Clinical trial NCT00917462
Conditions: Esophageal Cancer Gastroesophageal Junction Cancer
Keywords: ESOPHAGUS BAY 43-9006 (SORAFENIB) 09-016 Nexavar®.
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2009-06-01; Completion date: 2018-08-01
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Sorafenib is a drug being studied for the treatment of cancer. Sorafenib has been shown to block certain proteins on the surface of some cancer cells called "growth factor receptors." Blocking these growth factor receptors can slow or stop cancer cell growth.

Sorafenib is also known as Nexavar®. It has been studied in other types of cancers, including kidney cancer, and has been approved by the Food and Drug Administration (FDA) for treating advanced kidney cancer. Because it is not approved by the FDA for treating esophageal cancer, it is considered an experimental treatment.

The purpose of this study is to determine what effects sorafenib has on advanced esophageal cancer. These effects include whether sorafenib can shrink the tumor or slow down its growth and what side effects sorafenib will have on the tumor.

Detailed description:

Arms: arm 1: Sorafenib for patients with metastatic or recurrent esophageal and gastroesophageal junction cancer.
Interventions: intervention 1: Sorafenib, administered orally intervention 2: CT/MRI
Intervention descriptions: intervention 1: Sorafenib 400 mg twice daily administered continuously. Patients will continue on treatment until progression of disease. Each cycle consists of 28 days. The cycle start date will coincide with the physician visit date. Because of the potential need for physician visit scheduling to vary (due to both physician and patient issues), to avoid violation of, and deviation from, the protocol, these visits may vary by up to one to fourteen (1-14) days. A study diary will be completed by patients to ensure compliance with the study drug. intervention 2: A CT (computerized tomography) or MRI (magnetic resonance imaging) scan of the chest and abdomen will be obtained at baseline, after the first four weeks of therapy, at eight weeks, and then every eight weeks there afterwith a scheduling window of up to one to fourteen (1-14) days. The same imaging modality performed at baseline (CT or MRI) will be repeated at subsequent imaging.

Protocol documents:
Prot_SAP_000.pdf: 
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Phase II Trial Of Sorafenib For Patients With Metastatic Or Recurrent Esophageal And 
Gastroesophageal Junction Cancer 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
 
Principal Investigator/Department: David H. Ilson, MD, PhD 
Department of Medicine 
 
 
Co-Principal 
Investigator(s)/Department: 
Yelena Janjigian, MD 
Department of Medicine 
 
 
Investigator(s)/Department: 
Ghassan Abou-Alfa, MD 
Neil Segal, MD, PhD 
James Harding,MD 
Anna Varghese, MD 
Andrew Epstein, MD 
Zsofia Stadler,MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Diane Reidy-Lagunes, MD 
Eileen O’Reilly, MD 
Leonard Saltz, MD 
Andrea Cercek, MD 
Kenneth H. Yu, MD 
Maeve Lowery, MD 
Rona Yaeger, MD 
Louis Fuqua, MD 
Laura Tang, MD 
Marinela Capanu, PhD 
Department of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Department of Radiology 
Department of Pathology 
Department of Biostatistics 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 


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Consenting 
Professional(s)/Department: 
Ghassan Abou-Alfa MD 
 
David Ilson, MD, PhDYelena Janjigian, 
MD 
Neil Segal, MD, PhD 
David Kelsen MD 
Nancy Kemeny MD 
Geoffrey Ku, MD 
Eileen O’Reilly MD 
Diane Reidy-Lagunes, MD 
Leonard Saltz MD 
Andrea Cercek, MD 
Kenneth H. Yu, MD 
Maeve Lowery, MD 
Rona Yaeger, MD 
Department of Medicine 
 
 
 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 


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IRB#:09-016 A() 
 
TABLE OF CONTENTS 
 
 
 
1.0 PROTOCOL SUMMARY .......................................................................................... 3 
 
 
2.0 OBJECTIVES AND SCIENTIFIC AIMS .................................................................... 4 
2.1 Primary objective.................................................................................................................................. 4 
2.2 Secondary objectives............................................................................................................................. 4 
 
 
3.0 BACKGROUND AND RATIONALE ......................................................................... 4 
3.1 Esophageal cancer................................................................................................................................. 4 
3.2 Vascular endothelial growth factor (VEGF) and anti-angiogenic therapy ..................................... 5 
3.3 Angiogenesis in esophageal cancer ...................................................................................................... 6 
3.4 Ras/RAF/MEK/ERK pathway in esophageal cancer......................................................................... 6 
3.5 Sorafenib ................................................................................................................................................ 7 
3.5.1 Pre-clinical rationale ........................................................................................................................................7 
3.5.2 Clinical experience...........................................................................................................................................8 
3.5.3 Renal cell carcinoma (RCC) ............................................................................................................................8 
3.5.4 Hepatocellular carcinoma ................................................................................................................................9 
 
 
4.0 OVERVIEW OF STUDY DESIGN/INTERVENTION................................................ 12 
4.1 Design ................................................................................................................................................... 12 
4.2 Intervention ......................................................................................................................................... 12 
 
 
5.0 THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................... 13 
5.1 Sorafenib .............................................................................................................................................. 13 
 
 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................... 15 
6.1 Subject Inclusion Critieria ................................................................................................................. 15 
6.2 Subject Exclusion Criteria ................................................................................................................. 16 
 
 
7.0 RECRUITMENT PLAN ........................................................................................... 18 
7.1 Inclusion of women and minorities.................................................................................................... 18 
 
 
8.0 PRETREATMENT EVALUATION........................................................................... 18 
8.1 To be completed within four weeks prior to study entry ................................................................ 18 
8.2 To be completed within two weeks prior to study entry.................................................................. 18 
8.3 To be completed anytime prior to starting therapy ......................................................................... 19 
 
 
9.0 TREATMENT/INTERVENTION PLAN .................................................................... 19 
9.1 Agent administration .......................................................................................................................... 19 
9.2 Supportive care guidelines ................................................................................................................. 20 


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10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................... 21 
 
 
11.0 TOXICITIES/SIDE EFFECTS................................................................................ 24 
11.1 General considerations ..................................................................................................................... 24 
11.2 General toxicity profile ..................................................................................................................... 24 
11.3 Laboratory abnormalities ................................................................................................................ 26 
11.4 Special warning and precautions for use ........................................................................................ 27 
11.5 Dose delay/modification.................................................................................................................... 30 
11.6 Adverse events definitions ................................................................................................................ 34 
11.6.1 Adverse event ..............................................................................................................................................34 
11.6.2 Serious adverse event (SAE)........................................................................................................................35 
11.6.3 Adverse event documentation ......................................................................................................................35 
11.7 Reporting of serious adverse events (SAE) ..................................................................................... 35 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT......... 36 
12.1 Measurement of effect ...................................................................................................................... 36 
12.2 Definitions .......................................................................................................................................... 36 
12.2.1 Measurable disease ......................................................................................................................................36 
12.2.2 Non-measurable disease...............................................................................................................................37 
12.2.3 Target lesions ...............................................................................................................................................37 
12.2.4 Non-target lesions ........................................................................................................................................37 
12.3 Guidelines for evaluation of measurable disease............................................................................ 37 
12.4 Response criteria ............................................................................................................................... 38 
12.4.1 Evaluation of target lesions ..........................................................................................................................38 
12.4.2 Evaluation of non-target lesions ..................................................................................................................38 
12.4.3 Evaluation of best overall response..............................................................................................................39 
12.5 Confirmatory measurement/duration of response......................................................................... 40 
12.5.1 Confirmation ................................................................................................................................................40 
12.5.2 Duration of overall response ........................................................................................................................40 
12.5.3 Duration of stable disease ............................................................................................................................40 
12.6 Progression-free survival.................................................................................................................. 40 
 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................... 40 
 
 
14.0 BIOSTATISTICS ................................................................................................... 41 
 
 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES ............................................................................................................. 42 
15.1 Research participation registration................................................................................................. 42 
 
 
16.0 DATA MANAGEMENT ISSUES ........................................................................... 42 
16.1 Quality assurance.............................................................................................................................. 42 
16.2 Data and safety monitoring .............................................................................................................. 43 


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17.0 PROTECTION OF HUMAN SUBJECTS .............................................................. 43 
17.1 Privacy ............................................................................................................................................... 45 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................................ 45 
 
 
18.0 INFORMED CONSENT PROCEDURES .............................................................. 46 
 
 
19.0 REFERENCES...................................................................................................... 47 
 
 
20.0 APPENDICES ....................................................................................................... 50 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Protocol title: 
Phase II trial of sorafenib for patients with metastatic or recurrent 
esophageal and gastroesophageal junction cancer 
Study objectives 
Primary: 
To evaluate the 2-month progression-free survival (PFS) of sorafenib in 
patients with metastatic or recurrent esophageal and gastroesophageal 
(GE) junction cancer. With a total of 35 patients, we have 90% power to 
detect an improvement in the 2-month PFS from a historical control of 
50% to 70% with type I error rate of 10%. 
 
Secondary: 
a) To evaluate the overall response rate of sorafenib in the evaluable 
population; 
 
b) To evaluate the tolerability and adverse event profile of sorafenib in this 
patient population; 
 
c) To perform an exploratory analysis of differential response between 
squamous cell carcinoma and adenocarcinoma. 
 
d) To evaluate phosphorylated extracellular signal-regulated kinase 
(pERK) expression in tumor tissue and correlate with tumor control. 
 
Study population: 
Patients with metastatic or recurrent esophageal or GE junction squamous 
cell carcinoma or adenocarcinoma will be eligible. Patients will be 
allowed to have up to two prior chemotherapy regimens for metastatic 
disease or up to three prior therapies if they also received 
neoadjuvant/adjuvant chemotherapy or chemoradiotherapy. Prior therapy 
must be completed at least three weeks prior to initiation of sorafenib 
therapy. 
 
Study design: 
Single instutition, open-label, non-randomized, single-arm phase II 
 
Number of patients: 35 
 
Study drugs: 
Sorafenib, administered orally 
 
Dose and regimen: Sorafenib 400 mg twice daily administered continuously. Patients will 
continue on treatment until progression of disease. Each cycle consists of 
28 days. 
A CT (computerized tomography) or MRI (magnetic resonance imaging) 
scan of the chest and abdomen will be obtained at baseline, after the first 
four weeks of therapy, at eight weeks, and then every eight weeks 


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thereafter.  The same imaging modality performed at baseline (CT or 
MRI) will be repeated at subsequent imaging. 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary objective: 
To evaluate the 2-month progression-free survival (PFS) of sorafenib in patients with 
metastatic or recurrent esophageal and gastroesophageal (GE) junction cancer. 
 
Secondary objectives: 
a) To evaluate the overall response rate (partial response and complete response) of sorafenib. 
b) To evaluate the tolerability and adverse event profile of sorafenib in this patient population. 
c) To perform an exploratory analysis of differential response between squamous cell 
carcinoma and adenocarcinoma. 
 
d) To evaluate phosphorylated extracellular signal-regulated kinase (pERK) expression in 
tumor tissue and correlate with tumor response. 
 
3.0 BACKGROUND AND RATIONALE 
 
3.1 Esophageal cancer 
 
In 2007, there will be an estimated 15,560 new cases of esophageal cancer, with 13,940 
estimated deaths.1 The large majority of esophageal cancers are classified as squamous cell 
carcinoma (typically arising from the upper/middle thirds of the esophagus) or 
adenocarcinoma (distal esophagus or gastroesophageal (GE) junction). 
While squamous cell carcinoma used to be the predominant histological subtype, this is no 
longer the case in the United States and Western Europe. In the U.S., the incidence of 
adenocarcinoma of the distal esophagus, GE junction and gastric cardia has increased 4% to 
10% per year among U.S. men since 1976 so that it is now the most common histology.2,3 
 
As there is no standard screening procedure for esophageal cancer, 50% of patients present 
with metastatic disease, where chemotherapy is the mainstay of palliative therapy. Even for 
patients with localized disease, surgery alone results in 5-year survival of only about 20%, 
with the remainder of patients developing recurrent disease.4 The addition of neoadjuvant 
chemotherapy or chemoradiotherapy to surgery results in 5-year survival of no more than 25- 
35%.5,6 
 
For patients with metastatic or recurrent disease, chemotherapy results in responses in 20-40% 
of patients and median survivals of only 8-10 months.7 Prior standard chemotherapy included 
continuous infusion fluorouracil (5-FU) and cisplatin, the administration of which is 
cumbersome and requires placement of central intravenous access. Gastrointestinal and other 


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toxicities are also substantial. Recent investigations have focused on the addition of a third 
chemotherapy drug (docetaxel) to the standard two-drug regimen, resulting in a modest 0.6 
month improvement in overall survival, but at the expense of significant hematologic toxicity 
(including a 29% rate of febrile neutropenia versus 12% with 5-FU/cisplatin).8 
Clearly, there is a need for more active and tolerable therapies. 
 
3.2 Vascular endothelial growth factor (VEGF) and anti-angiogenic therapy 
 
Folkman and others have provided compelling evidence linking tumor growth and metastases 
with angiogenesis.9 Weidner et al. showed a statistically significant correlation between the 
density of microvessels in histologic specimens of human breast cancer and clinical outcome, 
including the incidence of metastases as well as overall and relapse-free survival.10,11 
 
Of the identified angiogenic factors, vascular endothelial growth factor (VEGF) is the most 
potent and specific and has been identified as a crucial regulator of both normal and 
pathologic angiogenesis. VEGF produces a number of biologic effects, including endothelial 
cell mitogenesis and migration and induction of proteinases, leading to remodeling of the 
extracellular matrix, increased vascular permeability, and maintenance of survival for newly 
formed blood vessels.12   Increased expression of VEGF has been measured in most human 
tumors examined to date, including tumors of the lung, breast, thyroid, gastrointestinal tract, 
kidney, bladder, ovary, and cervix, as well as angiosarcomas and glioblastomas.12 
 
Based on this pre-clinical rationale, bevacizumab, a chimeric murine monoclonal antibody 
against human VEGF, has been extensively investigated in a number of solid tumor 
malignancies. The addition of bevacizumab to cytotoxic chemotherapy has been shown in 
several phase III clinical trials to increase the efficacy of chemotherapy and to improve 
progression free survival in patients with colorectal cancer13, lung cancer14 and breast 
cancer15. 
 
Our group has previously performed a multi-center phase II evaluation of bevacizumab and 
cisplatin/irinotecan in patients with advanced gastric and GE junction adenocarcinoma.16 The 
addition of bevacizumab to cytotoxic chemotherapy significantly improved the time-to- 
progression (8.3 months; 95% CI, 5.5 to 9.9 months) and overall survival (12.3 months; 95% 
CI, 11.3 to 17.2 months) of patients, compared to a historical time-to-progression of 5 months. 
Therapy was well-tolerated, although a 6% incidence of gastric perforation or near-perforation 
and a 2% incidence of myocardial infarction were noted. 
 
Sunitinib, an oral multi-target tyrosine kinase inhibitor (TKI) that has activity against VEGF 
receptor (VEGFR), has also undergone preliminary evaluation in advanced gastric cancer.17 In 
data presented at ASCO 2007, in a multicenter phase II trial, 42 patients received sunitinib as 
second-line therapy. Of these, two patients (5%) had a PR while another 15 (36%) had SD. 
Median TTP was 17.1 weeks, while median OS was 50.7 weeks. Toxicities were comparable 
to those seen on other trials with sunitinib. Significant grade 3/4 toxicities included hand-foot 


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reaction (10%), fatigue (10%) and anorexia (10%). Grade 3/4 hematologic toxicities included 
neutropenia (31%), thrombocytopenia (29%) and anemia (14%). 
 
There are limited data to indicate what would be the expected progression free survival in 
patients either on supportive care alone, or receiving an inactive second line therapy. 
Erlotinib was inactive in our adenocarcinoma patients, and PFS was 1.6 months.  Three other 
trials of EGFR TKI’s, two limited to adenocarcinoma of the esophagus, indicated PFS of 1.9- 
2.0 months, consistent with our observation.53-55   It is likely that PFS is 1.6-2 months or less in 
this patient population, i.e. progression occurs at the first or second month of CT scan 
assessment.  As there are no data for best supportive care alone, these data represent the best 
estimate of PFS in patients treated with essentially inactive therapy. 
 
 
 
3.3 Angiogenesis in esophageal cancer 
 
A number of studies have evaluated the potential role of the VEGF pathway in esophageal 
cancer as a prognostic marker, and the potential changes in VEGF expression in patients 
receiving preoperative combined modality chemoradiotherapy.  Studies in squamous cancers 
have indicated that expression of VEGF in tumors correlates with more advanced tumor stage, 
the presence of nodal metastasis and distant metastasis, and with a poorer survival outcome.18 
 
In esophageal adenocarcinoma, increasing expression of VEGF correlates with the transition 
from Barrett’s esophagus to high grade dysplasia, and with the transition from microinvasive 
to locally advanced cancer.19,20 While several investigators have not detected a relationship 
between VEGF expression and outcome,21 one series of 75 tumor samples obtained at 
esophagectomy did show that VEGF expression was correlated with the presence of 
angiolymphatic invasion, nodal metastases and survival.22 
 
These pre-clinical data, coupled with the promising clinical data discussed in the previous 
section, suggest that angiogenesis is a viable and attractive target for therapy in advanced 
esophageal and GE junction cancer. 
 
3.4 Ras/Raf/MEK/ERK pathway in esophageal cancer 
 
The mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in 
transmitting proliferative signals generated by cell surface receptors and cytoplasmic signaling 
elements to the nucleus. Because derangements in the MAPK pathway have been linked to a 
number of human malignancies, many of its aberrant and critical components are potential 
therapeutic targets in human cancers.23 
 
The MAPK pathway consists of the ras family of oncogenes and encoded proteins. Ras plays 
a central role in an intricate array of signal transduction pathways, characterized by cross-talk, 
feedback loops and multi-component signaling complexes.24,25 


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The Raf serine/threonine kinases are the principal effectors of Ras in the MAPK pathway. Raf 
activation occurs immediately downstream of membrane and cytoplasmic receptors that relay 
mitogenic signals. 
In turn, Raf activation leads to the downstream activation and phosphorylation of MEK 
(mitogen-activated protein kinase kinase) and ERK (extracellular signal-regulated kinase).26 
 
While aberrancies in the MAPK pathway have been well-characterized in a number of 
cancers, its role in the pathogenesis of esophageal cancer is unclear. However, there is some 
evidence to suggest that it may be active. 
In one study, activation of ERK and Raf was identified in 63.3% and 60.3% of squamous 
esophageal cell carcinoma specimens respectively, whereas normal mucosal epithelial tissues 
were negative. Moreover, a close association was observed between ERK expression and the 
differentiation grade, with the ERK signal greater in poorly differentiated tissues than in well 
and moderately differentiated tissues.27 
 
In addition, the MAPK pathway is thought to be activated by signaling through the epidermal 
growth factor receptor (EGFR), a member of the ERBB growth factor receptor tyrosine kinase 
family. EGFR protein expression has been reported in 30% to 70% of esophageal cancers and 
has been correlated with poor patient outcome and inferior response to conventional 
therapies.28 
In a prior phase II evaluation of erlotinib, an anti-EGFR TKI, as second-line therapy for 
patients with advanced esophageal cancers performed here at MSKCC, 2 of 30 patients (7%) 
had a partial response.29 Both of these patients had squamous cell histology and EGFR 
overexpression by immunohistochemical (IHC) staining. 
In a phase II evaluation of gefitinib, another anti-EGFR oral TKI, as second-line therapy for 
patients with advanced esophageal cancers, 36% of tumors were found to express 
phosphorylated ERK (pERK) by IHC staining.30 However, there did not appear to be a 
difference in response to gefitinib therapy between pERK-positive and pERK-negative 
patients. 
 
3.5 Sorafenib 
 
3.5.1 Pre-clinical rationale 
 
Sorafenib (BAY 43-9006) is an oral multi-kinase inhibitor with effects on tumor proliferation 
and tumor angiogenesis.31 It has inhibitory activity against the tyrosine kinases for VEGFR 
and platelet-derived growth factor (PDGF) receptor, as well as Flt-3 and c-Kit.31 In addition, it 
was also initially selected on the basis of inhibitory activity against the serine/threonine 
kinases Raf-1 and wild-type B-Raf, which are pivotal components of the Ras/Raf/MEK/ERK 
signaling pathway.32 


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In preclinical studies, sorafenib demonstrated broad-spectrum anti-tumor activity by inducing 
complete tumor stasis and inhibition of tumor angiogenesis in a variety of tumor types,31 
including renal cell carcinoma (RCC), colon cancer, non-small cell lung cancer, hepatocellular 
cancer, pancreatic cancer, ovarian cancer and breast cancer cell lines.33 
 
3.5.2 Clinical experience 
 
The safety and clinical activity of sorafenib, either alone34-37 or in combination with 
chemotherapy38,39, has been examined in a series of phase I studies conducted in patients with 
solid tumors. 
 
The clinical activity of sorafenib in metastatic RCC was first demonstrated in a phase II 
randomized discontinuation trial in patients with metastatic RCC.40 In this study, all patients 
were treated with sorafenib 400 mg BID and were assessed at 12 weeks. Patients with tumor 
shrinkage ≥25% continued on open-label sorafenib and patients with tumor growth ≥25% 
were taken off-study. Patients with tumor shrinkage or tumor growth < 25% were randomized 
to receive either sorafenib or placebo. At 12 weeks post-randomization, 50% of the sorafenib 
patients were progression-free, compared to only 18% of patients receiving placebo. Sorafenib 
significantly prolonged median progression-free survival from randomization versus placebo 
(24 versus 6 weeks; p=0.009). 
 
The most common adverse events were fatigue (73% of patients), rash/desquamation (66%), 
hand-foot skin reaction (62%), pain (58%) and diarrhea (58%). The majority of these events 
were grade 1/2 in severity. Nine patients discontinued therapy because of toxicity. The most 
common grade 3/4 adverse event was hypertension, which was observed in 31% of patients; 
antihypertensive therapy was initiated in 46% of patients. 
 
3.5.3 Renal cell carcinoma (RCC) 
 
Based on the promising phase II results, a multicenter, double-blind randomized phase III 
evaluation of sorafenib 400 mg BID versus placebo was undertaken.41 The primary endpoint 
of the trial was overall survival (OS), with progression-free survival (PFS) as a secondary 
endpoint. Patients with advanced RCC with good performance status following one prior 
systemic therapy were randomized to either sorafenib or blinded placebo with best supportive 
care. 
From November 2003 to March 2005, 903 patients were randomized. In January 2005, a per- 
protocol interim analysis of PFS demonstrated a statistically significant benefit for sorafenib 
over placebo. As such, the study was unblinded in May 2005 and sorafenib was offered to 
patients who were initially randomized to receive placebo. 
 
At the time of cross-over, an interim analysis of OS was conducted. Median OS in the placebo 
group was 14.7 months and had not been reached in the sorafenib group  (hazard ratio 0.72; 
95% CI, 0.54 to 0.94, p=0.02). The threshold for statistical significance for this interim 
analysis was not reached (p< 0.0005). 


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Final analysis of OS was reported at ASCO 2007.42 Median OS in the sorafenib group was 
17.8 months and 15.2 months in the placebo group (hazard ratio 0.88, p=0.15). For this study, 
however, OS was likely confounded by the fact that approximately half of the placebo patients 
crossed over at the time of unblinding to receive sorafenib. Indeed, OS analysis with placebo 
patients censored at the time of crossover indicated that sorafenib treated patients had a 
statistically significant 22% reduction in mortality risk compared to placebo patients (OS 17.8 
months versus 14.3 months; hazard ratio 0.78, p=0.03). 
 
Median PFS was 5.5 months for sorafenib versus 2.8 months for placebo (p<0.0001). 
Sorafenib was associated with a reduction of 56% in the independently-assessed risk of 
progression (hazard ratio 0.44; 95% CI, 0.35 to 0.55). 
At the May 2005 cutoff, among the 451 evaluable patients in the sorafenib group, 1 patient 
had a complete response (<1%), 43 had a partial response (10%) and 333 had stable disease 
(74%). Among 452 patients in the placebo group, no patient had a complete response, 8 had a 
partial response (2%) and 239 had (53%) stable disease. Significantly more patients in the 
sorafenib group had a partial response or stable disease (p<0.001). 
 
In December 2005, the U.S. Food and Drug Administration (FDA) approved sorafenib for the 
treatment of patients with advanced RCC. 
 
3.5.4 Hepatocellular carcinoma 
 
A multicenter, randomized, placebo-controlled, double-blind phase III trial of sorafenib in 
advanced hepatocellular carcinoma (HCC) was reported at ASCO 2007.43 In the SHARP 
study, 602 patients with advanced HCC, Child-Pugh class A, with no prior systemic therapy 
were randomized to receive either sorafenib 400 mg BID (n=299) or placebo (n=303). In 
February 2007, based on a planned interim analysis of OS, the study group recommended 
unblinding and closure of the study. Median OS in the sorafenib group was 46.3 weeks versus 
34.4 weeks in the placebo-treated group. This represented a 44% increase in median OS 
(hazard ratio 0.69, p=0.001). Median PFS was also significantly increased in the sorafenib 
group (24 weeks) versus the placebo group (12.3 weeks) (hazard ratio 0.58, p=0.00001). 
 
In a prior open-label, single-arm, multicenter phase II evaluation of sorafenib in HCC led by 
our group, Abou-Alfa et al. demonstrated that higher tumor expression of pERK as 
determined by IHC was correlated with significantly improved time-to-progression compared 
to patients whose tumors had lower levels of pERK expression (p=0.0003).44 
 
3.5.5 Risk of bleeding complications and squamous cell histology on VEGF-targeted 
therapy trials. 
 
Data from squamous cancer lung cancer trials have indicated potential fatal bleeding 
complications with the use of the VEGF targeted agent bevacizumab (48,49).  However, the 
registration trial in NCSLC reported a small but finite rate of fatal pulmonary hemorrhage in 
non squamous cancers.  Recent non small cell lung cancer studies have also included 


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squamous cancer histology in trials of VEGF-targeted agents.  Data from recent and ongoing 
trials presented at the recent ASCO 2008 meeting indicate that VEGF targeted agents, 
including bevacizumab and sunitinib, were safe and tolerable in squamous cancer of the head 
and neck.  None of these trials reported bleeding complications that led to discontinuation of 
the trials. 
 
Two recent reviews discussed the historical experience of bevacizumab in NSCLC, and 
recent trials of VEGF-tarted agents (48,49).  The initial randomized phase II trial combining 
bevacizumab with carboplatin and paclitaxel in 99 patients with NSCLC reported an 
increased incidence of fatal pulmonary hemorrhage associated with squamous cell histology; 
6 events occurred in 62 patients receiving bevacizumab, five were fatal.  Six patients had 
centrally located tumors, 5 had cavitation, and 4 were squamous cell.  This observation led to 
subsequent exclusion of squamous cell patients on the pivotal phase III trial in non squamous 
cell patients, and patients with prior hemoptysis were also excluded.  This trial showed a 
response rate, time to progression and overall survival benefit for the addition of 
bevacizumab to chemotherapy.  However, pulmonary hemorrhage was more common on the 
bevacizumab arm (1.9% in 434 patients versus 0.2% in 444 patients), including 5 cases of 
fatal pulmonary hemorrhage in 1.2% on the bevacizumab arm. 
 
Other trials reviewed included a trial combining gefitinib with the VEGF-targeted agent 
sorafenib, in NSLC indicating no dose limiting toxicities in 32 patients.  A phase II trial of 
sorafenib in NSLC reported one one pulmonary hemorrhage (fatal) in 52 patients, in a patient 
with squamous cancer with a central, cavitary lesion which occurred one month after 
sorafenib therapy in the setting of palliative radiotherapy.  Sunitinib, another VEGF-tyrosine 
kinase inhibitor, was evaluated in a phase II trial in 63 patients, and reported one fatal 
pulmonary hemorrhage.  Phase III evaluation of both of these agents in NSLC is ongoing in 
combination with chemotherapy.  Cedaranib, another VEGF-tyrosine kinase inhibitor, is in 
ongoing phase II evaluation in combination with carboplatin and paclitaxel, and no 
pulmonary hemorrhages have been reported in 20 patients to date. 
 
In a recently reported phase II trial, 22 patients were treated with sunitinib in recurrent or 
metastatic head and neck cancer (50).  One partial response was observed, but the trial was 
closed due to failure to achieve efficacy endpoints.  Vascular complications included 2 
pulmonary hemorrhages, one primary tumor bleed, and 2 gastrointestinal bleeds.  The 
authors reported the agent as well tolerated and again the trial was not closed or amended for 
toxicity concerns. 
 
In a recent phase II trial, 25 patients with recurrent or metastatic head and neck cancer 
received pemetrexed in combination with bevacizumab (51).  2 grade 3 tumor bleeds were 
observed, and 1 from a gastric ulcer, and one patient had a fatal tracheal tumor bleed that the 
authors claimed was not treatment related but caused by aggressive suctioning.  The trial 
indicated activity and accrual continues. 


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A recent report updated results on a trial treating 18 patients with recurrent or metastatic head 
and neck cancer with the combination of cetuximab and bevacizumab (52).  Responses were 
seen in 4 patients, and no bleeding events were observed.  This trial also continues to accrue 
patients. 
 
Although bleeding is a potential complication of anti VEGF therapy, all of the above trials 
continued or are continuing patient accrual as the events were manageable. Because GI 
bleeding has even been reported for EGFR tyrosine kinase inhibitors, we will require that 
patients be treated with antacid therapy as we did on our prior phase II trial of erlotinib. 
There is therefore not an expectation, based on the above results, that bleeding complications 
will preclude safe administration of Sorafenib on this trial in squamous cancers of the 
esophagus. 
 
3.5.6 Rationale for the Current Study 
 
There is a clear rationale to study more than one VEGF targeted agent in esophageal cancer, 
as has been indicated by experience in other solid tumor malignancies and other targeted 
agents.  There have been inconsistent benefits for targeted agents within the spectrum of GI 
malignancies in addition to other solid tumors, underscoring the need to evaluate each new 
promising agent independently in each tumor type. 
 
For example, in GI malignancies, the EGFR tyrosine kinase inhibitors erlotinib and gefitinib 
have been inactive as single agents in adenocarcinoma of the colon, stomach, and esophagus, 
and trials combining these agents with chemotherapy in non small cell lung cancer have 
failed. However in pancreatic cancer, erlotinib plus chemotherapy with gemcitabine yielded 
positive results, including a progression free and overall survival benefit.  This is one of the 
first studies to show a benefit for an EGFR TKI combined with chemotherapy; indeed this is 
the only phase III trial in pancreatic cancer that has yielded a survival benefit compared to 
gemcitabine alone.  On the other hand, the EGFR targeted antibody cetuximab failed when 
combined with chemotherapy in pancreatic cancer. This is in contrast to the single agent 
activity for cetuximab, and even greater activity when combined with chemotherapy, in 
colorectal cancer; cetuximab also has some limited single agent activity in esophagogastric 
adenocarcinoma. 
 
Similarly, bevacizumab in combination with chemotherapy consistently improves response 
rates, progression free, and often overall survival in trials in colorectal, breast, and non small 
cell lung cancer; however, in pancreatic cancer, no benefit of any sort was seen for 
bevacizumab in combination with chemotherapy.  Lastly, in breast cancer, whereas 
cetuximab, erlotinib, and gefitinib have all failed to yield any signal of activity, the broader 
spectrum HER tyrosine kinase inhibitor lapatinib, which inhibits HER-1 (EGFR) and HER-2 
tyrosine kinases, has single agent activity and benefits chemotherapy effectiveness as well. 
Lapatinib however has failed in recent trials in esophagogastric adenocarcinoma. 


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It is clear that each new targeted agent, with individual variation in what specific targets are 
actually affected, needs to be evaluated in each solid tumor.  Sorafenib is of particular interest 
in GI malignancies given its recent demonstration as the only agent shown to improve 
survival in hepatocellular cancer.  Ongoing phase II trials of sorafenib in neuroendocrine 
carcinoma also indicate significant responses and protracted disease stabilization, in the 
setting of a modest toxicity profile.  Sorafenib, which inhibits the tyrosine kinases associated 
with the VEGF receptor and the PDGF receptor, also targets the serine/threonine kinases Raf- 
1 and B-Raf.  Its favorable toxicity profile may make this agent a promising partner with 
combination chemotherapy and radiation therapy and further development of this agent in 
gastrointestinal malignancies is clearly indicated. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1  Design 
 
This is a single institution, open-label, non-randomized, phase II evaluation of sorafenib 400 
mg BID in patients with metastatic or recurrent esophageal or gastroesophageal (GE) junction 
squamous cell carcinoma or adenocarcinoma. 
 
Patients may have received up to two prior chemotherapy regimens for their metastatic disease 
or up to three prior regimens if they received neoadjuvant/adjuvant chemotherapy or 
chemoradiotherapy. All patients must be able to provide informed consent prior to enrollment. 
 
See Section 10 for treatment schema. 
 
4.2  Intervention 
 
35 patients will be enrolled on this clinical trial. Patients will receive sorafenib 400 mg BID 
continuously until disease progression, unacceptable toxicity or serious intercurrent illness 
develops or if patient consent is withdrawn. 
 
The primary endpoint will be 2-month progression-free survival (PFS). With a total of 35 
patients, we have 90% power to detect an improvement in the 2-month PFS from a historical 
control of 50% to 70% with type I error rate of 10%. Secondary endpoints include the 
response rate to sorafenib and its toxicity.  Our basis for PFS estimate in this patient 
population comes from our prior phase II trial of erlotinib in esophageal cancer (which had 
essentially no activity in adenocarcinoma of the esophagus), and nearly identical PFS results 
reported for this patient population treated with either erlotinib or gefitinib (1.6-2.0 months 
PFS in all studies) (54-56). 
 
Patients must have measurable disease and will undergo a computerized tomography (CT) or 
magnetic resonance imaging (MRI) scan of the chest and abdomen at baseline, after the first 
four weeks of therapy, at eight weeks, and every eight weeks thereafter, with a scheduling 
window of up to one to fourteen (1-14) days.  If a complete response is achieved and 


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maintained for 12 months, patients with complete response will then be required to repeat CT 
or MRI evaluation every 4 months up to 5 years post complete response status, then every 6 
months thereafter, with a scheduling window of up to one to fourteen (1-14) days.  Response 
assessment will be by RECIST criteria.45 The same imaging modality performed at baseline 
(CT or MRI) will be repeated at subsequent imaging. 
 
Therapy will be administered in the outpatient setting, with each cycle consisting of 28 days 
of continuous therapy. The cycle start date will coincide with the physician visit date.  A study 
diary will be completed by patients to ensure compliance with the study drug (see Appendix 
A). 
 
Patients will be required to take antacid therapy to reduce the potential for gastrointestinal 
bleeding. Allowable agents include but are not limited to ranitidine, omeprazole, carafate or 
similar agents. 
 
5.0 THERAPEUTIC/DIAGNOSTIC AGENTS 
Sorafenib 
Other names: 
BAY 43-9006, Nexavar® 
 
Classification: 
Kinase inhibitor 
 
Molecular weight: Sorafenib tosylate: 637 Daltons; sorafenib (free base): 465 Daltons 
 
Mode of action: 
Sorafenib is a potent inhibitor of VEGF-R, PDFG-R, c-raf, wild-type and 
mutant b-raf, Flt3, c-KIT and p38α, a member of the MAPK family. 
 
Approximate 
0.19 mg/100 mL in 0.1 N HCl, 453 mg/100 mL in ethanol, 2971 
Solubility: 
mg/100mL in PEG 400 
 
How supplied: 
BAY 43-9006 sorafenib 200 mg is supplied as round, biconvex, red-film- 
coated tablets, debossed with the 'Bayer cross' on one side and '200' on 
the other side.  The tablets contain BAY 43-9006 tosylate equivalent to 
200 mg of the free base BAY 43-9006, and the excipients croscarmellose 
sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulfate, 
and magnesium stearate. The film-coat consists of hypromellose, 
polyethylene glycol, titanium dioxide and red iron oxide. The film 
coating has no effect on the rate of release of the active BAY 43-9006 
tosylate. 
 
The study drug can be supplied as BAY 43-9006 sorafenib 200 mg 
commercial tablets in bottles of 140 tablets with a product identification 
label affixed or as commercial Nexavar in bottles of 120 tablets. 


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Storage: 
Store at controlled room temperature (15 -25 oC). Storage conditions 
should not exceed 25 oC. 
Stability: 
Stability studies are ongoing. The current shelf life is 24 months when 
stored at controlled room temperature. 
 
Route of 
Orally 
Administration: 
 
Sorafenib is supplied as 200 mg tablets. The dose of sorafenib is 400 mg orally twice daily for 
28 days (continuously). There is no planned interruption between treatment cycles. The cycle 
start date will coincide with the physician visit date. Because of the potential need for 
physician visit scheduling to vary (due to both physician and patient issues), to avoid violation 
of, and deviation from, the protocol, these visits may vary by up to one to fourteen (1-14) 
days. 
 
Sorafenib will be taken in the outpatient setting on Days 1-28 of each 28-day cycle. Patients 
should swallow the tablet whole with approximately 250 ml (8 oz.) of water each morning and 
evening,. Sorafenib tablets may be crushed and administered via a feeding tube if necessary. 
 
Sorafenib should be taken without food (1 hour before or 2 hours after eating). If it is taken 
with meals, patients will be instructed to take sorafenib with a low- to moderate-fat diet. A 
high fat meal causes a decrease in sorafenib absorption (a 29% decrease in sorafenib area- 
under-the-curve (AUC) concentration and a 38% decrease in sorafenib maximum 
concentration (Cmax) value). 
 
Dose modifications for sorafenib are detailed in Section 11.5. Patients will be taken off 
sorafenib at disease progression. 
 
Drug metabolism interactions: Sorafenib is primarily metabolized by two parallel pathways: 
CYP3A4-mediated oxidation and UGT1A9-mediated glucoronidation.33 Pharmacokinetics 
analysis from previous clinical trials have not demonstrated any significant drug interactions 
when sorafenib was administered together with ketoconazole, a potent inhibitor of CYP3A4. 
Therefore, it is thought that sorafenib may be safely coadministered with substrates and 
inhibitors of CYP3A4, such as ketoconazole, itraconazole, fluconazole and ritonavir.33 
There is no clinical information on the effect of CYP3A4 inducers on the pharmacokinetics of 
sorafenib.33 Inducers of CYP3A4 activity (e.g. rifampin, Hypericum perforatum also known 
as St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may 
increase metabolism of sorafenib and thus decrease sorafenib plasma concentrations. 
 
Concomitant administration of midazolam, dextromethorphan and omeprazole, which are 
substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively, following four 
weeks of sorafenib administration did not significantly alter the exposure of these agents.33 


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This indicates that sorafenib is neither an inhibitor nor a clinically meaningful inducer of these 
cytochrome P450 isoenzymes. 
 
Sorafenib is also known to inhibit CYP2C9 in vitro. Substrates of CYP2C9 include warfarin 
and digoxin. However, the previous phase III evaluation of sorafenib versus placebo for 
advanced renal cell carcinoma did not reveal a significant difference in PT/INR between both 
groups, suggesting that sorafenib may not have in vivo inhibitory activity against CYP2C9.33 
Nevertheless, routine monitoring of the PT/INR for patients on coumadin therapy is 
warranted. 
 
Availability: Following submission and approval of the required regulatory documents, a 
supply of sorafenib may be ordered from Bayer Pharmaceuticals. 
 
6.0 
Criteria for subject eligibility 
 
6.1  Subject Inclusion Criteria 
To be included in the study, patients must fulfill all of the following inclusion criteria and not 
meet any of the exclusion criteria. Patients who give written informed consent prior to any 
study specific screening procedures proceed with the understanding that the patient has the 
right to withdraw from the study at any time, without prejudice. 
 
• 
Patients must have histologically proven or cytologically confirmed esophageal cancer 
(squamous cell carcinoma or adenocarcinoma) or adenocarcinoma of the 
gastroesophageal (GE) junction documented at MSKCC. 
 
 
 
• 
Metastatic disease measurable on a CT or MRI scan.  Locally recurrent disease that is 
not amenable to potentially curative surgery or radiation therapy is also allowed. 
Lesions must be ≥10 mm in size. The primary tumor is not considered measurable 
disease. Recurrent or metastatic lesions within a prior radiation field are acceptable as 
long as disease has progressed in the radiation field by RECIST criteria. See Section 
12.2 for definition of measurable lesions.  The same imaging modality performed at 
baseline (CT or MRI) will be repeated at subsequent imaging. 
 
• 
Patients are allowed to have a maximum of two prior chemotherapy regimens for 
metastatic disease. Patients are allowed to have a maximum of three prior regimens 
if they also previously received neoadjuvant/adjuvant chemotherapy or 
chemoradiotherapy. The last treatment must have been administered >3 weeks prior 
to initiation of therapy with sorafenib. 
  
• 
Pathologic tissue must be available for immunohistochemistry (IHC) staining for 
phosphorylated extracellular signal-regulated kinase (pERK). Both patients with 
and without pERK staining are eligible for treatment. Submission of slides and IHC 


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testing for pERK may be done during the course of therapy and are not required 
prior to protocol therapy. 
 
• 
Age ≥18 years. 
• 
Life expectancy >3 months. 
 
• 
Karnofsky performance status ≥60%. 
 
• 
At baseline, patients must have normal organ and marrow function as defined: 
Adequate bone marrow, liver and renal function as assessed by the following: 
Hemoglobin >  9.0 g/dl 
 
Absolute neutrophil count (ANC) > 1,500/mm3 
 
Platelet count >  100,000/mm3 
 
Total bilirubin <  1.5 times ULN 
ALT and AST <  2.5 times the ULN ( < 5 x ULN for patients with liver involvement) 
Creatinine < 1.5 times ULN 
 
• 
Patients must have the ability to comprehend and willingness to sign an informed 
consent document. 
 
6.2  Subject Exclusion Criteria 
 
• 
Patients who have not recovered from adverse events related to therapy administered 
>3 weeks earlier.  This does not include hemoglobin or other hematologic or 
laboratory criteria, as long as eligibility are met as outlined in 6.1. 
 
• 
Patients may not be receiving any other investigational agents. 
 
• 
Prior therapy with sorafenib-related compounds or compounds of similar biologic or 
chemical  components,  including  compounds  targeting  VEGF,  VEGF-R  or  RAF 
kinase. 
 
 
• 
Uncontrolled  intercurrent  illness  including,  but  not  limited  to,  ongoing  or  active 
infection, greater than New York Heart Association (NYHA) Class II congestive heart 
failure, unstable or new onset angina pectoris or myocardial infarction within the past 
six  months, unstable arrhythmia,  or psychiatric  illness/social  situation, e.g.  severe 


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schizophrenia,  that would limit compliance with study requirements. Patients with 
chronic 
arrhythmias, 
such 
as 
paroxysmal 
atrial 
fibrillation 
or 
paroxysmal 
supraventricular tachycardia, are eligible. 
 
 
• 
Uncontrolled hypertension, defined as systolic blood pressure >150 mmHg or diastolic 
blood pressure >90 mmHg, despite optimal medical management. 
 
• 
Thrombotic or embolic event, including cerebrovascular accident or transient ischemic 
attack within the past six months. Patients with prior deep vein thromboses or 
pulmonary emboli on a stable anticoagulation regimen will be eligible for enrollment. 
 
• 
Any factor that would significantly interfere with the inability to consume or absorb an 
oral medication, e.g. severe nausea/vomiting not controlled by an aggressive anti- 
emetic regimen, grade 3/4 dysphagia, extensive small bowel resection or active 
inflammatory bowel disease leading to chronic malabsorption. Patients with enteral 
feeding tubes are eligible as sorafenib can be crushed. 
 
• 
Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C 
infection. 
 
 
• 
Patients with any other concurrent disease which, in the judgment of the investigator, 
would make the patient inappropriate for participation in the study. 
 
• 
Patients  who  are  taking  St.  John’s  wort  or  rifampin  (as  there  may be  drug-drug 
interactions with sorafenib; see Section 5.0 and 11.4). 
 
• 
Patients  with  known  brain  metastases  or  meningeal  carcinomatosis  are  excluded. 
Patients with neurological symptoms must undergo a CT scan/MRI of the brain to 
exclude brain metastasis. 
 
• 
Pregnant women are excluded because sorafenib has the potential for teratogenic or 
abortifacient effects. Female patients must either not be of childbearing potential or 
must have a negative pregnancy test ≤ 7 days prior to treatment. Female patients are 
considered not of childbearing potential if they are surgically sterile (they have 
undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or if they 
are post-menopausal. Men must use effective birth control if their partners are of 
child-bearing potential. 
 
• 
No other malignancy is allowed except for adequately treated carcinoma in-situ of the 
cervix, superficial transitional cell carcinoma of the bladder or basal/squamous cell 
skin cancer. Other cancers are permissible if the patient has been disease free for ≥3 
years. 


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• 
Pulmonary hemorrhage/bleeding event >  CTCAE Grade 2 within 4 weeks of first 
dose of study drug. 
• 
Any other hemorrhage/bleeding event  > CTCAE Grade 3 within 4 weeks of first dose 
of study drug. 
• 
Serious non-healing wound, ulcer, or bone fracture. 
• 
Evidence or history of bleeding diathesis or coagulopathy 
• 
Major surgery, open biopsy or significant traumatic injury within 4 weeks of first 
study drug. 
• 
Known or suspected allergy to sorafenib or any agent given in the course of this trial. 
 
7.0 
RECRUITMENT PLAN 
 
This will be a single institution, phase II study. Patients with metastatic or recurrent 
esophageal and gastroesophageal (GE) junction cancer who are eligible will be identified 
for enrollment. No additional measures, e.g. advertisement, payment to patients, will be 
employed to recruit patients. 
 
Inclusion of women and minorities 
 
The investigators take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations. There will be no limitation with regards to 
race or gender. 
 
Our institutional demographics for accrual of patients on esophageal and GE junction 
cancer trials reflect the national incidence of this disease. 10-15% of our patients have 
been women. African-American males (almost exclusively with esophageal squamous 
cell carcinoma) comprise 3-5% of patients treated on protocol. Given that our protocol 
accrual closely reflects the national incidence of this disease, no specific strategy will be 
undertaken to recruit women or persons of color on this trial. 
 
This protocol/project does not include children because the number of children with 
esophageal and GE junction cancer is very small and because the majority are already 
accessed by a nation-wide pediatric cancer research network. This statement is based on 
exclusion 4b of the NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects. 
 
8.0 
PRETREATMENT EVALUATION 
 
To be completed within four weeks prior to study entry: 
 
• 
A 12-lead electrocardiogram (ECG). 
 
To be completed within two weeks prior to study entry: 


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• 
History and physical exam, including blood pressure, vitals, height, weight and 
performance status. 
• 
Documentation of all measurable disease with a baseline computerized tomography 
(CT) or magnetic resonance imaging (MRI) scan of the chest and abdomen. All 
measurable lesions used to define response must be ≥10 mm in size. The primary 
tumor is excluded. Lesions within prior radiation fields are permitted as long as these 
lesions have documented progression in size. 
 
• 
White blood cell (WBC) count, platelet count with automated differential. 
 
• 
Comprehensive metabolic panel, including electrolytes, glucose, blood urea nitrogen 
(BUN), creatinine, lactate dehydrogenase (LDH), albumin, aspartate aminotransferase 
(AST or SGOT), alanine aminotransferase (ALT or SGPT), alkaline phosphatase, total 
bilirubin, total protein, prothrombin time (PT), international normalized ratio (INR) 
and partial thromboplastin time (PTT). 
 
• 
Amylase/lipase. 
 
• 
Serum pregnancy test, for all women of childbearing potential. 
Prior to study enrollment, women of childbearing potential (WOCP) must be advised 
of the importance of avoiding pregnancy during trial participation and the potential 
risk factors of an unintentional pregnancy. In addition, men enrolled on this study 
should understand the risk to any partner of childbearing potential and should practice 
an effective method of birth control. 
 
All WOCP must have a negative pregnancy test ≤7 days prior to starting therapy. 
 
In addition, all WOCP should be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (e.g. late or missed period) at any time during 
study participation. 
 
To be completed anytime prior to starting therapy 
 
• 
Histological confirmation of metastatic esophageal or GE junction squamous cell 
carcinoma or adenocarcinoma prior to study enrollment. Patients without histological 
confirmation of recurrence or metastasis will undergo a biopsy to confirm recurrence, 
unless the risk of such a procedure outweighs the benefits of confirming recurrent 
disease. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1  Agent administration 


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Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 11. Appropriate dose modifications are described in Section 
11.5. Criteria for discontinuing treatment are listed in Section 13. 
 
Sorafenib is supplied as 200 mg tablets. The starting dose of sorafenib is 400 mg orally twice 
daily for 28 days (continuously). There is no planned interruption between treatment cycles. 
The cycle start date will coincide with the physician visit date. Because of the potential need 
for physician visit scheduling to vary (due to both physician and patient issues), to avoid 
violation of, and deviation from, the protocol, physician visits may vary by up to one to 
fourteen (1-14) days from a strict 28 day schedule. 
 
Sorafenib will be taken on Days 1-28 of each 28-day cycle. Patients shall swallow the tablet 
whole with approximately 250 ml (8 oz.) of water each morning and evening.  Tablets may be 
crushed and administered via a feeding tube. 
 
Sorafenib may be taken with or without food. If it is taken with meals, patients will be 
instructed to take sorafenib with a low- to moderate-fat diet. 
 
A study diary will be completed by patients to ensure compliance with sorafenib (see 
Appendix A). 
 
Patients will be required to take antacid therapy to reduce the potential for gastrointestinal 
bleeding. Allowable agents include but are not limited to ranitidine, omeprazole, carafate or 
similar agents. 
 
9.2  Supportive care guidelines 
 
• 
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics and anti-emetics. The reasons for treatment, dosage and dates of 
all supportive treatments should be recorded. 
 
• 
Use of erythropoietin alfa (Epoetin alfa, Procrit®) and/or darbepoetin (Aranesp®) is 
permitted at the discretion of the treating physician based on standard MSKCC 
criteria. 
 
• 
Patients who develop hand-foot reaction may receive topical emollients (such as 
Aquaphor®) or topical steroid or anti-histamine ointments, if appropriate. 


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10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Pre- 
studyI 
Cycle 1
J 
Cycle 2 & thereafterJ 
Off- 
study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Sorafenib twice daily 
Continuous 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
X 
Physical exam K 
X 
X 
X 
X 
X 
X 
Collect sorafenib 
diary 
X 
X 
Vitals K 
X 
X 
X 
X 
X 
X 
Blood pressure 
measurementA K 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight K 
X 
X 
X 
X 
X 
X 
Performance status K 
X 
X 
X 
X 
X 
X 
Concomitant 
medications K 
X 
X 
X 
X 
CBC with diff, plts K 
X 
X 
X 
X 
X 
X 
Comprehensive 
metabolic panelC K 
X 
X 
X 
X 
X 
Amylase/lipaseD 
X 
X 
X 
X 
X 
PT/INR/PTT – not on 
Coumadin 
X 
PT/INR/PTT – on 
coumadinE K 
X 
X 
X 
X 
X 
Adverse event 
evaluation 
Continuous 
Serum β-HCG
F 
X 
ECG 
X 
Radiographic tumor 
measurementG K 
X 
X 
X 
Tissue IHC for pERKH 
X 
A. Blood pressure measurement is required at baseline, weekly during Cycle #1 and then during Week #1 from 
Cycle #2 onwards. Patients will need to return to the clinic on weeks without scheduled physician evaluation for an 
RN evaluation or have their measurement obtained at their local physician’s office or some other venue (e.g. patient- 
operated machine at a drug store, ambulatory blood pressure cuff, etc.) If measurements are not performed at 
MSKCC, patients will need to record their blood pressure and contact their study physician if it is elevated or, if 
normal, to provide the recordings to the study physician or nurse at their next scheduled clinic visit. 
C. Comprising sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total bilirubin, total protein, 
AST, ALT, alkaline phosphatase. 
D. Asymptomatic grade 3/4 hyperamylasemia and hyperlipasemia without evidence of pancreatitis were noted in 1% 
and 12% of patients respectively in the large phase III randomized trial of sorafenib in advanced renal cell 
carcinoma. 
E. Because of a potential drug interaction with sorafenib, patients on chronic anticoagulation with coumadin will 
require periodic monitoring of their PT/INR every two weeks. 
F. For women of childbearing potential (see section 8.0). 
G. A CT or MRI will be obtained at baseline within two weeks of study enrollment. Repeat radiographic evaluation 
will be obtained after the first four weeks on study, at eight weeks, and then every eight weeks thereafter If a 


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complete response is achieved and maintained for 12 months, patients with complete response will then be required 
to repeat CT or MRI evaluation every 4 months up to 5 years post complete response status, then every 6 months 
thereafter. Patients with a partial/complete response require a confirmatory scan at least four weeks after the initial 
scan documenting response (see Section 12.5). The same imaging modality performed at baseline (CT or MRI) will 
be repeated at subsequent imaging. 
H. Prior archived tissue must be obtained at anytime prior to enrollment or during protocol therapy for 
immunohistochemical staining for phosphorylated extracellular signal-regulated kinase (pERK). 
I. If pre-treatment CBC, comprehensive metabolic panel and PT/INR/PTT are drawn within seven days of beginning 
therapy, they do not need to be re-drawn again during Cycle #1, Week #1. 
J. Cycle start date will coincide with the physician visit date. 
K. Because of the potential need for blood test, CT/MRI scan, and physician visit scheduling to vary (due to both 
physician and patient issues), to avoid violation of, and deviation from the protocol, blood tests, CT/MRI scans, and 
physician visits (including physical exam, vitals, blood pressure, weight, performance status, and concomitant 
medications) may vary by up to one to fourteen (1-14) days from a strict 28 day schedule. 
  
 
Evaluations during treatment 
 
Please note, because of the potential need for blood test, CT/MRI scans, and physician visit 
scheduling to vary (due to both physician and patient issues), to avoid violation of, and 
deviation from, the protocol, blood tests, CT/MRI scans and physician visits (which include 
physical exam, vitals, blood pressure, weight measurement, performance status assessment 
and concomitant medications) may vary up to one to fourteen (1-14)days from a strict 28 
day schedule. 
 
• 
A physical exam, vitals (including blood pressure) and weight measurement, and 
performance status assessment on Week 1, Week 2 and Week 3 of Cycle 1 and then on Week 
1 of each Cycle thereafter. 
• 
A CBC on Week 1, Week 2 and Week 3 of Cycle 1 and then on Week 1 of each Cycle 
thereafter. 
• 
A comprehensive metabolic panel (CMP) on Week 1 and Week 3 of Cycle 1 and then on 
Week 1 of each Cycle thereafter. 
• 
An amylase/lipase level on Week 1 and Week 3 of Cycle 1 and then on Week 1 of each 
Cycle thereafter. 
• 
For patients on coumadin therapy, a PT/INR/PTT on Week 1 and Week 3 of Cycle 1 and 
then on Week 1 of each Cycle thereafter. 
• 
Sorafenib diary to be collected on Week 1 of each new Cycle. 
• 
A list of concomitant medications to be obtained on Week 1 of each new Cycle. 
• 
A repeat CT or MRI of measurable disease after the first 4 weeks on study, at eight weeks, 
and then every 8 weeks thereafter.  If a complete response is achieved and maintained for 12 
months, patients with complete response will then be required to repeat CT or MRI 
evaluation every 4 months up to 5 years post complete response status, then every 6 months 
thereafter The same imaging modality performed at baseline (CT or MRI) will be repeated at 
subsequent imaging. 
 
Evaluation at the end of study treatment: 


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• 
A physical exam, vitals (including blood pressure) and weight measurement, and 
performance status assessment. 
• 
A list of concomitant medications. 
• 
Sorafenib diary to be collected. 
• 
A CBC, CMP and amylase/lipase level. For patients on coumadin, a PT/INR/PTT level. 
 
Immunohistochemistry for pERK 
 
Phosphorylated extracellular signal-regulated kinase (pERK) determination through 
immunohistochemical (IHC) staining of prior paraffin stored tumor blocks or unstained 
slides. pERK determination may be pending at the time of protocol registration, with prior 
material submitted for IHC during the course of protocol therapy. The pERK status is not 
required for enrollment on the protocol.  Studies will be performed at MSKCC. 
 
Whenever possible, the most recent tumor biopsy/pathologic specimen prior to study 
enrollment will be used. 
 
Paraffin-embedded tissue should be prepared by fixing tissues in 10% neutral buffered 
formalin. An optimal fixation time is 12 – 24 hours and should not exceed 48 hours. Slides 
should consist of a minimum of five unstained, positively charged microscope slides with 4 – 
6 µm tissue sections, cut from a paraffin block. The slides should be prepared in a 37 – 42 oC 
water bath without gelatin. Only one 4 – 6 µm cut section is placed on each slide, opposite 
the frosted end, before the slides are allowed to air dry. 
 
pERK tissue expression is assayed using a rabbit polyclonal antibody for pERK (phospho- 
p44/42 mitogen activated protein kinase [Thr202/Tyr204]; Cell Signaling Technology Inc, 
Danvers, MA). A standard secondary biotinylated anti-mouse antibody and streptavidin 
horseradish peroxidase are then applied for visualization. 
 
Briefly, the procedure involves: (1) Deparaffinization and rehydration of the tissues with 
xylene and graded alcohols; (2) Antigen unmasking by pretreatment with sodium citrate; (3) 
Incubation with primary antibody or negative control sera (non-specific mouse IgG); (4) 
Incubation with secondary biotinylated anti-mouse antibody; (5) Incubation with streptavidin 
horseradish peroxidase; (6) Incubation with substrate and chromogen (DAB) (7) 
Counterstaining the tissue with hematoxylin-eosin; (8) Mounting with an aqueous cover slip 
medium and; (9) Microscopy. 
 
A positive control cell line (derived from a gastrointestinal stromal tumor cell line that 
expresses pERK) is included with each assay. Each specimen is reviewed after staining for 
the presence of tumor cells, the localization of pERK staining to the cell nuclei or the 
cytoplasm, the staining intensity and the proportion of tumor cells that stain positive. pERK 
staining is graded semi-quantitatively using a five-point scale: 0, no staining; 1+, weak; 2+, 
moderate; 3+ strong  and; 4+, intense. 


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11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 General considerations 
Subjects must be carefully monitored for adverse events. This monitoring includes clinical 
laboratory tests. Adverse events should be assessed on a continuous basis, with the highest 
grade recorded according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), version 3.0.46 Adverse event should be assessed in terms of 
seriousness, severity, and relationship to the study drug (See Section 11.6). 
 
11.2 General toxicity profile 
For the most recent safety update, refer to the Nexavar® Prescribing Information. 
The overall safety profile of sorafenib is based on 1,286 cancer patients, who received 
sorafenib as a single agent.33 
Table 11.2.1 will be used to determine the “expectedness” of adverse drug reactions used for 
reporting of adverse events to Regulatory Agencies. It is not a complete list of adverse events 
reported in clinical trials. 
 
Table 11.2.1. Adverse drug reactions in patients in multiple clinical trials. 
System Organ Class 
Very Common 
> 10% 
Common 
> 1% to < 10% 
Uncommon 
> 0.1% to < 1% 
Infections and infestations 
Folliculitis infection 
Blood and lymphatic system 
disorders 
Lymphopenia 
Leukopenia 
Neutropenia 
Anemia 
Thrombocytopenia 
Immune system disorders 
Hypersensitivity reactions 
(including skin reactions and 
urticaria) 
Endocrine disorders 
Hypothyroidism 
Metabolism and nutrition 
disorders 
Hypophosphatemia 
Anorexia 
Hyponatremia 
Dehydration 
Psychiatric disorders 
Depression 
Nervous system disorders 
Peripheral sensory 
neuropathy 
Reversible posterior 
leukoencephalopathy* 
Ear and labyrinth disorders 
Tinnitus 
Cardiac disorders 
Myocardial ischemia and 
infarction* 
Congestive heart failure* 
Vascular disorders 
Hemorrhage (including 
gastrointestinal* and 
respiratory tract* and 
cerebral hemorrhage*) 
Hypertension 
Hypertensive crisis* 


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* Events may have a life-threatening or fatal outcome.  Such events are uncommon. 
**Palmar plantar erythrodysaethesia reaction 


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System Organ Class 
Very Common 
> 10% 
Common 
> 1% to < 10% 
Uncommon 
> 0.1% to < 1% 
Respiratory, thoracic and 
mediastinal disorders 
Hoarseness 
Rhinorrhea 
Gastrointestinal disorders 
Diarrhea 
Nausea 
Vomiting 
Constipation 
Stomatitis (including 
dry mouth and 
glossodynea) 
Dyspepsia 
Dysphagia 
Gastroesophageal reflux 
disease 
Pancreatitis 
Gastritis 
Gastrointestinal perforation* 
Hepato-biliary disorders 
Increase in bilirubin and 
jaundice 
Skin and subcutaneous tissue 
disorders 
Rash 
Alopecia 
Hand-foot reaction** 
Pruritis 
Erythema 
Dry skin 
Dermatitis exfoliative 
Acne 
Skin desquamation 
Eczema 
Erythema multiforme minor 
Musculoskeletal, connective 
tissue and bone disorders 
Arthralgia 
Myalgia 
Reproductive system and 
breast disorders 
Erectile dysfunction 
Gynecomastia 
General disorders and 
administration site conditions 
Fatigue 
Pain (inc. mouth, 
abdominal, bone pain, 
headache and tumor 
pain) 
Asthenia 
Fever 
Influenza-like illness 
Investigations 
Increased amylase 
Increased lipase 
Weight decreased 
Transient increase in 
transaminases 
Transient increase in blood 
alkaline phosphatase 
INR abnormal, prothrombin 
level abnormal 
* Events may have a life-threatening or fatal outcome.  Such events are uncommon. 
**Palmar plantar erythrodysaethesia reaction 
 
11.3 Laboratory abnormalities 
 
The following laboratory abnormalities were observed in the randomized phase III trial of 
sorafenib in patients with advanced renal cell carcinoma33: 
 
 
Elevated lipase and amylase: Elevated lipase and amylase levels were very commonly 
reported. Grade 3/4 lipase elevations occurred in 12% of patients in the sorafenib group 
compared to 7% of patients in the placebo group. Grade 3/4 amylase elevations were reported 


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in 1% of patients in the sorafenib group compared to 3% of patients in the placebo group. 
Clinical pancreatitis was reported in 2 of 451 sorafenib treated patients (Grade 4) and 1 of 451 
patients (Grade 2) in the placebo group. 
 
Hypophosphatemia: Hypophosphatemia was a common laboratory finding, observed in 45% 
of sorafenib treated patients compared to 12% of placebo patients. Grade 3 hypophosphatemia 
(1–2 mg/dl) occurred in 13% of sorafenib-treated patients and 3% of patients in the placebo 
group. There were no cases of Grade 4 hypophosphatemia (< 1 mg/dl) reported in either 
sorafenib or placebo patients. The etiology of hypophosphatemia associated with sorafenib is 
not known. 
 
Lymphopenia: Grade 3/4 lymphopenia was reported in 13% of sorafenib treated patients and 
7% of placebo patients. 
 
Neutropenia: Grade 3/4 neutropenia was reported in 5% of sorafenib treated patients and 2% 
of placebo patients. 
 
Anemia: Anemia was observed in 44% of sorafenib-treated patients and 49% of placebo 
patients. Grade 3/4 anemia was reported in 2% of sorafenib-treated patients and 4% of 
placebo patients. 
 
Thrombocytopenia: Thrombocytopenia was observed in 12% of sorafenib-treated patients 
and 5% of placebo patients. Grade 3/4 thrombocytopenia was reported in 1% of sorafenib- 
treated patients and 0% of placebo patients. 
 
 
11.4 Special warning and precautions for use 
 
Dermatological toxicities: Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and 
rash represent the most common adverse drug reactions with sorafenib. Rash and hand-foot 
skin reaction are usually Grade 1/2 and generally appear during the first six weeks of 
treatment with sorafenib. Management of dermatologic toxicities may include topical 
therapies for symptomatic relief, temporary treatment interruption and/or dose modification of 
sorafenib, or in severe or persistent cases, permanent discontinuation of sorafenib. See Section 
9.2.4 for supportive measures and Table 11.5.1 for suggested dose modifications for hand-foot 
reaction. 
 
Hypertension: An increased incidence of hypertension was observed in sorafenib-treated 
patients. Hypertension was usually mild to moderate, occurred early in the course of treatment 
and was amenable to management with standard antihypertensive therapy. Blood pressure 
should be monitored regularly and treated, if required, in accordance with standard medical 
practice. In cases of severe or persistent hypertension, or hypertensive crisis despite adequate 
antihypertensive therapy, permanent discontinuation of sorafenib should be considered. See 
Table 11.5.2 for suggested dose modifications for treatment-emergent hypertension. 


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Hemorrhage: An increase in the risk of bleeding may occur following sorafenib 
administration. The incidence of severe bleeding events is uncommon. If any bleeding event 
necessitates medical intervention, it is recommended that permanent discontinuation of 
sorafenib be considered. 
 
Wound healing complications: No formal studies of the effect of sorafenib on wound 
healing have been conducted. In patients undergoing major surgical procedures, temporary 
interruption of sorafenib therapy is recommended for precautionary reasons. There is limited 
clinical experience regarding the timing of reinitiation of therapy following major surgical 
intervention. Therefore, the decision to resume sorafenib therapy following a major surgical 
intervention should be based on clinical judgment of adequate wound healing. 
 
Cardiac Ischemia and/or Infarction: In the phase 3 randomized study of sorafenib in 
patients with advanced renal cell carcinoma, the incidence of treatment-emergent cardiac 
ischemia/infarction events was higher in the sorafenib group (2.9%) compared with the 
placebo group (0.4%).41 Patients with unstable coronary artery disease or recent myocardial 
infarction were excluded from this study. Sorafenib should be discontinued in patients who 
develop cardiac ischemia and/or infarction. 
 
Gastrointestinal perforation: Gastrointestinal perforation is an uncommon event and has 
been reported in <1% of patients taking sorafenib.33 In some cases, this was not associated 
with apparent intra-abdominal tumor. Sorafenib should be discontinued in patients with GI 
perforation. 
 
Effects on ability to drive and use machines: No studies on the effects of sorafenib on the 
ability to drive or use machines have been performed. There is no evidence that sorafenib 
affects the ability to drive or operate machinery. 
 
Patients with Hepatic Impairment:  In vitro and in vivo data indicate that sorafenib is 
primarily metabolized by the liver.  Systemic exposure and safety data were comparable in 
patients with Child-Pugh A and B hepatic impairment.  Sorafenib has not been studied in 
patients with Child-Pugh C hepatic impairment.  No dose adjustment is necessary when 
administering sorafenib to patients with Child-Pugh A and B hepatic impairment. 
 
 
Patients with Renal Impairment: Sorafenib has not been studied in patients with severe 
renal impairment (CrCl <30 mL/min) or in patients undergoing dialysis. 
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not 
been performed with sorafenib.  Sorafenib was clastogenic when tested in an in vitro 
mammalian cell assay (Chinese Hamster Ovary) in the presence of metabolic activation. 
Sorafenib was not mutagenic in the in vitro Ames bacterial cell assay or clastogenic in an in 
vivo mouse micronucleus assay.  One intermediate in the manufacturing process, which is also 
present in the final drug substance (<0.15%), was positive for mutagenesis in an in vitro 
bacterial cell assay (Ames test) when tested independently.  No specific studies with sorafenib 


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have been conducted in animals to evaluate the effect on fertility.  However, results from the 
repeat-dose toxicity studies suggest there is a potential for sorafenib to impair reproductive 
performance and fertility. Multiple adverse effects were observed in male and female 
reproductive organs, with the rat being more susceptible than mice or dogs.  Typical changes 
in rats consisted of testicular atrophy or degeneration, degeneration of epididymis, prostate, 
and seminal vesicles, central necrosis of the corpora lutea and arrested follicular development. 
Sorafenib-related effects on the reproductive organs of rats were manifested at daily oral 
doses =30 mg/m2 (approximately 0.5 times the AUC in cancer patients at the recommended 
human dose).  Dogs showed tubular degeneration in the testes at 600 mg/m2/day 
(approximately 0.3 times the AUC at the recommended human dose) and oligospermia at 
1200 mg/m2/day of sorafenib. Adequate contraception should be used during therapy and for 
at least 2 weeks after completing therapy. 33 
 
Pediatric Use: The safety and effectiveness of sorafenib in pediatric patients have not been 
studied.  Repeat dosing of sorafenib to young and growing dogs resulted in irregular 
thickening of the femoral growth plate at daily sorafenib doses =600 mg/m2 (approximately 
0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow 
adjoining the growth plate at 200 mg/m2/day (approximately 0.1 times the AUC at the 
recommended human dose), and alterations of the dentin composition at 600 mg/m2/day. 
Similar effects were not observed in adult dogs when dosed for 4 weeks or less. 
 
Geriatric Use:  In total, 32% of RCC patients treated with sorafeniab were age 65 years or 
older, and 4% were 75 and older. No differences in safety or efficacy were observed between 
older and younger patients, and other reported clinical experience has not identified 
differences in responses between the elderly and younger patients, but greater sensitivity of 
some older individuals cannot be ruled out. 
 
Drug-Drug Interactions: Caution is recommended when administering sorafenib together 
with compounds that are metabolized/ eliminated predominantly by the UGT1A1 pathway 
(e.g. irinotecan) 33 
 
CYP3A4 inducers: There is no clinical information on the effect of CYP3A4 inducers on 
the pharmacokinetics of sorafenib. Inducers of CYP3A4 activity (e.g. rifampicin, 
Hypericum perforatum also known as St. John’s wort, phenytoin, carbamazepine, 
phenobarbital, and dexamethasone) may increase metabolism of sorafenib and thus 
decrease sorafenib plasma concentrations. 
 
CYP3A4 inhibitors: Ketoconazole, a potent inhibitor of CYP3A4, administered once daily 
for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose 
of sorafenib. Therefore, clinical pharmacokinetic interactions of sorafenib with CYP3A4 
inhibitors are unlikely. 


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CYP2C9 substrates: The possible effect of sorafenib on the metabolism of the CYP2C9 
substrate warfarin was assessed indirectly by measuring PTINR. The mean changes from 
baseline in PT-INR were not higher in sorafenib patients compared to placebo patients, 
suggesting that sorafenib did not inhibit warfarin metabolism in vivo. However, patients 
taking warfarin should have their INR checked regularly. 
 
CYP isoform-selective substrates: Concomitant administration of midazolam, 
dextromethorphan and omeprazole, which are substrates of cytochromes CYP3A4, 
CYP2D6 and CYP2C19, respectively, following 4 weeks of sorafenib administration did 
not significantly alter the exposure of these agents. This indicates that sorafenib is neither 
an inhibitor nor a clinically meaningful inducer of these cytochrome P450 isoenzymes. 
 
Combination with other anti-neoplastic agents: In clinical studies, sorafenib has been 
administered together with a variety of other antineoplastic agents at their commonly used 
dosing regimens, including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. 
Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. 
Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of 
doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further 
metabolized by the UGT1A1 pathway, there was a 67-120% increase in the AUC of SN- 
38 and a 26-42% increase in the AUC of irinotecan. The clinical significance of these 
findings is unknown. However, caution is recommended when administering sorafenib 
with doxorubicin and with compounds that are metabolized/eliminated predominantly by 
the UGT1A1 pathway (e.g. irinotecan). 
 
Warfarin: Infrequent bleeding events or elevations in the International Normalized Ratio 
(INR) have been reported in some patients taking warfarin while on sorafenib therapy. 
Patients taking warfarin concomitantly should be monitored regularly for changes in 
prothrombin time, INR and for clinical bleeding episodes. 
 
11.5 Dose delay/modification 
 
Intrapatient dose reduction will be allowed depending on the type and severity of toxicity 
encountered provided that criteria for patient withdrawal from study treatment have not been 
met. The dose levels for sorafenib are as described below: 
 
Starting dose 0 
Sorafenib 400 mg twice daily 
Dose level -1 
Sorafenib 400 mg daily 
Dose level -2 
Sorafenib 400 mg every other day 
If further dose reduction is required, the patient should be taken off-protocol. 
 
Patients who require a treatment delay of >4 consecutive weeks should also be taken off- 
protocol. 


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The following tables describe the recommended dose modifications for sorafenib-associated 
toxicities, including hand-foot skin reaction (Table 11.5.1), treatment-emergent hypertension 
(Table 11.5.2), exacerbation of baseline hypertension (Table 11.5.3) and other general 
hematologic and non-hematologic toxicities (Table 11.5.4). 
 
Table 11.5.1: Suggested dose modifications for sorafenib for hand-foot skin reaction 
Grade 
Occurrence 
Suggested Dose Modification 
Grade 1 
Numbness, dysesthesia, 
paresthesia, tingling, 
painless swelling, 
erythema or discomfort of 
the hands or feet which 
does not disrupt the 
patient’s normal activities 
Any 
Promptly institute supportive measures such as topical therapy for symptomatic relief 
and continue sorafenib treatment. 
Grade 2 
Painful erythema and 
swelling of the hands or 
feet and/or discomfort 
affecting the patient’s 
normal activities 
First 
Promptly institute supportive measures such as topical therapy for symptomatic relief 
and consider a decrease of sorafenib dose to 400 mg daily for a minimum of 7 days 
and up to 28 days. 
• 
If toxicity resolves to grade 0-1 after dose reduction, increase sorafenib back to 
full dose of 400 mg BID. 
• 
If toxicity does not resolve to grade 0-1 despite dose reduction, interrupt 
sorafenib treatment for a minimum of 7 days and until toxicity has resolved to 
grade 0-1. 
• 
When resuming treatment after dose interruption, resume sorafenib at a reduced 
dose of 400mg daily. 
• 
If toxicity is maintained at grade 0-1 at reduced dose for a minimum of 7 days 
and up to 28 days, increase sorafenib back to full dose of 400 mg BID 
Second or Third 
occurrence 
As for first occurrence. 
Upon resuming sorafenib treatment, decrease dose by one dose level (400 mg daily or 
400 mg every other day). 
Decision whether to dose re-escalate should be based on clinical judgment and patient 
preference. 
Fourth 
occurrence 
Decision whether to discontinue sorafenib treatment should be made based on clinical 
judgment and patient preference 
Grade 3 
Moist desquamation, 
ulceration, blistering or 
severe pain of the hands 
or feet, or severe 
discomfort that causes the 
patient to be unable to 
work or perform activities 
of daily living 
First occurrence 
Institute supportive measures such as topical therapy for symptomatic relief and 
interrupt sorafenib treatment for a minimum of 7 days and until toxicity has resolved 
to grade 0–1 
• 
When resuming treatment after dose interruption, decrease sorafenib by one dose 
level (400 mg daily or 400 mg every other day) 
• 
If toxicity is maintained at grade 0-1 at reduced dose for a minimum of 7 days 
and up to 28 days, increase by one dose level (400mg BID or 400 mg daily) 
Second 
occurrence 
As for first occurrence. Upon resuming sorafenib treatment, decrease dose by one 
dose level (400 mg daily or 400 mg every other day). 
Decision whether to dose re-escalate should be made based on clinical judgment and 
patient preference. 


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Third occurrence Decision whether to discontinue sorafenib treatment should be made based on clinical 
judgment and patient preference. 
 
 
 
Table 11.5.2: Dose Modifications of Sorafenib for Hypertension 
Grade 
(CTCAE v3.0) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sorafenib Dose 
Grade 1 
None 
Routine 
No change 
Grade 2 
(asymptomatic) 
Initiate monotherapy 
(suggest 
dihydropyridine 
calcium-channel 
blocker) 
Increase frequency 
and 
monitor (by health 
professional) every 2 
days 
until stabilized 
No change 
Grade 2 
(symptomatic/ 
persistent) 
OR 
Diastolic BP > 110 
mm Hg 
OR 
Grade 3 
Add agent(s): 
Ca++ channel blocker 
(if not already used), 
K+ channel opener 
(angiotensin blockers), 
beta-blocker, 
thiazide diuretic 
Increase frequency 
and 
monitor (by health 
professional) every 2 
days until stabilized; 
continue qod 
monitoring 
to stabilization after 
dosing restarted. 
Hold* Sorafenib 
until symptoms 
resolve and 
diastolic BP < 100 
mm/Hg. 
Resume treatment at 
1 
dose level lower** 
Grade 4 
Off protocol therapy 
* Patients requiring a delay of > 21 days should go off protocol therapy unless, in the treating 
physician’s opinion, the patient may benefit from continued treatment.. 
** Patients requiring >2 dose reductions should go off protocol therapy. 
CTCAE v3.0 definitions 
Grade 1: asymptomatic, transient (<24 hrs) increase by > 20 mmHg (diastolic) or > 150/100 if 
previously 
WNL; intervention not indicated 
Grade 2: recurrent or persistent (>24 hrs) or symptomatic increase by >20 mmHg (diastolic) or to 
>150/100 if previously WNL; monotherapy may be indicated. 
Grade 3: requiring more than one drug or more intensive therapy than previously 
Grade 4: life threatening (e.g., hypertensive crisis) 
 
 
 
 
 
 
 
Table 11.5.3: Suggested dose modifications for sorafenib for exacerbation of hypertension 
in patients with baseline diagnosis of hypertension. 


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Hypertension grade 
Suggested dose modification 
Grade 1: Asymptomatic, transient (<24 hours) 
increase by >20 mmHg (diastolic) or to 
>150/100 mmHg if previously within normal 
limits (WNL) 
Increase blood pressure monitoring 
Grade 2: Recurrent or persistent (≥24 hours) 
increase by >20 mmHg (diastolic) or to 
>150/100 mmHg if previously WNL 
OR 
Grade 3: Requiring >1 drug or more intensive 
therapy than previously 
BUT diastolic blood pressure <110 mmHg 
Additional anti-hypertensive therapy per 
standard management and continue sorafenib 
Grade 2 but symptomatic 
OR 
Diastolic blood pressure ≥110 mmHg 
1.   Hold sorafenib until symptoms resolve and 
diastolic BP <100 mmHg 
2.   Additional anti-hypertensive therapy. 
3.   Restart sorafenib at one dose level lower.* 
4.   If diastolic BP is ≥100 mmHg on anti- 
hypertensive therapy, decrease by another 
dose level. 
Grade 4: Life-threatening consequences, e.g. 
hypertensive crisis 
Discontinue sorafenib; institute supportive 
measures 
*may be able to resume sorafenib at full-dose later if BP is <140/80 on anti-hypertensive therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.5.4: Dose modifications for sorafenib hematologic and non-hematologic toxicities 
(other than hand-foot reaction and hypertension) 
Toxicity 
Grade 1 
Grade 2 
Grade 3* 
Grade 4* 
Non- 
Continue at the 
Continue at the 
Withhold dose for at 
Withhold dose for 


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hematologic 
same dose level. 
same dose level. least 7 days until 
toxicity is grade <1, 
then resume 
treatment at one dose 
level lower. 
at least 7 days until 
toxicity is grade 
<1, then resume 
treatment at one 
dose level lower, 
or discontinue at 
the discretion of 
the principal 
investigator after 
discussion with 
study sponsor. 
Hematologic 
Continue at the 
same dose level. 
Continue at the 
same dose level. 
Withhold dose for at 
least 7 days until 
toxicity is grade <2, 
then resume 
treatment at one dose 
level lower. 
Withhold dose for 
at last 7 days until 
toxicity is grade 
<2, then resume 
treatment at one 
dose level lower, 
or discontinue at 
the discretion of 
the principal 
investigator after 
discussion with 
study sponsor. 
*Patients who develop grade 3 fever/chills, grade 3 elevation of hepatic transaminases with ALT and AST <10X 
ULN, grade 3 hyperlipasemia or hyperamylasemia without clinical or other evidence of pancreatitis, grade 3 
leukopenia, or grade 3/grade 4 lymphopenia may continue study treatment without interruption at the discretion of 
the investigator. 
 
11.6 
Adverse event definitions 
 
11.6.1 Adverse event 
An adverse event is any untoward medical occurrence in a subject or clinical investigation 
subject administered with a pharmaceutical product. The adverse event does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the medicinal product. 
Adverse events associated with the use of a drug in humans, whether or not considered drug 
related, include the following: 
• 
An adverse event occurring in the course of the use of a drug product in professional 
practice. 
• 
An adverse event occurring from an overdose whether accidental or intentional. 
• 
An adverse event occurring from drug abuse. 
• 
An adverse event occurring from drug withdrawal. 


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• 
An adverse event where there is a reasonable possibility that the event occurred purely as 
a result of the subject’s participation in the study (e.g. adverse event or serious adverse 
event due to discontinuation of anti-hypertensive drugs during wash-out phase) must also 
be reported as an adverse event even if it is not related to the investigational product. 
 
11.6.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
• 
Is an important medical event. 
 
11.6.3 Adverse event documentation 
 
All adverse events occurring after the subject has signed the informed consent must be fully 
recorded in the subject’s case record form. 
 
Documentation must be supported by an entry in the subject’s file. A laboratory test 
abnormality considered clinically relevant, e.g., causing the subject to withdraw from the 
study, requiring treatment or causing apparent clinical manifestations, or judged relevant by 
the investigator, should be reported as an adverse event. Each event should be described in 
detail along with start and stop dates, severity, relationship to investigational product, action 
taken and outcome. 
 
11.7 Reporting of serious adverse events (SAE) 
 
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. 
Serious adverse drug-related events should be reported to Bayer/Onyx.  In the event of such 
an event, the investigator should refer to the Pharmacovigilance section of the contract for 
reporting procedures. 


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In brief, the Investigator/Sponsor may report serious adverse drug reactions (SADRs) using a 
Clinical Research Database (CRDB) Adverse Event report. 
All reports shall be sent electronically to: 
Electronic Mailbox: 
DrugSafety.GPV.US@bayer.com 
 
Facsimile: 
(973) 709-2185 
 
Address: 
Global Pharmacovigilance - USA 
Mail only 
Bayer HealthCare Pharmaceuticals Inc. 
P.O. Box 1000 
Montville, NJ 07045-1000 
 
Address: 
340 Changebridge Road 
FDX or UPS only 
Pine Brook, NJ  07058 
 
Reports for all Bayer products can also be phoned in to the Clinical Communications 
Department: 
 
Phone: 
1-888-842-2937 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 Measurement of effect 
 
For the purposes of this study, patients should be re-evaluated after the first cycle, i.e. four 
weeks, of treatment and then every two cycles or eight weeks thereafter. Confirmatory scans 
should also be obtained no less than four weeks following initial documentation of objective 
response. 
 
12.2 Definitions 
Response and progression will be evaluated in this study using standard Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria.45 Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria. Note: 
Lesions are either measurable or non-measurable using the criteria provided below.  The term 
“evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
 
12.2.1 Measurable disease 
 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥20 mm with conventional X-rays or >10 mm 


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with CT or MRI scan. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
Tumor lesions within a prior radiation field are considered measurable as long as disease 
progression has been documented in these lesions after prior radiotherapy. 
 
12.2.2 Non-measurable disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm using 
X-ray or <10 mm using CT or MRI scan), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), 
and cystic lesions are all non-measurable. 
 
12.2.3 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 response. 
 
 
 
12.2.4 Non-target lesions 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Non-target lesions include measurable lesions that exceed the 
maximum numbers per organ or total of all involved organs as well as non-measurable 
lesions. Measurements of these lesions are not required but the presence or absence of each 
should be noted throughout follow-up. 
 
12.3 Guidelines for evaluation of measurable disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed within four weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment. 
 
Clinical lesions. Clinical lesions are not considered measurable. 


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Chest X-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI. These techniques should be performed with cuts of ≤10 mm in 
slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and 
neck tumors and those of extremities usually require specific protocols. 
 
Ultrasound (U/S). U/S should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. U/S might also be useful to confirm the complete disappearance 
of superficial lesions usually assessed by clinical examination. 
 
Endoscopy/laparoscopy. The utilization of these techniques for objective tumor evaluation has 
not yet been fully and widely validated. Their uses in this specific context require 
sophisticated equipment and a high level of expertise. Therefore, the utilization of such 
techniques for objective tumor response is not permitted. However, such techniques can be 
useful to confirm pathological complete response when biopsies are obtained. 
 
Tumor markers. There are no validated tumor markers for the assessment of esophageal and 
GE junction cancers. As such, they cannot be used to assess response. 
 
12.4 Response Criteria 
 
12.4.1 Evaluation of target lesions 
 
Complete Response (CR): 
Disappearance of all target lesions 
 
Partial Response (PR): 
≥30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD): 
≥20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new 
lesions 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
 
 
 
12.4.2 Evaluation of non-target lesions 


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Complete Response (CR): 
Disappearance of all non-target lesions 
 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances the opinion of the treating physician should prevail, and the progression status 
should be confirmed at a later time. 
  
 
12.4.3 Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria (see section 
12.4.1). 
 
 
 
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 
 
 
Note: 
1.   Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression, even after discontinuation of treatment. 
2.   In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 


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that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the 
complete response status. 
 
12.5 Confirmatory measurement/duration of response 
 
12.5.1 Confirmation 
 
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. In the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 4 weeks. 
 
12.5.2 Duration of overall response 
 
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
 
12.5.3 Duration of stable disease 
 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
 
12.6 Progression-free survival 
 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to 
time of progression or death from any cause. Patients who are taken off-study because of 
drug-related toxicity or other adverse event but who are alive and have stable or responding 
disease at the time of trial discontinuation will be not be censored and will be counted in the 
survival analyses. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Treatment will continue indefinitely until one of the following criteria apply: 
• 
Disease progression (as determined in Section 12.4.1); 
• 
Intercurrent illness that prevents further drug administration; 
• 
Unacceptable adverse events (as determined in Section 11); 
• 
A treatment delay of >4 consecutive weeks; 
• 
Patient’s death; 
• 
Patient’s decision to withdraw informed consent; 


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• 
General or specific changes in the patient’s condition that renders the patient unsuitable 
for further treatment; 
• 
Patient becomes pregnant; 
• 
Non-compliance by the patient with protocol requirements; 
• 
Patient is lost to follow-up. If the patient fails to return for follow-up evaluations, every 
effort should be made to re-establish contact and to determine patient outcome. 
 
14.0 
BIOSTATISTICS 
 
This is a single institution, open-label, non-randomized, single-arm phase II evaluation. The 
primary objective of this study is to determine the 2-month progression free survival (PFS) for 
patients with advanced or recurrent esophageal and gastroesophageal (GE) junction cancer 
who are treated with sorafenib 400 mg twice daily. PFS is defined in Section 12.6. 
 
The historical control 2 month PFS for patients with untreated advanced esophageal and GE 
junction cancer is approximately 50%29 . Using an exact binomial single stage design we 
require 35 patients to differentiate between 2-month PFS of 50% and 72% with type I and II 
error rates of 10% each. If 22 or more patients are alive and progression free at 2 months, the 
regimen is declared promising. With a total of 35 patients, we also have approximately 89% 
power to detect an improvement in the response rate from 5% to 18% with a type I error rate 
of 10%. 
 
If at any time there are 14 or more deaths or progressions before 2 months then the trial will 
close as it is mathematically impossible to achieve the desired endpoint. 
 
We assume an accrual rate of 1-2 patients per month for a study duration of 18-35 months. 
 
 
Secondary endpoints involve an assessment of the overall response rate (complete and partial 
responses), as determined by RECIST criteria. Toxicities will also be assessed and tabulated. 
While the small sample size precludes any definitive conclusions about differential responses 
based on the squamous cell carcinoma and adenocarcinoma histologies, any differences 
observed between the two histologies may be exploratory and hypothesis-generating. 
Finally, tumor tissue will undergo immunohistochemical staining for phosphorylated 
extracellular signal-regulated kinase (pERK). Any differential response based on different 
levels of pERK tumor expression will similarly be hypothesis-generating.  Fisher’s exact test 
will be employed to investigate these exploratory analyses. 


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15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1   Research participant registration 
 
 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003. Registrations can be phoned in or faxed. The completed 
signature page of the written consent/verbal script and a completed Eligibility Checklist 
must be faxed to PPR. 
 
16.0 
DATA  MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
 
The data collected for this study will be entered into a secure database. Source documentation 
will be available to support the computerized patient record. 
 
16.1 Quality assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 


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16.2 Data and safety monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute 
for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and 
II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials,  report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation 
 
17.0 PROTECTION OF HUMAN SUBJECTS 
Inclusion of women and minorities 
MSKCC has filed forms HHS 441 (civil rights), HHS 641 (handicapped individual), HHS 
639-A (sex discrimination) and HHS 680 (age discrimination); we also take due notice of the 
NIH/ADAMHA policy concerning inclusion of women and minorities in clinical research 
populations. Patients of all races, both males and female, will be enrolled into the protocol. In 
the New York metropolitan area, there is a high proportion of minority patients (e.g. African- 
American, Hispanic). In general, about 15% of patients at MSKCC are members of minority 
ethnic groups. We will actively try to recruit minority patients to this protocol. 
 
Exclusion of children and lactating or pregnant women 
 
Children are excluded from this protocol because there is insufficient data to determine the 
safety of sorafenib in children. In addition, the incidence of esophageal cancer in children is 
very low. Similarly, lactating and pregnant women are excluded because of the potential 
teratogenicity and embryotoxicity of sorafenib. 


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Benefits 
 
It is possible that this treatment will result in shrinkage of tumors or in stabilization of an 
otherwise progressive disease. It is not known, of course, whether these or any other favorable 
events will occur. It is not known if this treatment will affect the overall survival of patients. 
 
Costs 
 
The patient will be responsible for the cost of standard medical care, including all drug 
administration fees and all hospitalizations, even for complications of treatment. Sorafenib 
will be provided to the patient without charge. Correlative tests will be performed without 
charge to the patient. 
Incentives 
 
No incentives will be offered to patients/subjects to participate in this study. 
 
Alternatives 
 
For patients with metastatic or recurrent esophageal cancer, standard therapy includes 
standard palliative chemotherapy, radiation or possibly surgery. The patient may also be 
eligible to participate in other investigational studies. Supportive care is also an option. 
 
Confidentiality 
 
Every effort will be made to maintain patient confidentiality. Research and hospital records are 
confidential. Patient’s name or any other personally identifying information will not be used in 
reports or publications arising from this study. The Food and Drug Administration or other 
authorized agencies (e.g. qualified monitors from MSKCC, Bayer Pharmaceuticals) may 
review patient record and pathology slides, as required. The Investigator should contain Bayer 
Pharmaceuticals immediately if contacted by a regulatory agency about an inspection at 
his/her center. 
 
Institutional Review Board 
Before study initiation, the Investigator must have written and dated approval/favorable 
opinion from the IRB for the protocol form, informed consent, patient recruitment 
materials/process (e.g. advertisements) and any other written information to be provided to 
patients. The Investigator should also provide the IRB with reports, updates and other 
information (e.g. Safety Updates, Amendments, Administrative Letters) according to 
regulatory requirements or institutional procedures. Copies of the initial IRB approval as well 
as annual re-approvals must be submitted to the study sponsor, Bayer Pharmaceuticals. 


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17.1 Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
 
 
17.2 Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org containing the following information: 
Fields populated from the CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office.. 


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For industrial protocols: 
Serious adverse drug-related events should be reported to Bayer/Onyx.  In such an event, the 
investigator should refer to the Pharmacovigilance section of the contract for reporting 
procedures. 
 
Any safety information exchange between Bayer/Onyx and investigator shall be sent 
electronically (electronic mailbox) or via facsimile to the attention of the contacts listed 
below: 
Electronic Mailbox: 
DrugSafety.GPV.US@bayer.com 
 
Facsimile: 
(973) 709-2185 
 
Address: 
Global Pharmacovigilance - USA 
Mail only 
Bayer HealthCare Pharmaceuticals Inc. 
P.O. Box 1000 
Montville, NJ 07045-1000 
 
Address: 
340 Changebridge Road 
FDX or UPS only 
Pine Brook, NJ  07058 
 
Reports for all Bayer products can also be phoned in to the Clinical Communications Dept: 
 
Phone: 
1-888-842-2937 
  
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 
3.   Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 


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Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
 
 
19.0 
REFERENCE(S) 
 
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35.  Awada A, Hendlisz A, Gil T, et al: Phase I safety and pharmacokinetics of BAY 43-9006 
administered for 21 days on/7 days off in patients with advanced, refractory solid 
tumours. Br J Cancer 92:1855-61, 2005 
36.  Clark JW, Eder JP, Ryan D, et al: Safety and pharmacokinetics of the dual action Raf 
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IRB#: 09-016A(9)
Amended: 05/12/15
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20.0 
APPENDICES 
 
Appendix A: Sorafenib Medication Diary