ulcer, gastrointestinal 
bleeding and cholecystitis. As clinical experience with TheraSphere increased, the pre-
treatment high risk factors associated with these early serious events were identified, leading 
to improved patient selection criteria and thereby lowering the risk of these events occurring. 
These risk factors include infiltrative tumor type, bulk disease (tumor volume >70% or 
nodules too numerous to count), AST or ALT > five times the upper limit of normal, bilirubin 
> 2 mg/dL, tumor volume >50% in the presence of an albumin < 3 g/dL and those in whom 
extra-hepatic shunting to the lungs or gastrointestinal tract cannot be managed through 
standard angiographic techniques. 
For those patients without the pre-treatment high risk factors noted above, TheraSphere is 
very well tolerated, with treatment in the US commonly administered in an outpatient setting. 
Hospitalization for treatment effects associated with TheraSphere administration is rare.  
 
3. Study objectives 
The objective of this study is to evaluate the safety of continuous sorafenib 400 mg twice 
daily followed, after 3-5 weeks, by Yttrium-90 treatment in patients with child-Pugh A, 
BCLC-stage C HCC.   
          Primary objective: 
• Median progression-free survival (PFS) 
          Secondary objectives: 


 
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• Overall survival (OS) 
• Time to radiographic progression (TTRP) 
• To evaluate the safety of the combination of sorafenib and Yttrium-90; 
Adverse events (NCI-CTAE v 4.0)  
•  
Other objectives: 
 
Predictive Biomarkers of response to therapy and survival: will assess pre-treatment 
plasma level of IGF-1 as above, and assess its predictive ability of TTP and OS  
                                              
  
4. Study design 
This is a single-arm phase II clinical trial to evaluate the safety of continuous sorafenib at 400 
mg twice daily followed, after 4 (+/- 1 week) weeks from starting sorafenib, by Yttrium-90 
treatment concomitant with sorafenib, in patients with child-Pugh A, BCLC-stage C HCC. Of 
note, the time between starting sorafenib and Yttrium-90 administration will be 4 weeks 
regardless whether the patient underwent dose reductions or interruptions. Patients will 
continue taking the maximum tolerating dose of sorafenib, with no interruption during and 
after the Yttrium-90 procedures. This is a single-institution study that will be conducted at 
MDACC, Department of GI Medical Oncology and Department of Interventional Radiology. 
No sorafenib interruptions around the procedure will be applied, and only one Y-90 treatment 
only will be performed. 
Study schema: 
----------------------------------------------------------------------------------------------------------> 
 
      
                                               after 4 (+/- 1 wk) weeks 
 
 
 
 
                         
 
 
 
 
5. Study population 
5.1 
Eligibility 
Patients diagnosed with unresectable, measurable HCC, ECOG PS 0 or 1, Child-Pugh status 
A, BCLC class C, who have not received prior systemic anti-cancer treatment or Yttrium-90 
for HCC  may be screened for possible participation. 
Screening 
Start Sorafenib 
 
Continuous 
Y-90 procedure 
Imaging every 8 
weeks after Y-
90 procedure 
Sorafenib 
administration 
continues until patient 
discontinues study 
treatment


 
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5.1.1 
Inclusion criteria 
 
1. Subjects must be able to understand and be willing to sign the written informed 
consent form.  A signed informed consent form must be appropriately obtained prior 
to the conduct of any trial-specific procedure. 
2. Male or female patients ≥ 18 years of age  
3. Life expectancy of at least 12 weeks (3 months). 
4. Patients with histological or cytologically documented HCC (Documentation of 
original biopsy for diagnosis is acceptable if tumor tissue is unavailable) or clinical 
diagnosis by AASLD criteria in cirrhotic subjects is required{Bruix, 2005}. For 
subjects without cirrhosis histological confirmation is mandatory. 
 
5. Patients must have at least one tumor lesion that meets the following criteria: The 
lesion can be accurately measured in at least one dimension according to RECIST  
6. The target lesion(s) has not been previously treated with local therapy (such as 
surgery, radiation therapy, hepatic arterial therapy, chemoembolization, 
radiofrequency ablation, percutaneous ethanol injection or cryoablation). 
7. Patients who have received local therapy, such as surgery, radiation therapy, hepatic 
arterial embolization, chemoembolization, radiofrequency ablation, percutaneous 
ethanol injection or cryoablation are eligible if the previously treated lesions have 
progressed or recurred can be identified as target lesions.  Local therapy must have 
been completed at least 4 weeks prior to the baseline scan.  
8. Patients who have received Yttrium-90 microspheres are not eligible. 
9. Patients who have an ECOG PS  ≤ 1  
10. Patients who are categorized under BCLC-C stage 
11. Cirrhosis grade of Child-Pugh class A. Child-Pugh status should be calculated based 
on clinical findings and laboratory results during the screening period. 
12. The following laboratory parameters: 
a. Platelet count ≥ 60 x 109/L  
b. Hemoglobin ≥ 8.5 g/dL 
c. Total bilirubin ≤ 2.5 mg/dl 
d. Alanine transaminase (ALT) and AST ≤ 5 x upper limit of normal 
e. Serum creatinine ≤ 1.5 x the upper limit of normal  
13. Prothrombin time (PT)-international normalized ratio (INR) ≤ 2.3 or PT ≤ 6 seconds 
above control.  
14. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 
Grade 1 or less at the time of signing the Informed Consent Form (ICF). 
15. Women of childbearing potential must have a negative serum pregnancy test 
performed within 7 days prior to the start of study drug.  Post-menopausal women 
(defined as no menses for at least 1 year) and surgically sterilized women are not 
required to undergo a pregnancy test. 


 
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16. Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 30 days after the last 
dose of study drug.  The definition of adequate contraception will be based on the 
judgment of the principal investigator or a designated associate. 
17. Subject must be able to swallow and retain oral medication. 
 
5.1.2 
Exclusion criteria 
 
1. Main portal vein thrombosis (PVT)  
2. Patients who are eligible for curative treatment (ablation or resection or 
transplantation)  
3. Previous or concurrent cancer other than HCC unless without evidence of disease for 
5 or more years prior to entry, except cervical cancer in-situ, treated basal cell 
carcinoma, or superficial bladder tumor.   
4. Tumor replacement >70% of total liver volume based on visual estimation by the 
investigator OR tumor replacement >50% of total liver volume in the presence of 
albumin <3 mg/dL  
5. Contraindications to angiography and selective visceral arterial catheterization  
6. Any known contraindications to sorafenib including allergic reaction, pill-swallowing 
difficulty, uncontrolled hypertension or history of cardiac disease, significant GI bleed 
within 30 days, metastatic brain disease, renal failure requiring dialysis 
7. Concomitant treatment or within 28 days of  one of the following:  
 
a. Any other systemic anticancer agent other than agents used for cancer prevention  
 
b. Subjects who have used strong CYP3A4 inducers (eg, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort [Hypericum perforatum], 
dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], 
and/or rifabutin) within 28 days before treatment. 
 
c. UGT 1A1 and UGT 1A9 substrates (e.g., irinotecan) 
 
d. P-Gp substrates (e.g., Digoxin)  
 
8. Prior radiation therapy to the liver  
9. Prior systemic therapy for the treatment of HCC, including sorafenib  
10. Any history of symptomatic pulmonary compromise, such as chronic obstructive 
pulmonary disease  
11. Any prior intervention for, or ongoing compromise of, the Ampulla of Vater or 
biliary-enteric anastomosis.  


 
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12. Clinically evident ascites (trace ascites on imaging is acceptable)  
13. Pregnant or breast-feeding patients  
14. A positive serum pregnancy test within 14 days prior to treatment in women of 
childbearing potential  
15. Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure 
> 90 mm Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical 
management. 
16. Active or clinically significant cardiac disease including: 
a. Congestive heart failure – New York Heart Association (NYHA) > Class II. 
b. Active coronary artery disease. 
c. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers 
or digoxin. 
d. Unstable angina (anginal symptoms at rest), new-onset angina within 3 months 
before treatment, or myocardial infarction within 6 months before treatment. 
17. Evidence or history of bleeding diathesis or uncontrolled coagulopathy. 
 
18. Subject with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 2 
or higher within 4 weeks before treatment; any other hemorrhage/bleeding event of 
NCI-CTCAE v4.0 Grade 3 or higher within 4 weeks before treatment. 
19. Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular 
accident (including transient ischemic attacks) within 6 months of informed consent. 
20. Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
21. History of organ allograft. (Including corneal transplant). 
22. Known or suspected allergy or hypersensitivity to any of the study drugs, study drug 
classes, or excipients of the formulations given during the course of this trial. 
23. Any malabsorption condition. 
24. Inability to comply with the protocol and/or not willing or not available for follow-up 
assessments. 
5.1.3 
Excluded therapies and medications, previous and concomitant 
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than sorafenib. 
• Concurrent use of another investigational drug or device therapy (i.e., outside of study 
treatment) during, or within 4 weeks of trial entry (signing of the informed consent 
form). 
• Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with 
heparins and heparinoids. 
o However, prophylactic anticoagulation as described below is allowed: 


 
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 Low dose warfarin (1 mg orally, once daily) with PT-INR ≤ 1.5 x ULN 
is permitted.  Infrequent bleeding or elevations in PT-INR have been 
reported in some subjects taking warfarin while on sorafenib or 
capecitabine therapy.  Therefore, subjects taking concomitant warfarin 
should be monitored regularly for changes in PT, PT-INR or clinical 
bleeding episodes. 
 Low dose aspirin (≤ 100 mg daily). 
 Prophylactic doses of heparin. 
5.2 
Withdrawal of subjects from study 
Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons:  
• Subject withdraws consent from study treatment and study procedures.  A subject 
must be removed from the trial at his/her own request or at the request of his/her 
legally acceptable representative.  At any time during the trial and without giving 
reasons, a subject may decline to participate further.  The subject will not suffer any 
disadvantage as a result. 
• Subject is lost to follow-up. 
• Death. 
 
Subjects may be withdrawn from the study for the following reasons: 
• The subject is non-compliant with study drug, trial procedures, or both; including the 
use of anti-cancer therapy not prescribed by the study protocol. 
• Pregnancy.  Pregnancy will be reported as an SAE.  (Note: subjects who have been 
withdrawn from treatment with study drug because of pregnancy should not undergo 
CT scans [with contrast]/MRI or bone scans while pregnant.) 
• If, in the investigator's opinion, continuation of the trial would be harmful to the 
subject's well-being. 
• Severe allergic reaction to sorafenib (such as exfoliative erythroderma or Grade 3 or 
4 hypersensitivity reaction). 
• The development of a second cancer.  
• Development of an intercurrent illness or situation which would, in the judgment of 
the investigator, significantly affect assessments of clinical status and trial endpoints. 
• Deterioration of ECOG performance status to 4. 
• Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity or otherwise skewing trial result. 
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable. 


 
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In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's 
medical records. 
Details for the premature termination of the study as a whole (or components thereof 
[e.g. centers, treatment arms, dose steps]) are provided in Section 10 (Premature termination 
of the study).Screen Failures/Dropouts 
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already assigned to treatment/run-in/wash-out; administered at 
least one dose of study drug. 
A subject who discontinues study participation for reasons other than toxicity after receiving 
sorafenib but not the Y-90 procedure is inevaluable and will be replaced. Subjects who are 
discontinued from the study early due to toxicities will be counted in the toxicity assessment. 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see above) is regarded a 
“screening failure”. Replacement 
No withdrawn subjects will be replaced.  
6. Treatment[s] 
6.1 
Treatments to be administered 
6.2 
Sorafenib Dosage and administration 
Include the following regarding sorafenib therapy: 
Subjects will be instructed on the proper administration of sorafenib.  Sorafenib tablets should 
be taken 12 hours apart, at approximately the same time each morning and evening.  
Sorafenib tablets should be taken without food, at least 1 hour before or at least 2 hours after 
a meal, and with up to 240 mL (approximately 1 cup or 8 oz) of water.  Consumption of 
grapefruit and grapefruit juice should be avoided while receiving study drug. 
Sorafenib tablets are manufactured by Bayer HealthCare.  The 200-mg tablet formulation 
contains sorafenib tosylate and the excipients croscarmellose sodium, microcrystalline 
cellulose, hypromellose, sodium lauryl sulfate, and magnesium stearate.  The tablets have a 
film coating comprised of hypromellose, polyethylene glycol, titanium dioxide, and red ferric 
oxide, which has no effect on the release rate of the active ingredient, sorafenib tosylate.  The 
tablets are un-debossed, salmon colored, weigh approximately 350 mg each, and are 10 mm 
(millimeter) round in shape.  
The chemical name for sorafenib tosylate is 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-
ureido] -phenoxy}-pyridine-2-carboxylic acid methylamide-4-methylbenzene-sulfonate, and 
its molecular weight is 637 daltons.  The structure of sorafenib is depicted in Figure 6-1. 


 
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Figure 6-1: Structure of Sorafenib (BAY 43-9006) 
Sorafenib tablets do not need to be protected from light.  They are sufficiently stable with 
regard to light, oxidation, thermal stress, and hydrolytic degradation.  The formulation is 
presented as an immediate release (IR) dosage form, i.e., the active ingredient is completely 
dissolved under in vitro test conditions within a short period of time.Dose Modification for 
management of adverse events 
6.2.1.1 Dose Reduction Levels 
The starting dose of sorafenib is 400 mg twice a day.  Study medication will be 
administered daily on a continuous basis. 
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protocol therapy according to the guidelines shown in the Dose 
Delays/Dose Modifications table that follows.  Dose modifications will follow predefined 
dose levels: Dose adjustments for hematologic toxicity are based on the blood counts 
obtained in preparation for the day of treatment. 
Table 1: Dose modification levels for sorafenib 
Dose 
Sorafenib 
Starting Dose 
400 mg twice daily 
-1 
400 mg once daily 
-2 
400 mg every other day 
 
6.2.1.2 Dose modification for hematologic toxicities 
Recommended Dose Modification for Hematologic Toxicities [Table 2] 
Toxicity 
ANC/AGC 
(x 109/L) 
Hemoglobin 
(g/dL) 
Platelets 
(x 109/L) 
Sorafenib 
Grade 1 
≥ 1.5 
< LLN – 10.0 
≥75 
Treat on time 


 
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No change 
Grade 2 
≥ 1.0  to < 1.5 
< 10.0 – 8.0 
≥ 50 to < 75 
Treat on time 
No change 
Grade 3 
≥ 0.5  to < 1.0 
< 8.0 – 6.5 
≥ 25 to < 50 
Treat on time 
Reduce by one 
dose level 
Grade 4 
< 0.5 
Life-threatening 
consequence; 
urgent 
intervention 
indicated 
<25 
Delay sorafenib 
until toxicity 
resolves to Grade 2 
or less then 
Reduce by two 
dose levels 
Febrile 
Neutropenia 
 
 
 
Sorafenib held 
until toxicity has 
resolved to Grade 
2 or less; when 
sorafenib is 
restarted, reduce 
by one dose level 
ANC - absolute neutrophil count ; AGC - absolute granulocyte count 
• If no recovery after 30 day* delay, treatment should be permanently discontinued 
unless treating physician determines subject is deriving clinical benefit. 
       * Modify according to study specific cycle length. 
 
6.2.1.3 Dose modification for non-hematologic toxicities 
Table 3:  Recommended dose modification for non-hematologic toxicity 
(excluding hypertension and hand foot skin reaction, diarrhea and fatigue. 
Grade 
Dose Interruption 
Dose Modification 
Grade 0-2 
Treat on time 
No Change 
Grade 3 
Interrupt until ≤Grade 2 
DECREASE one dose level 
Grade 4 
OFF protocol therapy  
OFF protocol therapy 
• If no recovery after 30 day* delay, treatment will be discontinued unless subject is 
deriving clinical benefit 
       * Modify according to study specific cycle length. 
 
6.2.1.3.1 Prevention/management strategies for diarrhea and fatigue 
Diarrhea and fatigue are common side effects of sorafenib.  The same dose-modification 
algorithm used for skin toxicities can be used to address these toxicities.  However, the 


 
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preventive/management strategies for diarrhea and fatigue should be consistent with local 
standards (e.g., anti-diarrheals and optimized hydration status for diarrhea). 
6.2.1.4 Hand-foot-skin reaction 
 
Table 4: Recommended dose modification for hand foot skin reaction 
Toxicity Grade 
Suggested dose modification 
Grade 1 
Any occurrence 
Maintain dose level and consider topical therapy 
for symptomatic relief 
Grade 2 
1st occurrence 
Maintain dose level and consider topical therapy 
for symptomatic relief 
If no improvement within 7 days, see below 
 
No improvement 
within 7 days or 2nd 
occurrence  
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by one 
dose level 
 
3rd occurrence  
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by two 
dose levels 
 
4th occurrence 
Discontinue treatment permanently 
Grade 3 
1st occurrence 
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by one 
dose level 
 
2nd occurrence 
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by two 
dose levels 
 
3rd occurrence 
Discontinue treatment permanently 
 
At first occurrence of HFSR, independent of grade, prompt institution of supportive 
measures such as topical emollients, low potency steroids, or urea-containing creams 
should be administered. 
Recommended prevention/management strategies for skin toxicities consistent with HFSR 
are summarized below. 


 
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Table 5:  Recommended Prevention/Management Strategies for Skin Toxicities 
Consistent with Hand-Foot-Skin-Reaction 
Toxicity Grade 
Practical Prevention / Management Strategies for 
HFSR  
Grade 0 (Preventive strategies) 
• Maintain frequent contact with trial physician to 
ensure early diagnosis of HFSR. 
• Practical prevention strategies 
o Pedicurea for subjects with pre-existing 
hyperkeratosis. 
o Subjects should avoid hot water, and clothing or 
activities that can cause friction on the skin. 
o Moisturizing cream should be applied sparingly. 
• Padded gloves and open shoes with padded soles 
should be worn to relieve pressure points. 
Grade 1  
Any occurrence 
• Continue preventive strategies and in addition: 
o Soak hands in cool water. 
o Apply petroleum jelly to moist skin. 
• In the case of hyperkeratotic lesions, exfoliate the 
hands or feet and apply moisturizing cream 
immediately afterwards. 
Grade 2 Any occurrence or 
Grade 3 Any occurrence 
• Continue supportive/management measures and add 
analgesic(s) for pain. 
a:  Pedicure should be done by a podiatrist. 
 
6.2.1.5 Treatment-emergent hypertension 
Hypertension is a known and potentially serious AE associated with sorafenib treatment. 
Subjects will check blood pressure at home, on a weekly basis through the first 4 weeks of 
therapy.  Thereafter, blood pressure will be monitored on Day 1 of each cycle. Subjects with 
pre-existing hypertension will monitor blood pressure at home daily basis. 
Blood pressure measurements that are out of the normal range must be reported by the 
treating physician..  Blood pressure measurements considered out of the normal range are 
diastolic pressure > 90 mm Hg and/or systolic pressure > 140 mm Hg, or a  20 mm Hg 
increase in diastolic pressure if the previous measurement was within normal limits. 
The dose-modification schedule to be followed in the event of treatment-emergent 
hypertension is outlined below.  The choice of anti-hypertensive medication to be used in 
cases of treatment-emergent hypertension will be at the investigator's discretion and based on 
site-specific treatment guidelines as applicable.  All anti-hypertensive medications used for 


 
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the management of treatment-emergent hypertension should be recorded in the subject’s 
records. 
Once a dose-reduction modification has been made for treatment-emergent hypertension, NO 
dose re-escalation will be allowed. 
 
Table 6:  Management of Treatment-Emergent Hypertension 
Grade of Event (NCI-CTCAE v4.0) 
Management/ Next Dose 
Grade 1 
Consider increasing blood pressure monitoring.  
Continue sorafenib dosing as scheduled. 
Grade 2 asymptomatic and diastolic 
pressure 90-99 mm Hg  
Begin anti-hypertensive therapy.  Continue 
sorafenib dosing as scheduled. 
Grade 2 (symptomatic/persistent) 
OR 
Grade 2 symptomatic increase by > 
20 mm Hg (diastolic) or to > 140/90 
mm Hg if previously within normal 
limits 
OR  
Grade 3 
Sorafenib should be helda until symptoms resolve 
and diastolic blood pressure < 90 mm Hg; also 
treat subject with anti-hypertensives and when 
sorafenib is restarted, reduce by 1 dose level.b 
If diastolic blood pressure is not controlled (< 90 
mm Hg) on anti-hypertensive therapy, reduce 
another dose level.b 
Grade 4 
Discontinue sorafenib 
a:  Subjects requiring a delay of > 30 days (modify according to study specific cycle length) 
should discontinue sorafenib unless, in the opinion of the treating physician, the subject 
may benefit from continued treatment. 
b:  Subjects requiring dose reductions beyond 400 mg once daily, every other day, should 
discontinue sorafenib. 
6.3 TheraSphere 
 
 
TheraSphere treatment is performed in the outpatient setting. Prior to initial treatment, a 
Technetium-99 Macroaggregated Albumin (Tc-99m MAA) scan will be performed using 
standard institutional practices.  If there is an uncorrectable risk of flow to the gastrointestinal 
organs or risk of excessive shunting to the lungs, TheraSphere treatment will not be 
administered and the patient will receive alternative or no treatment as previously defined in 
the treatment plan  
 
Following treatment, patients will remain at the hospital under medical observation until the 
physician determines that they can safely be discharged to home (usually 2-6 hours). All 
patients will be evaluated post-treatment to assess clinical experience and adverse 
experiences.   
 


 
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Patients will have 1-2 outpatient visits for pre-treatment evaluation to determine initial 
eligibility to receive TheraSphere, followed by a treatment visit for outpatient delivery of 
TheraSphere,. 
 
Catheters will be placed in the hepatic artery in the angiography suites.  No scheduled 
hospitalizations will be required, unless the physician determines that the patient should be 
admitted following treatment for management of a complication or adverse experience. 
 
Pre-Therasphere Evaluation 
 
Pre-treatment evaluation will include the initial screening by history, physical examination, 
laboratory and diagnostic studies (hepatic angiography and Tc-MAA Scan).  A treatment plan 
will be developed, dosage will be calculated, and the initial TheraSphere activity vial will be 
ordered from the manufacturer (Nordion). 
 
 
 
Diagnostic Imaging Studies 
 
Contrast enhanced Computed Tomography Scanning of the Abdomen/Liver or Magnetic 
Resonance Imaging of the Abdomen/Liver 
 
Technetium-99 Macroaggregated Albumin (Tc-99m MAA) Scan.  
 
CT or MR scanning of the liver will be performed and the images used to calculate 
the appropriate liver volume for TheraSphere dose determination.  Reasonable 
attempts will be made to use the same imaging modality as that used for pre-treatment 
for all subsequent evaluations of the patient related to dose determination. 
 
The dose is calculated as described below (Section 7.3.3.4), using the appropriate 
reference liver volume and mass.  Dosimetric techniques for TheraSphere are 
discussed in detail in the peer-reviewed literature.  
 
The imaging scan is used to document the location and size of the hepatic lesion(s) 
and vascular anatomy where possible. 
 
Prior to first TheraSphere treatment a Tc-99m MAA scan will be performed to 
obtain a preliminary assessment of hepatic infusion and any potential 
extrahepatic shunting or gastrointestinal flow.  Lung Shunt Fraction will be 
determined as the ratio of total lung counts divided by total hepatic plus lung 
counts. 
 
If gastrointestinal flow is detected, steps will be undertaken (embolization, 
change in catheter position) to correct this flow, prior to TheraSphere 
administration.  If gastrointestinal flow cannot be corrected using established 
angiographic techniques, the patient may not receive TheraSphere treatment. 


 
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Only after extrahepatic exposure has been evaluated and the patient deemed to 
meet eligibility criteria, may TheraSphere be administered.  
 
To be eligible to receive TheraSphere treatment, the potential absorbed dose to the 
lungs must be < 30 Gy (< 16.5mCi of injected activity) per treatment. Any 
uncorrected detectable gastrointestinal flow is a contraindication to TheraSphere 
treatment. 
 
Treatment Planning  
The principal investigator with the Authorized User will formulate the initial 
treatment plan, indicating the number and sequence of planned TheraSphere 
treatments. The clinician will assure that the patient understands the two-stage 
screening process that is necessary for this treatment procedure.  The physician and 
patient will discuss and agree on a contingency treatment plan, including the option of 
no treatment, in the event that the patient is found ineligible to receive TheraSphere 
after catheter placement. The Treatment Plan may be modified following initial 
treatment, based on clinical experience and patient response to treatment.   
 
 
 
TheraSphere Dose Calculation  
The target dose of TheraSphere used is 80 – 150 Gy.  Depending on the timing of the product 
order relative to the TheraSphere production schedule, and the treatment date proposed for the 
patient, it may be necessary to allow TheraSphere to physically decay to the appropriate 
targeted activity before injection. 
 
The amount of radioactivity required to deliver the dose to the selected liver target is 
calculated using the following formula: 
 
Activity Required (GBq) = [Desired Dose (Gy)][ Mass of Selected Liver Target (kg)] 
                50   
 
In nearly all cases more than 95% of the glass microspheres are delivered. Calculation of the 
liver dose (Gy) delivered after injection uses the following formula: 
 
Dose (Gy) =     50 [Injected Activity (GBq)][1-F][1-R] 
 
 
Mass of Selected Liver Target (kg) 
 
Where F is the fraction of injected activity deposited into the lungs as measured by Tc-99m 
MAA and R is the calculated residual.  
 
 
TheraSphere Ordering 
The TheraSphere order will be placed by the Authorized User or designated colleague. Upon 
completion of the pre-treatment screening evaluation, treatment plan and dose calculation, a 
TheraSphere order form will be sent to TheraSphere Customer Support, either by E-mail to 
TheraSphereCustomerSupport@mdsinc.com or by fax to 1-800-268-5299).  The deadline for 
order is the Tuesday prior to calibration date to permit inclusion of your order in the weekly 
dispensing cycle.  


 
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TheraSphere is viable for therapeutic use for up to 12 days after the calibration date.  
TheraSphere will be shipped by MDS Nordion to ensure that TheraSphere is on-site by the 
proposed treatment date.  To meet the desired absorbed dose to the patient’s liver, the 
clinician must schedule the patient’s TheraSphere treatment visit to occur within 12 days of 
the calibration date, and take into consideration the appropriate physical decay of the dose 
activity.  
 
6.4 Procedures on Day of Treatment 
 
Treatment with TheraSphere may be performed in the outpatient setting.  The 
following sections describe the procedures performed on day of treatment.  
 
Catheter Placement and TheraSphere Infusion 
 
The goals of percutaneous catheter placement for TheraSphere administration are: first, to 
limit the perfusion to the normal liver, and, second, to deliver TheraSphere as specified in the 
treatment plan.  
  
On the day of treatment, TheraSphere is administered via infusion under imaging 
guidance through an hepatic arterial catheter appropriately positioned in the arterial 
anatomy to permit selective infusion of TheraSphere into the target tissue selected for 
treatment.  The interventional radiologist will perform this procedure.  The patency of the 
catheter will be maintained using standard techniques.Administration of TheraSphere 
Regardless of catheter size or infusion pressure used, the flow of the microspheres will 
mimic the flow dynamics of the vessel being infused. 
 
The TheraSphere administration procedure is described in the TheraSphere package insert  
and in peer-reviewed literature.Patient Management 
Following treatment, the patient will remain under observation consistent with standard care 
guidelines for aftercare procedures involving arterial catheterization.  The patient will be sent 
home when the physician determines that the patient is stable and that there is no risk of 
bleeding from the access site.  At the time of discharge, patients will be instructed per 
institutional guidelines regarding after-care including instructions if they develop a problem.  
 
Because there may be small unrecognized arterial vessels connecting to the gastrointestinal 
system, prophylactic anti-ulcer medication is recommended at discharge. Gastric coating 
agents and tapering 5 day steroid dose pack (to reduce fatigue unless contraindicated) may 
also be given. 
 
Special radiation isolation procedures are not necessary following TheraSphere 
treatment. 
 
 
 


 
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6.5 Radiation Safety in the Post-Treatment Period 
 
If a patient receives a liver transplant or dies in the immediate period following treatment with 
TheraSphere, radiation safety guidelines for handling of the body and/or body tissues should 
be followed, as dictated by institutional radiation safety policy. 
 
There are no federal regulations that clearly address the radiation safety issues related to 
handling of liver tissue following TheraSphere treatment.  The surgeon and oncologist 
will consider the risks and benefits of the clinical circumstances and relevant institutional 
policy, before determining whether, and when, it is safe to proceed with procedures that 
require direct handling of TheraSphere-treated liver tissue in the immediate post-
treatment period. 
Most patients have surface dose rates <20µSv/h at 30 days following treatment. Generally 
a patient skin surface dose rate of < 20µSv/h does not require special handling (such as 
lead gloves, special instruments and extremity radiation monitors) by the surgeon during 
the operation. Notify radiation safety personnel for transportation and storage of the 
explanted tissue. 
Very small amounts of longer-acting radioactive by-products have been noted. These by-
products are well within known toxicity levels but may present some post-mortem tissue 
handling issues. Some regulatory jurisdictions are developing policies regarding handling of 
long lived by-products post mortem, specifically in regards to cremation; relevant institutional 
policy should be considered.  
 
Travel documentation may be offered to patients who need to cross international borders, as 
the long lived activity may be detectable with the sensitive equipment at some facilities. 
 
6.6 Device Dosages 
 
The target dose of TheraSphere used is 80 – 150 Gy.    Standard radiation safety techniques 
should be used.  
 
Glass microspheres are typically 20-30 micrometers (µm) in diameter, or about 3-4 times the 
size of a red blood cell.  In a report of 420 independent pre- and post treatment angiographic 
observations, macroscopic embolization of the hepatic arteries was not observed indicating 
hepatic perfusion is maintained. 
 
7. Procedures and variables 
7.1 
Schedule of procedures 
 


 
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7.1.1 
Tabulated overview  
CLINICAL AND LABORATORY EVALUATIONS [Table 7] 
 
Pre- 
Study@ 
Cycle 1, 
Day 1 
Cycle 2  & 
Subsequent  
Cycles 
 Day 1f, # 
End of 
Cycle3, 5, 
& every 
2 cycles# 
End of 
Treatment
# 
Post Treatment 
Follow-up 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
 
X 
 
X 
 
Concurrent Medications* 
X 
 
X 
 
X 
 
Physical Exam 
X 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
Vital Signs (Includes 
SBP/DBP) 
X 
X 
X 
 
X 
 
Urinalysis w/urine protein 
X 
 
 
X 
X 
 
Performance status 
X 
 
X 
 
X 
 
Hepatitis profilei 
X 
 
 
 
 
 
PT/PTT/INRa 
X 
 
X 
 
X 
 
CBC with differential, platelets 
X 
 
X 
 
X 
 
Serum chemistry 
b 
X 
 
X 
 
X 
 
Liver function tests 
c 
X 
 
X 
 
X 
 
ECG 
X 
 
 
 
 
 
ß-HCG (women of child-
bearing potential) 
X 
 
 
 
 
 
AFP
d 
X 
 
X 
 
X 
 
CT/MRI abdomen and pelvis 
Tumor Assessment 
e 
X 
 
 
X 
X 
 
TheraSphere 
 
Therapy 4 (+/- 1) weeks after starting Sorafenib  
Sorafenib 
 
Daily continuous 400 mg, orally, twice a day 
Adverse events 
Xg 
 
X 
 
X 
 
Survival 
 
 
 
 
 
Xh 
Plasma samplesj 
X 
X 
Cycles 2, 
3, day of 
Y-90 
 
X 
 
 
@ Pre-study evaluations except for imaging studies, Hepatitis profile must be obtained within 
7 days prior to first day of treatment. Baseline imaging studies may be obtained up to 28 days 
prior to first day of treatment. Hepatitis profile must be obtained within 3 months prior to first 
day of treatment 
 
# Evaluations may be obtained within (+/-) 72 hours of starting a new cycle, except for 
imaging studies which may be obtained within 7 days prior to starting a new cycle.   
*All medications, including prescription and over-the-counter, vitamins, supplements and 


 
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"herbal" preparations must be disclosed by the patient and recorded.  Patients will be 
instructed to check with study staff before taking any new prescription or over-the-counter 
medication(s), vitamins, supplements and/or “herbal" preparations 
a Weekly monitoring of INR for patients on warfarin, however, these patients will be 
switched to enoxaparin if possible. 
b Includes BUN, creatinine, sodium, potassium, carbon dioxide, chloride, phosphorus, 
magnesium. calcium, protein, glucose. 
c Includes AST (SGOT), ALT (SGPT); total, direct and indirect bilirubin; LDH, alkaline 
phosphatase, albumin; (GGT will be run for alkaline phosphatase that is >/= 150 IU/L.  GGT 
will be run with the first elevation of alkaline phosphatase and will not be repeated for future 
alkaline phosphatase elevations) 
d Alpha-feto protein. 
e CT will be the radiographic study of choice for baseline (CT of the chest is included at 
baseline) and re-staging evaluations (CT of the chest may be included if needed in re-
staging); MRI may be substituted at any time in the course of the study as clinically 
warranted (eg iodine dye intolerance, elevated creatinine, tumor not clearly depicted on CT)  
f Treatment may continue after Course 2, including the same study assessment schedule, until 
one of the criteria for treatment discontinuation applies.   
g Patients who have an ongoing Grade ≥ 3 or serious adverse event that is at least possibly 
related to treatment will be contacted by the investigator or designee every week until the 
event is resolved or determined to be irreversible. 
h Every 3 months after discontinuation of treatment 
i  Hepatitis profile to include the following tests:  hepatitis B virus surface antigen (HBSAG), 
hepatitis B virus core antibody (HBCAB), and hepatitis C virus antibody (HCVAB).  
j Samples Collection:  Blood samples will be collected at the time of patients’ scheduled visits 
as follows:Procedure for samples collection: 
 
GI Medical oncology Research Staff will inform blood draw station to collect an extra set of 
blood sample (3 ml purple top tube with EDTA) for the purpose of the study, on the day of 
the patient’s initial visit and per scheduled samples collection per protocol. at the GI Medical 
Oncology clinic visits. Collection times will correspond to those at which subjects are already 
having blood drawn for other purposes. Maximum blood draws would be 6 total(1) 
Screening; (2) Cycle 1/Day 1; (3) Cycle 2/Day 1; (4) Cycle 3/Day 1; (5) Pre-Yttrium-90, on 
the same day; and (6) End of Treatment. Once blood is collected, GI Medical Oncology 
research personnel will pick it up and deliver it to the laboratory of Dr. Manal Hassan and Dr. 
Donghui LiSRB1 for processing in batch and storage in freezer in -80 F. Processing will 
involve isolating plasma samples.Cycle 1/Day 1 sample will be collected only if Screening 
sample was collected more than 7 days prior. Pre-Yttrium-90 sample will be collected only 
if Cycle 2/day 1 sample was collected more than 7 days prior. And vice versa, Cycle 2/Day 1 
sample will be collected if Pre-Yttrium-90 sample was collected more than 7 days prior.  
Samples will each be labeled according to the sample label listed below.   
 
Sample label or per Z code labeling 


 
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Protocol #                       
Subject Accession # -                                    
Date/Time prepared - 
 
7.1.2 
Timing of assessments 
One cycle is defined as 4 weeks of sorafenib therapy. Patients will be evaluated 
for toxicity every 4 weeks after start of study drug. This may include the 
sorafenib treatment and Y-90 procedure since the Y-90 procedure may be 
performed 4 weeks (+/- 1 week) after start of sorafenib treatment. 
7.1.3           Medical history 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected: 
• Not pertaining to the study indication 
• Start before signing of the informed consent  
• Considered relevant to the study. 
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 7.4.1.1. 
7.2 
Efficacy 
Time to tumor progression will be determined by CT or MRI imaging of index lesion(s). 
Baseline imaging will be obtained within 4 weeks prior to study entry and at the beginning of 
every alternate cycle i.e., every 2 cycles (= 8 weeks), after Yttrium-90 treatment. 
7.3 
Pharmacokinetics / pharmacodynamics 
None 
7.4 
Safety 
All subjects who receive at least one dose of study treatment will be valid for the safety 
analysis.  
All observations pertinent to the safety of the study treatment will be recorded and included 
in the final report. 
Safety variables include the following: AEs, laboratory changes (complete blood counts, 
electrolytes, chemistry, and coagulation), changes in vital signs (blood pressure, heart rate, 
respiratory rate, and temperature) and ECG at the investigator’s discretion . 
All AEs whether considered drug-related or not, will be reported in  with a diagnosis, 
start/stop dates, action taken, whether treatment was discontinued, any corrective measures 


 
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taken, outcome, and other possible causes.  For all events, the relationship to treatment and 
the intensity of the event will be determined by the investigator. 
This trial will use the NCI-CTCAE v4.0 criteria for assessment of toxicity and SAE reporting 
with regard to toxicity grade. 
7.4.1 
Adverse events 
Investigators should refer to the Safety Information section of the current IB for sorafenib, 
including the DCSI (development core safety information), for the expected side effects of 
sorafenib.  As with any agent, there is always the potential for unexpected AEs, including 
hypersensitivity reactions.  The IB will be updated if any new relevant safety data are 
obtained. 
Therapeutic monitoring should be performed following dose selection or modification of 
sorafenib in a manner consistent with the local clinical standard of care.  In general, subjects 
should be closely monitored for side effects of all concomitant medications regardless of the 
path of drug elimination. 
All concomitant medications must be recorded in the subject’s source documentation. 
Subjects must be carefully monitored for AEs.  This monitoring also includes significant 
changes to clinical laboratory test results.  Adverse events should be assessed in terms of their 
seriousness, intensity, and relationship to the study drug, or other chemotherapy/treatment. 
7.4.1.1 Definitions 
Definition of adverse event (AE) 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a 
patient or clinical investigation subject after providing written informed consent for 
participation in the study.  Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. 
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as AE (however, the condition for which the surgery is 
required may be an AE if the condition worsens compared to baseline). 
The clinical manifestation of any failure of expected pharmacological action (lack of efficacy) 
is not recorded as an AE if it is already reflected as a data point captured in the CRF.  If, 
however, the event fulfills any of the criteria of an SAE, it must be recorded as and AE and 
reported as an SAE. 
 
• Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints). 


 
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• Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis). 
• Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. 
Definition of serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
a. Results in death. 
b. Is life-threatening. 
The term ‘life-threatening’ in the definition refers to an event in which the patient 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization. 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met: 
- The admission results in a hospital stay of less than 12 hours. 
- The admission is pre-planned.  
(i.e. elective or scheduled surgery arranged prior to the start of the study) 
- The admission is not associated with an AE. 
(e.g. social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence. 
d. Results in persistent or significant disability / incapacity. 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
e. Is a congenital anomaly / birth defect. 
f. Is another medically important serious event as judged by the investigator. 
7.4.1.2 Classifications for adverse event assessment 
The following classifications should be used: 
• Seriousness 
 
• Intensity 
As an alternative to the grading system described in the standard text below 


 
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(mild, moderate, severe), other systems for intensity may be used (e.g. 
CTCAE, Grade 1 to Grade 5).  If used, this needs to be stated and definitions 
of the grades should be provided.  If applicable, a “translation” between the 
CTCAE system and the standard system of intensity grading may have to be 
provided. 
 
• Causal relationships to study drug: 
 
To be assessed separately for concomitant agents 
 
 
 
 
 
 
• Study treatment action 
 
• Other specific treatment of AE 
 
• Causal relationship to protocol-required procedures(s) 
 
• Outcome 
 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
7.4.1.2.1 Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 7.4.1.1. 
7.4.1.2.2 Intensity 
The intensity of the AE is classified according to the CTCAEv4.0.  Grade refers to the 
severity (intensity) of the AE: 
CTCAEv4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated. 
CTCAEv4 Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; 
limiting to age-appropriate instrumental activities of daily living (ADL; instrumental 
ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc). 
CTCAEv4 Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization is indicated; disabling; limiting to 
self care ADL (self care ADL refers to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden). 
CTCAEv4 Grade 4: life-threatening consequences; urgent intervention is indicated. 
CTCAEv4 Grade 5: death due to an AE. 


 
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7.4.1.2.3 Causal relationship  
The assessment of the causal relationship between an AE and the administration of treatment 
is a clinical decision based on all available information. 
The causality assessment should be done separately for each study treatment. 
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question. 
Possible answers are “yes” or “no”. 
An assessment of “no” would include: 
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at surgical 
site. 
or 
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration. 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is associated 
with the use of the study treatment. 
Factors to be considered in assessing the relationship of the AE to study treatment include: 
- The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event. 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re-
challenge): 
- Subject’s response after de-challenge or subjects response after re-challenge should be 
considered in the view of the usual clinical course of the event in question. 
- Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have. 
- Concomitant medication or treatment:  
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them may be suspected to cause the event in 
question. 
 [Causal relationship to protocol-required procedure(s)] 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s). 
Possible answers are “yes” or “no”. 


 
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7.4.1.2.4 Action taken with study treatment  
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
 
The study treatment action should be recorded separately for each study treatment. 
 ־Drug withdrawn 
 ־Drug interrupted 
 ־Dose reduced 
 ־Dose not changed 
 ־Dose increased 
 ־Not applicable 
 ־Unknown 
7.4.1.2.5 Other specific treatment(s) of adverse events 
 ־None 
 ־Remedial drug therapy 
 ־Other 
7.4.1.2.6 Outcome 
The outcome of the AE is to be documented as follows:  
 ־Recovered/resolved 
 ־Recovering/resolving 
 ־Recovered/resolved with sequelae 
 ־Not recovered/not resolved 
 ־Fatal 
 ־Unknown 
7.4.1.3 Assessments and documentation of adverse events 
7.4.1.4 Reporting of serious adverse events 
The definition of serious adverse events (SAEs) is given in Section 7.4.1.1. 
Each serious adverse event must be followed up until resolution or stabilization, by 
submission of updated reports to the designated person. An isolated laboratory abnormality 
that is assigned grade 4, according to CTC definition, is not reportable as an SAE; unless the 
investigator assesses that the event meets standard ICH criteria for an SAE.  CTC grade 4 
baseline laboratory abnormalities that are part of the disease profile should not be reported as 


 
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an SAE, specifically when they are allowed or not excluded by the protocol 
inclusion/exclusion criteria.   
 
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities.  
 
All serious adverse events should be reported to Bayer within 24 hours.  In the event of such 
an event, the investigator should refer to the Pharmacovigilance section of the contract for 
reporting procedures. 
 
The Investigator may report serious adverse drug reactions (SADRs) using either: 
 
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html   
 
OR 
  
 A MedWatch form available at http://www.fda.gov/medwatch/  
 
All reports shall be sent electronically to:  
 
Electronic Mailbox:  
DrugSafety.GPV.US@bayer.com  
 
Facsimile:    
 
(973) 709-2185  
 
Address: 
 
Global Pharmacovigilance - USA  
Mail only: 
 
Bayer HealthCare Pharmaceuticals Inc. 
P.O. Box 1000  
Montville, NJ 07045-1000  
 
Address:   
 
340 Changebridge Road  
FDX or UPS only   Pine Brook, NJ  07058  
 
Reports for all Bayer products can also be phoned in via our Clinical Communications 
Dept:  
 
Phone:  
 
1-888-842-2937 
7.4.1.5 Expected adverse events 
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB) / summary of product characteristics. 


 
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7.4.2 
Pregnancies 
The investigator must report to Bayer any pregnancy occurring in a study subject, or in his 
partner, during the subject’s participation in this study.  The report should be submitted 
within the same timelines as an SAE, although a pregnancy per se is not considered an SAE.   
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
abnormal outcome of the mother or the child should be reported. 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 
Progressive disease 
If progressive disease leads to signs and symptoms that meet the criteria for an SAE 
(i.e., hospitalization, disability, death, or important medical event), the signs and symptoms 
should be reported as an SAE and not the underlying progressive disease. 
Death 
If any subject dies during the trial or within 30 days of the end-of-treatment visit, the 
investigator will inform Bayer and record the cause of death in detail (using the SAE Form) 
within 24 hours. 
7.5 
Other procedures and variables 
7.6 
Appropriateness of procedures / measurements 
The assessments described in the previous sections are widely used and generally recognized 
as reliable, accurate, and relevant for determining the safety and efficacy of therapies in this 
disease. 
8. Statistical methods and determination of sample size 
8.1 
Statistical and analytical plans 
Statistical consideration for 2012-0870: study of sorafenib plus theraspheres for extrahepatic 
hepatocellular carcinoma (redesign, 20 patients have enrolled in study 2012-0870) 
 
This is a phase II study of sorafenib plus theraspheres for extrahepatic hepatocellular 
carcinoma (EHC). The primary objective is to evaluate the progression-free survival (PFS), 
where the progression-free survival will be measured from the start of therapy until failure to 
disease progression or death.  
 
Historical data showed that the median PFS was 4.1 months for EHC patients treated with 
sorafenib alone. We expect that the combination treatment would improve the PFS.   A 
maximum of 40 will be recruited for the study at a rate of 1-2 patients per month. The study 
will monitor toxicity and futility.    
 
Futility monitoring 


 
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The primary endpoint PFS will be monitored using the method of Thall et al. (2005), and we 
will stop enrolling patients to the study if, based on the available data, we have little reason to 
believe that the median PFS of the combination therapy (mE) is more than that of sorafenib 
alone (mS) in the historical data, which was 4.1 months. Formally, we’ll stop the study early 
if  
 
Prob(mE > mS |data) < 0.15    
 
That is, if there is less than 15% chance the median PFS of the combination therapy is more 
than that of sorafenib, the trial will be stopped. Where mS represents the median PFS for  
sorafenib alone in the historical data with an inverse gamma distribution  IG(11, 41), which 
corresponds to a mean of 4.1 months and a variance of 1.87. mE  represents the median PFS 
for the study combination therapy, assuming the prior for mE is  IG (2.17,4.8), which has the 
same mean as mS but with a much larger variance (i.e. 99) to reflect much greater uncertainty 
about the median PFS of the combination therapy of sorafenib and theraspheres.  
  
Futility monitoring will start once 20 patients have been enrolled. Assuming an accrual rate 
of 1.5 per month and an additional follow-up of 12 months, the operating characteristics for 
the futility stopping rule under various true states are summarized in the following table 8, 
with results based on 5000 simulations. 
Table 8. Operating characteristics for the time-to-progression monitoring 
 
True Median 
Time to 
progression  
Pr(stop 
early) 
Average Number of 
Patients Treated 
(25th, 75th 
percentiles) 
2 
0.993 
21 (20, 20) 
3 
0.529 
31.4 (20, 40) 
4 
0.100 
38.3 (40,40) 
5 
0.017 
39.7 (40, 40) 
 
If the trial continues to maximum accrual of 40 patients and maintains sufficient follow-up to 
observe 25 events (PD/death) with a median PFS of 4.1 months, then a 95% credible interval 
for median PFS would extend from 2.76 to 6.08 months. 
 
Toxicity Monitoring 
In addition, toxicity will be monitored closely in all patients using the method of Thall et al 
(1995). The interim monitoring will be first conducted after the first 20 patients have been 
evaluated and then be repeated after each cohort of 5 patients. Denote the probability of 
toxicity by θE, where toxicity is defined as any non-hematological Grade 3 or greater 
complications attributable to the treatment.  We assume θE ~ beta (0.6, 1.4).  We will stop the 


 
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trial if at any point Pr(θE > 0.30 | data)  >0.85. That is, we will stop the trial if, at any time 
during the study, we determine that there is more than 85% chance that the toxicity rate is 
more than 30%. Stopping boundaries corresponding to this stopping rule are listed in table 9. 
Table 9: Stopping boundaries for toxicity monitoring 
Among These Number of 
Patients  
Recommend Stopping if Toxicity 
Observed in n or more patients 
20 
9 
25 
11 
30 
12 
35 
14 
 
Table 10: The operating characteristics for toxicity monitoring are summarized in the 
following table 
True toxicity 
probability  
Probability of 
early stop 
Sample size 
percentiles (10, 25, 
50, 75, 90) 
0.1 
0.0001 
 40  40  40  40  40   
0.2 
0.017 
 40  40  40  40  40   
0.3 
0.211 
25 40  40  40  40 
0.4 
0.651 
20  20  25  40  40 
0.5 
0.938 
20  20  20  20  30 
  
Multc Lean V2.1 and OneArmTTE Version 4.1.1 were used for the trial design. 
 
Futility monitoring in CTC website  
 
The Department of Biostatistics will provide and maintain a website (“Clinical Trial 
Conduct”:  https://biostatistics.mdanderson.org/ClinicalTrialConduct/) for futility monitoring 
for each treatment arm on this study. The Clinical Trial Conduct website resides on a secure 
server, and access is gained through usernames and passwords provided to personnel 
responsible for enrolling patients and updating patient data.  The website is accessed through 
a browser using secure socket layer (SSL) technology. Personnel responsible for enrolling 
patients on trials, which includes the principal investigator(s), research nurse(s), and data 
coordinator(s), will be trained by members of the Department of Biostatistics in the use of the 
trial website; the importance of timely updating of follow-up times and recording of events 
will be emphasized in training. 
 
Analysis Plan: 
Primary analysis 
Once the trial is completed, the posterior median time to progression and it 95% credible 
interval will be estimated. In addition, posterior probability that the median PFS is more than 


 
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sorafenib will be assessed. Furthermore, Kaplan-Meier method will be used to estimate 
median PFS and the 95% confidence interval. Log rank test, univariate and multivariate Cox 
proportional hazards regression models will be used to identify prognostic factors for PFS.  
 
Secondary analysis 
 
Toxicity rate and mortality rate will be estimated with a 90% credible interval. the posterior 
probability that the toxicity rate is greater 30% will be evaluated as well. 
Binary endpoints such as response will be tabulated by frequency and the corresponding 95% 
confidence interval (CI). Fisher’s exact test will be applied to compare the patient 
characteristics between responders and non-responders. Univariate and multivariate logistic 
regression models will be fit to identify clinical factors associated with overall response. 
The time-to-event endpoints will be analyzed using Kaplan-Meier method, Log rank test and 
Cox proportional hazards regression modeling. Discrete or categorical patient-reported 
outcomes and quality of life assessments will be tabulated by frequency and 95% CI, while 
for the continuous data, summary statistics including n, mean, and standard deviation, 
median, minimum and maximum will be computed.   
 
8.2 
Planned interim analyses 
None 
8.3 
Determination of sample size 
Please see 8.1 
9. Data handling and quality assurance 
9.1 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the  institution. 
10. Premature termination of the study 
• If risk-benefit ratio becomes unacceptable owing to, for example, 
- Safety findings from this study (e.g. SAEs) 
- Results of any interim analysis 
- Results of parallel clinical studies 
- Results of parallel animal studies  
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity). 


 
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• If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame. 
11. Ethical and legal aspects 
11.1 Ethical and legal conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the investigator abide by Good 
Clinical Practice (GCP) guidelines and under the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers before start of the study, according to GCP, local laws, regulations and organizations.  
When necessary, an extension, amendment or renewal of the EC/IRB approval must be 
obtained and also forwarded to Bayer. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.   
Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by Bayer.  However, the investigator may implement a deviation 
from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects 
without prior IEC/IRB/Bayer approval/favorable opinion.  As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IEC/IRB/head of medical institution.  Any deviations 
from the protocol must be explained and documented by the investigator. 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Principal Investigator is responsible for personally overseeing the treatment of 
all study patients.  The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol and 
all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and properly documented. 
11.2 Subject information and consent 
Each subject / legal representative or proxy consenter will have ample time and opportunity 
to ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision. 
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study.  Additionally, the 


 
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investigator and other information provider (if any) will personally sign and date the form.  
The subject / legal representative or proxy consenter will receive a copy of the signed and 
dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed 
consent was obtained prior to these procedures. 
 
 
1. If the patient is not capable of providing a signature, a verbal statement of consent can 
also be given in the presence of an impartial witness (independent of Bayer and the 
investigator).  This is to be documented by a signature from the informing physician as 
well as by a signature from the witness. 
2. For minors or adults under legal protection, consent shall be given by the legal 
guardian(s).  The consent of a minor or adult under legal protection shall also be requested 
where such a person is able to express his/her own will.  His/her refusal or the withdrawal 
of his/her consent may not be disregarded. 
3. In emergency situations, when prior consent of the patient is not possible, the consent of 
the patient’s legal representative(s) or proxy consenter, if present, should be requested.  
The patient should be informed about the study as soon as possible and his/her consent to 
continue the study should be requested. 
The informed consent form and any other written information provided to subjects / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the subject information and / or the 
written informed consent form.  The investigator will inform the subject / legal representative 
or proxy consenter of changes in a timely manner and will ask the subject to confirm his/her 
participation in the study by signing the revised informed consent form.  Any revised written 
informed consent form and written information must receive the IEC/IRB`s approval / 
favorable opinion in advance of use. 
11.3 Publication policy 
The Principal Investigator should ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov. 
11.4 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 


 
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Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual. 
 
12. Reference list 
1. Wilhelm, S., et al., Discovery and development of sorafenib: a multikinase inhibitor 
for treating cancer. Nat Rev Drug Discov, 2006. 5(10): p. 835-44. 
2. Escudier, B., et al., Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J 
Med, 2007. 356(2): p. 125-34. 
3. Llovet, J.M., et al., Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 
2008. 359(4): p. 378-90. 
4. http://nccu.cancer.org/docroot/STT/content/STT_1x_Global_Cancer_Facts_and_Figu
res_2007.asp accessed November 25, 2010 at 11 :10 ET 
5. http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm129234.htm, accessed 
June 22, 2010 at 09:30 ET 
6. Llovet, J.M., et al., Design and endpoints of clinical trials in hepatocellular carcinoma. 
J Natl Cancer Inst, 2008. 100(10): p. 698-711. 
7. http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf accessed 
June 23 at 08:21 ET 
8. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&con
fID=55&abstractID=34552 accessed June 23, 2010 at 10:01 ET M. Sherman, V. 
Mazzaferro, D. Amadori, J. Seitz, M. Moscovici, M. Shan, A. Nadel, D. Voliotis, J. M. 
Llovet, J. Bruix, on behalf of the SHARP investigators study group Efficacy and safety 
of sorafenib in patients with advanced hepatocellular carcinoma and vascular 
invasion or extrahepatic spread: A subanalysis from the SHARP trial. J Clin Oncol 26: 
2008 (May 20 suppl; abstr 4584) 
9. Salem, R., et al., Radioembolization for hepatocellular carcinoma using Yttrium-90 
microspheres: a comprehensive report of long-term outcomes. Gastroenterology, 
2010. 138(1): p. 52-64. 
10. Hilgard, P., et al., Radioembolization with yttrium-90 glass microspheres in 
hepatocellular carcinoma: European experience on safety and long-term survival. 
Hepatology, 2010. 52(5): p. 1741-9. 
11. J. Bouteaud , M. Al-Jiffry , M. Hassanain , P. Chaudhury , C. Nudo , T. Cabrera , D. 
Valenti ,P. Metrakos. Combined Sorafenib and Yttrium-90 radio-embolization in the 
treatment of advanced HCC: preliminary survival data.  Poster Presentation (P-119) . 
ILCA meeting, Montreal, Canada Sep 2010. 
12. Thall, P.F., L.H. Wooten, and N.M. Tannir, Monitoring event times in early phase 
clinical trials: some practical issues. Clin Trials, 2005. 2(6): p. 467-78. 


 
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13. Thall, P.F., R.M. Simon, and E.H. Estey, Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Stat Med, 1995. 14(4): p. 357-79.