Conditions: Hepatocellular Cancer
Keywords: sorafenib FOLFOX
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
This research study is a Phase II clinical trial. Phase II clinical trials test the effectiveness of an investigational combination of drugs to learn whether the drug combination works in treating a specific cancer. "Investigational" means that the modified FOLFOX and sorafenib combination is still being studied and that research doctors are trying find out more about it-such as the safest dose to use, the side effects it may cause, and if the combination is effective for treating different types of cancer. It also means that the FDA has not yet approved the modified FOLFOX and sorafenib combination that will be used in this study for liver cancer.

FOLFOX is a combination of three drugs: folinic acid (leucovorin), fluorouracil (5-FU), and oxaliplatin. The dosage amounts for some of these FDA approved drugs will be modified slightly in this study. The FOLFOX combination is approved by the FDA and is a standard treatment of colorectal cancer. However, it is not approved for the treatment of liver cancer.

Sorafenib is a new drug, which is approved under the brand name Nexavar for the treatment of liver cancer. It is also currently being tested in various other cancers. Sorafenib works by slowing down and/or stopping the development of new cancer cells and new blood vessels. By slowing down and/or stopping the growth of new blood vessels around a tumor, it is believed that sorafenib prevents or slows down the growth of tumors.

In this research study, sorafenib, the standard treatment, is being combined with modified FOLFOX, which has shown some antitumor activity in liver cancer.

Detailed description:
After agreeing to participate in this study, the patient will be asked to undergo some screening tests or procedures to find out if he/she is eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that the patient does not take part in the research study. If the patient has had some of these tests or procedures recently, they may or may not have to be repeated. These tests and procedures include: a medical history, physical exam, performance status, electrocardiogram, assessment of tumor, blood tests, urine test, pregnancy test and optional research biopsy. If these tests show that the patient is eligible to participate in the research study, he/she will begin the study treatment. If the patient does not meet the eligibility criteria, he/she will not be able to participate.

If the patient takes part in this research study, he/she will be given a sorafenib study drug-dosing diary for each treatment cycle. Each treatment cycle lasts 28 days (4 weeks), during which time the patient will be taking the study drug twice daily. The diary will also include special instructions for sorafenib.

There will be a 2-week Lead-in period, in which the patient will receive sorafenib alone for the first two weeks of the study. Cycle 1 will begin once the patient receives the combination sorafenib and FOLFOX.

For FOLFOX, all three chemotherapy drugs will be injected through a central vein in the patient's chest (portacath) and will be given once every two weeks (14 days), starting on Day 15 of Cycle 1. The patient will receive oxaliplatin first as a 2-hour infusion, followed by leucovorin, and then 5-FU. The 5-FU infusion can last up to 46 hours and will be given through a small portable pump. The investigator will ask the patient to come back to the clinic on day 3 (46 hours after begin 5-FU dose) for pump discontinuance.

During all cycles the patient will have a physical exam and the patient will be asked questions about his/her general health and specific questions about any problems that he/she might be having and any medication he/she may be taking.

As part of the research study the patient will undergo research blood tests that will measure certain proteins in the blood to learn what affect the study treatment may have on you and your disease. About 1 teaspoon of blood will be drawn on Days 3 and 14 during your first two weeks of sorafenib alone, again on Days 14 and 28 post-treatment with FOLFOX-sorafenib and, if available, at the time of progression (if the patient's disease gets worse).

The patient's blood pressure will be monitored once every week for the first 6 weeks of the study (once a week during sorafenib lead-in period and Cycle 1). The investigator will asses the patient's tumor by chest, abdominal and pelvic CT or MRI scan once every 8 weeks throughout the study.

After the final dose of the study drug the investigator will ask the patient to come back to the clinic to repeat the following procedures: medical review, physical examination, blood tests, pregnancy test and tumor assessment by CT or MRI. The investigator would like to keep track of patient's medical condition for the rest of his/her life. The investigator would like to do this by calling the patient on the telephone once a year to see how the patient is doing. Keeping in touch with the patient and checking his/her condition every year helps the investigator look at the long-term effects of the research study.

Arms:
arm 1: FOLFOX (Leucovorin, Fluorouracil and Oxaliplatin) + Sorafenib Sorafenib: orally, twice daily FOLFOX: injected via portacath once every two weeks

Interventions: intervention 1: Leucovorin intervention 2: Fluorouracil intervention 3: Oxaliplatin intervention 4: Sorafenib
Intervention descriptions: intervention 1: 200mg/m2 administered IV on Days 1 and 15 of a 28 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. intervention 2: 5-FU continuous infusion: 2400mg/m2 total (1200mg/m2/d on day 1 and 2) to start on Day 1 and Day 15 of each 28 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. intervention 3: 85 mg/m2 IV on Days 1 and 15 of each 28 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. intervention 4: 400mg po BID continuously for a 2 week lead-in phase and then Days 1-28 of each 28 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.

Protocol document:
Prot_SAP_000.pdf: 
Page 1 
S-FOLFOX in HCC
DANA FARBER/PARTNERS CANCER CARE 
Study Title 
Phase II Trial of Sorafenib in Combination with Modified FOLFOX in Patients with 
Advanced Hepatocellular Carcinoma 
Study Drug 
Sorafenib (Bayer/Onyx) 
Oxaliplatin (Sanofi-aventis) 
Support Provided By 
Bayer/Onyx 
Principle Investigator 
Lipika Goyal, MD 
Co-Investigators 
Jill Allen, MD 
Lawrence Blaszkowsky, MD   
Jeffrey Clark, MD     
David P. Ryan, MD     
Eunice Kwak, MD  
Janet Murphy, MD     
Dushyant Sahani, MD 
Rakesh Jain, PhD 
Charles Fuchs, MD 
Jeffrey Meyerhardt, MD 
Robert J Mayer, MD 
Peter Enzinger, MD 
Matthew Kulke, MD 
Thomas Abrams, MD 
Brian Wolpin, MD 
Research Coordinator 
Susan Sheehan, RN 
Eileen Regan, RN 
Protocol Version Date: 
02/24/2015 
NCT01775501


Page 2 
S-FOLFOX in HCC
TABLE OF CONTENTS 
1.0 
OBJECTIVES…………………………………………………………………………..7 
Primary 
Secondary 
2.0 
INTRODUCTION……………………………………………………………………….7 
Disease Background 
VEGF and Anti-angiogenic Therapy 
Clinical Studies 
Phase I 
Phase II 
Ongoing Clinical Studies 
Summary of Clinical Trial Results 
Safety Plan 
Safety Concerns 
General Plan To Manage Safety 
Other Study Drug(s) Background
Study Rationale 
3.0 
STUDY POPULATION………………………………………………………………11 
Inclusion Criteria 
Exclusion Criteria 
4.0 
REGISTRATION PROCEDURES…………………………………………………..15 
5.0 
STUDY DESIGN………………………………………………………………………16 
Treatment Plan 
Pre-Treatment Evaluations 
Evaluations During Treatment 
Post-Treatment Evaluations 
6.0    DOSE MODIFICATION/TOXICITY MANAGEMENT……………………………20 
7.0 
STUDY MEDICATION………………………………………………………………31 
Sorafenib 
Other Study Drug(s) 
8.0 
CORRELATIVE STUDIES………………………………………………………….35 
9.0 
STUDY CALENDAR…………………………………………………………………36 


Page 3 
S-FOLFOX in HCC
10.0 EVALUATION OF RESPONSE……………………………………………………37 
Definitions 
Response Criteria 
11.0 REPORTING OF ADVERSE EVENTS……………………………………………41 
Adverse Event and Reporting Definitions 
Reporting Requirements for IND Holders 
12.0 DATA SAFETY AND MONITORING………………………………………………45 
13.0 REGULATORY CONSIDERATIONS……………………………………………....47 
14.0 STATISTICAL CONSIDERATIONS………………………………………………..48 
REFERENCES 
APPENDICES 
Appendix A : CLIP Score and CTP Classification 
Appendix B: BCLC Staging in HCC 
Appendix C: Correlative Studies 
Appendix D: Tissue Biopsies 


Page 4 
S-FOLFOX in HCC
SCHEMA 
Lead in Sorafenib alone: first two weeks 
Sorefenib 400 mg bid. 
Cycle 1 and beyond 
Drugs 
5-FU/LV
Oxaliplatin 
Sorafenib 
Treatment Dates 
Days 1, 15 
Days 1, 15 
Days 1-28 
Dosage 
5-FUCI: 2400mg/m2 total
(1200mg/m2/d on day 1 and 2)
LV: 200mg/m2 
85 mg/m2 
400 mg bid 
Each cycle (cycle 1 and beyond) is defined as 28-day treatments.  
Register: Sorafenib 400 mg bid continuously 
First two weeks 
Sorafenib 400 mg bid 
Modified FOLFOX, days 1, 15 
Every 28 days/cycle 
Continue treatment until PD or 
intolerable toxicity 


Page 5 
S-FOLFOX in HCC
Eligibility Criteria 
Key Inclusion Criteria: 
•
Histologically confirmed advanced HCC
•
No cirrhosis or Child-Pugh A (CTP score < 7) cirrhosis (See
Appendix A)
•
Barcelona Clinic Liver Cancer (BCLC) stage C, and those with BCLC-B stage who
can not tolerate or failed TACE (See Appendix B)
•
Patients must have measurable lesions
•
Participants must have adequate organ and marrow function as
defined below:
ANC 
 1500/mm3 
Platelets 
 100,000/mm3 
Hemoglobin 
 10 g/dl 
AST and ALT 
 6 x upper limits of normal 
Total bilirubin 
 2.0 mg/dL  
Renal function 
Creatinine  2.0 mg/dL and/or creatinine clearance 50 
ml/min 
•
No prior systemic regimens for HCC
•
Patients with a prior history of liver directed therapy for their HCC
(chemoembolization, radioembolization, bland embolization,
radiation therapy, radiofrequency ablation, microwave ablation) can
participate in the study if the liver-directed therapy was performed 
4 weeks prior to their first dose of sorafenib and measurable lesions
present outside of previously treated field
•
Chronological age ≥ 18 years.
•
ECOG performance status ≤ 1.
•
Life expectancy ≥ 12 weeks.


Page 6 
S-FOLFOX in HCC
•
All patients must sign informed consent.
Key Exclusion Criteria: 
•
Child-Pugh B or C Cirrhosis (CTP score  7) (See Appendix A)
•
The patient has either clinically apparent central nervous system
metastases or carcinomatous meningitis
•
The patient has a history of uncontrolled angina, arrhythmias, or
congestive heart failure.
•
The patient has a medical or psychiatric condition that constitutes
an unacceptable risk for participation in this trial, in the judgment of
the treating physician.
•
The patient has received any investigational agents within 4 weeks
prior to their first dose of sorafenib
•
The patient is a woman who is pregnant or lactating.  Both men and
women of childbearing potential must be advised of the importance
of using effective birth control measures during the course of the
study.
•
Patients with any previously untreated or concurrent cancer that is distinct in
primary site or histology from HCC except cervical cancer in-situ (CIS), treated
basal cell carcinoma (BCC), or superficial bladder tumor.  Patients surviving a
cancer that was curatively treated and without evidence of disease for more than
3 years before randomization are allowed. All cancer treatments must be
completed at least 3 years prior to the first dose of sorafenib except for local
treatments for cervical CIS, BCC, and superficial bladder tumors.
•
The patient has received previous sorafenib or FOLFOX treatment.
1.0 Objectives 
1.1 Primary Objective 
•
To assess the time to progression (TTP) in patients with HCC treated FOLFOX-S.
1.2 Secondary Ojective 
•
To evaluate the tolerability and toxicities of FOLFOX-S regimen in this population
of patients.
•
To assess the response rate, the duration of response, median PFS, and median OS
of FOLFOX-S in patients with HCC.


 
                                                         
Page 7 
 
S-FOLFOX in HCC 
 
 
• To assess changes of angiogenic and inflammatory parameters with treatment of 
sorafenib. 
 
 
2.0  Introduction 
 
2.1 
Disease Background 
Hepatocellular cancer (HCC) is a common malignancy worldwide, with greater than 
620,000 new cases reported annually, and accounts for 80-90% of primary liver cancers. 
The incidence of HCC is increasing and it now ranks as the 6th most common tumor 
worldwide. Due to its poor prognosis it is the 3rd most common cause of cancer-related 
death with the number of deaths (598,000) almost the same as the number of new cases. 
The majority of HCC cases develop in the presence of cirrhosis due to chronic liver 
disease mainly as a result of infection by hepatitis B virus (HBV) or hepatitis C virus (HCV) 
1. HBV is endemic in Southeast Asia and Africa, where the majority of HCC cases are 
concentrated. In the West, even though incidence rates are much lower, the number of 
HCC cases has been rising steadily since the 1960s and 1970s and are considered to be 
due to a rise in infection rates of HCV during that time 2 . In the last 20 years the incidence 
of HCC has doubled with a peak expected by 2020 2. 
Potentially curative therapies, such as surgical resection, liver transplant or other local 
treatments, result in survival rates of between 50-70% at 5 years for patients with early 
stage HCC 3. However, despite advances in diagnostic techniques and increased 
surveillance, the majority of HCCs present with advanced, inoperable stages.  
Untreated patients with intermediate stage HCC (multinodular asymptomatic tumors 
without an invasive pattern) have a median survival of 16 months. Treatment with 
transarterial chemoembolization (TACE) extends the median survival of this group of 
patients to approximately 19-20 months 3.  
 
 
2.2 Systemic therapy for HCC 
For patients with advanced stage HCC (defined as the presence of extrahepatic disease 
or vascular invasion), well preserved hepatic function and good performance status, 
systemic therapy with sorafenib or participation in clinical trials is the standard 
treatment. 
Sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals) is a 
small molecule that inhibits tumor-cell proliferation and tumor angiogenesis by targeting 
the serine–threonine kinases Raf-1 and B-Raf and the receptor tyrosine kinases of 
vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3 and platelet-derived 
growth factor receptor β (PDGFR-β) 4,5. Encouraged by the strong rationale of its 
mechanism of action, promising preclinical data against hepatocellular carcinoma (HCC), 
and early evidence of antitumor activity from the phase II study 6, the international, phase 
3, placebo-controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial 
was subsequently  conducted.  This study demonstrated improved overall survival (OS) 
and time to tumor progression (TTP) 7.  Median OS was 10.7 months in the sorafenib 


 
                                                         
Page 8 
 
S-FOLFOX in HCC 
 
 
group and 7.9 months in the placebo group (hazard ratio for the sorafenib group, 0.69; 
P<0.001). The median TTP was 5.5 months in the sorafenib group and 2.8 months in the 
placebo group (P<0.001).   In another randomized phase III study conducted in Asia, 
sorafenib also demonstrated improved OS in patients with advanced HCC 8.  Overall 
survival was 6.5 months in the sorafenib group versus 4.2 months in the placebo group 
(hazard ratio for the sorafenib group, 0.68; P=0.014).  These studies have led to the 
approval of sorafenib for the treatment of advanced HCC in the United States and many 
other countries around the world. 
 
Although a large number of controlled and uncontrolled studies have been performed with 
most classes of chemotherapeutic agents, no single or combination chemotherapy is 
particularly effective in HCC.  Despite the initial encouraging reports from Uganda using 
single-agent doxorubicin, subsequent studies have failed to confirm these data.  In the 
largest study of doxorubicin in advanced hepatocellular carcinoma, no responses were 
noted among 109 patients.  Among 475 patients who received doxorubicin in various 
studies, a 16% response rate was documented with a median survival of 3 to 4 months.  
 
Other drugs such as cisplatin, 5-fluorouracil, mitoxantrone and etoposide have failed to 
demonstrate meaningful activity.  Combination chemotherapy regimens have yielded 
similar response rates and median survivals.  The response rate tends to be low and the 
response duration is short.  More importantly, the survival benefit of systemic 
chemotherapy for HCC remains to be determined.  As a result, there appears to be little 
justification in treating patients with advanced hepatocellular carcinoma with systemic 
chemotherapy outside of a clinical trial. The most impressive result of combination 
chemotherapy comes from a Hong Kong study using the combination of cisplatin, alpha-
interferon, doxorubicin, and 5-FU (PIAF). This regimen produced a partial response rate 
of 26%.  In a follow up phase III study comparing PIAF against doxorubicin, PIAF failed 
to demonstrate any survival benefits.  Moreover, this regimen is associated with 
significant toxicity 9.   
 
Recently, oxaliplatin based combination chemotherapy has demonstrated moderate 
activity in advanced HCC and acceptable toxicity profile.   In phase II trial, the combination 
of gemcitabine and oxaliplatin (GEMOX) produced a response rate of 18% (95% 
confidence interval [CI]: 8-34) and a disease control rate of 76%. Median progression-
free and overall survival were 6.3 months (95% CI: 4.3-10.1 months) and 11.5 months 
respectively (95% CI: 8.5-14.3 months) 10.   Oxaliplatin in combination with 5-FU/LV 
(FOLFOX) has also been tested in advanced HCC.  Following the early experience in 
phase II study, the investigators from Asia conducted a randomized phase III trial.  
Patients with advanced HCC were randomized to receive either FOLFOX4 (n=183) or 
doxorubicin (N=174).  Based on the presented data, in comparison with doxorubicin arm, 
FOLFOX4 demonstrated improved response rate (8.2% vs. 2.67%, p=0.0233), improved 
median progression free survival (PFS) (2.93 m vs. 1.77 m, p=0.0002), and a trend 
towards improved median overall survival (6.40 m vs. 4.97 m, p=0.0695).  Toxicity profiles 
were comparable in both arms with the exception of more peripheral neuropathy in the 
FOLFOX4 arm 11. 
 




 
                                                         
Page 10 
 
S-FOLFOX in HCC 
 
 
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.  
 
Please refer to the IB for the complete list of observed adverse events seen in Phase III 
studies.  
 
2.4  Clinical experience with Sorafenib + FOLFOX and Sorafenib + XELOX 
 
The safety and efficacy of the combination of Sorafenib and FOLFOX was tested in the 
RESPECT trial, a Phase IIb placebo- controlled study of 198 patients with metastatic 
colorectal cancer.  Patients were randomized to modified FOLFOX combined with either 
sorafenib 400mg po bid or placebo in the first-line setting.  There was no significant 
difference in median PFS between the sorafenib and placebo groups (9.1 vs 8.7 
months; HR 0.88, 95% CI 0.64–1.23) or time to progression.  The grade 3 and 4 
adverse events included neutropenia (sorafenib > placebo), peripheral neuropathy 
(placebo > sorafenib) and grade 3 hand–foot syndrome (20% with sorafenib vs 0% with 
placebo) (Tabernero, ESMO Abstract, 2011). 
 
In patients with locally advanced or metastatic hepatocellular carcinoma, while the 
combination of sorafenib and FOLFOX has not been tested, the combination of 
sorafenib and XELOX (capecitabine and oxaliplatin) has been tested.  In the Phase IIa 
SECOX trial, patients with advanced HCC who had received no prior systemic therapy 
received sorafenib 400mg po BID (days 1-14), Capecitabine 850mg/m2 po BID (days 1-
7), and Oxaliplatin 85mg/m2  (day 1) on 2 week cycles. The best response rate was 
14%, and another 61% achieved stable disease.  The median TTP was 7.1 months 
(1.7–19.9) and OS was 10.2 months (2.1–20.5). The three most common adverse 
reactions were hand-hoot-skin reaction (73%), diarrhea (69%), and  
and neutropenia (63%)17.  The efficacy data was promising in this trial, but the 
tolerability of the regimen was poor, likely due to the combination of sorafenib and 
capecitabine. 
 
2.5 
Study Rationale 
 
 
HCC are commonly viewed as highly vascular tumors 15.  Vascular endothelial growth 
factor (VEGF) is a potent angiogenesis stimulator and an important regulator in 
pathological angiogenesis.  Increased levels of VEGF have been found in tumor and 
serum of patients with HCC. Increased VEGF expression has been associated with 
inferior survival in HCC. Thus, inhibition of VEGF and its receptor is a logical target in 
the treatment of patients with HCC.  Sorafenib (S) has emerged as the new standard 
treatment for patients with advanced HCC based on the improvement of overall survival 
benefits.  However, the benefits of sorafenib are still modest.  Combining doxorubicin 
with sorafenib has shown encouraging results in comparison with doxorubicin with 
placebo in a randomized phase II study 16.  Median TTP was 6.4 months in the 
sorafenib-doxorubicin group (95% confidence interval [CI], 4.8-9.2), and 2.8 months 
(95% CI, 1.6-5) in the doxorubicin-placebo monotherapy group (P = .02). Median OS 


 
                                                         
Page 11 
 
S-FOLFOX in HCC 
 
 
was 13.7 months (95% CI, 8.9-not reached) and 6.5 months (95% CI, 4.5-9.9; P = .006).  
FOLFOX has shown more favorable efficacy results when compared with doxorubicin 
(Improved RR and PFS and a trend of OS improvement) in a randomized phase III 
study conducted in Asia as discussed in Section 2.2.    
 
In this study, we will examine the efficacy and tolerability of combining FOLFOX with 
sorafenib.  As a multitargeted tyrosine kinase inhibitor with antiangiogenic activity, 
sorafenib may enhance chemotherapy-induced tumor kill by the destruction of tumor 
blood vessel as well as by inducing “normalization” of tumor vasculature with improved 
delivery of therapeutics.  During the first 2 weeks of treatment with sorafenib alone, we 
will also examine changes induced by sorafenib 1) in plasma angiogenic and 
inflammatory markers with serum biomarkers and 2) specific changes in the tumor and 
surrounding non-cancer liver tissues with optional on-treatment biopsies. 
 
 
3.0 
STUDY POPULATION 
 
3.1  
Inclusion Criteria 
 
• Histologically confirmed advanced HCC 
• No cirrhosis or Child-Pugh A (CTP score < 7) cirrhosis (See Appendix A) 
• Barcelona Clinic Liver Cancer (BCLC) stage C, and those with BCLC-B Stage who 
cannot tolerate or failed TACE  (See Appendix B) 
• Patients must have measurable lesions 
• All patients must have adequate hepatic function: total bilirubin ≤ 2.0 mg/dl; AST 
and ALT ≤ 6x upper limits of normal. 
• Adequate renal function: Serum creatinine ≤ 2.0 mg/dl. 
• Adequate bone marrow function defined as:  
o Absolute neutrophil count ≥ 1,500/mm3 
o Platelets ≥ 100,000mm3 
o Hemoglobin ≥ 10 g/dl 
• No prior systemic regimens for HCC 
• Patients with a prior history of liver directed therapy for their HCC 
(chemoembolization, radioembolization, bland embolization, radiation therapy, 
radiofrequency ablation, microwave ablation) can participate in the study if the 
liver-directed therapy was performed more than 4 weeks prior to their first dose of 
sorafenib and measurable lesions present outside of previously treated field 
• Chronological age ≥ 18 years. 


 
                                                         
Page 12 
 
S-FOLFOX in HCC 
 
 
• ECOG performance status ≤ 1 
• Life expectancy ≥ 12 weeks 
• 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). 
• Subject must be able to swallow and retain oral medication. 
• All patients must sign informed consent. 
 
 
3.2  
Exclusion Criteria 
• The patient has either clinically apparent central nervous system metastases or 
carcinomatous meningitis 
• The patient is a woman who is pregnant or lactating.  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. All patients (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. 
• Active or clinically significant cardiac disease including: 
o Congestive heart failure – New York Heart Association (NYHA) > Class II. 
o Active coronary artery disease. 
o Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin. 
o QTc > 500 ms 
o Unstable angina (anginal symptoms at rest), new-onset angina within 3 
months before randomization, or myocardial infarction within 6 months 
before randomization. 
• Evidence or history of bleeding diathesis or coagulopathy. 
• Subject with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 
2 or higher within 4 weeks before enrollment; any other hemorrhage/bleeding event 
of NCI-CTCAE v4.0 Grade 3 or higher within 4 weeks before enrollment. 
• Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
• History of organ allograft. (including corneal transplant). 
• Any malabsorption condition. 


 
                                                         
Page 13 
 
S-FOLFOX in HCC 
 
 
• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic 
pressure > 90 mmHg, despite optimal medical management.  
 
• Uncontrolled ascites defined as not easily controlled by stable doses of diuretics.  
 
• Known human immunodeficiency virus (HIV) infection. 
• The patient has a medical or psychiatric condition that constitutes an unacceptable 
risk for participation in this trial, in the judgment of the treating physician. 
• The patient has received any investigational agents within 4 weeks prior to their first 
dose of sorafenib. 
• ECOG status of ≥ 2  
• Child-Pugh B or C cirrhosis (CTP score ≥ 7) (See Appendix A) 
• CLIP score >3 (See Appendix A)  Inability to comply with study and/or follow-up 
procedures 
• Subjects with any previously untreated or concurrent cancer that is distinct in 
primarysite or histology from HCC except cervical cancer in-situ, treated basal cell 
carcinoma, or superficial bladder tumor.  Subjects surviving a cancer that was 
curatively treated and without evidence of disease for more than 3 years before 
randomization are allowed. All cancer treatments must be completed at least 3 years 
prior to the first dose of sorafenib except for local treatments for cervical CIS, BCC, 
and superficial bladder tumors. 
• History of other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that might affect the interpretation 
of the results of the study or render the subject at high risk from treatment 
complications 
Excluded therapies and medications, previous and concomitant 
• Concurrent systemic and local anti-cancer therapy (chemotherapy, radiation 
therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other 
than sorafenib. 
• Prior use of sorafenib, oxaliplatin, or 5FU. 
• 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). 
• Major surgery within 30 days prior to start of study drug.  For patients who had 
port-a-cath placement, they should have the port-a-cath placement at least one 
week prior the initiation of FOLFOX. 
• Concurrent use of Aspirin > 100 mg daily 


 
                                                         
Page 14 
 
S-FOLFOX in HCC 
 
 
• Concurrent use of  drugs that are known potent CYP3A4 inducers, including but 
not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and 
St. John’s wort. 
 
• Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with 
heparins and heparinoids. 
o However, prophylactic anticoagulation as described below is allowed: 
▪ 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. 
▪ Prophylactic doses of heparin. 
 
 
4.0 
Registration Procedures 
 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
All participants will be registered by the DF/HCC Quality Assurance Office 
for Clinical Trials (QACT). Registration must occur prior to the initiation of 
therapy. Any participant not registered to the protocol before treatment begins 
will be considered ineligible and registration will be denied.  
 
A designated member of the study team will confirm eligibility criteria and 
complete the protocol-specific eligibility checklist. 
  
Once registered, any issues that would cause treatment delays should be 
discussed with the Principal Investigator.   
 
If a participant does not receive protocol therapy following registration, the 
participant’s protocol status must be changed by the study coordinator.  
 
 
 
 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 
AM to 5:00 PM Eastern Standard Time. In emergency situations when a participant 
must begin treatment during off-hours or holidays, call the QACT registration line 
at 
 and follow the instructions for registering participants after hours. 


 
                                                         
Page 15 
 
S-FOLFOX in HCC 
 
 
   
The registration procedures are as follows: 
 
1. 
Obtain written informed consent from the participant prior to the 
performance of any study related procedures or assessments. 
 
2. 
Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. 
For phase II participants, include stratification information.  To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist.  
  
3. 
Fax the eligibility checklist(s) and all pages of the consent form to the 
QACT at 
 
  
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant 
on the study, and (c) randomize the participant when applicable (Phase 
2 part of the study).  The randomization tables will be designed by the 
study statistician.   
  
5. 
The QACT Registrar will send an email confirmation of the registration 
and/or randomization to the person initiating the registration and to the 
research pharmacist immediately following the registration and/or 
randomization. 
 
 
5.0  STUDY DESIGN 
 
5.1Treatment Plan   
 
5.1.1 Single arm, open label, phase II study 
 
5.1.2Dosing schedule 
 
Treatment will be administered on an outpatient basis.  Expected adverse events 
and appropriate dose modifications for sorafenib, 5-FU, oxaliplatin are as 
described in Section 6.0.  No investigational or commercial agents of therapies 
other than those described below may be administered with the intent to treat the 
patient’s malignancy. 
 
Patients will be treated as below: 
 
Register: 
 
Sorafenib 400 mg bid → 
Sorafenib 400 mg bid 
→   
continue treatment  
First two weeks 
 
modified folfox, days 1, 15   
until PD or intolerable toxiity 


 
                                                         
Page 16 
 
S-FOLFOX in HCC 
 
 
 
 
 
Every 28 days/cycle 
 
 
For first two weeks, sorafenib will be given alone. 
Cycle 1 and beyond: 
Sorafenib 400 mg bid + modified FOLFOX (Oxaliplatin 85 mg/m2 followed by 
leucovorin 200 mg/m2, followed by infusional 5-FU at 1200 mg/m2/d on Days 1 and 
2 (2400 mg/m2 total over 46 hours) repeated every 14 days for each cycle.   
Oxaliplatin will be delivered at 85 mg/m2as a 2-hour infusion on day 1 and day 15 
of every cycle. 
   
Drugs 
5-FU/LV 
Oxaliplatin 
Sorafenib 
 
  Treatment dates   Days 1,15               
Days 1,15         Daily (days 1-28) 
 
     Dosage               LV: 200 mg/m2 
5-FUCI: 2400 mg/m2 total 
(1200mg/m2/d on day 1 and 2)   
85 mg/m2 
400 mg bid 
 
 
Lead-in sorafenib alone treatment: first 2 weeks. 
 
Each cycle is defined as 28-day treatments.   
 
5.1.3 Estimated number of patients 
 
40 patients with advanced HCC 
 
5.1.4Estimated rate of accrual 
 
2-3 patients each month 
 
5.1.5.Estimated date of study completion 
 
Estimated date of study completion is July 2013 with an estimated start date of 
July 2012 
 
5.1.6Duration of therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: 


 
                                                         
Page 17 
 
S-FOLFOX in HCC 
 
 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Patient decides to withdraw from study 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
 
5.2 CLINICAL AND LABORATORY EVALUATIONS 
 
5.2.1 Pre-Treatment Evaluations 
 
Signed and informed consent should be obtained prior to specific protocol testing and 
evaluation.  The following evaluations must be performed prior to each patient’s first dose 
of sorafenib: 
 
5.2.1.1 Evaluations that must be performed within 1 week prior to the first dose of 
sorafenib: 
 
• Pregnancy test (serum or urine) for women of childbearing potential within 7 days prior 
to initiation of therapy. 
 
5.2.1.2 Evaluations that must be performed within 2 weeks prior to the first dose of 
sorafenib: 
 
• Medical history  
• Physical examination, including vital signs, height, weight, performance status. 
• Hematology:  complete blood count (CBC) with differential. 
• Serum Chemistries: glucose, BUN, creatinine, uric acid, total bilirubin, alkaline 
phosphatase, LDH, total protein, albumin, SGOT(AST), SGPT (ALT), calcium, 
phosphorus, amylase, lipase, and AFP. 
• PT/INR 
• Hepatitis B surface antigen, core antibody, and surface antibody, and Hepatitis C 
antibody must be obtained within 120 days of study enrollment. 
Urinalysis:  urine dipstick for protein.  Patients with a positive dipstick for urine protein 
(reading of 2+ or greater) will then undergo a 24 hour urine collection for protein. 
 
 
*If the screening labs have been completed within 7 days of Day 1 of the lead-in period, 
these labs do not need to be repeated.  However, baseline correlative studies need to be 
drawn on Day 1 of the lead-in period. 
 
5.2.1.3 Evaluations that must be performed within 3 weeks prior to the first dose of 
sorafenib:  
• EKG 


 
                                                         
Page 18 
 
S-FOLFOX in HCC 
 
 
• Imaging: Baseline radiologic evaluation of tumor burden by chest/abdomen/pelvis 
CT scan.  MRI of the liver can be used if patients have an IV contrast allergy or the CT 
scan is suboptimal based on the physician’s judgment. 
  
5.2.2 Evaluations During Treatment 
  
• Monitor CBC and selected chemistries (Glucose, BUN, Creatinine, ALT, AST, 
ALKP, total bilirubin, calcium, phosphorus, LDH, protein, albumin) weekly during 
the first 5 weeks of therapy (during the initial two weeks of sorafenib treatment and 
the first 3 weeks of Cycle 1 of FOLFOX-sorafenib) and every two weeks after that.  
Urinalysis and AFP will be performed prior to each cycle. 
• Imaging:  Radiologic evaluation (CT or MRI scan) by RECIST 1.1 criteria will be 
performed at the end of cycle 2 of FOLFOX-sorafenib and every 2 cycles 
thereafter. 
 
All non-radiological assessments must be performed prior to administration of any study 
medication. All study assessments should be done within +/- 3 days of the protocol-
specified date, unless otherwise noted. 
All radiological assessments should be done within +/7 days of the protocol specified 
date, unless otherwise noted. 
 
5.2.3 Post-Treatment Evaluations 
 
• All patients will be evaluated by history and physical examination, including vital 
signs, weight, and performance status, CBC with differential, chemistries, and 
reassessment of tumor at the end of treatment. 
• Female patients of childbearing potential will be evaluated with a repeat pregnancy 
test at end of treatment visit. 
• All sites of tumor progression and metastasis will be recorded. 
• Progression-free and overall survival will be determined. 
 
 
5.2.4  Correlative Studies 
 
• Only patients getting their treatment at MGH will be eligible for the correlative 
studies given that all samples need to be processed at the Steele Lab at MGH. 
 
• BASELINE AND ON-TREATMENT PLASMA STUDIES (see Appendix C for 
details): Circulating endothelial cells and plasma levels of growth factors will be 
assessed: 
o  On Day 1 (prior to the first dose of sorafenib) and Day 3 of lead-in phase 
o On C1D1, C1D15, and C1D29 of FOLFOX-Sorafenib. The Day 3 correlative 
can be drawn on Day 3, 4, or 5. The Day 15 correlative can be drawn on 
Day 14, 15, or 16. The Day 29 correlative can be drawn on Day 27, 28, or 
29. 
o At the time of progression if available  


 
                                                         
Page 19 
 
S-FOLFOX in HCC 
 
 
 
• ON-TREATMENT OPTIONAL BIOPSY (see Appendix D for details): All patients 
enrolled on this trial are required to have a baseline diagnostic biopsy for 
histological confirmation of HCC.  To be considered for the optional posttreatment 
tumor biopsy, the patient must have adequate tissue on their baseline biopsy (i.e. 
core biopsy) to have all necessary correlative studies run on the sample.  The 
optional posttreatment tumor biopsy  will be obtained any time from Day 10 to Day 
14 of the lead-in phase in patients who consent to a posttreatment tumor biopsy 
(n=6-12). 
 
 
 
6.0 DOSE MODIFICATION / TOXICITY MANAGEMENT 
Study drug treatment will be modified in the event of certain adverse events, as 
shown in the tables below. 
• Regardless of the reason for holding study drug treatment, the maximum 
allowable length of treatment interruption of FOLFOX is 6 weeks (the 
holding of 3 consecutive doses) and of Sorafenib is 3 weeks  If the patient 
needs to stop FOLFOX due to toxicity, they can stay on study as long as 
they continue with Sorafenib.  If the patient needs to stop Sorafenib due to 
toxicity, they can stay on the study as long as they continue FOLFOX.  If 
they need to stop both FOLFOX and Sorafenib for longer than the above 
time limits, they must be taken off the study and the Principle Investigator 
must be notified. 
• Doses of chemotherapy that have been reduced will not be re-escalated. 
• No held doses of Sorafenib or FOLFOX will be made up.  If a patient misses 
a dose for toxicity, the patient will proceed to the next treatment day or cycle 
as scheduled. 
 
6.1 Expected Adverse Events – 5-FU 
 
Nausea, vomiting (mild);  ileus, stomatitis (5-8 days after treatment initiation); 
 
gastric ulceration; myelosuppression:  leukopenia, granulocytopenia (9-14 days); 
 
thrombocytopenia (7-14days); alopecia; loss of nails; hyperpigmentation; 
 
photosensitivity; maculopapular rash; palmar-plantar erythrodysethesias (42-82% 
 
receiving continuous infusion); CNS effects: disorientation, confusion (rare); 
 
cardiotoxicity:  MI, angina, asymptomatic S-T changes (68%); rare ocular effects. 
 
 
6.2 Oxaliplatin 




 
                                                         
Page 21 
 
S-FOLFOX in HCC 
 
 
Dizziness 
7 
<1 
13 
<1 
Hand-foot 
syndrome 
1 
<1 
11 
<1 
Flushing 
3 
<1 
10 
<1 
Peripheral 
edema 
5 
<1 
10 
<1 
Allergic 
reaction 
3 
<1 
10 
<1 
Arthralgia 
7 
<1 
10 
<1 
Upper resp. 
tract infect. 
7 
<1 
10 
<1 
Pharyngitis 
2 
<1 
9 
<1 
Rash 
5 
<1 
9 
<1 
Insomnia 
11 
<1 
9 
<1 
Epistaxis 
2 
<1 
9 
<1 
Mucositis 
2 
<1 
7 
<1 
Alopecia 
3 
<1 
7 
<1 
Abnormal 
lacrimation 
1 
<1 
7 
<1 
Rigors 
9 
<1 
7 
<1 
Hematuria 
0 
<1 
6 
<1 
Dysuria 
1 
<1 
6 
<1 
Hiccup 
2 
<1 
5 
<1 
Flatulence 
3 
<1 
5 
<1 
 
6.3 Dose Modification of 5-FU and Oxaliplatin 
6.3.1 Toxicity will be evaluated weekly during the sorafenib lead-in period, 
weekly during the first 3 weeks of cycle 1 of FOLFOX-Sorafenib, and then 
once every two weeks for subsequent cycles.  Dose modifications based on 
significant weight changes can be made in accordance to institutional 
practice. 
 
 
6.3.2 Hematologic Toxicity  
• CBC will be obtained on days 1 and 15 of each cycle.   
• Patient must have ANC > 1000 and platelets > 75,000 in order to 
treat on any given treatment day.  
 
C1D1 dosing AND subsequent Day 1 and Day 15 dosing if previous dose 
was given:  
ANC 
Platelets 
%Previous dose 5-
FU/LV 
%Previous dose 
Oxaliplatin 
>1000  and  
>75,000 
100 
100 


 
                                                         
Page 22 
 
S-FOLFOX in HCC 
 
 
≤1000 
≤75,000 
HOLD dose and 
reassess in 2 weeks 
HOLD dose and 
reassess in 2 weeks 
≤500 
≤50,000 
HOLD dose and 
reassess in 2 weeks 
HOLD dose and 
reassess in 2 weeks 
 
 
Day 1 and 15 dosing if the immediate previous Day 1 or 15 dose was 
HELD: 
ANC 
Platelets %Previous dose 5-
FU/LV 
%Previous dose 
Oxali 
>1000  and  >75,000 
75% of previous 
dose if either ANC 
was 501-1000 or 
Plts were 51,000-
75,000 
 
50% of previous 
dose if either ANC 
was ≤500 or Plts 
were ≤50,000 
75% of previous 
dose if either ANC 
was 501-1000 or 
Plts were 51,000-
75,000 
 
50% of previous 
dose if either ANC 
was ≤500 or Plts 
were ≤50,000 
≤1000  or 
≤75,000 
HOLD dose and 
reassess in 2 
weeks  
HOLD dose and 
reassess in 2 weeks  
≤500  or 
≤50,000 
HOLD dose and 
reassess in 2 
weeks 
HOLD dose and 
reassess in 2 weeks 
 
 
If the patient requires two consecutive doses of FOLFOX to be held for 
hematologic toxicity, the patient should get 50% of the previous dose of 
FOLFOX if they meet criteria for treatment on the next scheduled treatment 
day.  
 
In addition, at any time during a cycle, if the patient experienced 1) febrile 
neutropenia or 2) any Grade 3 or higher hematologic toxicity (excluding 
thrombocytopenia and neutropenia, which will be addressed using the 
tables above) while on FOLFOX, then 5-FU and Oxaliplatin should be held 
until the toxicity resolves to <Grade 2.  When the patient meets treatment 
criteria, the 5-FU and Oxaliplatin should be resumed at 75% of most recent 
dose for all subsequent doses.   
 
Doses of chemotherapy that have been reduced will not be re-escalated.  A 
maximum of 4 dose reductions are allowed for 5-FU and Oxaliplatin (with 
the minimum allowed dose of 5-FU being 380 mg/m2/day and the minimum 
allowed dose for oxaliplatin being 27 mg/m2).   
 


 
                                                         
Page 23 
 
S-FOLFOX in HCC 
 
 
 
No held doses will be made up.  If a patient misses a dose for toxicity, the 
patient will proceed to the next treatment day or cycle as scheduled. 
 
If the FOLFOX is held for > 6 weeks (i.e. three consecutive doses of 
FOLFOX are held), FOLFOX will be permanently discontinued, and the 
patient can remain on the study as long as they are receiving Sorafenib.  
 
6.3.3 Non-Hematologic Toxicity  
6.3.3.1 Diarrhea 
Anti-diarrheal agents should be prescribed for diarrhea.  If greater than or 
equal to Grade 3 uncontrolled diarrhea despite maximal antidiarrheal 
therapy, temporarily discontinue both chemotherapy and sorafenib.  
Resume chemotherapy when symptoms have subsided to Grade 1 toxicity 
or less.  Resume with 5-FU and Oxaliplatin at 75% of the previous dose.  
Resume sorafenib at one dose reduction.    
 
6.3.3.2 Nausea, Vomiting 
For Grade 3 to 4 nausea/vomiting that remains uncontrolled despite 
maximal antiemetic therapy, temporarily discontinue both chemotherapy 
and sorafenib.  Maximal antiemetic therapy includes using such agents as 
5-HT3 receptor antagonists, corticosteroids, and benzodiazepines, where 
indicated.  Resume chemotherapy when symptoms have subsided to Grade 
1 toxicity or less.  Resume with 5-FU and oxaliplatin at 75% of the previous 
dose.  Sorafenib may be resumed at full dose. 
 
6.3.3.3 Melena and Hematemesis 
If melena or hematemesis occur during therapy, sorafenib and 
chemotherapy should be held for Grade 1 toxicities until they resolve.  For 
patients who develop Grade 3 or 4 toxicities, therapy should be 
discontinued and the Principal Investigator notified. 
 
 
6.3.3.4 Neurologic Toxicity 
Neurological toxicity has been observed in patients treated with oxaliplatin.  
This neurotoxicity has included paresthesias and dysesthesias of the 
hands, feet, and peri-oral region.  Patients treated with oxaliplatin in this 
study will be counseled to avoid cold drinks and exposure to cold water or 
air, especially 3-5 days following oxaliplatin administration.  Dose 
adjustments for neurological toxicity will be based on the following table. 
 
 
Duration of Toxicity 
Neurological Toxicity 
≤7 days 
>7 days 
PersistentA 


 
                                                         
Page 24 
 
S-FOLFOX in HCC 
 
 
A Not resolved by the beginning of the next cycle 
B May be cold-induced 
C May also be pretreated with benzodiazepines 
 
Note on laryngopharyngeal dysesthesia:  a loss of sensation of breathing (acute respiratory 
distress) without any objective evidence of respiratory distress (hypoxia, layngospasm, or 
bronchospasm) has been observed.  This neurotoxicity may be induced or exacerbated upon 
exposure to cold.  Should a patient develop laryngopharyngeal dysesthesia, the patient’s oxygen 
saturation will be evaluated via a pulse oximeter, and, if normal, an anxiolytic agent or 
benzodiazepine will be given and the patient should be observed in clinic until the episode has 
resolved.  The infusion may be continued at 1/3 the rate.  Because this syndrome may be 
associated with the rapidity of oxaliplatin infusion, subsequent doses of oxaliplatin should be 
administered as 6-hour infusions (instead of the normal 2-hour infusion). 
 
 6.3.3.5 Dose Modifications for Other Non-Hematologic Toxicity 
 
CTC Grade 
Action 
5-FU, % of 
Previous Dose 
Oxaliplatin, % of 
Previous Dose 
1 
Continue therapy 
100 
100 
2 
Continue therapy 
100 
100 
3 
Resume when 
toxicity <= Grade 1 
751, 3 
752, 3 
4 
Resume when 
toxicity <= Grade 1 
501, 3 
502, 3 
 
Paresthesias/dysesthesiasB  
that do not interfere with 
function (Grade 1) 
 
No change 
No change 
No change 
Paresthesias/dysesthesiasB 
interfering with function, but 
not activities of daily living 
(ADL) (Grade 2) 
 
No change 
No change 
Decrease dose by 
50% 
Paresthesias/dysesthesiasB 
With pain or with functional 
Impairment that also Interfere 
with ADL (Grade 3) 
 
No change 
Decrease dose by 
50% 
discontinue 
oxaliplatin 
Severe paresthesias/ 
dysesthesiasB that are 
disabling or life- 
threatening (Grade 4) 
 
Withdraw from 
study 
Withdraw from 
study 
discontinue 
oxaliplatin 
ACUTE (during or after the 2 
hour infusion) 
laryngopharyngeal 
 
 
dysesthesias (also see 
below) 
Increase duration 
of future infusions 
to 6 hoursC 
Increase duration 
of future infusions 
to 6 hoursC 
Increase duration 
of future infusions 
to 6 hoursC 


 
                                                         
Page 25 
 
S-FOLFOX in HCC 
 
 
1See section 6.4.4 for dose reductions of 5-FU for Hand-Foot-Skin Reaction. 
2No Dose reduction of Oxaliplatin for Grade 3 or 4 Hand-Foot-Skin Reaction. 
3No dose reduction of 5-FU or Oxaliplatin need to be made for asymptomatic Grade 3 or 
4 Amylase or Lipase elevation. 
 
 
Pertains to treatment-related toxicity, not including diarrhea, nausea/vomiting, 
melena/hematemesis, neurologic toxicity (see above).  Sorafenib dose should be 
adjusted as per the table in Section 6.4.1.  For hematologic toxicity, see Section 6.3.2. 
 
Doses of chemotherapy that have been reduced will not be re-escalated.  Patients 
who do not recover to Grade 1 within 6 weeks will go off study. 
 
 
6.4 
Dose Modification for Sorafenib 
 
Expected adverse events from sorafenib: diarrhea (43%), increased lipase (41%), 
increased amylase (30%), nausea (23%), anorexia (16%), vomiting (16%), and 
constipation (15%), rash/desquamation (40%), hand-foot skin reaction (30%), alopecia 
(27%), pruritus (19%), and dry skin (11%), hyperthyroidism, hypertension (17%), 
angioedema, and congestive heart failure, hypoalbuminemia (49%), hemorrhage (15%) 
(i.e., gastrointestinal, respiratory tract and rarely cerebral hemorrhage), dyspnea (14%) 
and cough (13%), hypocalcemia (20%), and hypophosphatemia (40%).   
 
6.4.1 
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. 
 
Dose modification levels for sorafenib 
Dose 
Sorafenib 
Starting Dose 
400 mg twice daily 
1st Dose Reduction 
Level 
400 mg once daily 
2nd Dose Reduction 
Level 
200 mg once daily 
 
 


 
                                                         
Page 26 
 
S-FOLFOX in HCC 
 
 
 
 
6.4.2 Dose modification of sorafenib for hematologic toxicities 
 
 
Recommended Dose Modification of sorafenib for Hematologic Toxicities  
Toxicity 
ANC(x 109/L) 
Hemoglobin 
(g/dL) 
Platelets 
(x 109/L) 
Sorafenib 
Grade 1 
<LLN-1.5 
 LLN – 10.0 
<LLN-75 
Treat on time 
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 
levels1 
Febrile 
Neutropenia 
 
 
 
Sorafenib held until 
toxicity has resolved 
to Grade 2 or less; 
when sorafenib is 
restarted, reduce by 
one dose level2 
ANC - absolute neutrophil count  
1If the patient is at the first dose reduction level (Sorafenib 400mg po QD) or the second dose 
reduction level (Sorafenib 200mg po QD) already, Sorafenib will be discontinued,  
2 If the patient is at the second dose reduction level (Sorafenib 200mg po QD) already, Sorafenib 
will be discontinued,  
 
• 
If no recovery after 21 day delay, treatment should be permanently discontinued. 
        
 
 
 
 
 
6.4.3 
Dose modification for non-hematologic toxicities1 
 
 
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 21 day delay, treatment will be discontinued unless subject is deriving 
clinical benefit 
        


 
                                                         
Page 27 
 
S-FOLFOX in HCC 
 
 
1For sorafenib dose reductions for diarrhea, nausea, and vomiting, see sections 6.3.4.1 and 
6.3.4.2. 
 
For HFSR, sorafenib and 5-FU should be both reduced; 
For diarrhea, sorafenib, 5-FU and oxaliplatin should all be reduced; 
For fatigue, sorafenib, 5-FU and oxaliplatin should all be reduced. 
 
6.4.4 Hand-foot-skin reaction: will dose reduce both sorafenib and 5-FU CI 
 
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  
Hold Sorafenib until resolved to Grade 0-1 
When resuming treatment, decrease dose by one 
dose level1 
 
3rd occurrence  
Hold Sorafenib until resolved to Grade 0-1 
When resuming treatment, decrease dose by two 
dose levels2 
 
4th occurrence 
Discontinue Sorafenib permanently 
Grade 3 
1st occurrence 
Hold Sorafenib and 5-FU until resolved to Grade 0-1 
When resuming treatment, decrease Sorafenib dose 
by one dose level1 and decrease 5-FU by 25% 
 
2nd occurrence 
Hold Sorafenib and 5-FU until resolved to Grade 0-1 
When resuming treatment, decrease Sorafenib dose 
by one dose level1 and decrease 5-FU by 50% 
 
3rd occurrence 
Discontinue treatment permanently 
1 If the patient is at the second dose reduction level (Sorafenib 200mg po QD) already, Sorafenib will be 
discontinued,  
2If the patient is at the first dose reduction level (Sorafenib 400mg po QD) or the second dose reduction 
level (Sorafenib 200mg po QD) already, Sorafenib will be discontinued,  
 
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. 
 
 
 
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 
Pedicurea for subjects with pre-existing hyperkeratosis. 
Subjects should avoid hot water, and clothing or activities 


 
                                                         
Page 28 
 
S-FOLFOX in HCC 
 
 
that can cause friction on the skin. 
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: 
Soak hands in cool water. 
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. 
 
 
6.4.5  Treatment-emergent hypertension 
 
Hypertension is a known and potentially serious AE associated with sorafenib treatment. 
Subjects will undergo brief physical examinations, including blood pressure monitoring, 
on a weekly basis through the first 5 weeks of therapy.  Thereafter, blood pressure will be 
monitored on Day 1 and 15 of each cycle.  
 
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 the management of treatment-emergent hypertension should be 
recorded in the patient’s records. 
 
 
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 systolic BP 
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 


 
                                                         
Page 29 
 
S-FOLFOX in HCC 
 
 
Management of Treatment-Emergent Hypertension 
> 140 mm Hg or diastolic BP>90 mm HG if 
previously within normal limits 
OR  
Grade 3 
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 > 21 days should discontinue sorafenib unless, in the opinion of the 
treating physician, the subject may benefit from continued treatment. 
b:  Subjects requiring dose reductions beyond 200 mg   every day, should discontinue sorafenib. 
 
Doses of sorafenib that have been reduced for any reason will not be re-escalated.  For 
treatment-related non-hematologic toxicities, patients who do not recover to Grade 1 
toxicity within 3 weeks will go off Sorafenib for the duration of the study, but they can 
continue with FOLFOX if they continue to meet treatment criteria for FOLFOX. 
 
6.5 Criteria for Treatment Discontinuation 
In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Patient decides to withdraw from study 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
 
 
 
7.0 STUDY MEDICATION  
 
Commercial supply of all drugs will be used. 
 
7.1  
Sorafenib 
The sorafenib tablets are manufactured by Bayer HealthCare AG, Germany.   
The 200 mg tablet formulation contains sorafenib and the excipients 
croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl 
sulfate, magnesium stearate.  The tablets have a film coating consisting of 
hypromellose, polyethylene glycol, titanium dioxide, and red ferric oxide. The 
formulation is presented as an immediate release (IR) dosage form, (i.e., the active 


 
                                                         
Page 30 
 
S-FOLFOX in HCC 
 
 
ingredient is allowed to completely dissolve under in vitro test conditions within a 
short period of time with no intention of delaying or prolonging dissolution The 
tablets have a salmon color in appearance, weigh approximately 350 mg each, 
and are 10 mm round in shape.  
The active compound of sorafenib is 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-
ureido]-phenoxy}-pyridine-2-carboxylicacidmethylamide-4 
methylbenzenesulfonate, and its molecular weight is 637 Daltons.  
Sorafenib will be given orally at two tablets (200 mgx2) twice daily. 
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.  Missed/vomited doses will not be made up. 
 
7.2 5-FU 
 
7.2.1Description 
 
5-FU is one of the most important drugs used in medical oncology today.  It is the 
key antitumor agent for colorectal carcinoma and is commonly employed in other 
malignancies, including breast cancer, throat cancer, and upper gastrointestinal 
malignancies.  5-FU belongs to the class of 5-fluoropyrimidines.  It is an analogue of the 
pyrimidine uracil.  At the carbon 5 (C-5) position, a fluorine atom is substituted in place of 
hydrogen.  The fluorine atom does not impede the activation of 5-FU to the nucleotide 
level, which is essential to the antitumor activity of these compounds.   
 
Although the precise antitumor mechanism of 5-FU remains uncertain, two pathways are 
thought to be central to its activity in certain cancers.  First, 5-FU is metabolized to 5-
fluoro-uridine triphosphate (FUTP) and is incorporated into RNA.  This interferes with 
RNA synthesis and function.  Second, 5-FU is metabolized to 5-fluoro-2’-deoxyuridylate 
(FdUMP) and acts as a quasi-substrate for the enzyme thymidylate synthase in the 
conversion of dUMP and methyltetrahydrofolate to dTMP and dihydrofolate. This in turn 
reduces pools of available thymidylate synthase, leading to the depletion of dTMP and 
dTTP and the accumulation of dUMP and dUTP, thereby inhibiting DNA synthesis. 
 
7.2.2Drug Administration 
5-FU will be prepared per institutional standard and administered as a continuous 
IV infusion over 46 hours through a central venous port-a-cath on days 1 and 15 .  
An ambulatory infusion pump will be given to each patient, and the 
chemotherapy cartridge will be changed every 2 weeks for each new 
administration of 5FU.   
 
7.2.3 Storage and Stability 


 
                                                         
Page 31 
 
S-FOLFOX in HCC 
 
 
 
Store at room temperature and protect from light.  Dark yellow color indicates 
decomposition.   Inspect for precipitate; if found, agitate or gently heat in water bath.  
Filter ampules with aspiration needle (5 mcm).  Compatible with D5W,  
0.9% NaCl, 
D5LR.  Stable in polypropylene syringes.  Stable in PVC reservoirs for infusion pump for 
12 days.  May adsorb to glass surfaces.  Stable in cellulose nitrate/acetate ester or 
Teflon filters. 
 
7.3 Oxaliplatin 
7.3.1Description 
Oxaliplatin is a third-generation platinum compound with activity in colorectal 
cancer. Its chemical name is trans-1-diaminocyclohexane oxalaplatinum or cis-
[oxalato(trans-1-1,2-diaminocyclohexane) platinum (II)]. 
Oxaliplatin is a white crystalline powder, slightly soluble in water and very slightly 
soluble in methanol but insoluble in ethanol or acetone.  The pH of an aqueous 
solution of 2 mg/mL is between 4.8 and 5.7. 
Oxaliplatin is presented in the form of a freeze-dried powder for infusion in vials 
containing 50 mg and 100 mg of oxaliplatin corresponding with the following 
formula: 
 
 
 
 
 
50 mg vials  
100 mg vials 
Oxaliplatin 
 
 
 
50 mg  
 
100 mg 
Lactose monohydrate 
 
450 mg 
 
900 mg 
Nominal volume of vial 
 
36 mL  
 
50 mL 
 
The finished product is presented in the form of a white to off-white cake or 
powder contained in a clear glass vial, sealed with a rubber stopper and 
aluminum seal with a flip-over cover. 
 
7.3.2 Drug Administration 
The freeze-dried powder is reconstituted by adding 10 to 20 mL (for the 50 mg 
vials) or 20 to 40 mL (for the 100 mg vials) of water for injection or 5% glucose 
solution and then by diluting in an infusion solution of 250 mL or 500 mL of 5% 
glucose solution.  Do not administer undiluted.  Dispose of any reconstituted 
solution that shows evidence of precipitation.  The reconstitution or final dilution 
must never be performed with a sodium chloride solution.  Oxaliplatin is 
incompatible with sodium chloride. 
 
Do not combine with alkaline medications or media which cause oxaliplatin to 
degrade.  Do not administer simultaneously by the same infusion line; flush line 
after oxaliplatin administration.  Do not use for the preparation or administration 
needles or intravenous infusion sets containing aluminum components (there is a 
risk of degrading oxaliplatin). 
 
Oxaliplatin will be administered at a dose of 85 mg/m2 intravenously as a 2 – 6 
hour infusion on days 1 and 15 of each cycle. 
 


 
                                                         
Page 32 
 
S-FOLFOX in HCC 
 
 
Antiemetics should be prescribed by the treating physician as clinically indicated 
if a patient develops nausea and/or vomiting.  It is recommended that patients 
receive ondansetron (Zofran) 16 mg IV or granisetron (Kytril) 10 mcg/kg IV +/- 
prochlorperazine (Compazine) 10 mg PO or lorazepam (Ativan) 1-2 mg PO or IV 
30 minutes prior to oxaliplatin administration if clinically indicated.  Alternatively, 
oral forms of these antiemetics may be used at the treating investigator’s 
discretion. 
 
7.3.3 Storage and Stability 
Information on expiration dates of oxaliplatin will be supplied on a lot-by-lot basis.  
The compound may be stored as freeze-dried powder for 3 years at room 
temperature.  Reconstituted solution may be stored in 5% glucose solution or water 
for injection in the original vial for up to 48 hours between 5o to 30o C.  After dilution 
in 5% glucose solution for infusion, the shelf-life is 24 hours at room temperature. 
 
7.4 Leucovorin 
 
7.4.1 Description 
Leucovorin calcium is commercially available in 50 mg, 100 mg, 350 mg vials for 
reconstitution. 
 
Please refer to the package insert for complete product information. 
 
7.4.2 Drug Administration 
Leucovorin will be administered as an IV infusion over 2 – 6 hours either concurrently 
with oxaliplatin through a separate line, or after oxaliplatin administration if a second 
line is not available. This can also be administered by institutional standard of care 
procedure policy. 
 
Leucovorin may be reconstituted with BWI or with sterile water for injection. Solutions 
should be further diluted in D5W, 0.9% Sodium Chloride, or Ringers solution for 
infusion over two hours. 
 
7.4.3 Storage and Stability  
Intact vials should be stored at room temperature and protected from light. Solutions 
reconstituted with bacteriostatic water for injection (BWI) are stable for at least 7 days at 
room temperature. 
 
7.5 Supportive Care Guidelines 
 


 
                                                         
Page 33 
 
S-FOLFOX in HCC 
 
 
7.5.1 H2 blockers or proton pump inhibitors can be prescribed for all patients as clinically 
indicated. 
 
7.5.2 Management of nausea and vomiting 
Antiemetics should be prescribed by the treating physician as clinically indicated if 
a patient develops nausea and/or vomiting. 
 
7.5.3 Anticoagulants 
See exclusion criteria section. 
 
7.5.4 Growth factors 
Prophylactic use of a colony-stimulating factor (G-CSF or GM-CSF) is not 
permitted on this trial.  Nonetheless, use of a colony-stimulating factor for the 
treatment of febrile neutropenia as per American Society of Clinical Oncology 
guidelines is permissible (Bennett et al.  J. Clin Oncol 1996 Sep; 14(9):2511-2520).  
Use of erythropoietin (including Procrit and Aranesp) for treatment of disease or 
treatment-related anemia is permitted. 
 
 
7.5.5 Anti-Hypertensives 
Patients who develop hypertension while on sorafenib may be treated with anti-
hypertensive agents at the investigator’s discretion.  Dose modification for Grade 
3 or 4 hypertension is described in Section 6.0. 
 
7.6      Medications to Avoid 
• Avoid use of  drugs that are known potent CYP3A4 inducers, including but not 
limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. 
John’s wort.  These drugs can decrease systemic exposure to sorafenib and 
should be avoided. For participants who discontinue sorafenib while on study, 
please note that the use of anti-emetic CYP3A4 inducers is allowed. 
• Avoid use of drugs that prolong QTc.  If these drugs must be used, monitor QTc 
closely at the discretion of the treating physician. 
 
8.0 Correlative Studies 
Please see Appendix C. 


 
                                                         
Page 34 
 
S-FOLFOX in HCC 
 
 
9.0 Study Calendar 
 
Screening 
Sorafenib 
2wk Lead-In 
Cycle 1 
Cycle 2 and 
subsequent cycles 
Every 8 
weeks 
End of 
Treatment6 
Study Week 
-3 
-2 
-1 
1 
2 
1 
2 
3 
4 
1 
2 
3 
4 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Weight 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Performance 
Status 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Toxicity  
 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Vital signs 
(including BP) 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Physical exam 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
CBC w/diff 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Platelets 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Urinalysis8 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
PT-INR 
 
X 
 
X1 
 
X 
 
 
 
X 
 
 
 
 
 
Glucose 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
BUN 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Creatinine 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Uric acid 
 
X 
 
X1 
 
X 
 
 
 
X 
 
 
 
 
 
Total Bilirubin 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Alk phos 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
LDH 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Protein 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Albumin 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
AST/ALT 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Calcium, Phos 
 
X 
 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Amylase 
 
X 
 
X1 
 
X 
 
 
 
X 
 
 
 
 
 
Lipase 
 
X 
 
X1 
 
X 
 
 
 
X 
 
 
 
 
 
AFP 
 
X 
 
X1 
 
X 
 
 
 
X 
 
 
 
 
 
Hepatitis BsAg, 
cAb, sAb 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C Ab 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(serum or urine) 
 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
Measurement 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
X2 
C/A/P CT or 
MRI 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
X4 
Sorafenib 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
mFOLFOX 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Correlative 
Studies7 
 
 
 
X 
and
D3 
 
X 
 
X 
 
X 
 
 
 
 
 


 
                                                         
Page 35 
 
S-FOLFOX in HCC 
 
 
 
1. Screen assessments need not be repeated for lead-in period. 
 
2. Baseline measurements of tumor by radiographic means should be completed within 21 
days prior to treatment and should include full evaluation of the extent of metastatic 
disease.  Assessments are repeated every 2 cycles (8 weeks).   Responses must be 
confirmed after 4-8 weeks with repeat radiological scans. 
 
3. Hepatitis B and C serology as listed in the study calendar must be obtained within 120 
days of study enrollment. 
 
4. If abdominal/pelvic CT scan or abdominal MRI are chosen as the  radiographic means 
of tumor measurement, then the same test should be repeated consistently every two cycles 
(8 weeks).  If chest CT or chest MRI are chosen as the radiographic means of tumor 
measurement, then the same test should be repeated consistently every 2 cycles (8 weeks). 
 
5. Female patients of childbearing potential only, within 7 days of initiation of treatment.  
 
6.  Every 6 months thereafter 
 
7.  Circulating endothelial cells and plasma levels of growth factors will be assessed on 
Day 1 (prior to first dose of sorafenib later that day) and Day 3 of lead-in phase, and on 
C1D1, C1D15, and C2D1 of FOLFOX-Sorafenib, and, if available, at the time of 
progression (see Appendix C for details). The Day 3 correlative can be drawn on Day 3, 4, 
or 5. The Day 15 correlative can be drawn on Day 14, 15, or 16. The Day 29 correlative 
can be drawn on Day 27, 28, or 29.  An optional posttreatment tumor biopsy will be 
obtained any time from Day 10 to Day 14 of the lead-in phase in patients who consent to a 
posttreatment tumor biopsy (see Appendix D for details). 
8.  24 hr urine must be done for 2+urine 
 
10.0 Evaluation of Response 
All patients with measurable disease who have received the first cycle of treatment and 
had a tumor re-assessment will be considered evaluable for response.  In addition, those 
patients who develop early progressive disease or who discontinue early from the study 
due to toxicity will also be considered evaluable for response.  Patients on therapy for at 
least the first cycle of treatment will have their responses classified according to the 
definitions below. 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the RECIST (Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
committee.  Changes in only the largest diameter (unidimensional measurement) of the 
tumor lesions are used in the RECIST criteria. 
 
 
 


 
                                                         
Page 36 
 
S-FOLFOX in HCC 
 
 
 
 
 
 
10.1Definitions 
Measurable disease - the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should 
be confirmed by cytology/histology.  
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter 20 mm using conventional techniques or 10 mm 
with spiral CT scan. 
 
Non-measurable lesions - all other lesions, including small lesions (longest diameter 
<20 mm with conventional techniques or <10 mm with spiral CT scan), i.e., bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory 
breast disease, lymphangitis cutis/pulmonis, cystic lesions, and also abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions 
and lesions occurring within a previously irradiated area unless they are 
documented as new lesions since the completion of radiation therapy. 
 
Target/Non-target Lesions - all measurable lesions up to a maximum of five lesions 
per organ and 10 lesions in total, representative of all involved organs should be 
identified as target lesions and  recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) for all target lesions 
will be calculated and reported as the baseline sum LD. The baseline sum LD will 
be used as reference by which to characterize the objective tumor.  All other 
lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but 
the presence or absence of each should be noted throughout follow-up. 
 
10.2 Response Criteria   
 
Method of Tumor Response Assessment 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and at reassessment during 
treatment.  Imaging-based evaluation is preferred to clinical examination. Clinical 
lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended. CT and MRI are the best currently available and reproducible 
methods to measure target lesions selected for response assessment. 
Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. Lesions on chest X-ray are acceptable as measurable 


 
                                                         
Page 37 
 
S-FOLFOX in HCC 
 
 
lesions when they are clearly defined and surrounded by aerated lung. However, 
CT is preferable.  Ultrasound is not an acceptable method of disease assessment. 
 
Definition of Response 
 
Overall tumor response will be based on an integration of the evaluation of target, 
non-target, and new lesions, as described below: 
 
Evaluation of target lesions 
 
Complete Response (CR):   Disappearance of all clinical and radiological 
evidence of target lesions. 
 
Partial Response (PR):  A 30% or greater decreased in the sum of LD of all 
lesions in reference to the baseline sum LD. 
 
Stable Disease (SD):  Neither sufficient increase to qualify for PD nor 
sufficient shrinkage to qualify for PR. 
 
Progressive Disease (PD):  A 20% or greater increase in the sum of  LD of 
all target lesions, taking as reference the smallest sum LD recorded since 
baseline. 
 
To be assigned a status of PR or CR, changes in tumor measurements must 
be confirmed by repeat evaluations which should be performed no less than 
4 weeks after the criteria for response are first met. 
 
Evaluation of non-target lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions. 
 
Non-Complete Response, Non-Progressive Disease (Non-CR, Non-PD):  
Persistence of one or more non-target lesions. 
 
Progressive Disease (PD):  Unequivocal progression of existing non-target 
lesion(s). 
 
Note:  Increased uptake on bone scan alone is insufficient evidence 
of progression; additional evidence of progressive disease would be 
present to declare unequivocal progression. 
 
Evaluation of new lesions 
 
No:  There are no new lesions. 
 


 
                                                         
Page 38 
 
S-FOLFOX in HCC 
 
 
Yes:  New lesions are present.  Note:  If new lesions are present, the patient 
is considered to have progressive disease overall. 
 
Overall Response 
 
Overall response will be determined as tabulated below, based on the 
evaluation of target, non-target, and new lesions: 
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
To be assigned a status of PR or CR, changes in tumor measurements must 
be confirmed by repeat assessments that should be performed no less than 
4 weeks after the criteria for response are first met. Longer intervals as 
determined by the study protocol may also be appropriate. 
 
In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval (in general, not less than 
6-8 weeks) that is defined in the study protocol. 
 
Every effort should be made to document tumor measurements and extent 
of disease, even after discontinuation of therapy, in order to classify patients 
for overall response as described above.  Patients who do not have tumor 
response assessment due to rapid progression or toxicity will be considered 
as non-responders, will be included in the denominator for the response rate, 
and will be classified into one of the following categories: 
 
- 
death attributed to disease progression 
- 
deterioration attributed to disease progression 
- 
death attributed to drug toxicity 
- 
early discontinuation attributed to drug toxicity 
 
Note:  If a patient receives subsequent therapy before tumor progression is 
documented, the reason for changing therapy must be reported; reasons 


 
                                                         
Page 39 
 
S-FOLFOX in HCC 
 
 
include clinical progression, drug toxicity, or secondary therapy for 
maintenance of tumor response. 
 
Duration of Overall Response 
The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever status is recorded first) until the first 
date that recurrence or PD is objectively documented, taking as reference for 
PD the smallest measurements recorded since the treatment started.  
Patients who do not relapse will be censored at the day of their last tumor 
assessment. 
 
Time to response 
 Time from date of initial treatment until first objective documentation of 
response. 
 
Time to tumor progression 
Time from date of initial treatment to first objective documentation of 
progressive disease or death.  Patients who die without a reported prior 
progression will be considered to have progressed on the day of their death.  
 
Time to treatment failure 
Time from date of initial treatment to first objective documentation of 
progressive disease, or off study date, whichever occurs first. 
 
Time to death 
  
 
Time from date of initial treatment to date of death 
 
11.0 REPORTING OF ADVERSE EVENTS 
 
11.1Adverse Event and Reporting Definitions (CTCAE version 4.0) 
 
In the event of an adverse event, the first concern will be for the safety of the subject.  
Investigators are required to report to Bayer Drug Safety any serious adverse event, 
whether expected or unexpected, and which is assessed by the investigator to be 
reasonably or possibly related to or caused by sorafenib.  All events meeting these 
criteria will be reported for the time period beginning with any amount of exposure to 
sorafenib through the protocol-defined follow-up period.  Serious criteria, definitions, and 
guidance for reporting follow. 
 
An adverse event (AE) is any untoward medical occurrence in a subject participating in 
an investigational study or protocol regardless of causality assessment.  An adverse 
event can be an unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, syndrome or disease associated with or occurring during the use of 
an investigational product whether or not considered related to the investigational 
product. 


 
                                                         
Page 40 
 
S-FOLFOX in HCC 
 
 
 
Serious adverse events (SAE) are adverse events occurring at any dose which meet 
one or more of the following serious criteria: 
 
• Results in death (i.e. the AE caused or lead to death) 
 
• Is life-threatening (i.e. the AE placed the subject at immediate risk of death; it does 
not apply to an AE which hypothetically might have caused the death if it were more 
severe) 
 
• Requires or prolongs inpatient hospitalization (i.e. the AE required at least a 24-hour 
inpatient hospitalization or prolonged a hospitalization beyond the expected length of 
stay; hospitalizations for elective medical/surgical procedures, scheduled treatments, or 
routine check-ups are not SAEs by this criterion) 
 
• Is disabling (i.e. the AE resulted in a substantial disruption of the subject’s ability to 
carry out normal life functions) 
 
• Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of 
a subject exposed to the study drug prior to conception or during pregnancy) 
 
• It does not meet any of the above serious criteria but may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed 
above 
 
Expected adverse events are those adverse events that are listed or characterized in 
the Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified.  This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B.  For example, 
under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred 
to elevated hepatic enzymes or hepatitis. 
 
11.2 Reporting of Serious Adverse Events  
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 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.  
 


 
                                                         
Page 41 
 
S-FOLFOX in HCC 
 
 
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:  
 
  
 
Facsimile:    
 
  
 
Address: 
 
Global Pharmacovigilance - USA  
Mail only: 
 
Bayer HealthCare Pharmaceuticals Inc. 
  
  
 
Address:   
 
  
   
  
 
Reports for all Bayer products can also be phoned in via our Clinical 
Communications Dept:  
 
Phone:  
 
 
 
AND: 
Dana Farber Cancer Institute IRB/ OHRS  
450 Brookline Avenue, 
Boston, MA 02115 
 
Phone:  
 
Fax:  
 
 
MedWatch 3500 Reporting Guidelines: 
 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500 form: 
 


 
                                                         
Page 42 
 
S-FOLFOX in HCC 
 
 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow-up information:   
 
Additional information may be added to a previously submitted report by any of the 
following methods: 
 
• Adding to the original MedWatch 3500 report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500 form  
• Summarizing new information and faxing it with a cover letter including subject 
identifiers (i.e. D.O.B. initial, subject number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted  (The patient identifiers are important so that the new 
information is added to the correct initial report) 
 
Occasionally Bayer may contact the reporter for additional information, clarification, or 
current status of the subject for whom and adverse event was reported.  For questions 
regarding SAE reporting, you may contact the Bayer Drug Safety representative noted 
above. 
 
Study Drug Relationship: 
 
The investigator will determine which events are associated with the use of study drug.  
For reporting purposes, an AE should be regarded as possibly related to the use of the 
investigational product if the investigator believes: 
 
• There is a clinically plausible time sequence between onset of the AE and sorafenib 
administration; and/or 
• There is a biologically plausible mechanism for sorafenib causing or contributing to 
the AE; and 
• 
The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures. 
 


 
                                                         
Page 43 
 
S-FOLFOX in HCC 
 
 
Follow-up Reports 
 
• The Investigator should take all appropriate measures to ensure the safety of the 
patients, notably he/she should follow up the outcome of any Serious Adverse Event 
submitted to the FDA on a 3500 form and complete follow-up forms as necessary.  
The patient must be followed up until clinical recovery is complete and/or laboratory 
results have returned to normal. This may mean that follow-up will continue after the 
patient has completed the trial and that additional investigations may be necessary.  
 
• Any reportable Serious Adverse Events brought to the attention of the Investigator at 
any time after cessation of the trial and considered by him/her to be reasonably 
associated with medication administered during the period should also be submitted 
to the FDA.  As for initial reports, a copy is to be provided to Sanofi-Synthelabo New 
York Safety Surveillance or the appropriate manufacturer of the product. within 24 
hours after FDA submission (see above) 
 
• The 3500 form providing follow-up information about a reportable SAE must be 
submitted to the FDA as soon as possible or within 15 calendar days.  
 
• As with the initial submission to the FDA of the 3500 form, the principal investigator is 
also responsible for providing all follow-ups for reportable Serious Adverse Events (on 
form 3500) to the IRB and co/sub-investigators (Dear Investigator Letter) participating 
on this protocol. 
 
IND Annual Report  
The principal investigator is responsible for preparing and submitting the IND annual 
reports to the FDA (CFR312.33) within 60 days of the anniversary date that the IND went 
into effect. A copy of the report shall be provided to New York Safety Surveillance within 
24 hours of submission to the FDA. 
 
12.0 Data Safety and Monitoring 
     12.1  Method 
 
The QACT will collect, manage, and monitor data for this study. 
 
     12.2 Data Submission 
The schedule for completion and submission of case report forms (paper 
or electronic) to the QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 


 
                                                         
Page 44 
 
S-FOLFOX in HCC 
 
 
On Study Form 
Within 14 days of registration 
Baseline Assessment 
Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the 
cycle 
Adverse Event Report 
Form 
Within 10 days of the last day of the 
cycle 
Response Assessment 
Form 
Within 10 days of the completion of the 
cycle required for response evaluation 
Off Treatment/Off Study 
Form 
Within 14 days of completing treatment 
or being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined 
follow up visit date or call 
 
     12.3 Safety Meetings 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and 
monitor toxicity and accrual data from this trial. The committee is composed of 
clinical specialists with experience in oncology and who have no direct 
relationship with the study. Information that raises any questions about 
participant safety will be addressed with the Principal Investigator and study 
team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-
date participant accrual; current dose level information; DLT information; all 
grade 2 or higher unexpected adverse events that have been reported; summary 
of all deaths occurring within 30 days for Phase I or II protocols; for gene transfer 
protocols, summary of all deaths while being treated and during active follow-up; 
any response information; audit results, and a summary provided by the study 
team. Other information (e.g. scans, laboratory values) will be provided upon 
request. 
 
     12.4 Monitoring 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by 
representatives designated by the DF/HCC Overall Principal Investigator (or 
Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these 


 
                                                         
Page 45 
 
S-FOLFOX in HCC 
 
 
activities were conducted and data were recorded, analyzed, and accurately 
reported in accordance with the protocol, institutional policy, Good Clinical 
Practice (GCP), and any applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and 
adherence to protocol requirements. Monitoring will begin at the time of 
participant registration and will continue during protocol performance and 
completion. 
 
13.0 Regulatory Considerations 
    13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) 
and any other necessary documents must be submitted, reviewed and approved 
by a properly constituted IRB governing each study location.  
 
Any changes made to the protocol must be submitted as amendments and must 
be approved by the IRB prior to implementation. Any changes in study conduct 
must be reported to the IRB. The DF/HCC Overall Principal Investigator (or 
Protocol Chair) will disseminate protocol amendment information to all 
participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
 
     13.2 Informed Consent 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file. 
 
     13.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, 
which represent good and sound research practice: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM12951
5.pdf  


 
                                                         
Page 46 
 
S-FOLFOX in HCC 
 
 
• 
US Code of Federal Regulations (CFR) governing clinical study 
conduct and ethical principles that have their origin in the Declaration 
of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr11 02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr50 02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical 
Investigators 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr54 02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr56 02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr312 02.html  
• 
State laws 
• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-
research-unit-cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except 
when necessary to eliminate an immediate hazard to a research participant. 
In such case, the deviation must be reported to the IRB according to the 
local reporting policy.  
     13.4 Study Documentation 
The investigator must prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the 
study for each research participant. This information enables the study to be 
fully documented and the study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include 
but are not limited to hospital records, clinical charts, laboratory and pharmacy 
records, recorded data from automated instruments, microfiches, photographic 
negatives, microfilm or magnetic media, and/or x-rays.  
     13.5 Records Retention 
All study-related documents must be retained for the maximum period 
required by applicable federal regulations and guidelines or institutional 
policies.  
     13.6 Multi-center Guidelines 


 
                                                         
Page 47 
 
S-FOLFOX in HCC 
 
 
N/A 
 
14.0 STATISTICAL CONSIDERATIONS 
14.1  Target Sample Size  
 
Forty patients will be entered in this phase II study.  Assuming the accrual rate is 
2-3 patients per month, the accrual will be completed in 18 months or less. 
 
14.2Planned Efficacy Evaluations 
 
14.2.1 Primary Efficacy Variables 
 
The primary objective of this study is time to tumor progression (TTP).  A sample size of 
40 achieves 80% power to detect the difference between the null hypothesis median TTP 
of 5 months and an alternative hypothesis median TTP of 7 months at a 10% significance 
level using a one-sided test based on the elapsed time, assuming a study follow-up period 
of 24 months.   The total study duration will be 42 months (18 months of accrual + 24 
months of follow-up). 
 
14.2.2 Secondary Efficacy Variables 
 
The secondary objectives are to assess the toxicity profiles of this regimen and the 
preliminary data on response rate and overall survival.  Overall survival is defined as the 
time from study entry until death from any cause.   Overall survival will be calculated using 
the Kaplan-Meier method, and confidence limits for survival estimates will be calculated 
using the Greenwood formula.  Progression free survival is defined as the time from study 
entry until disease progression or death from any cause.  Response rate is defined as the 
percentage of patients achieving either CR or PR.  Duration of response is defined as the 
time interval from the initial response to the time disease progression is observed. 
 
All categories of toxicity and complications of the treatment will be recorded. Toxicity and 
complications of the treatment will be assessed based on reports of adverse events, 
physical examinations, and laboratory measurements. 
 
 
 
REFERENCES/BIBLIOGRAPHY 
 
1. 
Parkin DM, Bray F, Ferlay J, et al: Global cancer statistics, 2002. CA Cancer 
J Clin 55:74-108, 2005 
 
2. 
El-Serag HB, Davila JA, Petersen NJ, et al: The continuing increase in the 
incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 
139:817-23, 2003 
 
3. 
Llovet JM, Bruix J: Molecular targeted therapies in hepatocellular 
carcinoma. Hepatology 48:1312-27, 2008 


 
                                                         
Page 48 
 
S-FOLFOX in HCC 
 
 
 
4. 
Carlomagno F, Anaganti S, Guida T, et al: BAY 43-9006 inhibition of 
oncogenic RET mutants. J Natl Cancer Inst 98:326-34, 2006 
 
5. 
Wilhelm SM, Carter C, Tang L, et al: BAY 43-9006 exhibits broad spectrum 
oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine 
kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099-109, 2004 
 
6. 
Abou-Alfa GK, Schwartz L, Ricci S, et al: Phase II Study of Sorafenib in 
Patients With Advanced Hepatocellular Carcinoma. J Clin Oncol, 2006 
 
7. 
Llovet J, Ricci S, Mazzaferro V, et al: Sorafenib improves survival in 
advanced Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-
controlled trial (SHARP trial). Journal of Clinical Oncology, 2007 ASCO Annual Meeting 
Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: LBA1, 2007 
 
8. 
Cheng AL, Kang YK, Chen Z, et al: Efficacy and safety of sorafenib in 
patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III 
randomised, 
double-blind, 
placebo-controlled 
trial. 
The 
Lancet 
Oncology 
doi:10.1016/S1470-2045(08)70285-7, 2008 
 
9. 
Yeo W, Mok TS, Zee B, et al: A randomized phase III study of doxorubicin 
versus 
cisplatin/interferon 
alpha-2b/doxorubicin/fluorouracil 
(PIAF) 
combination 
chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 97:1532-8, 
2005 
 
10. 
Louafi S, Boige V, Ducreux M, et al: Gemcitabine plus oxaliplatin (GEMOX) 
in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. 
Cancer 109:1384-90, 2007 
 
11. 
S. Qin, Y. Bai, S. Ye, et al: Phase III study of oxaliplatin plus 5-
fluorouracil/leucovorin 
(FOLFOX4) 
versus 
doxorubicin 
as 
palliative 
systemic 
chemotherapy in advanced HCC in Asian patients. J Clin Oncol 28:15s, 2010 (suppl; abstr 
4008) 2010 
 
12. 
Wilhelm SM, Adnane L, Newell P, et al: Preclinical overview of sorafenib, a 
multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase 
signaling. Mol Cancer Ther 7:3129-40, 2008 
 
13. 
Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced 
hepatocellular carcinoma. N Engl J Med 359:378-90, 2008 
 
14. 
Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial 
of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with 
previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 
 
15. 
Zhu AX, Duda DG, Sahani DV, et al: HCC and angiogenesis: possible 
targets and future directions. Nat Rev Clin Oncol 8:292-301 
 
16. 
Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, 
Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in 
patients with advanced hepatocellular carcinoma: a randomized trial.JAMA. 2010 Nov 
17;304(19):2154-60. 
 
17.  
T CP, Cheung FY, Lee AS, Yau TK, Choo SP, Lau J, Wong JS, Fan ST, 
Poon RT. Phase II trial of sorafenib with capecitabine and oxaliplatin (SECOX) in patients 
with locally advanced or metastatic hepatocellular carcinoma. Joint ECCO 15 – 34th 
ESMO Multidisciplinary Congress 2009; Berlin: European Journal of Cancer 
Supplements; 2009. p. Pages 1-24. 
 


 
                                                         
Page 49 
 
S-FOLFOX in HCC 
 
 
 
 
 


 
                                                         
Page 50 
 
S-FOLFOX in HCC 
 
 
APPENDIX  A: CLIP score and CTP classification  
CLIP Score
Variables
0
1
2
CTP score
A
B
C
Tumor Morphology Solitary &  Multiple &   Massive or
extension extension     extension
</= 50%     < /= 50%      > 50%
AFP
<400
> 400
PV thrombosis
No
Yes 
The CLIP Investigators, Hepatology 28:751-55, 1998.
 
Child-Turcotte-Pugh (CTP) 
Classification
Points
1
2
3
Bilirubin
< 2
2-3
>3
Albumin
>3.5
2.8-3.5
<2.8
Prothrombin time
<4 
4-6
>6
Encephalopathy
None
I-II
III-IV
Ascites
None
Slight
Moderate
Grade A
CTP score 5-6
Grade B
CTP score 7-9
Grade C
CTP score 10-15
 
 
 
APPENDIX  B: Barcelona Clinic Liver Cancer (BCLC) Staging 


 
                                                         
Page 51 
 
S-FOLFOX in HCC 
 
 
 
Llovet, J. M. et al. J. Natl. Cancer Inst. 2008 100:698-711
BCLC Staging and Treatment Strategy 


 
                                                         
Page 52 
 
S-FOLFOX in HCC 
 
 
Appendix C: Correlative Studies on Plasma Biomarkers 
Exploratory analyses of potential biomarkers of sorafenib activity will be performed by 
measuring proteins in the plasma on Day 1 (prior to first dose of sorafenib later that day) 
and Day 3 of lead-in phase, and on C1D1, C1D15 and C1D29 of FOLFOX-Sorafenib, 
and if available, at the time of progression. Plasma analysis will be carried out for a 
panel of circulating angiogenic and inflammatory molecules previously identified by 
others and us as potential biomarkers of response in HCC. They include soluble 
VEGFR1 (sFLT1), VEGF, placental-derived growth factor (PlGF), basic fibroblast 
growth factor (bFGF), interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF-
) using 2 multiplex protein array plates from Meso-Scale Discovery (Gaithersburg, 
MD), soluble VEGFR2, angiopoietin 2 (ANG2), HGF hepatocyte growth factor (HGF), 
soluble c-KIT, carbonic anhydrase 9 (CAIX) and stromal-derived factor 1 (SDF1) from 
R&D Systems (Minneapolis, MN).  Samples will be run in duplicate.  
 
Supplies 
The following supplies are needed for each blood sample drawn: 
• EDTA blood collection tubes (Sarstedt, #03.1068) 
 
Sample Labels 
Prior to use, EDTA tubes should be labeled with the following information: 
• Patient Initials 
• Patient ID number 
• Protocol number 
• Collection date 
• Institution 
 
Collection and handling (Please see attached Biomarker Manual for full details) 
Approximately 8 cc of venous blood will be collected in each of 2 EDTA blood collection 
tubes (Sarstedt, #03.1068). The tubes should be gently inverted several times to ensure 
mixing with the anticoagulant and kept on wet ice at all times. Within two hours the 
tubes should be sent to: 
Steele Laboratory 
 
 
 
 
   
 
 
 
 
 
 


 
                                                         
Page 53 
 
S-FOLFOX in HCC 
 
 
Appendix D: Tissue Collection Protocol 
 
To be considered for the optional posttreatment tumor biopsy, the patient must have 
adequate tissue on their baseline biopsy (i.e. core biopsy) to have all necessary 
correlative studies run on the sample.  The treating physician must also deem them to 
be a reasonable candidate for tumor biopsy based on laboratory and clinical evaluation.  
The optional posttreatment tumor biopsy  will be obtained any time from Day 10 to Day 
14 of the lead-in phase in patients who consent to a posttreatment tumor biopsy (n=6-
12). Only patients getting their treatment at MGH will be eligible for the posttreatment 
biopsy and the biopsy-related correlative studies given that all samples need to be 
processed at the Steele Lab. 
 
Gene expression profiles on the biopsy on the baseline and posttreatment biopsy 
samples will be assessed by laser capture microdissection (LCM) and quantification of 
genes by qPCR. These analyses will provide the first glimpse into the mechanism of 
action of sorafenib in HCC. 
 
Supplies: 
Tissue-Tek ®:  Cryomold 
• Standard size 25x20x5mm (#4557) 
o Fisher Scientific Cat# NC9511236 
OR 
• Intermediate size 15x15x5mm (#4566) 
o Fisher Scientific Cat# NC9542860 
Tissue-Tek ®:  O.C.T. Compound, 4oz (#4583): Fisher Scientific Cat# NC9638938 
 
Small specimen bag: Fisher Cat# 01-002-37 (or equivalent) 
Forceps: Fisher Cat# NC9832137 (or equivalent) 
Dry Ice and Cooler 
Cryoware Pen: Fisher Cat# 13-382-88 
 
Procedure: 
1. Bring all supplies needed to the biopsy as the tissue needs to be frozen immediately. 
2. Squeeze small amount of OCT into cyromolds* – enough for there to be a thin layer 
covering the bottom. 
3. As soon as the specimen is ready, use disposable forceps to gently place only 1 core 
into each cryomold. 
4. You should ideally collect between 3 and 5 separate cores. 
5. Once the specimen is in the cryomold, cover with more OCT making sure the tissue is 
entirely submerged. 
6. Immediately place cryomold with OCT and tissue onto dry-ice making sure the 
cryomold is level and will not tip over. 
7. The OCT will freeze into a solid white block within 5-10 minutes 


 
                                                         
Page 54 
 
S-FOLFOX in HCC 
 
 
8. Once the blocks have completely frozen they can be put into a specimen bag and 
sealed. More than one block can be put into a bag. 
9. The bag should be labeled with: 
 
a. Patient name 
b. MGH Study #: 12-218 
c. MGH MRN # 
d. Date of biopsy 
e. Time Point (Biopsy #1, Biopsy #2, etc) 
f. Number of blocks in the bag 
 
10. All research tissue should then be sent to the Steele Lab at MGH (Cox 734) on the 
day of collection. 
Attn.: 
 
 
 
 
   
 
 
 
*If time permits, the cryomolds can be placed onto the dry-ice once a thin layer of OCT 
has been put it but before the tissue is put in. Once this is frozen or begins to freeze, the 
tissue can be placed on top of the now frozen OCT and then covered with more liquid 
OCT and then placed back onto the dry ice to freeze completely.