Conditions: Recurrent Renal Cell Carcinoma Stage III Renal Cell Cancer AJCC v7 Stage IV Renal Cell Cancer AJCC v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
This phase I/II trial is studying the side effects and best dose of sorafenib, gemcitabine, and capecitabine and to see how well they work in treating patients with unresectable and/or metastatic kidney cancer. Sorafenib 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. Drugs used in chemotherapy, such as gemcitabine and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with gemcitabine and capecitabine may kill more tumor cells.

Detailed description:
OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of sorafenib administered in combination with gemictabine and capecitabine in patients with advanced renal cell carcinoma.

II. Determine the objective response rate for sorafenib in combination with gemictabine and capecitabine in patients with advanced renal cell carcinoma.

III. Determine the duration of overall survival and progression free survival in these patients.

OUTLINE: This is a multicenter, non-randomized, phase I dose-escalation study followed by a phase II study.

PHASE I: Patients receive sorafenib\* orally (PO) twice daily (BID) on days 1-21, gemcitabine intravenously (IV) over 30 minutes on days 1 and 8, and capecitabine PO BID on days 1-14. Treatment repeats every 21 days for at least 3 courses in the absence of unacceptable toxicity or disease progression.

Cohorts of 3-6 patients receive escalating doses of sorafenib, gemcitabine, and capecitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD.

Note: \*Patients who complete at least 3 courses of treatment with objective response or stable disease but are deemed poor candidates for continued chemotherapy may continue treatment with sorafenib

PHASE II: Patients receive sorafenib 200mg orally twice a day on days 1-21, gemcitabine 750 mg/m2 intravenously on days 1 \& 8, and capecitabine 415 mg/m2 orally twice a day on days 1-14 of each 21 day cycle, as in phase I at the MTD determined in phase I.

After completion of study treatment patients are followed periodically.

Arms:
arm 1: Patients receive sorafenib\* PO BID on days 1-21, gemcitabine IV over 30 minutes on days 1 and 8, and capecitabine PO BID on days 1-14. Treatment repeats every 21 days for at least 3 courses in the absence of unacceptable toxicity or disease progression.

Interventions: intervention 1: Capecitabine intervention 2: Gemcitabine Hydrochloride intervention 3: Sorafenib Tosylate
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 
NCI Version Date 2/14/12 
NCI Protocol #: NCI 6981 Local Protocol #: 0501007709 
Amendment 1: 4/20/05 Disapproved 
Amendment 2: 5/2/05 Disapproved 
Amendment 3: 5/13/05  
Amendment 4: 6/17/05  
Amendment 5: 12/1/05 Disapproved 
Amendment 6: 1/26/06  
Amendment 7: 3/2/06 Disapproved 
Amendment 8: 3/17/06  
Amendment 9: 7/14/06  
Amendment 10: 8/31/06  
Amendment 11: 11/29/06  
Amendment 12: 3/7/07  
Amendment 13: 3/27/07  
Amendment 14: 4/27/07  
Amendment 15: 5/29/07  
Amendment 16: 8/18/08 Disapproved 
Amendment 17: 8/26/08  
Amendment 18: 1/7/09 NCI Version Date 1/7/09 
Amendment 19: 5/23/11 NCI Version Date 5/23/11 
Amendment 20: 2/14/12 NCI Version Date 2/14/12 
A Phase I/II Trial of BAY 43-9006 plus Gemcitabine and Capecitabine in the Treatment of 
Patients with Advanced Renal Cell Carcinoma   
 
Coordinating Center: 
 
 
Montefiore Medical Center  
*Principal Investigator: 
Scott Tagawa, M.D. 
 
 
Div of Hematology & Medical Oncology 
 
 
New York Presbyterian Hospital/Cornell 
 
 
525 East 68th Street 
 
 
New York, NY 10065 
 
 
Tel  646-962-2072 
 
 
Fax  646-962-1603 
 
 
stt2007@med.cornell.edu 
Co-Investigators: 
 
 
 
 
David M. Nanus, M.D. 
Div of Hematology & Medical Oncology 
New York Presbyterian Hospital/Cornell 
525 East 68th Street 
New York, NY 10065 
Tel 646-962-2072 
Fax 646-962-1603 
 
 
dnanus@med.cornell.edu 
 
 
 
 
 


NCI Version Date 2/14/12 
 
 
 
Himisha Beltran, M.D. 
Div of Hematology & Medical Oncology 
New York Presbyterian Hospital/Cornell 
525 East 68th Street 
New York, NY 10065 
Tel 646-962-2072 
Fax 646-962-1603 
 
 
hip9004@med.cornell.edu 
 
Caryn Ecker, N.P. 
Div of Hematology & Medical Oncology 
New York Presbyterian Hospital/Cornell 
525 East 68th Street 
New York, NY 10065 
 
 
Tel  646-962-2072 
 
 
Fax  646-962-1603 
cae9012@med.cornell.edu 
 
Daniel Petrylak, M.D. 
Division of Medical Oncology 
New York Presbyterian Hospital/Columbia 
161 Fort Washington Avenue 
New York, NY 10032 
Tel 212 305 1731 
Fax 212 305 6762 
dpp5@columbia.edu 
 
Thomas Bradley, M.D. 
North Shore University Hospital 
Don Monti Division of Medical Oncology 
300 Community Drive 
Manhasset, NY 11030 
Tel 561 562 8937 
Fax 516 562 8924 
tbradley@nshs.edu 
 
Vincent Vinciguerra, M.D. 
North Shore University Hospital 
Don Monti Division of Medical Oncology 
300 Community Drive 
Manhasset, N 11030 
Tel 516 562 8954 
Fax 516 562 8950 
vincentv@nshs.edu 
 
Anna Ferrari, M.D. 


NCI Version Date 2/14/12 
New York University Medical Center 
160 East 34th Street 
New York, NY 10016 
Tel 212 731 5437  
Fax 212 652 1901 
anna.ferrari@med.nyu.edu 
 
Joseph Sparano, M.D. 
Montefiore Medical Center 
Department of Oncology 
1825 Eastchester Road 
Bronx, NY 10461 
Tel 718 904 2555 
Fax 718 904 2892 
jsparano@montefiore.org 
 
Sanjay Goel, M.D. 
Montefiore Medical Center 
Department of Oncology 
1825 Eastchester Road 
Bronx, NY 10461 
Tel 718 904 2515 
Fax 718 904 2892 
sgoel@montefiore.org 
 
Cy Stein, M.D. 
Montefiore Medical Center 
Department of Oncology 
111 East 210th Street 
Bronx, NY 10467 
Tel 718 920 8980 
Fax 718 920 7474 
cstein@montefiore.org 
 
Lakshmi Rajdev, M.D. 
Montefiore Medical Center 
Department of Oncology 
1825 Eastchester Road 
Bronx, NY 10461 
Tel 718 904 2558 
Fax 718 904 2892 
irajdev@montefiore.org 
 
Max Sung, M.D. 
Mount Sinai Medical Center 
One Gustave Levy Place 
New York, NY 10029 


NCI Version Date 2/14/12 
Tel 212 241 7902 
Fax 212 241 5425 
max.sung@mssm.edu 
 
 
 
Collaborating Radiologist 
Krishna Juluru, MD 
 
 
 Department of Radiology 
 
 
Weill Medical College of Cornell University 
 
 
525 East 68th Street, F-056 
 
 
New York, NY 10021 
 
 
Tel 212 746-7897 
 
 
kjuluru@med.cornell.edu 
 
 
Statistician: 
 
Madhu Mazumdar, Ph.D. 
Weill Medical College  
Division of Biostatistics and Epidemiology  
411 East 69th Street, Room KB-324A  
New York, NY 10021  
Tel 212 746-1460  
Fax 212 746-8544  
Mam2073@med.cornell.edu  
 
Responsible Research 
Nurse: 
 
Gina Mileo, RN 
Div of Hematology & Medical Oncology,  
New York Presbyterian Hospital 
523 East 70th Street 
Annex Building, Room 811 
New York, NY 10021 
Tel 212 746 5430 
Fax 212 746 8698  
gjm2003@med.cornell.edu 
 
Responsible Data 
Manager: 
 
Ankeeta Saran, BS 
Div of Hematology & Medical Oncology, Starr 341 
New York Presbyterian Hospital 
525 East 68th Street 
New York, NY 10021 
Tel 212 746 2608 
Fax 212 746 7954 
ans2056@med.cornell.edu 
 
NCI Supplied Agent: 
BAY 43-9006 (NSC 724772) 
 
 
 


NCI Version Date 2/14/12 
Commercially Supplied Agent: Gemcitabine 
 
 
Capecitabine 
 
Protocol Version Date: 
5/23/11 
   


NCI Version Date 5/23/11 
 
i
SCHEMA 
 
 
 
DAY 
Week 1 
 
1     2     3     4     5     6     7 
Week 2 
 
8     9     10     11     12     13     14 
Week 3 
 
15     16     17     18     19     20     21 
Gemcitabine 
X 
X 
 
Capecitabine 
X    X    X    X    X    X    X 
X    X     X      X      X      X      X 
 
BAY 43-9006 
X    X    X    X    X    X    X 
X    X     X      X      X      X      X 
X       X      X      X       X      X      X 
1 Cycle = 21 days 
Gemcitabine:  
750 (mg/m2) IV over 30 minutes on days 1 and 8. 
 
Capecitabine:  
415 (mg/m2) p.o. twice daily on days 1-14. 
 
BAY 43-9006:  
200 mg p.o. twice daily will be administered from day 1 until day 21.  
 
 
Treatment will be continued until disease progression or unacceptable toxicity.  Patients should receive a minimum 
of three cycles of therapy.  Patients may discontinue therapy if a complete response is achieved. 
 
 


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ii
TABLE OF CONTENTS 
Page 
 
SCHEMA ........................................................................................................................................ i 
 
1. OBJECTIVES ..........................................................................................................................2 
 
2. BACKGROUND ......................................................................................................................2 
2.1 
Renal Cell Carcinoma ..................................................................................................2 
2.2 
BAY 43-9006 .................................................................................................................2 
2.3 
Gemcitabine and Capecitabine ...................................................................................6 
2.4 
Rationale .......................................................................................................................7 
 
3. PATIENT SELECTION .........................................................................................................7 
3.1 
Eligibility Criteria  .......................................................................................................7 
3.2 
Exclusion Criteria ........................................................................................................9 
3.3 
Inclusion of Women and Minorities .........................................................................10 
 
4. PHASE I TREATMENT PLAN ...........................................................................................10 
4.1  
BAY 43-9006, Gemcitabine and Capecitabine Administration .............................10 
 
4.1.1 BAY 43-9006 ...................................................................................................11 
 
4.1.2 Gemcitabine .....................................................................................................12 
 
4.1.3 Capecitabine .....................................................................................................12 
4.2  
Supportive Care Guidelines ......................................................................................12 
 
 
4.2.1    General Guidelines ...........................................................................................12 
 
 
4.2.2    Palliative Radiation Therapy ............................................................................12 
 
 
4.2.3    Growth Factors .................................................................................................12 
 
 
4.2.4    Supportive Management of Hand/Foot Syndrome ...........................................13 
4.3  
Duration of Therapy ..................................................................................................13 
 
5. PHASE I DOSE LIMITING TOXICITY CRITERIA .......................................................14 
 
5.1  
Definition of Dose Limiting Toxicity ........................................................................14 
 
6. PHASE II TRIAL ..................................................................................................................14 
 
6.1  
General Guidelines .....................................................................................................15 
 
6.2  
Dose Modification Guidelines ...................................................................................15 
 
6.3  
Treatment-emergent Hypertension ..........................................................................16 
 
6.4  
Neutropenia/Thrombocytopenia ...............................................................................17 
 
6.4.1 Grade 3 Neutropenia/Thrombocytopenia .........................................................17 
 
6.4.2 Grade 4 Neutropenia/Thrombocytopenia .........................................................18 
 
6.4.3 Blood Counts on Day 1 of Cycle .....................................................................18 
 
6.5  
Hepatic Dysfunction ...................................................................................................18 
 
6.6  
Gastrointestinal Toxicities .........................................................................................19 
 
 
 
6.6.1 Grade 2 mucositis and diarrhea ........................................................................19 
 
 
 
6.6.2 Grade 3 mucositis and diarrhea ........................................................................19 
 
 
 
6.6.3 Grade 4 mucositis and diarrhea ........................................................................19 


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iii
 
6.7  
Skin Toxicity ...............................................................................................................20  
 
 
 
6.7.1 Grade 2 dermatitis or hand/foot syndrome.......................................................20 
 
 
 
6.7.2 Grade 3 dermatitis or hand/foot syndrome.......................................................20 
 
 
 
6.7.3 Grade 4 dermatitis ............................................................................................20  
 
6.8  
Pulmonary Toxicity ....................................................................................................21  
 
6.9  
Unspecified Grade 3 or 4 Toxicities ..........................................................................21 
 
6.10 
Dose Modification for Obese Patients ......................................................................21 
 
7. PHARMACEUTICAL INFORMATION ............................................................................21 
7.1  
BAY 43-9006 ...............................................................................................................21 
7.2  
Gemcitabine ................................................................................................................27 
7.3  
Capecitabine ...............................................................................................................29 
8. CORRELATIVE/SPECIAL STUDIES ...............................................................................31 
 
9. STUDY CALENDAR ............................................................................................................32 
 
10. MEASUREMENT OF EFFECT ..........................................................................................33 
10.1 
Definitions ...................................................................................................................33 
10.2 
Guidelines for Evaluation of Measurable Disease ..................................................34 
10.3 
Response Criteria .......................................................................................................35 
10.4 
Confirmatory Measurement/Duration of Response ...............................................37 
10.5 
Progression-Free Survival .........................................................................................38 
10.6 
Response Review ........................................................................................................38 
 
11. REGULATORY AND REPORTING REQUIREMENTS ................................................38 
11.1 
Expedited Adverse Event Reporting ........................................................................39   
11.1.1  Expedited Reporting Guidelines ......................................................................39 
 
 
11.1.2  Expedited Adverse Events Reporting Exclusions ............................................41 
 
11.1.3 Secondary AML/MDS .....................................................................................41 
11.2 
Data Reporting ...........................................................................................................41 
11.3 
CTEP Multicenter Guidelines ...................................................................................41 
11.4 
Cooperative Research and Development Agreement (CRADA)/ 
Clinical Trials Agreement (CTA) .............................................................................43 
 
12. STATISTICAL CONSIDERATIONS .................................................................................45 
 
13. REFERENCES .......................................................................................................................47 
APPENDIX A 
Performance Status Criteria .................................................................................................. A-1 
 
APPENDIX B 
Patient Medication Diary ...................................................................................................... A-2 
 
APPENDIX C 
Patient Medication Diary for subjects who remain on single-agent sorafenib .....................  A-3 


 
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4
1. OBJECTIVES 
 
 
1.1. 
To determine the Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity 
(DLT) of BAY 43-9006 administered in combination with gemictabine and 
capecitabine in patients with advanced renal cell carcinoma. 
 
1.2. 
To determine the objective response rate for BAY 43-9006 in combination with 
gemcitabine and capecitabine in patients with advanced renal cell carcinoma.  
 
1.3. 
To determine the duration of overall survival and progression free survival in these 
patients. 
 
2. BACKGROUND 
 
2.1  
Renal Cell Carcinoma 
 
 Renal Cell Carcinoma (RCC) accounts for approximately 3% of all malignant adult tumors, 
with an estimated 35,710 new cases and 12,480 RCC related deaths in the year 2004(1). 
Immunotherapy with interferon alpha or interleukin-2 has become the mainstay of treatment 
with low, but reproducible response rates in the 10% to 15% range and complete responses 
with long term survival in 5% or fewer patients(2).  The only therapy that has been 
demonstrated to improve survival is interferon alpha for which the median survival is 
approximately 2-3 months(3;4).  Novel agents are clearly needed in the treatment of patients 
with metastatic RCC.   
 
2.2  
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(5;6).  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(7-12).  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 (7;8). 
 


 
NCI Version Date 5/23/11 
5
In Vitro Activity 
 
The ability of BAY 43-9006 to inhibit a number of kinases was evaluated (Investigator’s 
Brochure, 2003).  The in vitro biochemical and cellular profile of 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 
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 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, 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.  BAY 43-9006 demonstrated an IC50 of 780 nM against p59 (bovine) Fyn kinase (Src 
family of protein tyrosine kinases).  In non-kinase targets 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.  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, BAY 43-9006 showed 


 
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6
≥100-fold more selectivity for raf kinase relative to other target proteins. 
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, 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). 
 
VEGF and PDGF receptors are involved in the mechanism of tumor angiogenesis (13;14).  
PDGF receptors may also play a role in patients with chronic myeloproliferative cancers (15). 
Flt-3 is important in acute myelogenous leukemia (16) and c-Kit plays a critical role in 
gastrointestinal stromal tumors (17). 
 
In Vivo Activity 
 
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. 
 
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 


 
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1  Compound dosed as 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, BAY 43-9006 was able to arrest tumor growth even if therapy was initiated against a 
substantially greater tumor burden. 
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 BAY 43-9006 was also evaluated 
against the human SKOV-3 ovarian tumor cell line that contains a wild-type Ras 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 (18). 
 
Taken together, data suggests that 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 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 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 BAY 43-9006 and 
Clinically Established Agents 
 
Combination 
Agent 
Tumor Model 
Combinability 
Y/N 
Paclitaxel 
NCI-H460 NSCLC 
MX-1 Mammary 
Yes 
Yes 
Irinotecan 
DLD-1 Colon 
             Yes 
Gemcitabine 
MiaPaCa-2 Pancreatic 
Yes 
Cisplatin 
NCI-H23 NSCLC 
Yes 


 
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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. 
 
Clinical Experience 
 
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 BAY 43-9006. 
The Phase 1 single agent clinical plan has focused on characterizing the safety and 
pharmacokinetic profile 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 have 
received doses ranging from 50 mg once weekly to 1600 mg daily of BAY 43-9006 on 
intermittent and continuous schedules.  The 800 mg bid continuous administration cohort has 
exceeded 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.   
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 reveal 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. 
 
2.3  
Gemcitabine and Capecitabine 
 
Historically, chemotherapy has been ineffective in the treatment of RCC(19), however, recent 
trials using gemcitabine in combination with 5-fluorouracil (5-FU) or capecitabine have 
demonstrated response rates as high as 21%(20;21;27).  The Cancer and Leukemia Group B 
recently completed a phase II study (#90008) of gemcitabine and capecitabine in patients with 
metastatic RCC(27).  Patients were treated with gemcitabine at 1000 mg/m2 day 1, 8, 15 and 


 
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capecitabine at 830 mg/m2 twice daily, days 1-21 on a 28 day cycle.  Partial responses were 
observed in 8 out of 55 patients for a response rate of 15% with a median duration of 
response and time to progression of 7.1 and 5.1 months, respectively.  Grade 3,4 toxicities 
included neutropenia (40%) with febrile neutropenia in 1 patient, anemia (15%), 
thrombocytopenia (6%), nausea (11%), fatigue (7%), diarrhea (7%), and hand/foot syndrome 
and stomatitis (2% each).  Grade 1, 2 toxicities included leukopenia (49%), fatigue (62%), 
nausea (42%), stomatitis (29%), diarrhea (27%), and hand/foot syndrome (36%).  The 
investigators concluded that the combination of gemcitabine and capecitabine has modest 
activity in metastatic RCC, however, further evaluation of the regimen would require a dose 
modification.  An evaluation of prognostic factors for survival with gemcitabine plus 5-FU 
based regimens concluded that although there is not a specific group of patients who are most 
likely to benefit from this combination, there is a continued suggestion that this regimen 
provides a modest improvement over past chemotherapy approaches(22).   
 
2.4  
Rationale 
 
Both gemcitabine and capecitabine have separately been evaluated in combination with BAY 
43-9006.  A phase I/II trial of BAY 43-9006 and gemcitabine in patients with advanced solid 
tumors and in advanced pancreatic cancer revealed a lack of pharmacokinetic interaction 
between the two and non-overlapping clinical toxicities(23).  A single-center phase I study of 
BAY 43-9006 in combination with capecitabine (Bayer Pharmaceuticals).  BAY 43-9006 was 
administered orally (bid) from day 8 until day 21 in cycle 1, and continuously thereafter in 
doses of: 200 mg bid (Cohort 1), 400 mg bid (Cohort 2), and (for Cohort 3 only) 200 mg bid 
for the first two cycles, then 400 mg bid for each subsequent cycle.  Capecitabine was given 
orally bid (2100 mg/m2 per day) from day 1 in a 2 weeks on/1 week off schedule.  The most 
frequent drug-related toxicities were hand/foot syndrome, diarrhea, fatigue, mucositis, and 
nausea.  Dose-limiting toxicities included grade 3 hand/foot syndrome and grade 3 diarrhea in 
Cohort 1, and grade 3 hand/foot syndrome and grade 3 mucositis in Cohort 2.  Treatment is 
ongoing in Cohort 3.  An additional cohort has been added to evaluate BAY 43-9006 400 mg 
bid and capecitabine 1700 mg/m2 per day.  Preliminary pharmacokinetic analysis of BAY 43-
9006 reveals no clinically significant interaction with capecitabine. 
 
Based on the activity of gemcitabine and capecitabine and single agent BAY 43-9006 in 
metastatic RCC, it is important to investigate this three drug combination.   
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria 
 
3.1.1 Patients must have histologically or cytologically confirmed renal cell 
carcinoma that is unresectable and/or metastatic.  Patients with collecting duct 
carcinoma, oncocytomas, or transitional cell carcinoma are not eligible.  
Patients with sarcomatoid renal cell carcinoma are eligible, but those with 
pure sarcomas are not.  Histologic documentation of metastatic disease is not 
required.  Clinical confirmation, but not pathologic staging, of metastatic 
disease is required.  


 
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3.1.2 Patients must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm with conventional techniques or as >10 mm with spiral 
CT scan.  See section 9.2 for the evaluation of measurable disease.  
 
3.1.3 Patients may have received one prior immunotherapy based regimen (i.e. 
interleukin-2 or interferon alpha) ending ≥ 4 weeks prior to enrollment.   
 
3.1.4 Patients may have received up to 2 prior regimens containing MAPK, VEGF 
pathway inhibitors (e.g. sunitinib or bevacizumab) and/or mTOR inhibitor 
(e.g. temsirolimus) ending > 4 weeks prior to enrollment. 
 
3.1.5 Age >18 years.  Because no dosing or adverse event data are currently 
available on the use of BAY 43-9006 in combination with gemcitabine and 
capecitabine in patients < 18 years of age, children are excluded from this 
study but will be eligible for future pediatric phase 2 combination trials. 
 
3.1.6 Life expectancy of greater than 3 months (assessed using MSKCC Criteria, J 
Clin Oncol 20:289-96, 2002). 
 
3.1.7 ECOG performance status <2 (Karnofsky >60%; see Appendix A). 
 
3.1.8 Patients must have normal organ and marrow function as defined below: 
 
- 
leukocytes  
 
 
 
 
>3,000/L 
- 
absolute neutrophil count  
>1,500/L 
- 
platelets 
 
 
 
 
 
>100,000/L 
- 
total bilirubin  
 
 
 
<1.5 X institutional upper limit of normal 
- 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
- 
creatinine  
 
 
 
 
<1.5 X institutional upper limit of normal 
OR 
- 
creatinine clearance 
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
 
 
3.1.9 
The effects of BAY 43-9006 on the developing human fetus at the 
recommended therapeutic dose are unknown.  For this reason and because raf 
kinase inhibitor agents as well as other therapeutic agents used in this trial 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 and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her treating physician 
immediately. 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent 
document. 


 
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3.2  
Exclusion Criteria 
 
3.2.1 Patients may not have received prior chemotherapy.  If patients have had prior 
definitive or other surgery, prior radiation therapy, they must have fully 
recovered from the effects of therapy with at least 4 weeks recovery time.  For 
patients who have had a surgical biopsy only, they must have simply 
recovered. 
 
3.2.2 Patients may not be receiving any other investigational agents. 
 
3.2.3 Patients with known active brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events. Previously treated brain metastases are 
allowed if they show no evidence of progression on CT or MRI at least 8 
weeks after completion of surgery and/or radiotherapy 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to BAY 43-9006, gemcitabine and capecitabine. 
 
3.2.5 No concurrent megestrol is permitted.  No megestrol therapy within 4 weeks 
prior to protocol treatment is allowed.  No concurrent cytochrome P450 
enzyme-inducing antiepileptic drugs (phenytoin, phenobarbitol or 
carbamazepine), rifampin, or St. John’s wort. 
 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, uncontrolled 
hypertension, ongoing or active infection, symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, pulmonary disease 
including asthma, chronic bronchitis, emphysema with requirements for 
chronic oxygen use or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.2.7 Pregnant women are excluded from this study because BAY 43-9006 is a 
kinase inhibitor agent with the potential for teratogenic or abortifacient effects. 
Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with BAY 43-9006, breastfeeding 
should be discontinued if the mother is treated with  BAY 43-9006.  The 
potential risks may apply to other agents used in this study. 
 
3.2.8 Because patients with immune deficiency are at increased risk of lethal 
infections when treated with marrow-suppressive therapy, HIV-positive 
patients receiving combination anti-retroviral therapy are excluded from the 
study because of possible pharmacokinetic interactions with BAY 43-9006, 


 
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gemcitabine, or capecitabine administered during the study.  Appropriate 
studies will be undertaken in patients receiving combination ant-retroviral 
therapy when indicated. 
 
3.2.9 Any swallowing dysfunction leading to difficulty taking the investigational 
therapy or capecitabine. 
 
3.2.10 Prior treatment with BAY 43-9006 (sorafenib). 
 
3.2.11 Patients with any history or evidence of a bleeding diathesis. 
 
3.2.12 Patients on therapeutic anticoagulation with coumarins (e.g. warfarin).  
Prophylactic coumarin-based anticoagulation (i.e. low dose warfarin) for 
venous or arterial access devices is allowed provided that the requirements for 
PT, INR and/or PTT are met. Prophylactic or therapeutic low molecular 
weight heparin is allowed. Patients with known brain metastases are excluded 
(even if treated and stable) if they are also on therapeutic doses of 
anticoagulation. 
 
3.2.13 Patients with known dihydropyrimidine dehydrogenase deficiency.  
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  
 
4. PHASE I TREATMENT PLAN 
 
4.1  
BAY 43-9006, Gemcitabine and Capecitabine Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks for BAY 43-9006, gemcitabine and capecitabine are described in 
Section 7.  Appropriate dose modifications for BAY 43-9006, gemcitabine and 
capecitabine are described in Section 6.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to 
treat the patient’s malignancy. 
 
The phase I dose escalation study will be conducted according to the dosing regimen 
described in the table below.   
 
Cohort 
BAY 43-9006 
Gemcitabine 
Capecitabine 
A 
200 mg p.o. bid x 21d 
750 mg/m2 IV d1 & 8 
415 mg/m2 p.o. bid x 14d 
B 
400 mg p.o. bid x 21d 
750 mg/m2 IV d1 & 8 
415 mg/m2 p.o. bid x 14d 
C 
400 mg p.o. bid x 21d 
1000 mg/m2 IV d1 & 8 
415 mg/m2 p.o. bid x 14d 
D 
400 mg p.o. bid x 21d 
1000 mg/m2 IV d1 & 8 
622 mg/m2 p.o. bid x 14d 
 


 
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Initially, 3 subjects will be enrolled into the cohort A.  Enrollment for the next dose 
level may begin when 3 of the subjects in cohort A or previous cohort, have 
completed day 21 of cycle 2 without experiencing a dose limiting toxicity (DLT) as 
defined in Section 5.  A cycle is defined as a 21-day period starting with the 
administration of BAY 43-9006, gemcitabine and capecitabine on day 1.   
 
If a DLT is observed in 1 of 3 subjects, then a total of 6 subjects will complete 2 
cycles prior to opening the next cohort.  If < 2 of the 6 subjects experience a DLT, 
dose escalation can continue.  However, if ≥ 2 of 6 subjects experience a DLT, then 
the maximum tolerated dose (MTD) has been exceeded.  The MTD is generally one 
dose below that at which DLT occurs in > 2 of 6 subjects in any given cohort.  Once 
the MTD is determined, 6 additional subjects will be enrolled at that dose level.  If the 
MTD is not determined after completion of cohort D, 6 additional subjects will be 
enrolled at a dose level thought by the Investigator to be the recommended dose for 
the Phase 2 part of the trial.  Cohorts will consist of a minimum of 3 subjects and a 
maximum of 6 subjects excluding the MTD or similar cohort.   
 
Patients should receive a minimum of three 21-day cycles of treatment.  Responding 
patients or those with stable disease may continue to receive treatment until disease 
progression.  
 
Patients with an objective response or stable disease, who at the discretion of the 
Principal Investigator, are unable to continue chemotherapy or patients meeting dose 
modification criteria for stopping chemotherapy as defined in Section 6 may receive 
BAY 43-9006 alone until disease progression. 
 
After establishing the MTD of BAY 43-9006 in combination with gemcitabine and 
capecitabine in the phase I trial, an additional 12 to 35 patients will be treated at the 
MTD regimen.  
 
4.1.1 BAY 43-9006 
 
 BAY 43-9006 is supplied as 200-mg tablets and is administered orally. 
Patients are to swallow the tablets whole with approximately 250 ml (8 oz.) of 
water, each morning and evening (i.e., 12-hourly). BAY 43-9006 is to be 
taken on an empty stomach (at least 1 hour before or 2 hours after a meal.  
 
BAY 43-9006 will be administered from day 1 until day 21. 
 
Patients receiving BAY43-9006 should have their blood pressure measured 
weekly during the first cycle of therapy.  Patients can have the blood pressure 
measurements in their doctor’s office, a clinic or using a calibrated machine 
such as can be found at a supermarket or shopping mall.  Patients should 
record their blood pressure measurements and if they are in the normal range,  
bring the measurements to the clinic at the time of routine follow-up.  If blood 
pressure readings are abnormal (e.g. >150/100) then patients should contact 


 
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their doctor promptly. 
 
 
 
4.1.2 Gemcitabine  
 
Gemcitabine will be administered intravenously over 30 minutes on days 1 
and 8. 
 
 
 
4.1.3 Capecitabine 
 
The capecitabine dose is given orally in two divided doses (approximately 12 
hours apart) at the end of a meal.  The tablets should be swallowed with water. 
Patients who take aluminum hydroxide- or magnesium hydroxide- containing 
antacids should be instructed not to take them within one hour of capecitabine 
administration.  Capecitabine will be administered p.o. bid from days 1-14 of 
each cycle, followed by a 7 day rest period. 
 
Patients will maintain a medication log to monitor compliance with BAY 43-9006 
and capecitabine.  The medication diary should be signed and dated by the patient 
and/or person who completes the diary so that it may serve as source documentation 
of treatment administration.  A copy of the medication diary is included as Appendix 
B. 
 
4.2  
Supportive Care Guidelines 
 
 
 
4.2.1 General Guidelines 
 
Institutional guidelines and the discretion of the treating physician should be 
used for decisions regarding transfusions of blood and blood products, 
erythropoietin (EPO), antibiotics, and antiemetics.   
 
Chemotherapy induced diarrhea should be managed as per ASCO guidelines. 
 
4.2.2 Palliative Radiation Therapy 
 
Palliative radiation therapy may not be administered while patient is on the 
protocol.  The need for palliative radiation indicates progressive disease and 
the patient should be removed from the protocol treatment.  Irradiate any 
lesion that may produce disability (e.g., unstable femur) prior to study 
initiation. 
 
4.2.3 Growth Factors 
 
Filgrastim (G-CSF) and sargramostim (GM-CSF) may NOT be used: 
 


 
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a. to avoid dose reductions, delays or to allow for dose escalations specified 
in the protocol. 
 
b. prophylactically because of concern about myelosuppression from prior 
therapies. 
For the treatment of febrile neutropenia the use of CSF’s should not be 
routinely instituted as an adjunct to appropriate antibiotic therapy.  However, 
the use of CSF’s may be indicated in patients who have prognostic factors that 
are predictive of clinical deterioration such as pneumonia, hypotension, multi-
organ dysfunction (sepsis syndrome) or fungal infection, as per the ASCO 
guidelines.  Investigators should therefore use their own discretion in using the 
CSF’s in this setting.  The use of CSF (filgrastim and sargramostim) must be 
documented and reported on flow sheets. 
 
 4.2.4 Supportive Management of Hand/Foot Syndrome 
 
Patients who develop hand/foot syndrome may receive topical emollients 
(such as Aquaphor) as well as topical steroids or antihistamine agents if 
appropriate.  Vitamin B6 (pyridoxine 50-150 mg orally daily) may also be 
used. 
 
4.3  
Duration of Therapy 
 
Patients should receive a minimum of 3 cycles of therapy.  Patients may discontinue 
protocol therapy if a complete response is achieved.   
 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 
 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse events(s), 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 
 
Subjects who complete at least 3 cycles of treatment with objective response or stable 
disease who are deemed poor candidates for continued chemotherapy may continue 
therapy with BAY 43-9006 at their current dose.  The dose of BAY 43-9006 may be 
escalated at the discretion of the investigator after 3 weeks at the current dose up to a 
maximum of 400 mg BID.  Subjects who continue on BAY 43-9006 alone will 
continue with weekly follow up until resolution of toxicities attributable to 
chemotherapy (gemcitabine and capecitabine) to < Gr 1.  Following resolution of 
chemotherapy-atributable toxicities to < Gr 1, investigators may elect to lengthen the 
interval between study visits to a maximum of 4 weeks provided that study drug-
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should continue, but for those subjects on single-agent sorafenib with disease control 
past 12 cycles and non-hematologic toxicities stable at Gr <1, study procedures may 
be performed every 4 weeks.  Radiographic evaluation should continue every 3 cycles 
(i.e. for those stable on 4-week cycles, scan should be performed every 12 weeks). 
 
 
 
 
 
 
All patients who receive at least one cycle of treatment will be followed until disease 
progression, or for a maximum of 6 months following termination of treatment. 
 
 
 
Following progression of disease, all subjects will be followed until death.  Mortality 
follow up should be performed at least annually, and may be obtained by contacting 
the subject and/or the referring physician or via medical record review. 
 
5. PHASE I DOSE LIMITING TOXICITY CRITERIA 
 
The current version (3.0) of the NCI Common Terminology Criteria for Adverse Events 
will be used to grade toxicity (http://ctep.info.nih.gov/). 
 
5.1  
Definition of Dose Limiting Toxicity 
 
A dose limiting toxicity is defined as one of the following occurring during the first two 
cycles of therapy: 
 
1. Treatment Emergent Hypertension as follows: 
a. Any Grade 2 symptomatic/persistant (requiring a treatment delay for > 2 
weeks)  
b. Diastolic BP  110 mm Hg  
c. Any Grade 3 or 4 
2. Any Grade 3 or 4 dermatitis or hand/foot syndrome. 
3. Any Grade 3 neutropenia or thrombocytopenia. 
4. Any Grade 4 neutropenia or thrombocytopenia consisting of: 
a. Febrile neutropenia (defined as temperature ≥ 38.5°C [101°F] sustained 
for more than one hour concomitant with an ANC < 500/mm3) 
b. granulocytes < 500/µl 
c. platelets < 10,000/µl 
5. Any non-hematologic Grade 3 or 4 toxicity “possibly” or “probably related” to 
one of, or the combination of the study drugs being evaluated. 
 
 
 
At the discretion of the Principal Investigator, patients experiencing DLT may  
continue to receive treatment using the Phase II dose modifications as defined in 
Section 6. 
 
6.  PHASE II TRIAL 
 
After establishing the MTD of BAY 43-9006 in combination with gemcitabine and 
capecitabine in the phase I trial, an additional 12 to 35 patients will be treated at the MTD 


 
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regimen.    
 
 
 
 
 
The MTD has been determined in the phase I portion of the trial: 
 
BAY 43-9006 200 mg p.o. BID D1-D21 
Gemcitabine 750 mg/m2 IV D1, D8 
Capecitabine 415 mg/m2 p.o. BID D1-D14 
 
General guidelines and dose modifications for the combination are outlined below: 
 
 
6.1 
General Guidelines 
                   
                  Depending on the type of toxicity, a cycle interrupted may either not be completed or 
may continue with dose/treatment modification as defined throughout Section 6 
below. A new cycle may begin as soon as all laboratory eligibility criteria are met (see 
Section 3.1.7) and all other toxicity has resolved to baseline or at least grade 1, as 
long as at least one and not more than three weeks have elapsed since therapy was 
interrupted i.e. a delay of > 3 weeks in the re-initiation of therapy will result in the 
removal of the patient from the protocol treatment. 
 
Doses will not be re-escalated. 
 
6.2  
Dose Modification Guidelines  
 
Dose modification for BAY 43-9006, gemcitabine and capecitabine will occur as 
illustrated in the tables below. Due to differences in the toxicity profiles of the 
individual agents, dose modification may occur for one drug only (section 6.4). 
 
BAY 43-9006 dose modifications will take place according to the table below: 
 
Dose Level 
BAY 43-9006 
0 
200 mg BID 
-1 
50% reduction (200 mg 
daily) 
-2 
STOP BAY 43-9006 
 
Gemcitabine dose modifications will take place according to the table below: 
 
Dose Level 
Gemcitabine 
0 
750 mg/m2 
-1 
25% reduction (563 
mg/m2) 


 
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-2 
50% reduction (375 
mg/m2) 
-3 
STOP GEMCITABINE 
 
 
 
Capecitabine dose modifications will take place according to the table below: 
 
Dose Level 
Capecitabine 
0 
415 mg/m2  
-1 
25% dose reduction 
-2 
STOP CAPECITABINE  
Capecitabine is available in two tablet sizes, 500 mg (peach colored) and 150 
mg (light peach colored).  The following tables display the total daily dose by 
body surface area and the number of tablets to be taken at each dose. 
 
Capecitabine Dose Calculation According to Body Surface Area 
                         
                              Capecitabine Dose Level 0-1 
 
415 mg/m2 bid 
Number of tablets to be taken at each dose 
(morning and evening) 
Surface area (m2) 
Total Daily Dose (mg) 
150 mg 
500 mg 
≤ 1.29 
1000 
0 
1 
1.30-1.47 
1000 
0 
1 
1.48-1.68 
1300 
1 
1 
1.69-1.89 
1600 
2 
1 
1.90-2.07 
1600 
2 
1 
2.08-2.28 
1900 
3 
1 
≥ 2.29 
2000 
0 
2 
 
                              Capecitabine Dose Level 1-2 
 
311 mg/m2 bid 
Number of tablets to be taken at each dose 
(morning and evening) 
Surface area (m2) 
Total Daily Dose (mg) 
150 mg 
500 mg 
≤ 1.29 
900 
3 
0 
1.30-1.47 
900 
3 
0 
1.48-1.68 
1000 
0 
1 
1.69-1.89 
1000 
0 
1 
1.90-2.07 
1200 
4 
0 
2.08-2.28 
1300 
1 
1 
≥ 2.29 
1600 
2 
1 
 
6.3  
Treatment-emergent Hypertension 


 
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With initiation of therapy, monitor BP at least weekly until stable on therapy for at 
least the first 4 weeks. 
 
Dose modification for BAY 43-9006 will occur for treatment-emergent hypertension 
as outlined in the table below:  
                   Management of Treatment-emergent Hypertension 
 
 
Current CTCAE definitions used by CTEP: 
Grade 1:  asymptomatic, transient (< 24 hours) increase by > 20 mmHg (diastolic) or to 
                  
    >150/100 if previously WNL; intervention not indicated 
Grade 2:  recurrent or persistent (> 24 hours) or symptomatic increase by > 20 mmHg        
 
     
    (diastolic) or to > 150/100 if previously WNL; monotherapy may be indicated 
Grade 3:  requiring more than one drug or more intensive therapy than previously 
Grade 4:  life threatening (e.g. hypertensive crisis) 
 
6.4  
Neutropenia/Thrombocytopenia 
 
6.4.1 Grade 3 Neutropenia/Thrombocytopenia 
 
 
 
 
 
If grade 3 neutropenia or thrombocytopenia develops in any cycle, all therapy 
should be held with the exception of BAY 43-9006, which may be continued 
at 200 mg p.o. b.i.d or at current dose.  
 
 
 
 
 
Therapy should be reinitiated as a new cycle according to the guidelines 
outlined in Section 6.1. Capecitabine should be decreased by 1 dose level, but 
gemcitabine can be resumed at the previous dose. If capecitabine has already 
been discontinued and a patient experiences grade 3 or 4 neutropenia or 
thrombocytopenia on Day 8 of any given cycle, gemcitabine should be 
Grade of 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 when 
    agent is restarted, reduce by 1 dose level.**  
2. If diastolic BP not controlled (≤ 100) on 
    therapy, reduce another dose level *** 
grade 4 
Discontinue protocol therapy  
  * Patients requiring a delay of > 2 weeks should go off protocol therapy. 
** May be able to resume full dose later. 
      *** Patients requiring > 2 dose reductions should go off protocol therapy.  Patients who experience 
treatment-emergent hypertension while receiving BAY 43-9006 200 mg b.i.d. and require > 1 dose reduction 
should go off protocol therapy.   
 


 
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reduced by 50% for that dose. A full dose of gemcitabine should be resumed 
with the next cycle. If grade 3 neutropenia or thrombocytopenia reoccurs, a 
permanent dose-reduction of 25% should be made. In the event that 
capecitabine must be stopped, at the discretion of the Principal Investigator, 
patients may continue to receive gemcitabine alone with BAY 43-9006 until 
disease progression. If both capecitabine and gemcitabine must be stopped, 
patients may continue on with BAY 43-9006 alone at the discretion of the 
Principal Investigator. 
 
6.4.2 Grade 4 Neutropenia/Thrombocytopenia 
 
 
 
 
 
Grade 4 neutropenia or thrombocytopenia includes: 
 
• Febrile neutropenia (defined as temperature ≥ 38.5°C [101°F] 
sustained for more than one hour concomitant with an ANC < 
500/mm3), 
 
• granulocytes < 500/µl, or 
 
• platelets < 10,000/µl 
 
 
  
If grade 4 neutropenia or thrombocytopenia develops in any given cycle, all 
therapy should be held with the exception of BAY 43-9006, which may be 
continued at current dose. When therapy is reinitiated according to the 
guidelines in Section 6.1, the dose of gemcitabine should  remain the same 
and capecitabine should be decreased by 1 dose level.  If capecitabine has 
already been discontinued and a patient experiences grade 3 or 4 neutropenia 
or thrombocytopenia on Day 8 of any given cycle, gemcitabine should be 
reduced by 50% for that dose. A full dose of gemcitabine should be resumed 
with the next cycle. If grade 3 or 4 neutropenia or thrombocytopenia reoccurs, 
a permanent dose-reduction of 25% should be made. In the event that 
capecitabine must be stopped, at the discretion of the Principal Investigator, 
patients may continue to receive gemcitabine alone with BAY 43-9006 until 
disease progression. If both capecitabine and gemcitabine must be stopped, 
patients may continue on with BAY 43-9006 alone at the discretion of the 
Principal Investigator.   
   
6.4.3 Blood Counts on Day 1 of Cycle 
 
As noted in Section 6.1, all blood count eligibility criteria must be met before 
beginning a new cycle (ANC ≥ 1,500/µl, platelets ≥ 100,000/µl).  A delay of > 
3 weeks in the re-initiation of therapy will result in the removal of the patient 
from the protocol treatment. 
 
6.5  
Hepatic Dysfunction 
If grade 3 hepatic toxicity develops in any given cycle, gemcitabine, capecitabine and 


 
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BAY 43-9006 should be held and that cycle of therapy considered complete.  If 
therapy is reinitiated according to the guidelines in Section 6.1 (i.e. all laboratory 
eligibility criteria are met), the dose of gemcitabine should be decreased by 2 dose 
levels.  If grade 3 hepatic toxicity occurs on a subsequent cycle despite these dose 
reductions or if a 2 dose level reduction would lead to a dose less than Dose Level -2, 
the patient should be removed from protocol treatment.   
A delay of > 3 weeks in the re-initiation of therapy will result in the removal of the 
patient from the protocol treatment. 
 
If grade 4 hepatic toxicity develops, the patient should be removed from protocol 
treatment. 
 
6.6 
Gastrointestinal Toxicities 
 
6.6.1 Grade 2 mucositis and diarrhea 
 
If grade 2 mucositis or diarrhea develops in a given cycle, capecitabine and 
gemcitabine therapy should be stopped until resolved to grade 0-1.  Patients 
may continue BAY 43-9006.  BAY 43-9006 and gemcitabine may be resumed 
without dose modification.  The dose of capecitabine from that point forward 
should be decreased by 1 dose level.  If dose reduction of capecitabine would 
lead to a dose less than Dose Level -1, at the discretion of the Principal 
Investigator, patients may continue to receive gemcitabine alone with BAY 
43-9006 until disease progression.   A delay of > 3 weeks in the re-initiation of 
therapy will result in the removal of the patient from the protocol treatment. 
 
6.6.2 Grade 3 mucositis and diarrhea 
 
If grade 3 mucositis or diarrhea develops in a given cycle, all therapy should 
be held and that cycle of therapy considered complete.  When therapy is 
reinitiated according to the guidelines in Section 6.1, the dose of capecitabine 
should be decreased by 1 dose level.  BAY 43-9006 and gemcitabine may be 
resumed without dose modification.  If grade 3 mucositis or diarrhea occurs on 
a subsequent cycle despite these dose reductions or if a dose level reduction of 
capecitabine would lead to a dose less than Dose Level -1, at the discretion of 
the Principal Investigator, patients may continue to receive gemcitabine alone 
with BAY 43-9006 until disease progression. A delay of > 3 weeks in the re-
initiation of therapy will result in the removal of the patient from the protocol 
treatment.   
   
6.6.3 Grade 4 mucositis and diarrhea 
 
If grade 4 mucositis or diarrhea develops in a given cycle, all therapy should 
be held and that cycle of therapy considered complete.  Capecitabine should 
be stopped and at the discretion of the Principal Investigator, patients may 
continue to receive gemcitabine alone with BAY 43-9006 until disease 


 
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progression. A delay of > 3 weeks in the re-initiation of therapy will result in 
the removal of the patient from the protocol treatment.     
 
 
6.6.4 GI Perforation (NOS) 
 
If GI perforation occurs, the patient must be taken off therapy completely. 
6.7 
Skin Toxicity 
 
 
The following table should be used for grading hand/foot syndrome: 
 
 
Grade 
Clinical Domain 
Functional Domain 
1 
Numbness, dysesthesia/paresthesia, 
tingling, or painless swelling or 
erythema 
Discomfort which does not disrupt 
normal activities 
2 
Painful erythema, with swelling 
Discomfort which affects activities of 
daily living 
3 
Moist desquamation, ulceration, 
blistering, severe pain 
Severe discomfort, unable to work or 
perform activities of daily living 
 
  In the case of a discrepancy between the clinical domain and the functional domain, the assigned grade  
  should correspond to the most important intensity from one domain or the other. 
 
6.7.1 Grade 2 dermatitis or hand/foot syndrome 
 
If grade 2 dermatitis or hand/foot syndrome develops in a given cycle, BAY 
43-9006 and capecitabine should be stopped until resolved to grade 0-1.  The 
dose of capecitabine from that point forward should be decreased by 1 dose 
level.  Gemcitabine and BAY 43-9006 may be resumed without dose 
modification. In the event that capecitabine must be stopped, at the discretion 
of the Principal Investigator, patients may continue to receive BAY 43-9006 
with gemcitabine until disease progression.  A delay of > 3 weeks in the re-
initiation of therapy will result in the removal of the patient from the protocol 
treatment 
 
6.7.2 Grade 3 dermatitis or hand/foot syndrome 
 
If grade 3 dermatitis or hand/foot syndrome develops in a given cycle, all 
therapy should be held and that cycle of therapy considered complete.  When 
therapy is reinitiated according to the guidelines in Section 6.1, the dose of   
capecitabine should be decreased by 1 dose level.  Gemcitabine and BAY 43-
9006 may be resumed without dose modification.    In the event that 
capecitabine must be stopped, at the discretion of the Principal Investigator, 
patients may continue to receive BAY 43-9006 with gemcitabine until disease 
progression.  A delay of > 3 weeks in the re-initiation of therapy will result in 
the removal of the patient from the protocol treatment 
 
6.7.3 Grade 4 dermatitis  
 


 
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If grade 4 dermatitis develops, the patient should be removed from protocol 
treatment. 
 
 
 
 
6.8 
Pulmonary Toxicity 
 
If a patient develops gemcitabine-induced pulmonary toxicity with  Grade 3 
dyspnea, gemcitabine should be discontinued and further protocol therapy terminated. 
      
6.9 
Unspecified Grade 3 or 4 Toxicities 
 
For any other grade 3 or 4 non-hematologic, drug-related toxicity not listed in 
Sections 6.2- 6.8, except for alopecia and isolated anemia, all therapy should be held 
and that cycle of therapy considered complete.  When therapy is reinitiated according 
to the guidelines in Section 6.1, the doses of BAY 43-9006, gemcitabine and 
capecitabine should be decreased by 1 dose level.  If the same grade 3 or 4 toxicity 
occurs on a subsequent cycle despite these dose reductions or if a dose level reduction 
of any agent would lead to a dose less than Dose Level –1 for BAY 43-9006. Dose 
Level -2 for gemcitabine or Dose Level –1 for capecitabine, the patient should be 
removed from protocol treatment.  A delay of > 3 weeks in the re-initiation of therapy 
will result in the removal of the patient from the protocol treatment 
 
6.10 
Dose Modification for Obese Patients 
 
There will be no dose modification for obese patients.  All dosing is to be determined 
solely by (1) the patient’s BSA as calculated from actual weight or (2) actual weight 
without modification unless explicitly described in the protocol.   
  
7. PHARMACEUTICAL INFORMATION 
 
 
7.1  
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 
 
Classification:  
Kinase inhibitor (Raf, VEGF-R, and PDGF-R) 
 
Mechanism of Action: 
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.  
 


 
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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. 
 
Molecular Formula: C12H16CIF3N4O3 X C7H8O3S  
 
M.W.:  
BAY 43-9006 tosylate: 637 Daltons; BAY 43-9006 (free base): 465 Daltons  
 
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.  
 
How Supplied:  
 
BAY 43-9006 tosylate is supplied as an immediate-release film-coated, 
round, and salmon color tablet containing 200 mg of the free base, 
BAY 43-9006, and the excipients croscarmellose sodium, 
microcrystalline cellulose, hydroxypropylmethylcellulose, sodium 
lauryl sulfate, and magnesium stearate. The film-coat consists of 
hydroxypropylmethyl cellulose, polyethylene glycol, tiranium dioxide 
and red iron oxide. The film coating has no effect on the rate of release 
of the active BAY 43-9006 tosylate.  
 
BAY 43-9006 tosylate 200 mg tablets are supplied in bottles of 140 
tablets. 
 
Storage:  
 
 
Store at controlled room temperature (15ºC – 25ºC). Storage conditions 
should not exceed 25ºC. 
 
Stability:  
 
 
Stability studies with the 200 mg dosage form are ongoing. The current 
shelf life is 24 months when stored at controlled room temperature.  
 
Route(s) of Administration:  Orally 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Sorafenib (BAY 43-9006, NSC 724772) 
 
The Comprehensive Adverse Event 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 via AdEERS (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 2157 patients. Below is the CAEPR for sorafenib (BAY 43-
9006). 
 


 
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25
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 2.4, December 21, 20111 
 
 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006) 
 (CTCAE 4.0 Term) 
[n= 2157] 
 
  Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
 
(formerly known as ASAEL) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
  
CARDIAC DISORDERS 
  
 
 
Acute coronary syndrome   
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
 
Anal mucositis 
 
  
 
Ascites 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Gastrointestinal hemorrhage2  
 Gastrointestinal hemorrhage2  
(Gr 3) 
 
 
Gastrointestinal 
perforation3 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Rectal mucositis 
 
  
 
Small intestinal mucositis 
 
  
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Non-cardiac chest pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INVESTIGATIONS 
  
 
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) 


 
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Blood bilirubin increased 
 
 
 Blood bilirubin increased (Gr 3) 
 
Cholesterol high 
 
  
Creatinine increased 
 
 
 Creatinine increased (Gr 3) 
 
GGT increased 
 
  
INR increased 
 
 
 INR increased (Gr 2) 
 
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) 
 
Hypercalcemia 
 
  
Hyperglycemia 
 
 
 Hyperglycemia (Gr 3) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 3) 
 
Hypernatremia 
 
  
 
Hyperuricemia 
 
  
Hypoalbuminemia 
 
 
 Hypoalbuminemia (Gr 3) 
Hypocalcemia 
 
 
 Hypocalcemia (Gr 3) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr2) 
 
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 spasms) 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
 
 Pain in extremity (Gr 3) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
 
Peripheral sensory 
neuropathy 
 
  
 
 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Hematuria 
 
  
 
Renal hemorrhage 
 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  


 
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Hematosalpinx 
 
  
 
Ovarian hemorrhage 
 
  
 
Prostatic hemorrhage 
 
  
 
Spermatic cord hemorrhage  
  
 
Testicular hemorrhage 
 
  
 
Uterine hemorrhage 
 
  
 
Vaginal hemorrhage 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Bronchopulmonary 
hemorrhage 
 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
Laryngeal mucositis 
 
  
 
Pharyngeal mucositis 
 
  
 
Tracheal mucositis 
 
  
 
Voice alteration 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Alopecia 
 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 3) 
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
 
Stevens-Johnson 
syndrome 
  
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 includes 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 includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
4Includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
 
 
Also reported on sorafenib (BAY 43-9006) trials but with the relationship to sorafenib (BAY 43-
9006) still undetermined: 
 


 
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CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Extraocular muscle paresis  
GASTROINTESTINAL DISORDERS - Abdominal distension; Dyspepsia; Dysphagia; Flatulence; Ileus; 
Pancreatitis; Rectal fistula; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Flu like 
symptoms; Pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Fibrinogen decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypermagnesemia; Hypertriglyceridemia; 
Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Generalized muscle 
weakness 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Ischemia cerebrovascular; Memory 
impairment; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Depression 
RENAL AND URINARY DISORDERS - Proteinuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia; Pleural effusion; Pneumonitis; 
Pneumothorax 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Purpura; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (non-life threatening squamous cell carcinoma of skin:  
keratoacanthoma type); Skin hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypotension; 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. 
 
 
 
 
 
Method of Administration:  
Following oral administration, 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. It is 
recommended that 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. 
 
Potential Drug Interactions:  
BAY-9006 tosylate is metabolized by the P450 CYP3A enzyme 
and has been shown in preclinical studies to inhibit multiple 
CYP isoforms. Therefore, it is possible that BAY-9006 tosylate 
may interact with drugs that are metabolized by the P450 CYP 
isoenzymes or with drugs that inhibit CYP 3A. Close monitoring 
is recommended for patients taking agents with narrow 
therapeutic indices and metabolized by the liver, such as 
warfarin, phenytoin, quinidine, carbamazepine, phenobarbital, 


 
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cyclosporine, and digoxin.  Additionally, BAY-9006 tosylate is 
97% to 99% protein bound; however, no drug interactions have 
been reported in studies, thus far. 
 
Availability:   
 
 
 
      BAY 43-9006 is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and 
Diagnosis (DCTD), NCI. 
 
BAY 43-9006 is provided to the NCI under a Cooperative 
Research and Development Agreement (CRADA) between 
Bayer Corp./Onyx and the DCTD, NCI (see Section 10.4). 
 
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:   
 
 
      NCI-supplied agents may be requested by the Principal 
Investigator (or their authorized designees) at each participating 
institution.  Pharmaceutical Management Branch (PMB) policy 
requires that the 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).  Completed Clinical Drug Requests 
(NIH-986) should be submitted to the PMB by fax (301) 480-
4612 or mailed to the Pharmaceutical Management Branch, 
CTEP, DCTD, NCI, 9000 Rockville Pike, EPN Rm. 7149, 
Bethesda, MD 20892. 
 
Agent Accountability: 
 
      The Investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory 
and disposition of all agents received from DCTD using the 
    NCI Drug Accountability Record Form.  See the CTEP web site 
for Policy and Guidelines for Accountability and Storage of 
InvestigationalDrugs(http://ctep.cancer.gov/requisition/storage
.html). 
 
7.2  
Gemcitabine 
 
Product description:  
     Gemcitabine is supplied in Vials: 200 mg white, lyophilized 
powder in a 10 mL size sterile single use vial (No. 7501) (NDC 
0002-7501-01) or 1 g white, lyophilized powder in a 50 mL 
size sterile single use vial (No. 7502)  (NDC 0002-7502-01). 
store at controlled room temperature (20° to 25°C) (68° to 
77°F). The recommended diluent for reconstitution of 
emcitabine is 0.9% Sodium Chloride Injection without 
preservatives. Due to solubility considerations, the maximum 


 
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concentration for gemcitabine upon reconstitution is 40 
mg/mL. Reconstitution at concentrations greater than 40 
mg/mL may result in incomplete dissolution, and should be 
avoided.  
Preparation:  
 
      To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection 
to the 200 mg vial or 25 mL of 0.9% Sodium Chloride 
Injection to the 1 g vial. Shake to dissolve. These dilutions each 
yield a gemcitabine concentration of 38 mg/mL which includes 
accounting for the displacement volume of the lyophilized 
powder (0.26 mL for the 200 mg vial or 1.3 mL for the 1 g 
vial). The total volume upon reconstitution will be 5.26 mL or 
26.3 mL, respectively. Complete withdrawal of the vial 
contents will provide 200 mg or 1 g of gemcitabine, 
respectively. The appropriate amount of drug may be 
administered as prepared or further diluted with 0.9% Sodium 
Chloride Injection to concentrations as low as 0.1 mg/mL.  
Reconstituted gemcitabine is a clear, colorless to light straw-
colored solution. After reconstitution with 0.9% Sodium 
Chloride Injection, the pH of the resulting solution lies in the 
range of 2.7 to 3.3. The solution should be inspected visually 
for particulate matter and discoloration, prior to administration, 
whenever solution or container permit. If particulate matter or 
discoloration is found, do not administer.  
 
 
Stability: 
 
 
     When prepared as directed, gemcitabine solutions are stable for 
24 hours at controlled room temperature 20° to 25°C (68° to 
77°F) [ See USP]. Discard unused portion. Solutions of 
reconstituted gemcitabine should not be refrigerated, as 
crystallization may occur.  
The compatibility of gemcitabine with other drugs has not been 
studied. No incompatibilities have been observed with infusion 
bottles or polyvinyl chloride bags and administration sets.  
Unopened vials of gemcitabine are stable until the expiration 
date indicated on the package when stored at controlled room 
temperature 20° to 25°C (68° to 77°F) [ See USP].  
Caution should be exercised in handling and preparing 
gemcitabine solutions. The use of gloves is recommended. If 
gemcitabine solution contacts the skin or mucosa, immediately 
wash the skin thoroughly with soap and water or rinse the 


 
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mucosa with copious amounts of water. Although acute dermal 
irritation has not been observed in animal studies, two of three 
rabbits exhibited drug-related systemic toxicities (death, 
hypoactivity, nasal discharge, shallow breathing) due to dermal 
absorption.  
Procedures for proper handling and disposal of anti-cancer 
drugs should be considered. Several guidelines on this subject 
have been published. 1-7  There is no general agreement that all 
of the procedures recommended in the guidelines are necessary 
or appropriate.  
1. Recommendations for the safe handling of parenteral antineoplastic drugs. NIH 
publication No. 83-2621. US Government Printing Office, Washington, DC 20402.  
2. Council on Scientific Affairs: Guidelines for handling parenteral antineoplastics. JAMA 
1985;253:1590.  
3. National Study Commission on Cytotoxic Exposure—Recommendations for handling 
cytotoxic agents, 1987. Available from Louis P Jeffrey, ScD, Director of Pharmacy 
Services, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02902.  
4. Clinical Oncological Society of Australia: Guidelines and recommendations for safe 
handling of antineoplastic agents. Med J Aust 1983;1:426.  
5. Jones RB, et al. Safe handling of chemotherapeutic agents: A report from the Mount Sinai 
Medical Center. CA 1983;33(Sept/Oct): 258.  
6. American Society of Hospital Pharmacists: Technical assistance bulletin on handling 
cytotoxic drugs in hospitals. Am J Hosp Pharm 1990;47:1033.  
7. Yodaiken RE, Bennet D, OSHA work-practice guidelines for personnel dealing with 
cytotoxic (antineoplastic) drugs. Am J Hosp Pharm 1988;43:1193-1204.  
 
Availability:   
 
     Gemcitabine is commercially available.  
 
Solution preparation:  
     Please see the package insert for standard preparation 
instructions.  
Route of administration:       Gemcitabine is to be administered as a short intravenous 
infusion over 30 minutes. 
Expected adverse events:         See manufacturer’s package insert for expected adverse events.  
 
7.3  
Capecitabine 
Product description:                Capecitabine is provided as biconvex, oblong film-coated tablets 
for oral administration.  Each light peach-colored tablet contains 
150 mg capecitabine and each peach-colored tablet contains 500 
mg capecitabine.   
 
Preparation: 
 
    Instructions regarding the calculation of the number of tablets to 
achieve the appropriate dosing can be found in Section 4.1.3. 
 
Stability:  
 
   Capecitabine tablets should be stored at room temperature (25°C 


 
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32
or 77°F). 
 
Availability: 
 
   Capecitabine is commercially available. 
 
Route of administration:      Capecitabine is administered by mouth twice a day.  Prior studies 
of capecitabine have included administration within 30 minutes 
of food (and safety/efficacy data are based on this schedule), 
therefore, capecitabine will be administered similarly in this 
study.  The tablets should be swallowed with water.  
 
Expected adverse events:  
   See manufacturer’s package insert for expected adverse events. 
 
Drug Interactions:  
   See manufacturer’s package insert for information on drug 
interactions including leucovorin, coumarin derivatives and 
phenytoin


 
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8. CORRELATIVE/SPECIAL STUDIES 
 
Tissue Analysis for MAPK and VEGFR2 Expression  
 
BAY 43-9006 is a potent inhibitor of wild-type and mutant B-Raf and c-Raf kinase isoforms in 
vitro, with no effects on EGFR, PKC and HER2/neu kinase activities. Activation of Raf initiates 
a signaling cascade that results in MAP kinase phosphorylation(24).  The effect of BAY 43-9006 
on Raf activation and MAP kinase activation in patients receiving the drug has not been well-
studied. Specifically, it is unknown if to what extent 1) activation of Raf kinase - MAP kinase 
signaling axis can predict likelihood of response 2) inhibition of Raf kinase and/or MAP kinase 
activation is necessary for patients to respond to BAY 43-9006 based therapy;  3) VEGFR2 
activation and subsequent correlates with tumor microvessel density and clinical response; and 4) 
Raf kinase inhibition correlates with phospho-Akt status, a negative upstream regulator of both 
Raf-kinase isoforms. Therefore, we propose to measure MAP kinase activation in pre- and post-
treatment tumor specimens when available.  
 
Pre- and, when available, post-treatment paraffin-embedded tumor tissue specimens will be 
analyzed using monoclonal antibodies specific for activated MAP kinase, c-raf, VEGFR2(25;26), 
MEK, PDGF-R, AKT and PCNA.   To assess potential role of VEGFR2 blockade on 
angiogenesis paraffin-embedded sections will be stained for CD31, an endothelial-specific cell 
marker.   
 
Please send paraffin-embedded tumor tissue samples to: 
 
 
 
 
 
 
Scott Tagawa, M.D. 
 
 
 
 
 
Div. of Hematology & Medical Oncology 
 
 
 
 
 
New York Presbyterian Hospital/Cornell 
 
 
 
 
 
525 East 68th Street 
 
 
 
 
 
New York, NY 10065 
 
 
 
 
 
Tel 646-962-2072 
 
 
 
 
 
Fax 646-962-1603 
 
 
 
 
 


 
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9. STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  
Scans and x-rays must be done ≤4 weeks prior to the start of therapy.  In the event that the 
patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
 
Note that for subjects with stable disease or better past cycle 12 who remain on single-agent 
sorafenib with stable non-hematologic toxicities of Gr < 1, cycles may be moved to q4 weeks 
with study procedures performed on D1 of each cycle; radiographic evaluation should 
continue every 3 cycles unless clinically indicated sooner regardless of the length of the 
cycle. 
 
   
 
Pre- 
Study 
 
Wk 
1 
 
Wk 
2 
 
Wk 
3 
 
Wk  
4 
 
Wk 
5 
 
Wk 
6 
 
Wk 
7 
 
Wk 
8 
 
Wk 
9 
 
Wk 
10 
 
Wk 
11 
 
Wk 
12 
 
Off 
Studyc 
 
BAY 43-9006 
 
 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
 
 
Gemcitabine 
 
 
 
B 
 
B 
 
 
 
B 
 
B 
 
 
 
B 
 
B 
 
 
 
B 
 
B 
 
 
 
 
 
Capecitabine 
 
 
 
C 
 
C 
 
 
 
C 
 
C 
 
 
 
C 
 
C 
 
 
 
C 
 
C 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
X-------------------------------------------------------------------------------------------------X 
 
 
 
Physical exam 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Vital signse 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Performance status 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
CBC w/diff, plts 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Serum chemistrya 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 Urine protein/creatinineratiof 
 
X 
 
A urine protein/creatinine ratio (UPC ratio) will be done on day 1 of every 3rd cycle for 
the first 9 cycles. After cycle 9, the UPC ratio will be repeated on day 1 of every cycle. 
 
 
EKG (as indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
 
X-------------------------------------------------------------------------------------------------X 
 
X 
 
 
Tumor measurements 
 
 
X 
 
Tumor measurements are repeated  after every 3 cycles.  Documentation (radiologic) 
must be provided for patients removed from study for progressive disease. 
 
 
Xc 
 
Radiologic evaluation 
 
X 
 
Radiologic measurements should be performed after every 3 cycles. 
 
Xc 
 
B-HCG 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: 
BAY 43-9006:  200 mg p.o. BID for each  cycle (1 cycle = 21 days). Dose modifications will occur if indicated (see Section 5); BAY 43-9006 will be administered 
day 1 through day 21, and continuously thereafter. 
B: 
Gemcitabine:  750  mg/m2 IV over 30 minutes. Dose modifications will occur if indicated (see Section 5); Gemcitabine will be administered on days 1 and 8 of 
each 21-day cycle. 
C:       Capecitabine:  415 mg/m2 p.o. twice daily. Dose modifications will occur if indicated (see Section 5); Capecitabine will be administered on days 1-14 of each 
21-day cycle. 


 
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a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
Off-study evaluation.  Two consecutive measurements taken 4 weeks apart must be used to document progressive disease if the patient is removed from 
study for this reason. 
e.       Blood pressure monitoring will be conducted weekly for the first treatment cycle. 
f.        Obtain at least 4ml of a random urine sample in a sterile container (does not need to be 24-hour sample). Determine protein concentration (mg/dl) and creatinine 
concentration (mg/dl). Divide protein  concentration by creatinine concentration for the UPC ratio. If spot urine protein/Cr is > 0.2, a 24 hour collection 
for protein and creatinine should be assessed and the level of proteinuria should be graded per CTCAE. 
 


 
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36
10. MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should be reevaluated for response every 9 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following 
initial documentation of objective response. 
 
10.1. 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 [JNCI 92(3):205-216, 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. 
 
Final determination of response categorization will be determined by independent 
radiographic review. See section 10.6 
 
10.1.1 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.  
All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters). 
 
10.1.2 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), 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. 
 
10.1.3 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  


 
NCI Version Date 5/23/11 
37
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. 
 
10.1.4 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.  
10.2 
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.   
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Clinical lesions.  Clinical lesions 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.  Head and neck tumors and those of extremities usually require 
specific protocols. 
 
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 


 
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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 can 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 initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response.  Specific additional criteria for 
standardized usage of prostate-specific antigen (PSA) and CA-125 response in 
support of clinical trials are being developed. 
 
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. 
 
10.3 
Response Criteria 
 
10.3.1 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 


 
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10.3.2 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 markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
10.3.3 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). 


 
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40
 
 
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: 
 
 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. 
 
 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. 
 
10.4 
Confirmatory Measurement/Duration of Response 
 
10.4.1 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 9 weeks (see section 9.3.3). 
 
10.4.2 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 objectively documented (taking as 


 
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41
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. 
 
10.4.3 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.  
 
10.5 
Progression-Free Survival 
 
PFS will be measured from the time of the patient’s initial best response (PR or CR) 
until documented progression. 
 
10.6 
Response Review 
 
All objective responses will be evaluated by an independent panel. All radiographs 
(such as CT, MRI, bone scan) will be sent to Weill Cornell Medical College for 
central review by the independent study radiologist. Electronic format (e.g. on CD) is 
preferred, but hard copies are acceptable. 
 
11. REGULATORY AND REPORTING REQUIREMENTS 
 
Expedited adverse event (AE) reporting for this study is via AdEERS (Adverse Event 
Expedited Reporting System), accessed via the secure CTEP web site 
https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup).  The reporting 
procedures to be followed are presented in the “NCI Guidelines: Expedited Adverse Event 
Reporting Requirements for NCI Investigational Agents” which can be downloaded from the 
CTEP web site (http://ctep.cancer.gov/reporting/adeers.html).  
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A list of 
adverse events that have occurred or might occur (Reported Adverse Events and Potential 
Risks) can be found in Section 6 (Pharmaceutical Information).  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/reporting/ctc.html).   
 
 
 
 
 


 
NCI Version Date 5/23/11 
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11.1 
Expedited Adverse Event Reporting 
(AE; formerly known as Adverse Drug Reaction) 
For this consortium effort, participating institutions will report to the Coordinating 
Center who in turn will report to CTEP. 
 
Expedited reports are submitted to CTEP via the secure AdEERS application 
accessed via the CTEP web site 
(https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup).  Those AEs 
that do not require expedited reporting must be reported in routine (CDUS) study data 
submissions.  AEs reported through AdEERS must also be reported in routine study 
data submissions. 
11.1.1  
Phase 1 Trials Utilizing an Agent under a CTEP IND:  AdEERS Reporting Requirements 
for Adverse Events That Occur Within 30 Days1 of the Last Dose of the Investigational 
Agent 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Unexpected  
and Expected 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
and 
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 
24-Hour; 
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 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: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 4 unexpected events  
• 
Grade 5 expected events and unexpected events 
 
2 Although an AdEERS 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 
AdEERS within 24 hours of learning of the event followed by a complete AdEERS 
report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete AdEERS report on the AE must be submitted within 
10 calendar days of the investigator learning of the event.  
 


 
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43
• 
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 AdEERS 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. 
 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  AdEERS Reporting 
Requirements for Adverse Events That Occur Within 30 Days1 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 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
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: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
AdEERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an AdEERS 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 
AdEERS within 24 hours of learning of the event followed by a complete AdEERS 
report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete AdEERS 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. 


 
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44
• 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via AdEERS 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. 
11.1.2 Expedited Adverse Event Reporting Exclusions. 
N/A 
 
 
11.1.3 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 AdEERS but 
should be submitted as part of the study results via routine CDUS reporting. 
 
11.2 
Data Reporting 
 
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). 
 
11.3 
CTEP Multicenter Guidelines 
 
 
 
Procedures for Central Patient Registration 
 
Registration will be done centrally by the Phase II Coordinating Center.  Patients must 
be screened for eligibility and then registered with the Coordinating Center by calling 
718 904-2730 or via fax to 718 822-0335.  The first page and the signature page of 
the Informed Consent will be sent via fax to the Coordinating Center as well as the 
eligibility criteria and a one page registration form.  These documents should be faxed 
Monday to Friday from 9:00 AM to 5:00 PM.  The following information will be 
obtained or assigned at that time:  
Protocol Number 
Investigator Identification 
Patient Identification (grant number, institution number, sequence number) 
 
Data Collection Forms: All data forms must be sent to the Coordinating Office on a 
quarterly basis (every 3 months).  
Responsibility of the Protocol Chair  
• 
The Protocol Chair will be the single liaison with the CTEP Protocol and 


 
NCI Version Date 5/23/11 
45
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 
• 
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.  
There are two options for AE reporting: (1) participating institutions may report 
directly to CTEP with a copy to the Coordinating Center, or (2) participating  
institutions report to the Coordinating Center who in turn report to CTEP.  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. 
Agent Ordering 
• 
Except in very unusual circumstances, each participating institution will 


 
NCI Version Date 5/23/11 
46
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.  
 
 
 
11.4 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) 
Covered by a Clinical Trials Agreement (CTA) or a Cooperative Research and 
Development Agreement (CRADA), hereinafter referred to as Collaborative 
Agreement: 
 
The agent(s), supplied by CTEP, DCTD, NCI, used in this protocol is/are provided to 
the NCI under a Collaborative Agreement (CRADA, CTA) between the 
Pharmaceutical Company(ies) [hereinafter referred to as Collaborator(s)] 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   
Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators.  The protocol 
documents for studies utilizing investigational agents 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 participating on the study 
or patient’s family member, 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. 


 
NCI Version Date 5/23/11 
47
 
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.  All data made available will comply with HIPAA 
regulations. 
 
4. 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. 
 
5. 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. 
 
6. 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 abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and 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 
 
 
 
 
6130 Executive Boulevard, Suite 7111 
Rockville, MD  20852 
FAX 301-402-1584 
 
 
 
E-mail: anshers@ctep.nci.nih.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 
Collaborator’s confidential/proprietary information. 
 
12. STATISTICAL CONSIDERATIONS 


 
NCI Version Date 5/23/11 
48
 
12.1 
Study Design/Endpoints 
 
The study is a prospective, non-randomized, multi-institutional phase II trial with 
objective response as the major endpoint.  Recent trials using gemcitabine in 
combination with 5-flurouracil or capecitabine have demonstrated response rates in 
the range of 15- 21%(20;27).  The trial is designed to effectively discriminate between 
true response rates of no more than 10% and at least 30%.  The maximum trial size 
will be set at 35 evaluable patients.  If at least 6 responses (at least 17%) were 
observed among the 35 evaluable patients, this regimen would be considered worthy 
of further testing in this disease.  If no more than 1 response (no more than 8%) were 
observed among the initial 12 patients, the study would be terminated early and 
declared negative.  This design yields at least 90% power to detect a true response rate 
of at least 30%.  It yields at least .90 probability of a negative result if the true 
response rate is no more than 10%, with at least .65 probability of early negative 
stopping.   
 
12.2 
Sample Size/Accrual Rate 
 
The maximum trial size will be set at 35 evaluable patients.  If at least 6 responses 
were observed among the 35 evaluable patients, this regimen would be considered 
worthy of further testing in this disease.  If no more than 1 response were observed 
among the initial 12 patients, the study would be terminated early and declared 
negative.   
 
An estimated accrual of 3-4 patients per month is expected with a goal to complete 
the trial within one year 
 
12.3 
Stratification Factors 
 
N/A 
 
12.4 
Analysis of Secondary Endpoints 
 
Progression free survival and overall survival will be assessed.  Because of the 
heterogeneity in outcome of patients with advanced renal cell carcinoma, assessment 
of survival will be limited.  Nevertheless, median survival for this group of patients 
has historically been < 12 months.  Improvement over that level will be encouraging.  
Likewise, PFS > 3 months is suggestive of a durable benefit from the treatment. 
 
The study will be monitored for unacceptable toxicity defined as death or grade 4 
toxicity. 
 
 
When available, pre- and post-treatment paraffin-embedded tumor tissue specimens 
will be analyzed using monoclonal antibodies specific for total and activated MAP 


 
NCI Version Date 5/23/11 
49
kinase, VEGFR2 as well as others as defined in Section 8.  Although this is a limited 
analysis, it has the potential to provide preliminary data for future larger scale studies.  
 
 
 
 
 
 
 
12.5 
Reporting and Exclusions 
 
 
 
12.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment with BAY 43-9006. 
 
 
 
12.5.2 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).  [Note:  By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception 
of those who received no study medication) 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.  
 


 
NCI Version Date 5/23/11 
50
13. REFERENCES 
 
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 3.  Pyrhonen S, Salminen E, Ruutu M, Lehtonen T, Nurmi M, Tammela T et al. Prospective 
randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients 
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 4.  Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised 
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1999;353:14-7. 
 5.  Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ. Increasing complexity of 
Ras signaling. Oncogene 1998;17:1395-413. 
 6.  Chong H, Vikis HG, Guan KL. Mechanisms of regulating the Raf kinase family. Cell 
Signal. 2003;15:463-9. 
 7.  Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al. Mutations of the BRAF 
gene in human cancer. Nature 2002;417:949-54. 
 8.  Mercer KE, Pritchard CA. Raf proteins and cancer: B-Raf is identified as a mutational 
target. Biochim.Biophys.Acta 2003;1653:25-40. 
 9.  Pollock PM, Meltzer PS. A genome-based strategy uncovers frequent BRAF mutations in 
melanoma. Cancer Cell 2002;2:5-7. 
 10.  Singer G, Oldt R, III, Cohen Y, Wang BG, Sidransky D, Kurman RJ et al. Mutations in 
BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. 
J.Natl.Cancer Inst. 2003;95:484-6. 
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Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. 
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 12.  Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B et al. BRAF mutation in papillary 
thyroid carcinoma. J.Natl.Cancer Inst. 2003;95:625-7. 
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2002;2:795-803. 
 
 


 
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pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J.Clin Invest 
2003;111:1287-95. 
 15.  Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ et al. Response 
to imatinib mesylate in patients with chronic myeloproliferative diseases with 
rearrangements of the platelet-derived growth factor receptor beta. N.Engl.J.Med. 
2002;347:481-7. 
 16.  Sawyers CL. Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute 
myeloid leukemia. Cancer Cell 2002;1:413-5. 
 17.  Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase 
activity: a novel molecular approach to the treatment of KIT-positive malignancies. J.Clin 
Oncol 2002;20:1692-703. 
 18.  Alavi A, Hood JD, Frausto R, Stupack DG, Cheresh DA. Role of Raf in vascular protection 
from distinct apoptotic stimuli. Science 2003;301:94-6. 
 19.  Milowsky MI, Nanus DM. Chemotherapeutic strategies for renal cell carcinoma. Urol 
Clin.North Am 2003;30:601-9, x. 
 20.  J.S.Waters, C.Moss, S.Hackett, M.James, L.Pyle, R.A'Hern, M.Gore, and T.Eisen. A phase 
II trial of gemcitabine (GEM) plus capecitabine (CAPE) in patients with metastatic renal 
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using phospho-specific antibodies to MEK and ERK: potential for pharmacodynamic 
monitoring of signal transduction inhibitors. Cytometry 2001;46:72-8. 
 27.  W.M.Stadler, S.Halabi, M.S.Ernstoff, R.Barrier, E.Davila, J.Picus, and E.J.Small. A phase 
II study of gemcitabine (G) and capecitabine (C) in patients with metastatic renal cell 
cancer (mRCC): A report of Cancer and Leukemia Group B #90008. Proc Annu Meet Am 
Soc Clin Oncol 4515, 2004 (abstr).  
 
 


NCI Version Date 5/23/11     
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. 
 
 
 
 
 
 
 
 
 
 
 
A-1


NCI Version Date 5/23/11     
APPENDIX B 
 
Patient Medication Log 
 
Patient’s Name ________________________                 Cycle # _________ 
Day of Cycle 
Date 
Capecitabine 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
 
BAY 43-9006 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
 
1 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
2 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
3 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
4 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
5 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
6 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
7 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
8 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
9 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
10 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
11 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
12 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
13 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
14 
__/__/__ 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
15 
__/__/__ 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
16 
__/__/__ 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
17 
__/__/__ 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
18 
__/__/__ 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
19 
__/__/__ 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
20 
__/__/__ 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
21 
__/__/__ 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
A-2 
 


NCI Version Date 5/23/11     
APPENDIX C 
 
Patient Medication Log – For subjects who remain on single-agent sorafenib 
A-3 
 
 
 
Day of 
Cycle 
Date 
BAY 43-9006 
 
Time ___:___(AM)   ____# pills taken 
Time ___:___(PM)   ____# pills taken 
 
1 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
2 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
3 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
4 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
5 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
6 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
7 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
8 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
9 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
10 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
11 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
12 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
13 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
14 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
15 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
16 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
17 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
18 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
19 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
20 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
21 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
22 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
23 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
24 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
25 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
26 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
27 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken 
28 
__/__/__ 
Time ___:___(AM)   ____# pills taken Time ___:___(PM)   ____# pills taken