Clinical trial NCT00390325
Conditions: Hereditary Thyroid Gland Medullary Carcinoma Locally Advanced Thyroid Gland Medullary Carcinoma Multiple Endocrine Neoplasia Type 2A Multiple Endocrine Neoplasia Type 2B Recurrent Thyroid Gland Medullary Carcinoma Sporadic Thyroid Gland Medullary Carcinoma Stage III Thyroid Gland Medullary Carcinoma AJCC v7 Stage IV Thyroid Gland Medullary Carcinoma AJCC v7 Stage IVA Thyroid Gland Medullary Carcinoma AJCC v7 Stage IVB Thyroid Gland Medullary Carcinoma AJCC v7 Stage IVC Thyroid Gland Medullary Carcinoma AJCC v7
Sponsor: National Cancer Institute (NCI)
Start date: 2006-11-03; Completion date: 2022-12-22
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well sorafenib tosylate works in treating patients with medullary thyroid cancer that has spread to other parts of the body (metastatic), spread to the tissue surrounding the thyroid (locally advanced), or has returned after a period of improvement (recurrent). Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess objective response rate of sorafenib tosylate (sorafenib \[BAY 43-9006\]) in metastatic medullary thyroid carcinoma in setting of inherited tumor syndromes, such as multiple endocrine neoplasia (MEN) 2A, MEN 2B, or familial medullary thyroid carcinoma (FMTC).

II. To assess objective response rate of sorafenib (BAY 43-9006) in sporadic metastatic medullary thyroid carcinoma.

SECONDARY OBJECTIVES:

I. To assess toxicity of sorafenib (BAY 43-9006) in patients with metastatic medullary thyroid carcinoma.

II. Measure serum tumor markers calcitonin and carcinoembryonic antigen (CEA) pre-, during, and post-treatment to correlate with disease response.

III. Correlate nuclear medicine functional imaging (fludeoxyglucose F 18 \[F-18 fluorodeoxyglucose\] positron emission tomography \[PET\] scan) data obtained at pre-, during, and post-treatment with tumor response.

IV. Correlate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data obtained at pre-, during, and post-treatment with changes in tumor permeability and vascularity with tumor response.

V. Perform pharmacogenomic studies on procured peripheral blood mononuclear cells (PBMCs) if clinical responses are observed.

VI. To correlate between the degree of retrovirus-associated sequence (Ras)-mitogen-activated protein kinase (MAPK) signaling inhibition and vascular endothelial growth factor (VEGF) expression in the tumor and clinical response.

VII. To correlate between the presence and type of ret proto-oncogene (RET) gene defects in tumor and clinical response.

OUTLINE:

Patients receive sorafenib tosylate orally (PO) twice daily (BID) in the absence of disease progression or unacceptable toxicity.

Arms: arm 1: Patients receive sorafenib tosylate PO BID in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Sorafenib Tosylate
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol #: NCI-7609 
Version Date: 12/14/2017 
1 
 
 
 
 
NCI Protocol #: 7609 
 
Local Protocol #: OSU-06054 
 
TITLE: Phase II Study of Sorafenib (BAY 43-9006) in Patients with Metastatic Medullary 
Thyroid Carcinoma 
 
Coordinating Institution: 
The Ohio State University (OSU) 
Principal Investigator: 
Bhavana Konda, MBBS, MPH 
The Ohio State University 
A440 Starling Loving Hall 
320 W 10th Avenue 
Columbus, OH 43210 
Phone: 614-293-8629 
Fax: 614-293-3112 
Pager: 293-PAGE ext: 3920 
Email:bhavana.konda@osumc.edu 
 
Participating Institutions: 
 
Washington University School of Medicine 
Institutional P.I.: 
Jeffrey F. Moley MD 
Professor of Surgery 
Washington University School of Medicine 
Associate Director, Alvin Siteman Cancer Center 
Box 8109 
660 S. Euclid 
St. Louis MO 63110 
Phone: 314-747-0064 
Fax: 314-747-1310 
Pager: 314-823-2025 
Email: moleyj@wustl.edu 
 
Institutional Co-Is.: 
Samuel A. Wells, Jr., M.D. 
Professor of Surgery 
Phone: 919-668-8435 
Fax: 919-668-7123 
Email:wells029@surgerytrials.duke.edu 
NCI-Supplied Agent: 
Sorafenib (BAY 43-9006) (NSC 724772) 
IND for Sorafenib: 
69896 
IND Sponsor: 
DCTD, NCI 


NCI Protocol #: NCI-7609 
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Protocol Type / Version# / Version Date: 
Original Protocol / Version 1 / March 28, 2006 
Original Revision / Version 2 / May 23, 2006 
Original Revision / Version 3 / June 29, 2006 
Amendment 1 / Version 4 / December 19, 2006 
Amendment 2 / Version 5 / April 09, 2007 
Amendment 3 / Version 6 / May 30, 2007 (NCI Disapproved) 
Amendment 4 / Version 7 / June 12, 2007 (NCI Disapproved) 
Amendment 5 / Version 8 / July 16, 2007 
Amendment 6 / Version 9 / August 27, 2007 
Amendment 7 / Version 10 / March 14, 2008 
Amendment 8 / Version 11 / April 29, 2008 
Amendment 9, Version 12 / January 02, 2009 
Amendment 10 / Version 13 / June 29, 2009 
Amendment 11 / Version 14 / March 13, 2012 
Amendment 12 / Version 15 / August 19, 2014 
Amendment 13 / Version 1 / September 06, 2016 
Amendment 14 / Version 1 / December 15, 2016 
Amendment 15 / Version 1 / April 03, 2017 (NCI Disapproved) 
Amendment 16 / Version 1 / April 20, 2017 
Amendment 17/ Version 1 / December 14, 2017 


NCI Protocol #: NCI-7609 
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Sorafenib (BAY 43-9006) administered orally at 400 
mg PO BID on a continuous basis as an outpatient 
Tumor response assessment every 16 weeks 
 
SCHEMA  
Phase II Trial of Sorafenib (BAY 43-9006) in Patients with 
Metastatic Medullary Thyroid Carcinoma 
 
Arm A: (n=16 or 25) 
MTC in setting of inherited 
syndromes 
(MEN-2A, 2B or FMTC) 
plus 
Measurable disease 
Plus 
No prior ZD6474 or AMG 706 
Arm B: (n=16 or 25) 
MTC in setting of sporadic ds 
plus 
Measurable disease 
Plus 
No prior ZD6474 or AMG 706 
 
 
 
 
Correlatives Studies 
(Section 7.0 for details as some of these tests are done in a selected group of patients) 
▪ Serum calcitonin and CEA at pre-therapy, on-therapy and post-therapy. 
▪ PET scan at pre-therapy and on-therapy as clinically indicated. 
▪ Dynamic contrast enhanced MRI at pre-therapy, on-therapy and post-therapy 
(Optional per Section 7.3 of protocol). 
▪ Pharmacogenomics studies in case clinical responses are observed. 
▪ Tumor biopsies for MAPK, AKT phosphorylation and VEGF expression at pre- 
therapy, at 8-weeks and at post-therapy (Optional per Section 7.5 of protocol). 
▪ Obtain formalin-fixed, paraffin-embedded tumor specimen collected any time prior to 
study for evaluating the presence/type of RET gene defects. 
▪ RET mutation studies in peripheral blood obtained pre-study if not been previously 
tested. 
(n=16 or 25) 
 
 
Progressive disease 
Complete Response 
Stable disease or 
Partial Response 
 
No further therapy- 
off study 
8 more weeks of therapy and 
off study 
8 more weeks of 
therapy and reassess 


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TABLE OF CONTENTS 
SCHEMA ................................................................................................................................3 
TABLE OF CONTENTS..........................................................................................................4 
1 OBJECTIVES ..................................................................................................................6 
1.1 
Primary Objective:......................................................................................................6 
1.2 
Secondary Objectives .................................................................................................6 
2 BACKGROUND ..............................................................................................................6 
2.1 
Metastatic Medullary Thyroid Carcinoma (MTC) ........................................................6 
2.2 
Tumor markers and imaging studies in MTC ...............................................................7 
2.3 
Genetics of MTC ........................................................................................................7 
2.4 
Sorafenib (BAY 43-9006) ...........................................................................................8 
2.5 
Clinical Experience .................................................................................................. 11 
2.6 
Rationale .................................................................................................................. 12 
3 PATIENT SELECTION ................................................................................................. 13 
3.1 
Eligibility Criteria specific for Arm A: ...................................................................... 13 
3.2 
Eligibility Criteria specific for Arm B: ...................................................................... 13 
3.3 
Eligibility Criteria common for Arms A and B........................................................... 13 
3.4 
Exclusion Criteria for Arm A and Arm B .................................................................. 14 
3.5 
Inclusion of Women and Minorities .......................................................................... 15 
4 TREATMENT PLAN ..................................................................................................... 15 
4.1 
Sorafenib (BAY 43-9006) Administration ................................................................. 15 
4.2 
Supportive Care Guidelines....................................................................................... 16 
4.3 
Duration of Therapy ................................................................................................. 16 
5 DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 17 
6 PHAMACEUTICAL INFORMATION ........................................................................... 18 
6.1 
Sorafenib (BAY 43-9006) (NSC 724772) .................................................................. 18 
6.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) For Sorafenib........ 21 
7 CORRELATIVE/SPECIAL STUDIES ............................................................................ 27 
7.1 
Serum tumor marker studies ...................................................................................... 28 
7.2 
Nuclear medicine PET functional imaging ................................................................. 28 
7.3 
DCE-MRI. ............................................................................................................... 28 
7.4 
Pharmacogenomic studies ......................................................................................... 29 
7.5 
Assess the signaling inhibition in the tumor biopsies .................................................. 29 
7.6 
RET gene defects in the tumor specimen ................................................................... 30 
7.7 
RET gene mutations in the blood............................................................................... 31 
8 STUDY CALENDAR..................................................................................................... 32 
9 MEASUREMENT OF EFFECT...................................................................................... 33 


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9.1 
Definitions................................................................................................................ 33 
9.2 
Guidelines for Evaluation of Measurable Disease....................................................... 34 
9.3 
Response Criteria for patients with measurable disease: ............................................. 35 
9.4 
Confirmatory Measurement/Duration of Response ..................................................... 36 
9.5 
Response Review...................................................................................................... 37 
10 REGULATORY AND REPORTING REQUIREMENTS ................................................ 37 
10.1 
Expedited Adverse Event Reporting....................................................................... 37 
10.2 
Data Reporting ...................................................................................................... 39 
10.3 
CTEP Multicenter Guidelines ................................................................................ 39 
10.4 
Clinical Trials Agreement (CTA) ........................................................................... 42 
11 STATISTICAL CONSIDERATIONS ............................................................................. 44 
11.1 
Study design/Endpoints ......................................................................................... 44 
11.2 
Sample Size/Accrual Rate:..................................................................................... 45 
11.3 
Analysis of secondary endpoints ............................................................................ 45 
11.4 
Reporting and Exclusions ...................................................................................... 46 
REFERENCES....................................................................................................................... 47 
APPENDIX A ........................................................................................................................ 49 
APPENDIX B ........................................................................................................................ 50 
APPENDIX C ........................................................................................................................ 51 
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OBJECTIVES 
 
1.1 
Primary Objective: 
 
1.1.1 To assess objective response rate of sorafenib (BAY 43-9006) in metastatic medullary 
thyroid carcinoma in setting of inherited tumor syndromes, such as multiple endocrine 
neoplasia (MEN) 2A, MEN 2B, or familial medullary thyroid carcinoma (FMTC). 
1.1.2 To assess objective response rate of sorafenib (BAY 43-9006) in sporadic metastatic 
medullary thyroid carcinoma. 
 
1.2 
Secondary Objectives: 
 
1.2.1 To assess toxicity of sorafenib (BAY 43-9006) in patients with metastatic medullary 
thyroid carcinoma. 
1.2.2 Measure serum tumor markers calcitonin and carcinoma embryonic antigen (CEA) pre-, 
during-, and post-treatment to correlate with disease response. 
1.2.3 Correlate nuclear medicine functional imaging [F-18 fluorodeoxyglucose positron 
emission tomography (PET) scan] data obtained at pre-, during- and post-treatment with 
tumor response. 
1.2.4 Correlate dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI) data 
obtained at pre-, during- and post-treatment with changes in tumor permeability and 
vascularity with tumor response. 
1.2.5 Perform pharmacogenomic studies on procured PBMCs if clinical responses are 
observed. 
1.2.6 To correlate between the degree of Ras-MAPK signaling inhibition and vascular 
endothelial growth factor (VEGF) expression in the tumor and clinical response. 
1.2.7 To correlate between the presence and type of RET gene defects in tumor and clinical 
response. 
 
 
 
2 BACKGROUND 
 
2.1 
Metastatic Medullary Thyroid Carcinoma (MTC): 
 
MTC is one of the best characterized solid tumors in regard to its pathologic, biochemical, and 
molecular genetic properties. MTC derives from the neuroendocrine parafollicular or C cells of 
the thyroid. Sporadic MTC accounts for about 75-80% of all cases of the disease. The remaining 
cases consist of inherited tumor syndromes, such as multiple endocrine neoplasia (MEN) 2A, 
MEN 2B, or familial medullary thyroid carcinoma (FMTC). Because the C cells are 
predominantly located in the upper portion of each thyroid lobe, patients with sporadic disease 
typically present with upper pole nodules. The ability of the tumor to secrete measurable 
quantities of calcitonin, occasionally along with other hormonally active peptides (such as 
adrenocorticotrophic hormone [ACTH] or calcitonin-gene related peptide [CGRP]) can 
contribute to the development of diarrhea, Cushing's syndrome, or facial flushing in many 
patients with advanced disease. Sporadic disease typically presents in the fifth or sixth decade. 
There may be a slight female preponderance. Sporadic patients typically present with an 


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asymptomatic mass in the thyroid. Patients with bulky disease with extremely high levels of 
calcitonin may have severe secretory diarrhea as a principal symptom. Metastatic cervical 
adenopathy appears in about 50% of patients at initial presentation. Symptoms of upper 
aerodigestive tract compression or invasion are reported by up to 15% of patients with sporadic 
disease. 
 
Chemotherapy and external-beam radiation therapy are ineffective against MTC, rendering 
surgical resection the only definitive therapy (Moley JF et al, 1998; Evans DB et al 1999). 
Chemotherapeutics used in treatment of MTC include adriamycin, dacarbazine, streptozocin, and 
5-fluorouracil (Schlumberger M et al, 1995). Single-agent response rates are poor, with 
aggressive adriamycin regimens producing 20% to 30% objective responses. A study of 
combination chemotherapy showed that a regimen of 5-fluorouracil, streptozocin, and 
dacarbazine produces objective responses in only 15%. Due to failure of chemotherapy and 
radiation therapy to offer significant benefit for patients with MTC, innovative therapeutic 
strategies for systemic treatment of MTC need to be developed. 
 
2.2 
Tumor markers and imaging studies in MTC: 
 
Serum calcitonin is a reliable prognostic tumor marker in patients with metastatic MTC (Brunt 
LM. et al., 1987) while reliability of CEA maker in MTC is not well-established. Serum 
calcitonin is widely used in the clinic to assess the response to therapy as well as to detect the 
subclinical and/or recurrent disease. FDG-PET has been widely applied in oncology primarily as 
a staging and restaging tool that can guide patient care. However, because it accurately detects 
recurrent or residual disease, FDG-PET also has significant potential for assessing therapy 
response. In this regard, it can improve patient management by identifying responders early, 
before tumor size is reduced; non-responders could discontinue futile therapy. For example, PET 
imaging is valuable in assessing tumor response to some tyrosine kinase inhibitors         
(Gleevec, SU11248) in the patients where conventional imaging studies may reveal stable 
disease. 
 
Dynamic contrast enhanced MRI has recently been shown to be a valuable tool to assess tumor 
permeability and vascularity (Stevenson et al., 2003; Morgan et al.,, 2003;Galbraith et al.,, 
2003). Our group has extensive experience in using this imaging tool in the setting of clinical 
trials. 
 
2.3 
Genetics of MTC 
 
The RET protooncogene codes for a cell membrane-associated tyrosine kinase receptor for a 
glial, cell line-derived neurotrophic factor. Mutations in the RET proto-oncogene are found in at 
least 95% of kindreds with MEN 2A and 88% of FMTC. Mutations associated with MEN 2A 
and FMTC have been primarily identified in several codons of the cysteine-rich extracellular 
domains of exons 10, 11, and 13, whereas MEN 2B and some FMTC mutations are found within 
the intracellular exons 14-16. About 6% of patients with clinically sporadic MTC carry a 
germline mutation in RET, leading to identification of new kindreds with multiple previously 
undiagnosed affected individuals. 
 
Somatic mutations in exons 11, 13, and 16 have also been found in at least 25% of sporadic 
MTC tumors, particularly the codon 918 mutation that activates the tyrosine kinase function of 


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the receptor and is associated with poorer patient prognosis. The genetic basis of MTC in the 
other 75% of patients is not well understood. It is possible that genetic defects other than point 
mutations in RET gene (ie: duplication of chromosome 10) might be present. RET point 
mutation results in constitutive activation of signaling, thus inhibition of RET signaling has the 
potential of being a good therapeutic target. 
 
2.4 
Sorafenib (BAY 43-9006) 
 
Activation of the ras oncogene signaling pathway is considered to be an important mechanism 
by which human cancer develops. Raf kinase is a protein involved in the Ras signal transduction 
pathway. Ras regulates several pathways which synergistically induce cellular transformation, 
including the Raf/Mek/Erk cascade and the rac and rho pathways (Campbell et al., 1998, Chong 
et al., 2003). In particular, Ras activates the Raf/Mek pathway by first localizing Raf to the 
plasma membrane, where Raf initiates a mitogenic kinase cascade.  Activated Raf 
phosphorylates and activates Mek which in turn phosphorylates and activates Erk. Activated Erk 
then translocates from the cytoplasm into the nucleus and modulates gene expression via the 
phosphorylation of transcription factors. Thus activation of Raf kinase, via activation of Ras, is 
thought to play an important role in carcinogenesis. 
 
In particular, B-raf, a serine/threonine kinase, has been shown to be activated in a number of 
human tumor types including melanoma, ovarian and papillary thyroid carcinomas (Davies et al., 
2002, Mercer and Pritchard, 2003, Pollock and Meltzer, 2002, Singer et al., 2003, Tannapfel et 
al., 2003, Cohen et al., 2003). A survey of 43 cancer cell lines showed that all B-raf mutations 
resided in exons 11 or 15. Remarkably, 80% of these B-raf mutations represent a single 
nucleotide change of T-A at nucleotide 1796 resulting in a valine to glutamic acid change at 
residue 599 (V599E, exon 15) in the CR3 domain (ATP binding and substrate recognition)  
which in turn confers constitutive kinase activity (Davies et al., 2002, Mercer and Pritchard, 
2003). 
 
In Vitro Activity 
 
The ability of sorafenib (BAY 43-9006) to inhibit a number of kinases was evaluated 
(Investigator’s Brochure, 2003). The in vitro biochemical and cellular profile of sorafenib (BAY 
43-9006) is summarized below: 
 
Biochemical Assay 
IC50 (µM) 
c-raf b 
0.002/0.006 
b-raf wild-type 
0.025 
b-raf V599E mutant 
0.038 
VEGFR-2 (human) 
0.090 
VEGFR-2 (murine) 
0.006 
VEGFR-3 (murine) 
0.010 
PDGFR-β (murine) 
0.028 
Flt-3 
0.058 
c-KIT 
0.068 
FGFR-1 
0.580 
p38α 
0.038 


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Cellular Mechanismc 
IC50 (µM) 
MDA-MB-231 MEK phosphorylation (Human 
Breast) 
0.04 
BxPC-3 MEK phosphorylation (Human 
Pancreatic) 
1.00 
LOX ERK phosphorylation (Human 
Melanoma) 
0.80 
b-raf ER MEK activation (Human Chimera, 
3T3 cells) 
2.30 
VEGFR-2 phosphorylation (Human, 3T3 cells) 
0.03 
VEGFR-3 phosphorylation (Mouse, 293 cells) 
0.10 
PDGFR-β phosphorylation (Human, AoSMC)d 
0.02 
Cellular Proliferation 
IC50 (µM) 
MDA-MB-231 (10% FCS)e 
2.60 
MDA-MB-231 (0.1% FCS) 
0.10 
VEGF-HUVEC (2.0% FCS)f 
3.00 
PDGFR-β AoSMCd (0.1%  BSA)g 
0.23 
a Recombinant enzyme assay 
b Raf kinase activated with Lck (truncated/full length c-raf) 
c Mechanistic cellular assays all performed in 0.1% BSA 
d Human aortic smooth muscle cells 
e Fetal calf serum 
f Human umbilical vein endothelial cells 
g Bovine serum albumin 
 
In vitro kinase assays demonstrated that sorafenib (BAY 43-9006) is a potent inhibitor of 
wildtype and mutant (V599E) B-Raf and c-Raf Kinase isoforms in vitro (Investigator’s 
Brochure, 2003). In addition, sorafenib (BAY 43-9006) did not inhibit human EGFR or Her2 
kinases at 10 
M.   Nor were PKC-α, PKC-β, PKC-γ, and PKA (rat, rabbit and bovine sources) 
kinase activity inhibited in vitro. sorafenib (BAY 43-9006) demonstrated an IC50 of 780 nM 
against p59 (bovine) Fyn kinase (Src family of protein tyrosine kinases). In non-kinase targets 
sorafenib (BAY 43-9006) had moderate potency against the adenosine A3, dopamine D1, and 
muscarinic M3 receptors with IC50 of 1.6 
M, 2.0 M, and 3.1 M, respectively.  sorafenib 
(BAY 43-9006) did not inhibit MEK-1, ERK-1, EGFR, HER2/neu, c-met, PKA, PKB, Cdk- 
1/cyclin B, pim-1, GSK 3-b, CK-2, PKC-α (r), PKC-β (r), PKC-γ at concentrations as high as 10 
µM. In summary, sorafenib (BAY 43-9006) showed ≥100-fold more selectivity for raf kinase 
relative to other target proteins. 
 
Sorafenib (BAY 43-9006) also inhibited in vitro several receptor tyrosine kinases (RTKs) that 
are involved in tumor progression; human VEGFR-2, murine VEGFR-2, murine VEGFR-3, 
murine PDGFR-β, Flt-3, c-KIT, and p38α (MAPK family). In cellular assays, sorafenib (BAY 
43-9006) was found to be a potent inhibitor of human and murine VEGFR-2, murine VEGFR-3, 
and murine PDGFR-β receptor phosphorylation (Investigator’s Brochure, 2003). 
 
Finally, Santoro et al. has shown that sorafenib (BAY 43-9006) inhibits RET kinase activity in 
vitro (IC50 dose 100 nM) (Carlomagno et al, 2006) 


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In Vivo Activity 
 
Sorafenib (BAY 43-9006) has demonstrated in vivo anti-tumor efficacy as a single agent against 
a broad range of human tumor xenografts as summarized in the following table. The models 
evaluated include HCT-116 and DLD-1 colon tumor xenografts, MX-1 mammary tumor 
xenograft, NCI-H460 and A549 NSCLC xenografts, MiaPaCa-2 pancreatic tumor xenografts, 
and SK-OV-3 ovarian tumor xenografts. In this table, compound efficacy is expressed as percent 
tumor growth inhibition (TGI) and is calculated as ((1-(T/C)) *100, where T and C represent the 
mean tumor size in the Treated and Control groups respectively at the first measurement after the 
end of treatment. 
 
Sorafenib (BAY 43-9006) Demonstrates Broad Spectrum Anti- 
Tumor Efficacy in Preclinical Xenograft Models 
 
Tumor Type 
Model 
Dose (mg/kg/dose 
free base equiv.)1 
Percent TGI 
((1-(T/C))*100) 
Colon 
HCT-116 
10 
30 
100 
45 
64 
68 
Colon 
DLD-1 
15 
30 
60 
31 
66 
75 
NSCLC 
NCI-H460 
10 
30 
27 
56 
NSCLC 
A549 
30 
60 
60 
68 
Mammary 
MX-1 
30 
60 
51 
67 
Pancreatic 
Mia-PaCa-2 
10 
30 
100 
45 
66 
73 
Ovarian 
SK-OV-3 
10 
30 
100 
58 
64 
81 
1 Compound dosed as sorafenib (BAY 43-9006) or equivalent dose levels of tosylate 
salt, BAY 54-9085 
 
The majority of the initial anti-tumor efficacy evaluations in vivo were conducted in the HCT116 
colon tumor model since the tumorigenicity of this cell line was previously shown to be 
dependent on K-ras activation. Additional studies indicated that prolonged anti-tumor efficacy 
could be attained by extending the duration of treatment and that, in this tumor model, sorafenib 
(BAY 43-9006) was able to arrest tumor growth even if therapy was initiated against a 
substantially greater tumor burden. 
Sorafenib (BAY 43-9006) also showed significant oral activity against two additional human 
tumor xenograft models that contain K-ras mutations: MiaPaCa-2 pancreatic carcinoma and 
H460 non-small cell lung carcinoma. The anti-tumor efficacy of sorafenib (BAY 43-9006) was 
also evaluated against the human SKOV-3 ovarian tumor cell line that contains a wild-type Ras 
 
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but over-expresses both the EGF and Her2 growth factor receptors. These receptors also signal 
through the Ras/Raf/Mek pathway. 
 
In human tumor xenografts, MDA-MB-231 (breast) and Colo-205 (colon), there was a dramatic 
reduction of tumor neo-vascularization (Investigator’s Brochure, 2003). Recent data also 
indicated that inhibition of c-raf may promote cell death in endothelial cells as a downstream 
event of VEGFR-2 stimulation (Alavi et al., 2003). 
 
Taken together, data suggests that sorafenib (BAY 43-9006) may be of therapeutic value not 
only in human tumors containing ras gene mutations, but also in tumors over-expressing growth 
factor receptors in the Ras/Raf/Mek pathway, and by inhibiting tumor angiogenesis or neo- 
vascularization through inhibition of VEGFR-2, VEGFR-3, and/or PDGFR-β. 
 
The ability of sorafenib (BAY 43-9006) (or its tosylate salt, BAY 54-9085) to be combined with 
paclitaxel, irinotecan, gemcitabine, or cisplatin was evaluated in preclinical in vivo models. In 
these studies, the focus was to evaluate if the co-administration of sorafenib (BAY 43-9006) 
would adversely affect the tolerance or anti-tumor efficacy of the ‘standard of care’ agent. The 
general health of mice was monitored and mortality was recorded daily. Tumor dimensions and 
body weights were recorded twice a week starting with the first day of treatment. Treatments 
producing greater than 20% lethality and/or 20% net body weight loss were considered ‘toxic’. 
The results of these combinability analyses are summarized below: 
 
Combinability of Concurrent Treatment with sorafenib (BAY 43-9006) and 
Clinically Established Agents 
 
Combination 
Agent 
Tumor Model 
Combinability 
Y/N 
Paclitaxel 
NCI-H460 NSCLC 
MX-1 Mammary 
Ye
s 
Irinotecan 
DLD-1 Colon 
Yes 
Gemcitabine 
MiaPaCa-2 Pancreatic 
Yes 
Cisplatin 
NCI-H23 NSCLC 
Yes 
 
Sorafenib (BAY 43-9006) can be safely combined with a variety of standard cytotoxic cancer 
chemotherapy agents, including paclitaxel, irinotecan, gemcitabine and cisplatin with no 
significant increase in the toxicity associated with those agents and without diminishing their 
anti-tumor efficacy in preclinical models. 
 
2.5 
Clinical Experience 
 
Sorafenib (BAY 43-9006) has been evaluated in multiple Phase 1 and Phase 2 studies in a 
variety of tumor types. To date, over 500 patients have been treated with single agent sorafenib 
(BAY 43-9006). The Phase 1 single agent clinical plan has focused on characterizing the safety 
and pharmacokinetic profile sorafenib (BAY 43-9006) in several different dosing regimens. All 
Phase 1 patients had a variety of advanced refractory solid tumors, and some of the patients 
stayed on trial for more than one year. Four different regimens have been tested: continuous 
treatment, 4 weeks on/ 1 week off, 3 weeks on /1 week off, and 1 week on/ 1 week off.  Patients 
 
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have received doses ranging from 50 mg once weekly to 1600 mg daily of sorafenib (BAY 43- 
9006) on intermittent and continuous schedules. The 800 mg bid continuous administration 
cohort has exceeded the maximum tolerated dose (MTD) in all tested schedules. The 600 mg bid 
cohort exceeded the MTD in all but the less dose intensive regimen of 1 week on / 1 week off. 
The most frequent drug-related adverse events were hand-foot skin reaction, dermatitis, rash, 
fatigue, anorexia and diarrhea. There was an increase in the number of serious adverse events, 
discontinuations due to adverse events, and a number of skin toxicities at the higher dose levels ≥ 
600 mg bid. Therefore, 400 mg bid was selected as the recommended dose for Phase 2. 
In general, sorafenib (BAY 43-9006) at 400 mg PO BID dosing was well tolerated chronically 
by most patients. The most common drug-related adverse events (>5%) seen at this dose 
schedule were skin-related findings. The adverse events include hand-foot skin reaction 
occurring in 11 patients (35.5%), pruritus in 9 patients (29%), dermatology/skin-other in 9 
patients (29.0%), alopecia in 8 patients (25.8%), and rash/desquamation in 7 patients (22.6%). 
Other common adverse events include fatigue in 11 patients (35.5%), anorexia in 7 patients 
(22.6%), diarrhea in 11 patients (35.5%), and pain-other in 5 patients (16.1%). Liver function 
abnormalities did occur, with SGOT elevation occurring in 6 patients (19.4%), SGPT elevation 
in 5 patients (16.1%), and alkaline phosphatase and bilirubin elevation in 4 patients each 
(12.9%).  Of note, unlike most cytotoxic agents, myelosuppression was rarely observed. 
 
Currently, the Phase 2 program includes studies designed to explore anti-tumor efficacy in 
certain tumor types and to gain additional experience with pharmacokinetics and safety. Thus 
far, Phase 2 studies have enrolled over 300 patients with a variety of tumor types including 
colorectal, renal cell, hepatocellular, pancreatic, and thyroid cancer and melanoma as well as 
several less common tumors. 
In general, available information from the ongoing Phase 2 studies reveals toxicities that are 
similar to the Phase 1 data.  Again, the five most frequent drug-related toxicities observed 
include hand-foot skin reaction, rash, anorexia, diarrhea, and fatigue. When all available data 
from the various studies/schedules are combined, the incidence of greater than grade 3 treatment 
emergent skin toxicity (e.g. hand-foot syndrome and “dermatology/skin reaction”) for an initial 
dose of 400 mg bid and 600 mg bid, was 0% and 30%, respectively. Anti-tumor activity was 
observed in both Phase 1 and 2 studies. In December 2005, Sorafenib Tosylate (BAY 43-9006; 
NEXAVAR®) was approved by the FDA for the treatment of patients with advanced renal cell 
carcinoma. 
 
2.6 
Rationale 
 
There is no standard systemic therapy for metastatic MTCs. Systemic chemotherapy has 
extremely limited value and local external beam radiation therapy only may help with palliation 
of symptoms. A median disease-specific survival in this group of patients is only 3 to 5 years. 
Targeted therapy for such chemo-resistant tumors is desperately needed. 
 
RET mutation is a hallmark of genetic defect in MTC. Mutations in the RET proto-oncogene are 
found in at least 95% of kindreds with MEN 2A and 88% of FMTC and in about 25% of patients 
with sporadic MTC. It is possible that other mechanisms of RET gene defects in MTC are not 
discovered yet, but play a role in the pathogenesis of sporadic MTC. Sorafenib (BAY 43-9006) 
inhibits the RET/Ras/Raf/Mek pathway, and may indirectly inhibit the RET/Akt pathway. In 
addition, it also inhibits tumor angiogenesis or neo-vascularization through inhibition of 
VEGFR-2, VEGFR-3, and/or PDGFR-β.  Sorafenib (BAY 43-9006) is an orally active small 


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13 
 
 
 
molecule that was generally well tolerated in phase I clinical trials. Thus, sorafenib (BAY 43- 
9006) targeting the RET signaling pathway represents an excellent oral agent for the possible 
treatment of patients with metastatic medullary thyroid carcinoma. 
 
 
3 PATIENT SELECTION 
 
3.1 
Eligibility Criteria specific for Arm A: All patients enrolled on Arm A must meet all 
eligibility criteria outlined in sections 3.1 and 3.3. 
 
3.1.1 Histologically confirmed medullary thyroid carcinoma under the clinical setting of 
inherited tumor syndromes, such as multiple endocrine neoplasia (MEN) 2A, MEN 2B, 
or familial medullary thyroid carcinoma (FMTC). 
 
3.2 
Eligibility Criteria specific for Arm B: All patients enrolled on Arm B must meet all 
eligibility criteria outlined in sections 3.2 and 3.3. 
 
3.2.1 Histologically confirmed medullary thyroid carcinoma under the clinical setting of 
sporadic MTC. 
 
3.3 
Eligibility Criteria common for Arms A and B: All patients enrolled on Arm A must 
meet all eligibility criteria outlined in sections 3.1 and 3.3. All patients enrolled on 
Arm B must meet all eligibility criteria outlined in sections 3.2 and 3.3. 
 
3.3.1 Patients must have measurable disease as define in section 9.1.1. 
 
3.3.2 Metastatic and/or locally advanced or locally recurrent disease. 
 
3.3.3 Oral or intravenous (IV) bisphosphonates therapy will be allowed for patients with bony 
metastasis at the investigator’s discretion. Bisphosphonate usage should be recorded if 
used since these agents may have anti-farnesyl transferase activity and may have some 
therapeutic effect in combination with sorafenib. 
 
3.3.4 Age > 18 years. Because no dosing or adverse event data are currently available on the 
use of sorafenib (BAY 43-9006) in patients <18 years of age, children are excluded from 
this study. 
 
3.3.5 Life expectancy must be > six months. 
 
3.3.6 Patients must have an Eastern Cooperative Oncology Group performance status 0-2 (see 
Appendix A). 
 
3.3.7 Patients must have normal organ and marrow function as defined below in the 10 days 


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14 
 
 
 
prior to patient enrollment. 
 
▪ Leukocytes 2,000/L 
▪ Absolute neutrophil count 1,000/L 
▪ Platelets 100,000/L 
▪ Total bilirubin within 2 x upper limit of normal 
▪ AST (SGOT)/ALT (SGPT) within 3 x upper limit of normal 
▪ Serum creatinine 
within normal institutional limits 
o OR 
▪ Creatinine Clearance > 30 mL/min (by Cockcraft-Gault formula) 
 
3.3.8 The effects of sorafenib (BAY 43-9006) on the developing human fetus at the 
recommended therapeutic dose are unknown. For this reason and because kinase 
inhibitors are known to be teratogenic, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for at least 30 
days after completion of therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 
3.3.9 Ability to understand and the willingness to sign a written informed consent document. 
 
3.4 
Exclusion Criteria for Arm A and Arm B: 
 
3.4.1 Patients who have had systemic anti-tumor therapy (such as chemotherapy, biologic 
modifiers or antiangiogenic therapy) within 4 weeks (6 weeks if nitrosourea or 
mitomycin chemotherapy) prior to study entry. 
 
3.4.2 Patients who have had external beam radiation therapy within 1 week or if the adverse 
events associated with radiation are not resolved to grade 1 or less prior to study entry. 
 
3.4.3 Prior therapy with sorafenib (BAY 43-9006), ZD 6474 or AMG-706. 
 
3.4.4 Patients currently receiving any other tumor-specific therapy for thyroid cancer or 
investigational therapy. Patients receiving adjuvant hormonal therapy for a second 
primary (such as breast cancer or prostate cancer) are allowed to participate as far as 
there are no known drug interactions. 
 
3.4.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to sorafenib (BAY 43-9006). 
 
3.4.6 Patients unable to swallow sorafenib tablets. (e.g. Any condition that impairs patient’s 
ability to swallow pills) 
3.4.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
uncontrolled hypertension, or psychiatric illness/social situations that would limit 


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compliance with study requirements. 
 
3.4.8 Patients with any evidence of a bleeding diathesis. 
 
3.4.9 Patients actively receiving anticoagulation with therapeutic intent. Prophylactic 
anticoagulation (i.e. low dose warfarin) or venous or arterial access devices is allowed 
provided that the PT, INR or PTT are normal. 
 
3.4.10 Pregnant women or women who are breast-feeding are excluded from this study because 
sorafenib (BAY 43-9006) is an investigational agent and teratogenicity has not been 
evaluated yet. Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with sorafenib (BAY 43-9006), 
breastfeeding should be discontinued if the mother is treated with sorafenib (BAY 43- 
9006). 
 
3.4.11 HIV-positive patients receiving combination anti-retroviral therapy because of possible 
pharmacokinetic interactions with sorafenib (BAY 43-9006). Patients with immune 
deficiency are at increased risk of lethal infections when treated with marrow-suppressive 
therapy. 
 
3.4.12 Patients taking the cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, 
carbamazepine, or Phenobarbital), rifampin or St. John’s Wort due to potential drug 
interactions with sorafenib. 
 
3.5 
Inclusion of Women and Minorities 
 
Entry to this study is open to both men and women, and to all racial and ethnic subgroups. 
Patients will not be excluded from this study on the basis of a history of known HIV positive 
status. 
 
 
4 TREATMENT PLAN 
 
4.1 
Sorafenib (BAY 43-9006) Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 6.  Appropriate dose modifications for sorafenib (BAY 43-9006) 
are described in Section 5. No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat thyroid cancer. 
Sorafenib (BAY 43-9006) will be administered at the dose of 400 mg orally twice a day on a 
continuous basis. Sorafenib (BAY 43-9006) is supplied as 200-mg tablets.  Patients are to 
swallow the tablets whole with approximately 250 ml (8 oz.) of water, each morning and evening 
(i.e., approximately 12-hourly).  When given with a moderate fat meal, bioavailability was 
similar to that in the fasted state. With a high fat meal, sorafenib (BAY 43-9006) tosylate’s 
bioavailability was reduced by 29% compared to administration in the fasted state. Thus, it is 
recommended that sorafenib (BAY 43-9006) be taken on an empty stomach (at least 1 hour 
before or 2 hours after eating). 


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Patients will be given monthly calendars (patient diaries) to document the time when the 
sorafenib (BAY 43-9006) pills are taken.  At monthly visits, patients will bring back this record. 
 
Hypertension is a known and potentially serious adverse event associated with Sorafebnib (BAY 
43-9006) treatment. Patients will have their blood pressure monitored and recorded weekly 
during the first cycle of therapy, either at the doctor’s office or using any calibrated electronic 
device (such as those found at a local drug store or pharmacy). Patients will be provided with a 
Blood Pressure Check Diary on which to record the measurements.  An increase in blood 
pressure of > 20 mm Hg (systolic) and 10 mm Hg (diastolic) should be reported to the treating 
physician immediately. See dose modification guidelines in section 5 in event of drug related 
hypertension. 
 
Oral or intravenous (IV) bisphosphonates therapy will be allowed for patients with bony 
metastasis at the investigator’s discretion. 
 
Close monitoring is recommended for patients taking BAY 43-9006 tosylate and CYP3A4 
inducers. The CYP3A4 inducers such as antiepileptic drugs (phenytoin, carbamazepine, or 
Phenobarbital), rifampin or St. John’s Wort are not permitted on the protocol due to potential 
drug interactions with sorafenib. 
 
4.2 
Supportive Care Guidelines 
 
Prophylactic use of anti-emetics, anti-diarrheal treatment, or growth factors is not recommended. 
However, anti-emetics, anti-diarrheal treatment or growth factors may be used for acute 
treatment of toxicities and growth factors may be offered as per the ASCO guidelines. 
 
For patients who develop hand-foot reaction, treatment with topical emollients (such as 
Aquaphor) for symptom relief is recommended. Topical and/or oral steroids or anti-histamine 
agents may be used. High dose vitamin B6 (pyridoxine; up to 400 mg orally each day) may also 
be used. 
 
4.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment will continue until one of 
the following criteria applies: 
▪ Progressive Disease and no clinical benefit (Note: patients who have continued clinical 
benefit such as symptomatic or tumor marker improvement or decreased tumor burden 
compared to baseline or limited progression in non-target lesion treated with radiation or 
surgery will be able to continue therapy) 
▪ Completion of 8 weeks of therapy after complete remission 
▪ Off of study drug due to any reason for more than 21 consecutive days 
▪ Intercurrent illness that prevents further administration of treatment 
▪ Unacceptable adverse event(s) 
▪ Patient decides to withdraw from the study 
▪ General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 


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5 DOSING DELAYS/DOSE MODIFICATIONS 
 
▪ For delay of treatment due to toxicity for more than 21 days, patient will be removed 
from the study. 
 
Dose should be modified and/or delayed according to the following guidelines: 
 
In the event of grade 3 or 4 drug-related non-hematologic toxicity, therapy will be held till 
the toxicity has resolved to baseline or grade 1. For delay of treatment due to toxicity for more 
than 21 consecutive days, patient will be removed from the study. Once toxicity is resolved to 
baseline or  grade 1, sorafenib (BAY 43-9006) should be started at a reduced dose of 200 mg 
PO BID. If tolerated, the dose can be re-escalated to 600 mg/day given as 400 mg in the AM and 
200 mg in the PM.  If 600 mg/day dose is tolerated, further re-escalation to the full dose of 400 
mg PO BID may be done after discussing with protocol chair. 
 
In the event of grade 2 hand-foot skin reaction or recurrent grade 2 drug-related non- 
hematologic toxicity, therapy may be held till the toxicity has resolved to baseline or grade 1. 
For delay of treatment due to toxicity for more than 21 consecutive days, patient will be removed 
from the study. Once toxicity is resolved to baseline or grade 1, sorafenib (BAY 43-9006) 
should be started at a reduced dose of 200 mg PO BID. If tolerated, the dose can be re-escalated 
to 600 mg/day given as 400 mg in the AM and 200 mg in the PM. If 600 mg/day dose is 
tolerated, further re-escalation to the full dose of 400 mg PO BID may be done after discussing 
with protocol chair. 
 
In the event of GI-Perforation, patient will be removed from the study and followed until 
adverse event is resolve. 


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In the event of treatment-emergent Hypertension: 
 
 
Grade of hypertension Event 
(CTCAE v.3) 
Management/ Next Dose 
grade 1 
Consider increased BP monitoring 
grade 2 asymptomatic and 
diastolic BP < 110 mm Hg 
Begin anti-hypertensive therapy and continue agent 
grade 2 symptomatic/ persistent 
OR 
diastolic BP ≥ 110 mm Hg 
OR 
grade 3 
1. Agent should be held* until symptoms resolve 
and diastolic BP ≤ 100 mm Hg; also treat patient 
with anti-hypertensives and restart at reduced dose of 
600 mg/day given as 400 mg in the AM and 200 mg 
in the PM. Dose can be re-escalated to full dose as 
tolerated. 
2. If diastolic BP not controlled (≤ 100 mm Hg) on 
therapy, reduce to another dose level with a dose of 
400 mg/day given as 200 mg in the AM and 200 mg 
in the PM. ** 
grade 4 
Discontinue protocol therapy 
* Patients requiring a delay of > 3 weeks should go off protocol therapy. 
** Patients requiring > 2 dose reductions should go off protocol therapy. 
 
 
6 PHAMACEUTICAL INFORMATION 
6.1  Sorafenib (BAY 43-9006) (NSC 724772) 
Chemical Name: 4–{4-[3-(4-chloro-3-trifluoromethyl-phenyl) ureido]-phenoxy} pyridine-2 
carboxylic acid methylamide-4-methylbenzensulfonate. 
 
Other names: BAY 54-9085 is the tosylate salt of BAY 43-9006; sorafenib; Nexavar®. 
 
Molecular Formula: C12H16CIF3N4O3  X C7H8O3S 
 
M.W.: BAY 43-9006 tosylate: 637 Daltons; BAY 43-9006 (free base): 465 Daltons 
 
Classification: Kinase inhibitor (Raf, VEGF-R, and PDGF-R). 
 
Description: The ras/raf signaling pathway is an important mediator of responses to growth 
signals and angiogenic factors. This pathway is often aberrantly activated in human tumors due 
to presence of activated ras, mutant b-raf, or over expression of growth factor receptors. BAY 
43-9006 is a potent inhibitor of c-raf, and wild-type and mutant b-raf in vitro. Additionally, 
further characterization of BAY 43-9006 tosylate revealed that this agent inhibits several 
receptor tyrosine kinases (RTKs) that are involved in tumor progression (VEGF-R, PDGF-R, 
Flt3, and c-KIT) and p38α, a member of the MAPK family. 


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How Supplied: Sorafenib tosylate is supplied by Bayer Healthcare AG and distributed by PMB, 
CTEP, DCTD, NCI. The tablets are available as 200 mg immediate release tablets. The inactive 
ingredients are microcrystalline cellulose, croscarmellose sodium, hydroxypropylmethyl 
cellulose, magnesium stearate, sodium lauryl sulfate, and a film- coat with 
hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and red iron oxide. 
■ The commercially labeled 200 mg tablets are round, biconvex, red film-coated tablets, 
debossed with the “Bayer cross” on one side and “200” on the other side and packaged in HDPE 
bottles of 120 tablets. 
 
NOTE: Sorafenib tablets may be repackaged in HDPE pharmacy dispensing bottle other than 
the original container with expiration date not to exceed 30 days. 
Route of Administration: Orally. 
 
Method of Administration: Following oral administration, sorafenib (BAY 43-9006) tosylate’s 
mean relative bioavailability is 38-49%. When given with a moderate fat meal, bioavailability 
was similar to that in the fasted state. With a high fat meal, BAY 43-9006 tosylate’s 
bioavailability was reduced by 29% compared to administration in the fasted state. Thus, it is 
recommended that sorafenib (BAY 43-9006) be taken on an empty stomach (at least 1 hour 
before or 2 hours after eating) and with at least 250 mL of water. 
 
Drug Product Storage: Store intact bottles at controlled room temperature, not to exceed 25ºC. 
 
If a storage temperature excursion is identified, promptly return sorafenib to controlled room 
temperature (not to exceed 25°C) and quarantine the supplies. Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Drug Product Stability: Stability studies are ongoing for investigationally-labeled supplies. 
Refer to package labeling for shelf life of commercially-labeled supplies. 
 
Approximate Solubility: 0.19 mg/100 mL in 0.1 N HCl, 453 mg/100 mL in Ethanol, 
and 2971 
mg/100 mL in PEG 400. 
 
Potential Drug Interactions: Sorafenib metabolizes primarily by CYP3A4 during phase I 
metabolism (oxidation) and primarily by UGT1A9 in phase II (conjugation). Co-administration of 
rifampin resulted in sorafenib AUC reduction of approximately 37%. Therefore, use caution when 
co-administering with strong CYP3A4 inducers, such as St. John’s wort, phenytoin, carbamazepine, 
phenobarbital and dexamethasone as they can reduce sorafenib exposure.  CYP3A4 inhibitors are 
not expected to cause clinically relevant changes to sorafenib exposure. 
 
In vitro, sorafenib is a moderate inhibitor CYP2C19, 2D6, and 3A4 and a strong inhibitor of 
CYB2B6, 2C8, and 2C9. It also inhibits pathway enzymes UGT1A1 and UGT1A9 in phase II 
conjugation. Clinical data suggests sorafenib does not increase exposure of other drugs metabolized 
by CYP pathways and therefore does not appear to be clinically relevant. Use caution when co- 
administered with sensitive substrates of UGT1A1. 
 
While sorafenib solubility is pH dependent, co-administration with omeprazole did not result in 
clinically relevant change in sorafenib exposure. 


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Sorafenib may prolong the QT/QTc interval. Avoid concomitant drugs that may induce the QTc 
prolongation. 
 
Patient Care Implications: Hand-foot skin rash can be treated with topical emollients, high- 
potency topical steroids, or keratolytic cream (urea/salicyclic acid). 
 
Females of childbearing potential should avoid becoming pregnant while they or their male partners 
are taking sorafenib and should use effective contraception during and for at least 30 days after 
completion of therapy. 
 
Availability: 
 
Sorafenib (BAY 43-9006) is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Sorafenib (BAY 43-9006) is provided to the NCI under a Clinical Trials Agreement (CTA) 
between Bayer Corp./Onyx and the DCTD, NCI (see Section 10.4). 
 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated. PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained). The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents. The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP- 
supplied investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for enrollment 
onto the study. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status and a “current” 
password. For questions about drug orders, transfers, returns, or accountability, call or email 
PMB any time. Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the 


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CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records 
for each agent, strength, formulation and ordering investigator on this protocol. 
 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password. Questions about IB access 
may be directed to the PMB IB coordinator via email. 
 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• PMB Online Agent Order Processing (OAOP) application: https://eapps- 
ctep.nci.nih.gov/OAOP/pages/login.jspx 
• CTEP Identity and Access Management (IAM) account: https://eapps- 
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help: ctepreghelp@ctep.nci.nih.gov 
• PMB email: PMBAfterHours@mail.nih.gov 
• IB Coordinator: IBCoordinator@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 
 
6.2 Comprehensive Adverse Events and Potential Risks list (CAEPR) For Sorafenib (BAY 
43-9006, NSC 724772) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2571 patients. Below is the CAEPR for 
Sorafenib (BAY 43-9006). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower 
of the grades to determine if expedited reporting is required. 
Version 2.7, November 16, 20151 


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Adverse Events with Possible 
Relationship to Sorafenib (BAY 43-9006) 
(CTCAE 4.0 Term) 
[n= 2571] 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
Anemia (Gr 3) 
CARDIAC DISORDERS 
Acute coronary 
syndrome 
Chest pain - cardiac 
Heart failure 
Left ventricular 
systolic dysfunction 
Myocardial infarction 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Abdominal pain (Gr 3) 
Ascites 
Constipation 
Constipation (Gr 2) 
Diarrhea 
Diarrhea (Gr 3) 
Gastrointestinal 
hemorrhage2 
Gastrointestinal hemorrhage2 (Gr 
3) 
Gastrointestinal 
perforation3 
Mucositis oral 
Nausea 
Nausea (Gr 3) 
Vomiting 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
Edema limbs 
Fatigue 
Fatigue (Gr 3) 
Fever 
Fever (Gr 2) 
HEPATOBILIARY 
DISORDERS 
Hepatic Failure 
IMMUNE SYSTEM DISORDERS 
 
Anaphylaxis 
INFECTIONS AND INFESTATIONS 
 
Infection4 
INVESTIGATIONS 
 


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Adverse Events with Possible 
Relationship to Sorafenib (BAY 43-9006) 
(CTCAE 4.0 Term) 
[n= 2571] 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
Activated partial 
thromboplastin time 
prolonged 
Activated partial thromboplastin 
time prolonged (Gr 2) 
Alanine 
aminotransferase 
increased 
Alanine aminotransferase 
increased (Gr 3) 
Alkaline phosphatase 
increased 
Alkaline phosphatase increased 
(Gr 3) 
Aspartate 
aminotransferase 
increased 
Aspartate aminotransferase 
increased (Gr 3) 
Blood bilirubin increase 
Blood bilirubin increased 
(Gr 3) 
Creatinine increased 
Creatinine increased (Gr 3) 
GGT increased 
Electrocardiogram QT 
corrected interval 
prolonged 
INR increased (Gr 3) 
INR increased 
Investigations - Other 
(bicarbonate-serum low) 
Lipase increased 
Lipase increased (Gr 3) 
Lymphocyte count 
decreased 
Lymphocyte count decreased (Gr 
3) 
Neutrophil count 
decreased 
Neutrophil count decreased (Gr 4) 
Platelet count decreased 
Platelet count decreased (Gr 4) 
Serum amylase 
increased 
Serum amylase increased (Gr 3) 
Weight loss 
Weight loss (Gr 2) 
White blood cell 
decreased 
White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
Anorexia (Gr 3) 
Hyperglycemia 
Hypercalcemia 
Hyperglycemia (Gr 3) 
Hyperkalemia 
Hyperkalemia (Gr 3) 
Hypernatremia 
 
Hypoalbuminemia 
Hypoalbuminemia (Gr 3) 


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Adverse Events with Possible 
Relationship to Sorafenib (BAY 43-9006) 
(CTCAE 4.0 Term) 
[n= 2571] 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
Hypocalcemia 
Hypocalcemia (Gr 3) 
Hypoglycemia 
Hypoglycemia (Gr 2) 
Hypokalemia 
Hypokalemia (Gr 3) 
Hyponatremia 
Hyponatremia (Gr 3) 
Hypophosphatemia 
Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Arthralgia 
Arthralgia (Gr 3) 
Back pain 
Back pain (Gr 3) 
Bone pain 
Musculoskeletal and 
connective tissue 
disorder - Other (muscle 
spasm) 
Myalgia 
Pain in extremity 
Pain in extremity (Gr 3) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) 
Treatment related 
secondary malignancy 
NERVOUS SYSTEM DISORDERS 
Dizziness 
 
Headache (Gr 3) 
Headache 
Intracranial 
hemorrhage 
Reversible posterior 
leukoencephalopathy 
syndrome 
 
PSYCHIATRIC DISORDERS 
Insomnia 
 
RENAL AND URINARY DISORDERS 
Acute kidney injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Cough 
Cough (Gr 2) 
Dyspnea 
Dyspnea (Gr 3) 
Respiratory hemorrhage5 
 


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Adverse Events with Possible 
Relationship to Sorafenib (BAY 43-9006) 
(CTCAE 4.0 Term) 
[n= 2571] 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
Alopecia (Gr 2) 
Dry skin 
Dry skin (Gr 2) 
Palmar-plantar 
erythrodysesthesia 
syndrome 
Erythema multiforme 
Palmar-plantar 
erythrodysesthesia syndrome (Gr 
3) 
Pruritus 
Pruritus (Gr 3) 
Rash maculo-papular 
Rash maculo-papular (Gr 3) 
Stevens-Johnson 
syndrome 
Toxic epidermal 
necrolysis 
VASCULAR DISORDERS 
Hypertension 
Hypertension (Gr 3) 
Thromboembolic event 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Gastrointestinal hemorrhage may include Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal perforation may include Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and 
Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
4Infection may include any of the 75 infection sites under the INFECTIONS AND 
INFESTATIONS SOC. 
 
5Respiratory hemorrhage may include bronchopulmonary hemorrhage, epistaxis, laryngeal 
hemorrhage, mediastinal hemorrhage, pharyngeal hemorrhage, and pleural hemorrhage under the 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC. 


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6Febrile neutropenia is seen mostly in combination with other agents. 
 
 
Adverse events reported on sorafenib (BAY 43-9006; Nexavar) trials but for which there is 
insufficient evidence to suggest that there was a relationship possibility that sorafenib 
(BAY 43-9006; Nexavar) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (Thrombotic microangiopathy [e.g., TTP or HUS]); Febrile neutropenia6 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Palpitations; 
Pericardial effusion; Pericarditis; Right ventricular dysfunction; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia; Ventricular arrhythmia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
ENDOCRINE DISORDERS - Adrenal insufficiency; Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye 
disorders - Other (color vision deficits); Eye disorders - Other (light to dark adaptation); Eye 
disorders - Other (retinal vein occlusion); Eye disorders - Other (retinal hemorrhage); Eye 
disorders - Other (visual field distortion); Flashing lights; Keratitis; Photophobia; Retinal 
detachment 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fistula; Anal mucositis; 
Anal pain; Anal ulcer; Cheilitis; Colitis; Colonic obstruction; Colonic ulcer; Dry mouth; 
Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophageal pain; Esophagitis; Flatulence; 
Gastric ulcer; Gastritis; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(diverticulitis); Gastrointestinal disorders - Other (small bowel NOS fistula); Gastrointestinal 
fistula; Hemorrhoids; Ileal fistula; Ileus; Oral pain; Pancreatitis; Proctitis; Rectal fistula; Rectal 
mucositis; Rectal obstruction; Rectal pain; Small intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
face; Facial pain; Flu like symptoms; Localized edema; Multi-organ failure; Non-cardiac chest 
pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic hemorrhage; Hepatobiliary 
disorders - Other (biliary obstruction secondary to multiple biliary stones) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Cytokine release syndrome; Immune 
system disorders - Other (systemic inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Fall; 
Fracture; Hip fracture; Vascular access complication; Wound complication; Wound dehiscence 
INVESTIGATIONS - CPK increased; Cardiac troponin I increased; Cardiac troponin T 
increased; Cholesterol high; Ejection fraction decreased; Fibrinogen decreased; Investigations - 
Other (blood urea nitrogen high) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Alkalosis; Dehydration; 
Hypermagnesemia; Hypertriglyceridemia; Hyperuricemia; Hypomagnesemia; Tumor lysis 
syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall 
pain; Generalized muscle weakness; Joint range of motion decreased; Muscle weakness left- 
sided; Muscle weakness lower limb; Muscle weakness right-sided; Muscle weakness upper limb; 
Musculoskeletal and connective tissue disorders - Other (cramping); Myositis; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Leukemia secondary to oncology chemotherapy; Myelodysplastic syndrome; 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor 


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hemorrhage); Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; 
Hydrocephalus; Ischemia cerebrovascular; Lethargy; Leukoencephalopathy; Memory 
impairment; Neuralgia; Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; 
Stroke; Syncope; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Libido decreased; 
Personality change; Psychosis 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Proteinuria; 
Renal and urinary disorders - Other (focal segmental glomerulosclerosis); Renal and urinary 
disorders - Other (nephrotic syndrome); Renal and urinary disorders - Other (right ureter 
rupture); Renal calculi; Renal hemorrhage; Urinary frequency; Urinary incontinence; Urinary 
retention; Urinary tract obstruction; Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; 
Gynecomastia; Hematosalpinx; Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; 
Spermatic cord hemorrhage; Testicular hemorrhage; Uterine hemorrhage; Vaginal fistula; 
Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Allergic rhinitis; Bronchospasm; Hiccups; Hoarseness; Hypoxia; Laryngeal 
mucositis; Pharyngeal mucositis; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; 
Pneumothorax; Pulmonary edema; Pulmonary fibrosis; Respiratory, thoracic and mediastinal 
disorders - Other (nasal septal perforation); Tracheal mucositis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Hyperhidrosis; Nail 
loss; Pain of skin; Purpura; Rash acneiform; Scalp pain; Skin and subcutaneous tissue disorders - 
Other (folliculitis); Skin and subcutaneous tissue disorders - Other (non-life threatening 
squamous cell carcinoma of skin: keratoacanthoma type); Skin hyperpigmentation; Skin 
hypopigmentation; Skin ulceration; Urticaria 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypotension; Phlebitis; 
Vascular disorders - Other (ruptured aortic aneurysm); Vascular disorders - Other (visceral 
arterial ischemia); Vasculitis 
 
 
Note: Sorafenib (BAY 43-9006) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
 
 
7 CORRELATIVE/SPECIAL STUDIES: 
 
Several studies listed in this section are not necessarily research tests but they have been outlined 
below as the information obtained from following tests may not be needed to determine objective 
response (primary endpoint of the study) while they may be helpful in clinical care of the patient. 
Informed consent must be obtained prior to obtaining research studies [any tissue specimen, 
biopsies, research blood draws, and DCE-portion of MRI]. 


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7.1 
Measure serum tumor markers (calcitonin and CEA) pre-, during-, and post- 
treatment to correlate with disease response. 
This will be done in all the patients participating on the study as it is considered standard of care. 
This will be done pre-treatment, every 16 weeks during treatment and post-treatment [within 2-4 
weeks after last dose of sorafenib (BAY 43-9006)]. All the centers participating in this study 
perform calcitonin and CEA routinely as a part of standard clinical care. 
 
In addition to drawing samples for serum calcitonin and CEA at the baseline, extra 10-mL of 
blood (research blood draw) will be drawn in red top tube on ice at pre-study visit. Serum will 
be separated, aliquoted in 0.5 mL/tube and stored for possible future re-measurement of 
calcitonin and/or CEA. Such frozen samples will be utilized if clinical laboratory changes the 
calcitonin and/or CEA assays while patient is on study, to avoid inter-assay variation. In such 
cases, such baseline sample may be re-run concurrently with specimen drawn during treatment. 
 
7.2 
Perform a nuclear medicine functional imaging F-18 fluorodeoxyglucose positron 
emission tomography (PET) scan] pre-, and during-treatment. 
PET scans are not required as a part of this research study. Per protocol, PET scans are not used 
for response assessment. PET scans may be done in any patient on the study as clinically 
indicated pre-treatment and every 16 weeks during treatment. This will be determined by the 
treating physician. 
 
7.3 
Perform a dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI) pre- 
, and during-treatment to correlate change in tumor permeability and vascularity 
with tumor response. 
All the centers participating in this study perform MRI routinely as a part of standard clinical 
care for the cancer patients. These centers also have capacity to perform DCE-MRI. While 
DCE-portion of this test is considered research, MRI is considered a standard imaging for 
patients with medullary thyroid carcinoma. All centers participating in the study will use a 
standard uniform acquisition protocol for DCE-MRI scan (see Appendix C for the details). 
Digital images will be transferred to Dr. Knopp’s OSU imaging laboratory for central reading. 
DCE-MRI scans are performed as a part of laboratory correlative studies only and the results will 
not be used to assess the response. 
 
DCE-MRI scan will be preferred in at least 16 patients entered on the Arm A and at least 
16 patients entered on Arm B of the study except under the following circumstances: 
 
Patients who have: 
• 
Cardiac pacemaker 
• 
Other ferromagnetic metal implants not authorized for use in MRI such as some types of 
cerebral aneurysm clips 
• 
Claustrophobia not helped by pre-medications 
• 
Obesity (exceeding the equipment limits) 
• 
Following circumstances exist: 
• 
In case, MRIs are not suitable for evaluating response per RECIST criteria 
• 
Investigator’s disapproval 
• 
Funding for the research part of DCE-MRI is not sufficiently available 
 
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study per investigator’s discretion. 
 
Time points: Performed pre-therapy (within 4 wks prior to treatment), at 8 weeks on therapy. 
DCE-MRI scans at the time points beyond 8 weeks (at every 8 week interval while on the study 
and at off study visit time point) may be done per investigator’s discretion. 
 
Note: MRI scans will be continued to be utilized to measure response. 
 
7.4 
Pharmacogenomic studies: 
 
We will procure PBMCs from all the patients enrolled on the study. Pharmacogenomic studies 
will be performed in all the patients if any clinical responses are observed on this trial. We will 
examine for selected polymorphisms of genes influencing sorafenib (BAY 43-9006) metabolism 
and/or resistance genes that may predict response or toxicity. These changes will be correlated 
with toxicity and clinical response to therapy. 
 
Blood will be drawn for all the patients enrolled on the study. 
 
Sample collection and shipping: 20 ml peripheral blood in heparinized tube (usually solid 
green top tubes) will be collected, kept at the room temperature till shipped on the same day of 
collection (see Appendix B for shipping instructions). Blood specimens will be collected from 
all patients and PBMCs will be isolated. 
 
Time Points: Performed pre-therapy (within 4 weeks prior to registration). 
 
7.5 
Assess the degree of Ras-MAPK signaling inhibition, and vascular endothelial growth 
factor (VEGF) expression in the tumor and clinical response. (Maximum of 24 
patients to participate) 
 
Perform MAP kinase and AKT phosphorylation assay by immunohistochemistry to evaluate the 
degree of RET-Ras-MAPK signaling inhibition by sorafenib (BAY 43-9006) in tumor biopsies. 
Given that sorafenib (BAY 43-9006) also inhibits VEGFR, we will evaluate VEGF expression in 
tumor biopsies to correlate with DCE-MRI parameters and with clinical response when possible. 
 
These tests will be performed in any patients on Arm A or B of the study who has 
biopsiable disease and is willing to undergo biopsies for research purposes. 
 
Biopsies will not be performed under one of the following circumstances: 
▪ Investigator’s disapproval 
▪ Funding for the biopsies is not sufficiently available 
▪ Patient refuses to undergo the procedure. 
 
In such cases biopsies may be performed pre-treatment (within 4 weeks prior to starting 
treatment) and at 8 wks on treatment. Post-treatment (within 4 wks after last dose of 
treatment) biopsies in these patients may be performed per investigator’s discretion. Please 
note that the CT or MRI, DCE-MRI, and PET scan that might need to be done at these time 
points should be done prior to doing biopsy procedure. No specific time interval is necessary 
between these imaging studies and biopsy. 
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30 
 
 
 
Sample collection and processing: Fine needle aspiration (FNA) biopsies (using 18-21 gauge 
needle) of the tumor (ie: either cervical lymph nodes or bulky bony or lung or liver metastasis) 
will be performed under imaging guidance or blindly depending on the location and size of the 
tumor. 
 
Fine needle aspirated material will be collected in the tubes containing RPMI media. No direct 
smears slides will be made from FNA. Using Autocyte PREP system standard protocol, slides 
will be prepared using CytoRich® Red (Tripath Imaging) cytological preservative. The actual 
slides used will be PLUS slides; as these are precoated that facilitates the cells staying on the 
slides during processing. At least 8 unstained slides will be prepared using the standard protocol. 
Two slides will be stained with PapStain for cytologic diagnosis so that we verify that tumor was 
indeed present in the FNA specimen. 
 
Principle of Autocyte PREP system: The AutoCyte PREP System converts a liquid suspension of 
a cell sample into discretely stained, homogenous thin-layer of cells while maintaining diagnostic 
cell clusters. The process includes cell preservation, randomization, enrichment of diagnostic 
material,  autmated  pipetting,  sedimentation,  and  discrete staining portions  of the  process.        
The AutoCyte PREP presents a wellpreserved population of stained cells present within   a   
13mm diameter circle. Using this system, we have been able to perform immunohistochemistry 
studies   on   specimens   prepared   from   FNA   material   in   our   ongoing   CTEP-  sponsore                       
d phase II trial (NCI 6609). 
 
All stained and unstained slides will be shipped to Dr. Shah at the OSU (see Appendix B for 
shipping instructions) who then will transfer batched specimen to Dr. Ringel’s laboratory. 
 
Methods: Studies on unstained slides will be processed at Dr. Ringel’s laboratory at the OSU. 
Immunohistochemical staining Sections will be dewaxed, soaked in alcohol and after 
microwave treatment in antigen unmasking solution for 10 min incubated in 3% hydrogen 
peroxide for 15 min to inactivate endogenous peroxidase activity. Sections will be incubated at 
4C overnight with anti- phospho-Akt (dilution 1:100), with anti-Ret (C-19) (dilution 1:100), 
with anti-p44/42 MAP kinase (dilution 1:100), with anti VEGF (dilution 1:100). Immunostaining 
will be performed by use of the Vectastain Universal Quick kit according to the manufacture’s 
instruction. Peroxidase staining will be revealed with 3, 3 - diaminobenzidine. Negative control 
will be applied by omission of antiserum. Results will be interpreted independently by three 
blinded investigators and scored for the presence or absence of staining. Scoring will be 
compared between the three investigators independently and agreement between two of the three 
investigators will be required for a positive result to be assessed. 
 
7.6 
Assess the presence and type of RET gene defects in the tumor to correlate with 
clinical response. 
As the presence of RET gene mutations in patients with metastatic sporadic medullary thyroid 
carcinoma is highly variable but on average about 25%, we plan to examine the presence and 
type of such gene defects in our patient population while treating them with sorafenib (BAY 43- 
9006) that inhibits the downstream signaling pathway for RET. 
 
As patients on Arm A are expected to have germ-line mutations in RET, collection and 
studies on tumor tissue blocks may not be necessary in those patients. In this group of 
patients, we will have RET germ-line mutation information available from the genotyping 


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31 
 
 
 
studies performed in the peripheral blood (see section 7.7). 
 
All patients on Arm B on the study will have this test performed except under the  following 
circumstances: 
▪ Tissue block is not sufficient for research purposes. 
▪ Tissue block is not transferable for research purposes. 
Sample collection and shipping: There is no new biopsy performed for this test. The tissue 
block preserved routinely at clinical pathology laboratory of previously performed thyroid cancer 
biopsy/surgery will be obtained and shipped to Dr. Shah at the OSU (see Appendix B for 
shipping instructions). 
 
Time point: Anytime prior to registration on the study. 
 
Methods: Ten micron/slice will be cut from the tumor paraffin tissue block and such 3-4 
unstained slides will be used for isolating tumor DNA. H&E slides will be prepared to verify 
pathologic diagnosis.  Tumor DNA will be isolated in Dr. Ringel’s laboratory at the OSU. 
DNA extraction: After microdissection of tumor on slides, DNA will be extracted using QI- 
Amp DNA mini kit (Qiagen SA) according to the manufacturer’s instruction. All PCR products 
will be electrophoresed on 3% agarose gel in TAE buffer and stained with ethidium bromide. 
 
RET mutation studies will be performed in Dr. Thomas Prior’s laboratory at the OSU using 
standard protocol for RET genotyping. 
 
7.7 
Assess the presence and type of RET gene defects in the peripheral blood to correlate 
with clinical response. 
RET genotyping in peripheral blood is a clinical test that is standard of care in all patients with 
medullary thyroid carcinoma. Each participating center will use their clinical laboratories to 
perform such RET genotyping tests. 
 
This test will be sent out to the clinical laboratory (5 mL blood in one purple top/EDTA tube) in 
all the patients enrolled on the study during their pre-study visit unless the RET mutation 
analysis report from previously performed analysis is available. 


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8 
STUDY CALENDAR 
 
 
 
 
Pre-therapya 
Course I 
(subsequent courses 
as course Ii,) 
Off-therapyc 
Week 4b 
Week 8 
Sorafenib (BAY 43-9006)d 
Patient diaries 
X 
X 
X 
History/Physical Exam 
X 
X 
X 
X 
Vital signs/Weight 
X 
X 
X 
X 
Blood pressure monitoring 
Once a week till stable or 
at least for the first 4 weeks. 
X 
Adverse Event Evaluation 
X 
X 
X 
CBC w/diff, platelets 
X 
X 
X 
X 
Serum chemistrye 
Xe 
Xe 
Xe 
Xe 
Serum -HCGf 
Xf 
CT or MRI scan of neck/chest/abdomeng 
Xg 
Xg 
Xg 
Serum Calcitonin and CEA 
X 
X 
X 
Following tests may be done in selected group of patients ONLY. See Sec7.0 for the details. 
10-mLblood for procurement of serum (Section 7.1) 
X 
PET scan (Section 7.2)h 
X 
X 
X 
DCE-MRI scan (Section 7.3) 
X 
X 
Xj 
20-mLblood for plasma and PBMCs  (Section 7.4) 
X 
FNA biopsy of the tumor (Section 7.5) 
Xk 
Xk 
Xj 
Paraffin tumor tissue block (Section 7.6) 
X 
RET genotyping to clinical lab (Section 7.6) 
X 
a. Pre-therapy evaluations are to be conducted within 10 days prior to administration of sorafenib (BAY 43-9006) except imaging studies, research blood 
draws, and tumor biopsies that should be done within 4 weeks prior to the start of therapy. 
b: Week 4 evaluations may be done at local doctor’s office. However, AE eval must be by research staff via phone interview with the patient and principal 
investigator must sign off on adverse event data forms within 36 hours of the phone interview. 
c. Off-therapy evaluations are to be conducted within 4 weeks after last dose of sorafenib (BAY 43-9006) treatment. Serum calcitonin and CEA, CT/MRI 
scans will be optional if a patient received sorafenib (BAY 43-9006) for <4 weeks. 
d: Oral sorafenib (BAY 43-9006) will be given with 250 ml (about 8 ounces) of water at the dose of 400 mg BID. 
e: Sodium, Potassium, Chloride, Bicarbonate, Creatinine, BUN, Glucose, Phosphorus, Total protein, Albumin, Total bilirubin, S GOT (AST), SGPT (ALT), 
Alkaline phosphatase, LDH. 
f: Pregnancy test (sensitivity of at least 50 mIU/mL) will be performed for all women of childbearing potential before beginning sorafenib (BAY 43-9006). 
g: CT or MRI scans as determined by investigators to assess the response per RECIST criteria. 
h: PET scans are performed only as clinically indicated as determined by treating physicians. 
i: Research blood draws and tumor biopsies will not be required in subsequent courses. 
j: Optional per investigator’s discretion. 
k: If patient has biopsiable disease and agrees to have biopsies for research purpose. 
: After six months, we will eliminate week 4 visits and all associated testing at week 4 of the each course. Patients will return to OSU every 16 weeks for an 
evaluation visit. 


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9 MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should be reevaluated for response every 16 weeks. 
Confirmatory scans should also be obtained 4 weeks following initial documentation of 
objective response. 
 
9.1 
Definitions 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Therasse 
et al., 2000). 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. 
 
9.1.1 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 techniques (CT, MRI, 
x-ray) or as >10 mm with spiral CT scan or MRI performed with following technique: 
 
MRI images acquired in at least two imaging planes (such as axial and coronal) that give 'in- 
plane' resolution of at least 2.5 mm. 
 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless the lesion in irradiated area shows progression. 
 
9.1.2 Non-measurable disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm using spiral CT scan or MRI with ‘in-plane resolution of 2.5 
mm’), 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. 
 
9.1.3 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. 


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9.1.4 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. 
 
9.2 
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 as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless the lesion in irradiated area shows progression. 
 
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 
anti-tumor effect of a treatment. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
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 or less 
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. 
 
Ultrasound (US). When the primary endpoint of the study is objective response evaluation, US 
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. 
US 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 that may only be available in some centers. 
Therefore, the utilization of such techniques for objective tumor response should be restricted to 
validation purposes in reference centers. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are 


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initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response. 
 
Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
9.3 
Response Criteria for patients with measurable disease: 
DCE-portions of MRI scans and PET scans will not be used to assess the response as they are not 
part of RECIST criteria.  Please see section 9.4 for patients who have only assessable disease. 
 
9.3.1 Evaluation of target lesions 
 
Complete Response (CR): 
Disappearance of all target lesions 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD): 
At least a 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 
 
9.3.2 Evaluation of non-target lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level 
 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 
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 by the review panel (or study chair). 
Note: If tumor marker (calcitonin) is initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
35 


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9.3.3 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 9.3.1). 
 
 
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 that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
 
9.4 
Confirmatory Measurement/Duration of Response 
 
9.4.1 Confirmation 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed 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 16 weeks (see section 9.3.3). 
 
9.4.2 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 


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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. 
 
9.4.3 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. 
 
9.5 Response Review 
 
As the primary endpoint for this trial is response rate, it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion. 
Simultaneous review of the patients’ files and radiological images is the best approach. 
 
Note: When a review of the radiological images is to take place, it is also recommended that 
images be free of marks that might obscure the lesions or bias the evaluation of the reviewer(s). 
 
 
10 REGULATORY AND REPORTING REQUIREMENTS 
 
The reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements” which can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf). 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 3.0 will be utilized for adverse event reporting. 
 
All appropriate treatment areas should have access to a copy of the CTCAE version 3.0. A copy 
of the CTCAE version 3.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
10.1 Expedited Adverse Event Reporting 
(AE; formerly known as Adverse Drug Reaction) 
▪ Expedited reports are submitted to CTEP via the secure CTEP-AERS 
application accessed via the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_ 
events.htm). 
▪ In the rare occurrence when Internet connectivity is lost, an adverse event report 
may be submitted using CTEP's Adverse Event Expedited Report-Single Agent 
or Multiple Agent paper template (available at http://ctep.cancer.gov) and faxed 
to 301-230-0159. A 24-hour notification is to be made to CTEP by telephone 
at 301-897-7497, only when Internet connectivity is disrupted. Once Internet 
connectivity is restored, an AE report submitted on a paper template or a 24- 
hour notification phoned in must be entered electronically into CTEP-AERS by 
the original submitter at the site. 


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▪ Those AEs that do not require expedited reporting must be reported in routine 
(CDUS) study data submissions. AEs reported through CTEP-AERS must also 
be reported in routine study data submissions. 
 
10.1.1 Expedited Reporting Guidelines –Phase 2 and 3 Trials Utilizing an Agent under a 
CTEP IND: 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur Within 30 Days 1 of 
the Last Dose of the Investigational Agent 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
Unexpected Expected 
Unexpected 
Expected 
 
 
Unexpected Expected 
with 
Hospitali 
-zation 
without 
Hospitali- 
zation 
with 
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as  follows: 
CTEP-AERS 24-hour notification follow ed by complete report w ithin 5 calendar days for: 
• Grade 4 and Grade 5 unexpected events 
CTEP-AERS 10 calendar day report: 
• Grade 3 unexpected events w ith hospitalization or prolongation of  hospitalization 
• Grade 5 expected events 
2 Although an CTEP-A ERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
December 15, 2004 
Note: All deaths on study require both routine and expedited reporting regardless of causality. 
Attribution to treatment or other cause must be provided. 
• 
Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event. 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions. 
• 
Any event that results in persistent or significant 
disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 


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10.1.2 Expedited Adverse Event Reporting Exclusions 
 
None. 
 
10.1.3 Secondary AML/MDS 
 
Investigators are required to report cases of secondary AML/MDS occurring on or following 
treatment on NCI-sponsored chemotherapy protocols using the NCI/CTEP Secondary 
AML/MDS Report Form. This form can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/reporting/index.html). Second malignancies and non-AML/MDS 
secondary malignancies (e.g., endometrial cancer in a breast cancer patient receiving tamoxifen) 
should NOT be reported via CTEP-AERS but should be submitted as part of the study results via 
routine CDUS reporting. 
 
10.1.4 Data Safety Monitoring Plan 
 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness. Investigators will conduct continuous review of data and patient safety at 
their regular Disease Group meetings (at least monthly) and the discussion will be documented in 
the minutes. The PI of the trial will review toxicities and responses of the trial where applicable 
at these disease center meetings and determine if the risk/benefit ratio of the trial changes. 
Frequency and severity of adverse events will be reviewed by the PI and compared to what is 
known about the agent/device from other sources; including published literature, scientific 
meetings and discussions with the sponsors, to determine if the trial should be terminated before 
completion. Serious adverse events and responses will also be reviewed by the OSUCCC Data 
and Safety Monitoring Committee (DSMC). The PI will also submit a progress report biannually 
for this Phase II study that will be reviewed by the committee per the DSMC plan. All reportable 
Serious Adverse Events (SAE) will also be reported to the IRB of record as per the policies of 
the IRB. 
 
10.2 Data Reporting 
 
The OSU clinical trials’ office will be responsible for the submission of the CDUS data to CTEP. 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are 
due January 31, April 30, July 31, and October 31. 
 
Instructions for submitting data using the CDUS can be found on the CTEP web site 
(http://ctep.cancer.gov/reporting/cdus.html). 
 
10.3 CTEP Multicenter Guidelines 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair: Dr. Bhavana Konda serves as a protocol chair for this 
multi-center study. 


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• The Protocol Chair will be the single liaison with the CTEP Protocol and 
Information Office (PIO). The Protocol Chair is responsible for the coordination, 
development, submission, and approval of the protocol as well as its subsequent 
amendments. The protocol must not be rewritten or modified by anyone other than 
the Protocol Chair. There will be only one version of the protocol, and each 
participating institution will use that document. The Protocol Chair is responsible 
for assuring that all participating institutions are using the correct version of the 
protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all 
participating 
institutions 
and 
for 
monitoring 
its 
progress. 
All 
reporting 
requirements to CTEP are the responsibility of the Protocol Chair. 
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to 
assure safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of 
data for study analysis. 
 
Responsibilities of the Coordinating Center: The Ohio State University serves as a coordinating 
center for this multi-institutional study. 
• Each participating institution will have an appropriate assurance on file with the 
Office for Human Research Protection (OHRP), NIH. The Coordinating Center is 
responsible for assuring that each participating institution has an OHRP assurance 
and must maintain copies of IRB approvals from each participating site. 
• Prior to the activation of the protocol at each participating institution, an OHRP 
form 310 (documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration. The 
Coordinating Center is responsible for assuring that IRB approval has been 
obtained at each participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports. The 
participating institutions must report directly to CTEP with a copy to the 
Coordinating Center. The Coordinating Center will submit AE reports to the 
Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways: (1) source documents and 
research records for selected patients are brought from participating sites to the 
Coordinating Center for audit, or (2) selected patient records may be audited on- 
site at participating sites. If the NCI chooses to have an audit at the Coordinating 
Center, then the Coordinating Center is responsible for having all source 
documents, 
research records, all IRB approval documents, NCI 
Drug 
Accountability Record forms, patient registration lists, response assessments scans, 
x-rays, etc. available for the audit. 
 
Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information: 
➢ The title page must include the name and address of each participating 
institution and the name, telephone number and e-mail address of the 
responsible investigator at each participating institution. 


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➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required. The procedures for registration must 
be stated in the protocol. 
➢ Data collection forms should be of a common format. Sample forms should be 
submitted with the protocol. The frequency and timing of data submission 
forms to the Coordinating Center should be stated. 
 
➢ Describe how AEs will be reported from the participating institutions, either 
directly to CTEP or through the Coordinating Center. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order 
DCTD-supplied investigational agents directly from CTEP. Investigational agents 
may be ordered by a participating site only after the initial IRB approval for the site 
has been forwarded by the Coordinating Center to the CTEP PIO. 
 
10.3.1 Institutional Review Board (IRB) 
 
A copy of the IRB approval for this protocol must be submitted to the coordinating office along 
with the approved consent form prior to patient registration. Yearly approvals and revised 
consent forms must also be submitted to the OSU clinical trials office. Patients will not be 
registered if the IRB approval date is greater than one year prior to the date of registration. 
Patients must sign a copy of the current, approved consent form. 
 
10.3.2 Patient Registration 
 
All patients will be registered with the OSU clinical trials office from 8:00 am to 4:30 pm 
Eastern Standard Time, Monday through Friday, excluding holidays, by calling Dr. Shah’s office 
at 614-293-8629 and faxing the registration forms to 614-293-3112. Patients must be registered 
prior to initiation of treatment. 
 
The following must be faxed to the OSU clinical trials office at 614-293-3112 prior to patient 
registration: 
▪ Copy of signed informed consent Form 
▪ Eligibility Checklist 
▪ Baseline Pathology Report 
▪ Baseline Radiology Report 
▪ Pre-therapy Laboratory Reports 
▪ History and physical exam note 
▪ Documentation of prior therapy 
▪ Documentation of current medications 
▪ Patient demographics 
 
No patient will be registered in the OSU clinical trials office unless every question on the 
submitted forms is answered satisfactorily.  NO PROTOCOL DEVIATIONS are allowed. 
 
Patients will not begin treatment until a confirmation of registration is received from the OSU 
clinical trials office.  A registration number will be given to each patient and will be used as a 


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unique identifier on all patient materials and data sheets submitted thereafter. 
 
10.3.3 Data Forms and Data Submission Guidelines 
 
Data must be submitted according to the protocol requirements for ALL patients registered 
whether or not assigned treatment is administered, including patients deemed to be ineligible. 
Patients for whom documentation is inadequate to determine eligibility will generally be deemed 
ineligible. 
 
   On Study Data Submission Schedule 
 
Flowsheets : Data to include history, physical exam, vital signs, weight, 
laboratory values, dose and duration of study drug given, toxicities, concomitant 
medications will be recorded and must be submitted at the end of each month. 
 
Disease Assessment Form: Lesions identified at baseline must also be assessed 
and measured at subsequent protocol-specified courses. 
 
 Off study and follow up Data Submission Schedule 
 
Contact the study protocol chair or the OSU clinical trials office nurse 
representative to advise them of when patients are deemed to be off study. 
 
Off Study Form: The form should indicate the primary reason the patient is 
being taken off study.  The date of off study determination should also be noted. 
 
Follow up form: Once a patient goes off-therapy due to disease progression or 
toxicity, the patient will be followed until the toxicity is resolved and for no less 
than thirty days after the last treatment. 
 
10.3.4 Auditing 
 
Patient medical records, study charts, patient scans, protocol regulatory documents, IRB 
approvals and correspondence, and drug accountability records are subject to periodic audit by 
the CTEP Quality Assurance and Data Monitoring Committee, the NCI, and the FDA. 
 
10.4   Clinical Trials Agreement (CTA) 
 
The agent sorafenib (BAY 43-9006) supplied by CTEP, DCTD, NCI used in this protocol is 
provided to the NCI under a Collaborative Agreement (CTA) between Bayer Corp. and Onyx 
Pharmaceuticals (hereinafter referred to as “Collaborator”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the Intellectual Property Option to “Collaborator” contained within the terms of 
award, apply to the use of the sorafenib (BAY 43-9006) in this study: 
 
1. 
Sorafenib (BAY 43-9006) may not be used for any purpose outside the scope of this 
protocol, nor can sorafenib (BAY 43-9006) be transferred or licensed to any party not 
participating in the clinical study. Collaborator(s) data for sorafenib (BAY 43-9006) are 
42 


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confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing investigational sorafenib (BAY 43- 
9006) contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data"): 
 
a. NCI must provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by 
any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, 
obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order. Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 
45 C.F.R. Part 164. 
 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
4. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
 
5. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to submission for 
publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator 
shall have the right to request that publication be delayed for up to an additional 30 days in order 
to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstract should be provided to CTEP for 
forwarding to Fujisawa in sufficient advance to investigator's presentation for allowing Fujisawa 
to review it and protect intellectual property rights. Copies of abstracts must be provided to 


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CTEP for forwarding to Collaborator(s) preferably at least three (3) days prior to submission, but 
in any case, prior to presentation at the meeting or publication in the proceedings. Press releases 
and other media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland 20892 
FAX 301-402-1584 
Email: anshers@ctep.nci.hih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborators’ confidential/ 
proprietary information. 
 
 
11 STATISTICAL CONSIDERATIONS 
 
11.1 Study design/Endpoints: 
 
Arm A and Arm B 
 
The primary endpoint of this phase II study is to assess objective response rate of 
sorafenib (BAY 43-9006) in metastatic medullary thyroid carcinoma in setting of 
inherited tumor syndromes as well as in setting of sporadic medullary thyroid 
cancer. 
 
For this Phase II study, we have chosen the minimax two-stage design of Simon 
resulting in a trial with two stages with decisions to continue after 16 and 25 
response-evaluable patients are accrued to each cohort (Arms A and B) (Simon et 
al., 1989). 
 
This design minimizes the expected sample size given specified alpha and beta 
error rates. For example, we will define the true minimum response rate, p0 . This 
is a response probability, at which or below, we consider the agent to be clinically 
unimportant, ineffective, or uninteresting. Associated with this probability is the 
alpha error rate, the probability of failing to reject an agent with a response rate < 
p0. On the other hand, we will designate 'upper' target response rate, p1, with its 
associated error rate, beta. The beta error is the probability of falsely rejecting an 
agent with a response rate of > p1. Using exact binomial probabilities, the Simon 
design generates two study sample sizes. At the first stage, if r1 or fewer responses 
are observed in n1 patients, the study is terminated. If the number of observed 
responses is greater than r1, the study is continued to the maximum sample size, n. 
If in n patients, r or fewer responses are observed, the agent is considered 
ineffective and no further study is warranted. For the given p0, one can calculate 
the expected sample size, EN (p0), and the probability of early termination, PET 
(p0). 


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We will consider sorafenib (BAY 43-9006) to be ineffective or uninteresting if the 
true response [PR+CR using unidimensional RECIST/WHO response criteria] 
probability is less than 10% (p0). We will also assume that the regimen is worthy 
of further study if the true response probability or target response rate is 30% or 
greater (p1). These figures result in a two-stage design of 16 and 25 patients, with 
an alpha of 0.10 and beta of 0.10. If one or no responses are seen in the first 16 
response-evaluable patients, the study is terminated early and this regimen is 
deemed ineffective for this patient population. If two or more patients respond in 
the first 16, an additional 9 patients are treated for a total of 25. If 5 or more patients 
respond of the 25, we will recommend that the regimen be studied further. If 25 
patients are treated, we will be able to estimate the frequency of response with a 
95% confidence interval of not greater than 19.6%. 
 
Similarly, the 25 patients in each of Arms A and B will allow us to estimate the 
probability of a specific toxicity to within 19.6% in each cohort. Any toxicity 
occurring with at least a 10% probability has a 92.8% chance of being seen at least 
once in 25 toxicity-evaluable patients. 
 
11.2 Sample Size/Accrual Rate: 
 
For this study of 16 or 25 patients in Arm A and 16 or 25 patients in Arm B, we 
estimate that we will accrue 3-4 patients per month, and meet our total accrual goal 
of 50 response-evaluable patients in 12-16 months or less. 
 
11.3 Analysis of secondary endpoints: 
 
▪ To assess toxicity of sorafenib (BAY 43-9006) in patients with metastatic 
medullary thyroid carcinoma. 
▪ Measure serum tumor markers calcitonin and carcinoma embryonic antigen 
(CEA) pre-, during-, and post-treatment to correlate with disease response. 
▪ Correlate nuclear medicine functional imaging [F-18 fluorodeoxyglucose 
positron emission tomography (PET) scan] data obtained at pre-, during- and 
post-treatment with tumor response. 
▪ Correlate dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI) 
data obtained at pre-, during- and post-treatment with changes in tumor 
permeability and vascularity with tumor response. 
▪ Perform pharmacogenomic studies on procured PBMCs if clinical responses 
are observed. 
▪ To correlate between the degree of Ras-MAPK signaling inhibition and 
vascular endothelial growth factor (VEGF) expression in the tumor and clinical 
response. 
▪ To correlate between the presence and type of RET gene defects in tumor and 
clinical response. 


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With little preliminary data on the biological variability of tumor markers, VEGF 
expression, ERK phosphorylation, RAS-MAPK signaling pathway inhibition, 
DCE-MRI parameters, or their assay variation in our laboratories, it is difficult to 
provide the usual sample size estimates given specified levels of significance and 
power. Our normal procedure is to use preliminary data of variation coupled with 
clinically based definitions of reasonable differences to be evaluated to arrive at 
objective sample size estimates. The 16-patient estimate for estimating a 
confidence interval for the objective response rate may be insufficient for 
comparisons of biological correlates. 
To address this concern, we will perform an initial analysis of data for secondary 
endpoints from the first eight patients. This analysis will be done solely to estimate 
variance and to compute formal sample size estimates based on these findings. 
While we assume that the 16 patients will provide a sample size sufficient to give 
general indications of the effect of sorafenib (BAY 43-9006) in cohorts for Arms 
A and B, our interim assessment will allow us to refine the overall sample size 
estimate. Depending on biological and experimental variation, we will adjust our 
definition of a clinically important difference using specified levels of significance 
and power. 
 
11.4 Reporting and Exclusions 
 
11.4.1 Evaluation of toxicity: All patients will be evaluable for toxicity from the time of their 
first treatment with sorafenib (BAY 43-9006). 
 
11.4.2 Evaluation of response: 
▪ All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). 
▪ All of the patients who met the eligibility criteria should be included in the main analysis 
of the response rate.  Patients in response categories 4-9 should be considered as failing 
to respond to treatment (disease progression). Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the response rate. 
Precise definitions for categories 4-9 will be protocol specific. 
▪ All conclusions should be based on all eligible patients. 
▪ Sub-analyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.). However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported. 
▪ The 95% confidence intervals should be provided. 


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Carlomagno F, Anaganti S, Guida T, et al. BAY 43-9006 inhibition of oncogenic RET mutants. 
J Natl Cancer Inst. 2006;98(5):326-34. 
 
Chong, H., H.G. Vikis, and K.L. Guan. Mechanisms of regulating the Raf kinase family. Cell 
Signal.  15:463-469. 2003 
 
Cohen, Y., M. Xing, E. Mambo, et al. BRAF mutation in papillary thyroid carcinoma. J Natl 
Cancer Inst.  95:625-627. 2003 
 
Davies, H., G.R. Bignell, C. Cox, et al. Mutations of the BRAF gene in human cancer. Nature. 
417:949-954. 2002 
 
Evans DB, Fleming JB, Lee JE, Cote G, Gagel RE. The surgical treatment of medullary thyroid 
carcinoma. Semin Surg Oncol 1999;16(1):50. 
 
Galbraith SM, Maxwell RJ, Lodge MA, et al. Combretastatin A4 Phosphate Has Tumor 
Antivascular Activity in Rat and Man as Demonstrated by Dynamic Magnetic Resonance 
Imaging. J Clin Oncol. 21(15):2831-2842. 2003 
 
Investigator’s Brochure, versions 3 and 4.1. Shah, A., C. Lathia, K. Heininger, et al. (Eds.), 
Bayer Corporation, West Haven, CT.  2002 & 2003 
 
Mercer, K.E., and C.A. Pritchard. Raf proteins and cancer: B-Raf is identified as a mutational 
target.  Biochim Biophys Acta.  1653:25-40. 2003 
 
Moley JF, Debenedetti MK, Dilley WG, Tisell LE, Wells SA. Surgical management of 
patients with persistent or recurrent medullary thyroid cancer. J Intern Med 
1998;243(6):521. 
 
Morgan B, Thomas AL, Drevs J, et al. Dynamic Contrast-Enhanced Magnetic Resonance 
Imaging As a Biomarker for the Pharmacological Response of PTK787/ZK 222584, an 
Inhibitor of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, in Patients 
With Advanced Colorectal Cancer and Liver Metastases: Results From Two Phase I Studies. 
J Clin Oncol. 21(21):3955-3964. 2003 
 
Pollock, P.M., and P.S. Meltzer. A genome-based strategy uncovers frequent BRAF mutations 
in melanoma.  Cancer Cell.  2:5-7. 2002 
 
Schlumberger M, Abdelmoumene N, Delisle NJ, Couette JE, Groupe d'Etude des Tumeurs  a 


NCI Protocol #: NCI-7609 
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48 
 
 
 
Calcitonine (GETC). Treatment of advanced medullary thyroid cancer with an alternating 
combination of 5 FU-streptozocin and f FU-dacarbazine. Br J Cancer 1995; 71:363. 
 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 10(1):1- 
10. 1989 
 
Singer, G., R. Oldt, 3rd, Y. Cohen, et al. Mutations in BRAF and KRAS characterize the 
development of low-grade ovarian serous carcinoma.  J Natl Cancer Inst.  95:484-486. 2003 
 
Stevenson JP, Rosen M, Sun W, et al. Phase I Trial of the Antivascular Agent Combretastatin 
A4 Phosphate on a 5-Day Schedule to Patients With Cancer: Magnetic Resonance Imaging 
Evidence for Altered Tumor Blood Flow. J Clin Oncol. 21(23):4428-4438. 2003 
 
Tannapfel, A., F. Sommerer, M. Benicke, et al. Mutations of the BRAF gene in 
cholangiocarcinoma but not in hepatocellular carcinoma.  Gut.  52:706-712. 2003 
 
Therasse P, Arbuck SG, Eisenhauer EA, et al. New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors. JNCI Cancer Spectrum.; 92(3):205-216. 2000 


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APPENDIX A 
 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


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APPENDIX B 
 
Sample Shipping Instructions 
 
a) Research peripheral blood (Section 7.4) 
 
▪ All samples must have a label that includes subject no, name of the institution, 
date/time of collection, and 'NCI 7609'. 
▪ All samples must be shipped on the same day of collection. 
▪ Ship on Monday-Friday only. 
▪ Notify the technician of impending arrival of the sample. 
▪ Ship at room temperature to the following address by overnight mail for AM delivery. 
 
Shipping Address: 
Manisha Shah, M.D./Attention: Donna Bucci 
The Ohio State University 
James Cancer Hospital Lobby 
300 West 10th Avenue 
Columbus, OH 43210 
Phone: 614-293-3300 
 
b) For slides of FNA biopsies (Section 7.5) or tissue blocks (Section 7.6) 
 
▪ All samples must have a label that includes subject no, name of the institution, 
date of collection, and 'NCI study no’. 
▪ Sample may be shipped as soon as available or in a batch. 
▪ Ship on Monday-Thursday only. 
▪ Notify the technician of impending arrival of sample. 
▪ Ship at room temperature to following address by overnight mail for AM delivery. 
 
Shipping Address 
 
Manisha H. Shah, M.D. 
The Ohio State University 
A438 Starling Loving Hall 
320 West 10th Ave 
Columbus, OH 43210 
Phone: 614-293-8629 
 
For questions or notifying impending arrival contact: 
Ms. Beth Scholl/Dr. Manisha Shah 
Phone: 614-293-8629 
Fax: 614-293-3112 


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APPENDIX C 
 
Confidential 
 
 
 
 
SITE MANUAL for DCE - MRI Imaging Procedures 
 
Drug: Sorafenib (BAY 43-9006) 
Protocol Title: 
Phase II Study of Sorafenib (BAY 43-9006) in Patients with Metastatic 
Medullary Thyroid Carcinoma 
 
Document type: Protocol – Appendix C 
 
 
 
 
Property of The Ohio State University, Division of Imaging Research 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of the Division of Imaging Research of the Ohio State University 


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Table of Content 
TABLE OF CONTENT 
52 
INTRODUCTION: 
53 
CONTACTS: 
54 
Imaging Expert: 
54 
Imaging Core Lab / Central Image Analysis Laboratory (CIAL) 
54 
IMAGING RELEVANT COMPONENTS OF THE OVERALL PROTOCOL: 
56 
THE IMAGING PROCEDURE: 
57 
DATA TRANSFER: 
61 
EQUIPMENT AND PROCEDURE CHECKLIST: 
62 
INITIAL EQUIPMENT AND PROCEDURE CHECKLIST FORM: 
63 
EQUIPMENT AND PROCEDURE UPDATE CHECKLIST FORM: 
64 
DCE-MRI SCAN SCHEDULE: 
65 
DCE-MRI Site Summary Sheet to be handy at the time of imaging 
65 


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Introduction: 
 
The purpose of this site manual is to document the standard imaging procedure, serve as a handy 
reference in case of questions and as an information resource. 
 
This document will be subject to revisions, so please make sure that you have the most recent 
manual. 
 
This document does not supersede any trial document or IRB (Internal Review Board or local 
Ethics committee) guidelines or requirements. 
 
In case of any questions, do not hesitate to contact the protocol chair, the Study Imaging expert 
and copy the Imaging Trial Lab. All appropriate information is found in the Contact Section of 
this document. 
 
Please inform the Imaging Corelab of any changes in equipment and procedures, and use the 
Equipment and Procedure Checklist Section check list for guidance. If you are unsure about any 
topic or question, please contact the above resources with details in the Contact Section of this 
document. 
 
Dynamic contrast enhanced MRI (DCE-MRI) will provide data revealing the changes in the 
vascular perfusion and permeability characteristics of tumors. Successful biologic inhibition will 
reduce both vascular perfusion and permeability causing a decrease in the peak and rate of contrast 
enhancement. Dynamic MRI therefore offers a more direct biologic 'in vivo' assessment of 
therapeutic efficacy. 


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Protocol Chair: 
Bhavana Konda, MBBS, MPH 
Bhavana.konda@osumc.edu 
Contacts: 
 
Imaging Expert: 
Michael V. Knopp, MD, PhD 
knopp.16@osu.edu 
 
Imaging Core Lab / Central Image Analysis Laboratory (CIAL) 
The Ohio State Research Foundation- 
Image Analysis Lab -Wright Center of Innovation in Biomedical Imaging 
 
The lab has the following generic E-Mail which is automatically forwarded to the staff in charge: 
E-mail: XXXXX@imagingcorelab.com (XXXXX) will be the assigned name of the opened 
protocol and will be specified prior to start up. 
 
This e-mail address should be included in all correspondence and will be read and 
accessible to all relevant staff at OSU. 
 
Administrative Director: 
Robert McKenney, PhD 
Department of Radiology 
The Ohio State University 
University Hospitals 
659 Means Hall 
1654 Upham Drive 
Columbus, Ohio 43210-1228 
Office Phone: 614-293-7165 
Fax: 
614-293-9275 
E-Mail: mckenney.1@osu.edu 
 
Lab Manager: 
Steffen Sammet, M.D., Ph.D. 
Department of Radiology 
The Ohio State University 
University Hospitals 
647 Means Hall 
1654 Upham Drive 
Columbus, Ohio 43210-1228 
 
Office Phone: 614-293-2929 
Fax: 
614-293-9275 
E-Mail: sammet.5@osu.edu 
OSU Data Management – IMRES Project Leader 
Guang Jia 


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Department of Radiology 
The Ohio State University 
University Hospitals 
646 Means Hall 
1654 Upham Drive 
Columbus, Ohio 43210-1228 
 
Office Phone: 614-293-9151 
Fax: 
614-293-9275 
E-Mail: jia.11@osu.edu 
 
OSU Data Analysis – IMRES Project Leader 
Xiangyu Yang 
Department of Radiology 
The Ohio State University 
University Hospitals 
646 Means Hall 
1654 Upham Drive 
Columbus, Ohio 43210-1228 
 
Office Phone: 614-293-9151 
Fax: 
614-293-9275 
E-Mail: yang.367@osu.edu 
 
Director: 
Michael V. Knopp, MD, PhD 
Chairman and Professor of Radiology 
Novartis Chair of Imaging Research 
Department of Radiology 
The Ohio State University 
University Hospitals 
657 Means Hall 
1654 Upham Drive 
Columbus, Ohio 43210-1228, USA 
 
Office Phone: 614-293-9998 
Direct Line: 
614-293-9227 
Fax: 
614-293-9275 
E-Mail: knopp.16@osu.edu 


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Imaging relevant components of the overall protocol: 
 
Dynamic contrast enhanced MRI (DCE-MRI) will provide data revealing the changes in the 
vascular perfusion and permeability characteristics of tumors. DCE-MRI therefore offers a more 
direct 'in vivo' assessment of efficacy. 
Imaging time is estimated at 45-60 minutes per scan. 
Standard morphologic MRI sequences (scanning has to cover all tumor areas in at least two planes 
(such as axial and coronal)) will be used for tumor size determination for all patients undergoing 
DCE-MRI. These standard sequences (see 1 and 2 below) are performed without contrast; 
sequences used should be the same at all time points for a given patient. These standard sequences 
are performed at any time point requiring tumor size measurement. At those time points where 
DCE-MRI is to be performed, the DCE-MRI protocol is performed after the standard pre-contrast 
sequences. The standard imaging follows your institutional protocol and should include: 
1. 
T2 weighted (Fast or turbo spin echo) breath-hold 
2. 
T1 weighted Fast Multi-planar Gradient Recalled Echo breath-hold 
Both sequences will be performed in the plane suitable to the studied body part. Axial will be the 
standard plane with better than 2.5 mm in plane resolution and 8 mm slice thickness. Further planes 
may be implemented as appropriate. The same plane and slice thickness must be used for tumor 
measurements. 
Uni- and bi-dimensional measurements of disease will be recorded of all tumors that can be 
measured and documented. These measurements and the clinical decision-making accompanying 
the measurements will be made at the site. 
At timepoints where DCE-MRI is being performed, prior to imaging, an IV cannula with a long 
line is inserted into an arm vein (the ante cubital fossa where possible) for contrast injection. 
After completion of the standard sequences, the supervising radiologist will then plan a oblique - 
coronal slice for the dynamic study which will include the target lesion and major artery such as 
the aorta or iliac artery. This will remain the studied lesion throughout the trial. T1- and T2- 
weighted images should be used to select the target lesion and the position for the dynamic image 
set. For consistency the slice should traverse the mid-line of the tumor. Where possible highly 
necrotic tumor lesions should NOT be selected for the DCE-MRI. 
A T1-weighted dynamic contrast enhanced sequence (3D spoiled gradient echo) will then be 
performed. 
Three additional measurement series (5 repetitions each) similar to the DCE sequence will be 
performed with three different low flip angles for normalization of MRI signal data. 
A low molecular weight Gd-chelate MRI contrast agent licensed for i.v. use in humans 0.1 
mmol/kg body weight will be injected, preferably by power injector. Injection will commence 
after 5th (fifth) measurement in order to allow a steady state to develop and to provide baseline 
signal intensities. Power injector rate should be 0.6 ml/sec. Contrast injection is followed by a 20 
ml saline flush, also injected at the same speed. Contrast agent and injection technique should be 
the same at each visit for a given patient. 


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Because the individual measurements are rapid, breath-hold is not required. As the plane of 
imaging is in a coronal /oblique orientation, quiet breathing has to be encouraged. 
From this dynamic imaging sequence, data will be obtained showing an increase in signal intensity 
in the various areas over time. The area of maximum enhancement of the tumor will be used for 
the tumor region of interest (ROI). Regions of interest will also be taken from a major arterial 
vessel such as the aorta. 
The signal intensity versus time data for the tumor, and the major artery (aorta, carotid or iliac 
artery) will be graphed. From these enhancement curves, several parameters will be calculated 
including the AUC under the contrast enhancement curve, peak enhancement, Ki and Ktrans 
(transfer coefficient, a parameter similar to Ki) as well as A [Amplitude] and kep [exchange rate 
constant]. Where necessary for calculation, the low flip angle sequences will be used to normalize 
data. Data will be presented as % of baseline value of a given parameter. 
Studies will be stored in the PACS system, on MR manufacturer-specific storage media as an exact 
copy for trial purposes and will be forward per FTP to the imaging corelab. 
Clinical decision-making will be made on the basis of on-site reading of tumor dimensions from 
the standard MR images. DCE-MRI is done as laboratory correlative study and will not be used to 
assess objective response per RECIST. An independent central analysis of combined multi-site 
DCE-MRI data will be performed, but not used for clinical care. 
 
The Imaging Procedure: 
 
The following information details the imaging procedure. Please note that this does not detail 
information you will need to enter into the Case Report Form. The imaging procedure need to be 
adhered to, but was designed to be comparable with your local procedures. The most unique feature 
of this imaging series is the dynamic imaging sequence used to monitor the contrast agent passage. 
 
Upon registration of the patient for the exam please verify that the patient has signed the informed 
consent form. 
 
Please assign or get a unique trial patient identifier which will be used for identification purposes 
in the anonymized image assessment. 
 
Please make sure that the patient understands the imaging procedure and that her or his cooperation 
is essential for best quality. Please explain that multiple imaging sequences will be acquired and 
that you will be giving instructions and comments via the intercom. 
 
Prior to imaging an i.v. cannula with a long line is inserted into a vein in the arm (the ante cubital 
fossa where possible) for contrast injection. In the undesirable event that a different route of access 
has to be chosen, please document it appropriately. 
 
The imaging procedure consists of the following steps: 
i. 
Localizer series 
ii. 
Pre-contrast T2w 


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iii. 
Pre-contrast T1w 
iv. 
Pre-contrast low flip angle series (same parameters as the dynamic sequence, flip angles 
set to 4°, 8° and 12°) 
v. 
Dynamic Series with injection of the contrast agent 
vi. 
Post-contrast imaging as necessary 
vii. 
Image archiving, clinical plus trial copy 
viii. 
Image anonymization and data transfer to the Imaging Core Lab 
 
The overall imaging time is estimated at 45 minutes per procedure. Standard sequence scanning 
should cover the whole liver including all tumor areas. 
 
For the pre-contrast T1w scan, a T1-weighted Fast Multi-planar Gradient Recalled Echo or 
balanced-field echo (FIESTA, TRUEFISP) breath-hold sequence will be used. 
 
For the T2 weighted image set, a Fast or Turbo Spin Echo breath-hold sequence will be used. Axial 
imaging will be the standard plane with 8 mm slice thickness. Further planes may be implemented 
as appropriate. The same plane and slice thickness must be used for tumor measurements in the 
follow up procedures. 
 
The supervising radiologist will then plan the plane and location of the dynamic study which will 
remain the evaluation (target) lesion throughout the trial for the specific patient. T1 and T2 
weighted images should be used to select the target lesion volume. For consistency, the mid slice 
should traverse the mid-line of the tumor. Where possible highly necrotic tumors or tumor regions 
should not be selected. 
 
A pre-contrast set of multi low flip angle (12, 8 and 4 degrees) 3D SPGR sequences in the selected 
plane and location will be performed to aid normalization of MRI signal data (T1 estimation) 
immediately prior to the dynamic series. 
 
A T1-weighted dynamic contrast enhanced sequence (3D SPGR) is then performed with the 
following scan parameters (see also: Detailed parameter for the dynamic imaging sequence): 
 
14 slices through the representative tumor lesion, 7 mm each with no gap; sequential imaging 
measurements will be repeated approximately every 10 seconds for about 8 minutes (at least 50 
measurements after contrast injection). 
 
A commercially available MR-contrast agent for human use should be used at a dosage of 0.1 
mmol/kg body weight. 
 
The preferable method of contrast agent injection is a power injector. Injection is started after the 
first 5 measurements (data sets) in the continuous dynamic series to allow a steady state to develop 
and provide baseline signal intensities. Power injector rate should be 0.6 ml/sec. Contrast injection 
need to be followed by a 20 ml saline flush injected at the same rate. If hand injection is done, it 
should be performed as a rapid bolus through a long line of tubing which has been filled with the 
MR contrast agent. Contrast agent and injection technique should be the same at each visit for a 
given patient. 


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As the individual measurements are rapid, breath hold is not required. The patient is to be 
instructed to use shallow breathing. As the plane of imaging should be in a coronal /oblique- 
coronal orientation, quiet breathing does not move the volume of interest out of the imaging slab. 
 
From this acquisition series, data will be obtained showing an increase in signal intensity due to 
the contrast agent passage of the various areas over time. The area of maximum enhancement of 
the tumor will be used for the tumor region of interest (ROI). Regions of interest will also be taken 
from a major arterial vessel to assess the vascular enhancement and kinetics. From the 
enhancement curves, several parameters will be calculated. For some quantifications, the T1 
estimation sequence (three low flip angles), will be used to normalize data. 
 
A post-contrast T1w  scan can be acquired similar to the pre-contrast T1-weighted scan. 
 
After completion of the imaging, data storage and data preparation for the off-site, core lab 
assessment needs to be performed. 
 
Images should be: 
A, stored in the same procedure as standard clinical patients at the local site for local patient care 
and assessment 
B, an additional data-backup of the complete imaging set should be done onto CD (preferable) or 
magneto-optical disk. 
C, the complete data set should be anonymized and transferred via secure FTP to the imaging core 
lab as outlined in the data transfer section. 
 
Clinical decision-making will be made on the basis of on-site reading of tumor dimensions from 
the standard MR images. 
 
An independent central analysis of combined multi-site DCE-MRI data will be performed, but 
these evaluations will not be used for clinical decision making. 
 
Relative exclusion Criteria to MRI imaging 
Patients who have: 
1. 
Cardiac pacemaker 
2. 
Ferromagnetic metal implants not authorized for use in MRI such as some types of 
cerebral aneurysm clips 
3. 
Claustrophobia not helped by pre-medications 
4. 
Obesity (exceeding the equipment limits) 
5. 
In case, MRIs are not suitable for evaluating response per RECIST criteria 
 
 
In these patients who have a contraindication to MRI imaging, other radiologic imaging (i.e. CXR 
and CT scans) must be used to assess response as outlined in the clinical trial protocol. 


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Detailed parameter for the dynamic imaging sequence will be tailored to the specific MR system 
used. Below is a generic description for a 1.5T GE MR system: 
 
Parameter for Dynamic Series: 
Type: 
3D spoiled gradient echo 
Repetitions in dynamic series: 
at least 50 
Averages: 
1 
Field of view: 
about 360 mm 
Flip: 
16 deg. 
Slice Thickness: 
7 mm 
Spacing (gap): 
 
0 mm 
TE: 
min 
TR: 
min 
Matrix: 
256 x 160 or better 
Voxel size (approx.) 
2.5 x 2.5 x 7.0 mm3  or better 
 
Parameter for Dynamic Series (specific example GE protocol at OSU): 
Type: 
3D SPGR 
Repetitions in dynamic series: 
50 
Averages: 
1 
Bandwidth: 
244 Hz/pixel equals 62.5 kHz 
Field of view: 
360 mm 
Flip: 
16 deg. 
Slice Thickness: 
7 mm 
Spacing (gap): 
 
0 mm 
TE: 
3.092 msec 
TR: 
10.287 msec 
Matrix: 
256 x 192 
Voxel size (approx.) 
1.4 x 1.9 x 7.0 mm3 
 
For the T1 estimation acquisition prior to the dynamic series, the flip angle has to be set to 12°, 8° 
and 4°, everything else including the imaging volume remains the same. 


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Data Transfer: 
Overview: 
Imaging data will be stored using the local onsite storage procedure (PACS) and on an additional 
copy of manufacturer -specific storage media. Electronic storage of data to a common media such 
as CD or optical disc in DICOM format is the preferred method of secondary storage. 
 
The study data will be transferred to an imaging core lab for off-site analysis. The data transfer 
should be performed preferably via secure FTP to facilitate rapid review of the imaging studies; if 
these direct data transfers can not be achieved, then an express shipment of data in a digital format 
such as CD will be arranged. 
 
The imaging data will be anonymized at the central image analysis laboratory and a secure master 
file will be generated for cross-referencing. The imaging corelab will review the imaging study for 
technical and quality control and provide feedback in case of identifiable problems. The imaging 
corelab will also perform image analysis of the DCE-MRI by placing ROIs and generating signal 
intensity data, which will then be quantified using different quantitative methods as outlined 
above. Volumetric data will be quantified whenever possible to allow comparison between 
dynamic MRI parameters and tumor size changes. The local imaging site will have access via 
secure web-link to the placed ROIs and source signal intensity plots for review and comment of 
its own performed cases. 
 
Details: 
All data will be handled in DICOM format and all data management will adhere to GCP and other 
established guidelines. The following information details the data transfer procedure. Please note 
that this does not detail information you will need to enter into the Case Report Form. 
 
As mentioned in the imaging section, the local site needs to generate safe and secure backups for 
their local needs including patient care and should generate a CD backup (preferable) or Optical 
Disk as a second source of data for this trial. These backup data will be collected per request. 
 
Initiation of data transfer: 
This procedure is being used until all firewall issues within the local institution are resolved. The 
recommended software is WS-FTP and a copy was provided during the initial site visit. Copies 
can be requested form the Imaging Core Lab and copies as well as updates will be placed within 
the software subdirectory of the FTP account. 
Any FTP software can be used to initiate access to the FTP Server of the Imaging Core Lab. 
IP address: 
140.254.8.48 
User / account: 
XXXXX@ftp2.IMRES.med.ohio-state.edu 
Password: 
tobedefined 
The secure SSL account will be access after the secure key has been established. The secure 
access information will not be documented in this manual. 
IP address: 
140.254.8.48 


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User / account: 
Tobesupplied@ftp.IMRES.med.ohio-state.edu 
Password: 
Tobesupplied 
 
Once you have access to be main directory, change to the data directory, create a new directory 
with the anoymized identifier. You can also use the unique DICOM identifier generate by your 
PACS system if you so choose. Then just upload or copy your imaging files. 
 
Once the upload is completed, please send an e-mail to McKenney.-1@medctr.osu.edu to inform 
the imaging core lab, that the study has been completely uploaded from your site, report the patient 
weight and the place of injection site 
 
The imaging core lab will review the received data and will generate a confirmation e-mail that 
the data have been received and appear readable. Once the case is analyzed, a detailed report and 
access information will be send to you local imaging investigator. 
 
 
Equipment and Procedure Checklist: 
 
As this trial will be performed over a longer time period, equipment and procedure changes could 
potentially occur and any changes need to be documented and passed on to the Imaging Core Lab. 
In case of any relevant changes, the Imaging Expert needs to be consulted. 
 
At the time of the first patient inclusion and imaging for this trial study at the local site, the 
Initial Equipment and Procedure Checklist Form needs to be completed. In case of any changes, 
use the Equipment and Procedure Update Checklist Form for documentation. 


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Initial Equipment and Procedure Checklist Form: 
Are you using multiple MRI systems for patient studies? 
If yes, please fill out each form for every MRI system that is being used in this trial 
 
 
 
Please enter your local description of used MRI bay (e.g. Research Scanner 1. Floor) 
 
 
 
 
Please enter you MRI model 
 
 
 
 
Please enter the type of coil used for the procedures of this type 
 
 
 
 
Please enter the software release you use on your above MRI system 
 
 
 
 
Please enter the type and model of the injector you use to perform the contrast injection 
 
 
 
 
Please enter the MR Contrast Agent you intend to use for this study 
 
 
 
 
Are you using any other software (PACS) system prior to data transfer and storage? If yes, 
kindly identify the software, version and manufacturer 
 
 
 
 
You will be archiving the image sets on the following media type 
(CD –ROM   /  Magneto-Optical  / Tape) 
 


NCI Protocol #: NCI-7609 
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Equipment and Procedure Update Checklist Form: 
Are you using multiple MRI systems for patient studies? 
If yes, please fill out each form for every MRI system that is being used in this trial 
64 
 
 
 
Has there been a major change in MR hardware or software? 
If so, please identify and explain: 
 
 
 
 
 
 
 
 
 
Please enter your local description of used MRI bay (e.g. Research Scanner 1. Floor) 
 
 
 
 
Has there been a change in type or model of coil used for the procedures of this trial? 
 
 
 
 
Please enter the software release you use on your above MRI system 
 
 
 
 
Please enter the type and model of the injector you use to perform the contrast injection 
 
 
 
 
Please enter the MR Contrast Agent you currently use for this trial 
 
 
 
 
Are you using any other software (PACS) system prior to data transfer and storage? If yes, 
kindly identify the software, version and manufacturer 
 
 
 
 
You will be changing your archiving of the image sets in the near future? If yes, please explain 
and does it affect the current procedures? 
 
 


65 
 
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DCE-MRI Scan Time schedule: 
Per section 7.3 in the protocol. 
 
MRI Imaging Site Summary Sheet 
• 
Did the patient sign the informed consent form? 
• 
Assign or get unique trial patient identifier for anonymized image handling 
• 
Place an IV cannula (preferable in the antecubital fossa) for contrast injection 
• 
Record the patient weight for contrast dose calculation and the place of injection site 
 
Imaging procedure (Sample of a 1.5T GE system (will be tailored to site specific system): 
1. Localizer 
2. Pre-contrast T2- weighted axial images covering the entire neck and upper thorax 
(according to the standard protocol for thyroid cancer); TR 2450, TE 104.2, Flip 90º, 
thick: 4 mm, 256x256 . 
3. Pre-contrast T1- weighted axial images covering the same volume; TR 400, TE 9.0, Flip 
90º, thick: 4 mm, 256x256 
4. Identify appropriate target lesion and position the target volume in oblique coronal to 
have at least one slice through the carotid artery or aorta 
5. Parameter for Dynamic Series: 
Type: GE, saturation recovery FGRET, PSD Filename: ufgret 
Repetitions in dynamic series: 
100 
Averages: 
1 
Bandwidth: 
244 Hz/pixel equals 62.5 kHz 
Field of view: 
500 mm 
Flip: 
25 deg. 
Slice Thickness: 
8 mm 
Spacing (gap): 
2 mm 
TE: 
3.092 msec 
TR: 
10.287 msec 
Matrix: 
256 x 256 
Voxel size (approx.)   1.8 x 1.8 x 8.0 mm3 
6. Pre-contrast T1w image set (5 repetitions, parameters of the dynamic sequence with the 
saturation pulse turned off. All other dynamic images with pulse turned on) 
7. Dynamic Series with injection of the contrast agent (Contrast injection after the fifth 
measurement. Injected volume: 0.1mmol/kg bw followed by 30 ml saline flush. Injection 
rate is 2.0 ml/sec for contrast and saline injection.) 
8. Post-contrast Imaging as necessary (T1-weighted similar to 3.) 
9. Image archiving, clinical plus trial copy on separate media 
10. Image anonymization and data transfer to the Imaging Core Lab. Send e-mail that study 
was performed to XXXX@imagingcorelab.com and please report any technical issues, 
dosage and patient weight. 
11. In case of questions, please do not hesitate to contact in addition to your local staff: TBA 
or Dr. Michael Knopp, at the Imaging Core Lab at OSU knopp.16@osu.edu and cc 
XXXX@imagingcorelab.com