Clinical trial NCT00090545
Conditions: Prostate Cancer
Keywords: Hormone-Refractory Proteomics Angiogenesis VEGFR Prostate Cancer Metastatic Prostate Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2004-09-01; Completion date: 2009-04-01
Enrollment: 46 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
BAY 43-9006 (Sorafenib) is an experimental cancer drug produced by Bayer Health Care Corporation. It represents a new class of anticancer agents known as bi-aryl ureas. This study will investigate its effect on prostate cancer and its side effects. Researchers expect to enroll a maximum of 46 men with prostate cancer for this study. The duration of the study will depend on its results.

Before beginning to take the drug, patients will be admitted to the hospital for 2 days, have a medical examination and give blood samples, and have a tumor or bone marrow biopsy. On the first day of the study, patients will begin taking the drug as 2 tablets twice daily, morning and evening. Blood will be taken throughout the day to determine the drug's level in the bloodstream.

Patients will be discharged from the hospital on the second day, and will continue to take the drug twice daily until instructed to stop. During each of the first 4 weeks, patients will be required to have their blood pressure checked. At the end of the first 4 weeks, patients will have a physical examination and blood tests, as well as a second tumor or bone marrow biopsy.

After the first 4 weeks, patients will continue with their drug regimen. At the end of each 4-week cycle, patients will have a physical examination and blood tests. Patients will also have x-Rays, computed tomography (CT) scans, and/or magnetic resonance imaging (MRIs) at every other 4-week examination or as required. Patients will be asked to keep a diary recording the time and amount of their medication for this study.

Detailed description:
BAY 43-9006 (Sorafenib) is a potent inhibitor of wild-type and mutant b-Raf and c-Raf kinase isoforms in vitro. In addition, this agent also inhibits p38, c-kit, vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor beta (PDGFR-beta) affecting tumor growth as well as possibly promoting apoptosis by events downstream of c-Raf. At this time, over 500 patients have been treated with this drug with tolerable side effects.

The primary objective of this study is to determine if BAY 43-9006 (Sorafenib) is associated with a 50% 4 month probability of progression free survival in patients with metastatic androgen independent prostate cancer (AIPC) as determined by clinical, radiographic, and prostatic specific antigen (PSA) criteria.

The secondary objective of this study will be demonstration of biologic effect by the drug in the patient and on the tumor (when possible). Correlative studies will be conducted on serially obtained tissue biopsies, bone marrow biopsies, and white blood cell collections. These laboratory correlates will include elucidation of activation of components of the Raf-extracellular-signal regulated kinase (ERK)-methyl ethyl ketone (MEK) and angiogenesis pathways using protein microarray technologies developed by the National Cancer Institute (NCI)/Food and Drug Administration (FDA) clinical proteomics program.

Per Amendment D, a secondary objective of this study will also be to determine the time to progression measured by clinical and radiographic criteria. The 22 patients treated on the first stage of this protocol will be retrospectively evaluated with respect to this secondary endpoint possible. Please refer to the statistics section for further details.

The combination of correlated clinical and laboratory endpoints with emphasis on molecular signaling will provide new information on the anti-tumor effects helping to characterize its role in the treatment of androgen independent prostate cancer (AIPC).

Arms: arm 1: The first stage was to rule out the probability of 4 month progression free survival.

Patients were given 400 mg BAY 43-9006 orally twice daily in 28 day cycles. arm 2: Due to prostatic specific antigen and radiographic discordance during the first stage, the protocol was amended to allow accrual to a second stage.

Patients were given 400 mg BAY 43-9006 orally twice daily in 28 day cycles.
Interventions: intervention 1: BAY 43-9006
Intervention descriptions: intervention 1: 400 mg BAY 43-9006 orally twice daily in 28 day cycles.

Protocol documents:
Prot_000.pdf: 


  1
NCI Protocol #:
CC Protocol #: 04-C-0262 (Version I)  
 
 
                CTEP # 6594  
 
A Phase II Study of BAY 43-9006 (Sorafenib) in Metastatic, Androgen-Independent Prostate Cancer 
 
Principal Investigator: 
William L. Dahut, M.D., MOB/CCR/NCI 
Protocol chairperson: 
William L. Dahut, M.D., MOB/CCR/NCI 
 
Co-Investigators: 
 
Elise C. Kohn, M.D., MOB/CCR/NCI 
William D. Figg, Pharm.D., MPS/CTB/CCR/NCI  
 
James Gulley, M.D.-Ph.D., LTIB/CCR/NCI 
 
Philip M. Arlen, M.D., LTIB/CCR/NCI 
 
Howard Parnes, M.D., DCP/PUCR/NCI 
 
David Kohler, Pharm.D., PD/CCR/NIH 
 
Peter Pinto, M.D., UOB/CCR/NCI 
 
 
 
 
 
 
Statistician: 
Seth M. Steinberg, Ph.D., BDMS/CCR/NCI 
 
 
Research Nurses: 
 
 
Lea Latham, B.S.N.-R.N., MOB/CCR/NCI 
 
 
 
 
 
Study Conducted by: 
Genitourinary/Gynecologic Malignancies Clinic 
 
Medical Oncology Branch 
 
National Cancer Institute 
 
Clinical Center (Bldg 10) 
 
National Institutes of Health 
 
Bethesda, MD 20892 
 
Drug Monitor:
John Wright, M.D.-Ph.D., CTEP/CCR/NCI 
 
Drug Sponsor: 
CTEP 
 
NCI Supplied Agent: 
BAY 43-9006 (NSC724772) 
 
Protocol Version Date:      11/18/2008 
 
 
 
            BAY43-9006 IND #: 
 
38583
 


  2
Prior to Day 0 
Baseline CT Scan (chest, abdomen, pelvis) 
 
Baseline bone scan 
 
Baseline electrocardiogram (within 30 days of enrollment) 
 
Baseline PSA 
 
Baseline laboratory studies (chemistry, blood profile) 
 
H&P 
 
Pathologic confirmation 
 
Tumor biopsy and/or bone marrow biopsy and aspiration 
 
C1D1-C1D28 
Begin BAY 43-9006 400 mg bid 
 
Begin PK studies 
 
C2D1 
Return to Clinic 
 
H&P 
 
PSA #2 
 
Tumor biopsy and/or bone marrow biopsy and aspiration #2 prior 
 
Start cycle 2 day 1 BAY 43-9006 
 
C2D1-C2D28 
Continue BAY 43-9006 400 mg bid 
 
C3D1 prior to therapy 
Return to clinic 
 
Restaging CT Scan (Chest/Abdomen/Pelvis) 
 
Restaging Bone scan 
 
PSA #3 
 
If no evidence of progressive disease, begin C3D1


  3
 
PRÈCIS
BAY 43-9006 (sorafenib) is a potent inhibitor of wild-type and mutant b-Raf and c-Raf kinase isoforms in 
vitro.  In addition, this agent also inhibits p38, c-kit, VEGFR-2 and PDGFR-E affecting tumor growth as well 
as possibly promoting apoptosis by events downstream of c-Raf.  At this time, over 500 patients have 
been treated with this drug with tolerable side effects. 
The primary objective of this study is to determine if BAY 43-9006 is associated with a 50% 4 month 
probability of progression free survival in patients with metastatic AIPC as determined by clinical, 
radiographic, and PSA criteria.   
The secondary objective of this study will be demonstration of biologic effect by the drug in the patient and 
on the tumor (when possible).  Correlative studies will be conducted on serially obtained tissue biopsies, 
bone marrow biopsies, and white blood cell collections.  These laboratory correlates will include 
elucidation of activation of components of the Raf-ERK-MEK and angiogenesis pathways using protein 
microarray technologies developed by the NCI/FDA clinical proteomics program.   
Per Amendment D, a secondary objective of this study will also be to determine the time to progression 
measured by clinical and radiographic criteria. The 22 patients treated on the first stage of this protocol will 
be retrospectively evaluated with respect to this secondary endpoint if possible. Please refer to the 
statistics section for further details. 
The combination of correlated clinical and laboratory endpoints with emphasis on molecular signaling will 
provide new information on the anti-tumor effects helping to characterize its role in the treatment of AIPC. 


  4
TABLE OF CONTENTS 
SCHEMA......................................................................................................................................................................2
PRÈCIS.........................................................................................................................................................................3
TABLE OF CONTENTS ……………………………………………………………………………………………..4
1.
OBJECTIVES…………………………………………………………………………………………….….6
2.
BACKGROUND………………………………………………………………………………………….….6
2.1
ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC)...................................................................................6
2.2
BAY 43-9006 (SORAFENIB).............................................................................................................................6
TUMOR MODEL……………………………………………………………………………………………………10
2.3
RATIONALE....................................................................................................................................................11
3.
PATIENT SELECTION……………………………………………………………………………...........11
3.1
ELIGIBILITY CRITERIA.................................................................................................................................11
3.2
EXCLUSION CRITERIA ..................................................................................................................................12
3.3
INCLUSION OF WOMEN AND MINORITIES....................................................................................................13
3.4
BASELINE EVALUATION................................................................................................................................13
3.5
PATIENT REGISTRATION..............................................................................................................................13
4.
TREATMENT PLAN……………………………………………………………………………...............14
4.1
BAY 43-9006 (SORAFENIB) ADMINISTRATION............................................................................................14
4.2
SUPPORTIVE CARE GUIDELINES ..................................................................................................................14
4.3
DURATION OF THERAPY...............................................................................................................................14
5.
DOSING DELAYS/DOSE MODIFICATIONS………………………………………………………….15
6.
PHARMACEUTICAL INFORMATION………………………………………………………………...16
7.
CORRELATIVE/SPECIAL STUDIES…………………………………………………………………...18
8.
STUDY CALENDAR………………………………………………………………………………………23
9.
MEASUREMENT OF EFFECT…………….……………………………………………………………24
9.1
DEFINITIONS .................................................................................................................................................24
9.2
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE........................................................................24
9.3
RESPONSE CRITERIA ....................................................................................................................................25
9.4
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE ......................................................................27
9.6
PROGRESSION-FREE SURVIVAL ...................................................................................................................28
9.7
RESPONSE REVIEW- N/A .............................................................................................................................28
10.
REGULATORY AND REPORTING 
REQUIREMENTS…………….………………………………...28
10.1
EXPEDITED ADVERSE EVENT REPORTING..............................................................................................29
10.1.1
Expedited Reporting Guidelines ..........................................................................................................29
10.1.2
Expedited Adverse Event Reporting Exclusions- N/A ........................................................................30
10.1.3
Secondary AML/MDS.........................................................................................................................30
10.2
DATA REPORTING....................................................................................................................................30
10.3
CTEP MULTICENTER GUIDELINES- N/A................................................................................................30
10.4
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)/CLINICAL TRIALS
AGREEMENT (CTA)................................................................................................................................................30


  5
11.
STATISTICAL
CONSIDERATIONS………………………………………………………………………………………………...31
12.
HUMAN SUBJECTS PROTECTIONS…………………………………………………………………..33
13.
DATA AND SAFETY MONITORING PLAN…………………………………………………………...34
APPENDIX A………………………………………………………………………………………………...............38
APPENDIX B: NCI/FDA PROTEOMICS PROGRAM STANDARD OPERATING PROCEDURE FOR 
TISSUE CORE COLLECTION- NEEDLE BIOPSY – CRYOPRESERVATION IN OCT…………………...39
FROZEN SECTION SLIDES..........................................................................................................................................40
SHIPPING SLIDES OR FROZEN TISSUE........................................................................................................................40
APPENDIX C: CYTOCHROME P450 3A4 METABOLIZED DRUGS………………………………………...41
 


  6
1. 
OBJECTIVES 
1.1 
Primary Objective 
The primary objective of this study is to determine if BAY 43-9006 is associated with a 50% 4 month 
probability of progression free survival in patients with metastatic AIPC as determined by clinical, 
radiographic and PSA criteria.   
1.2  
Secondary Objectives 
x 
Measurement of overall response rate and overall survival 
x 
Per Amendment D, a secondary objective of this study is to determine whether BAY 43-9006, 
when used to treat metastatic AIPC, is associated with 50% of patients progression free at 4 
months by clinical and radiographic criteria. The 22 patients treated on the first stage of this 
protocol will be retrospectively evaluated with respect to this secondary endpoint. Please refer to 
the statistics section for further details. 
x 
Demonstration of biologic effect by BAY 43-9006 in the patient and on the tumor (when possible) 
via correlative studies will be conducted on serially obtained tissue biopsies, bone marrow 
biopsies, and white blood cell collections.  Laboratory correlates will include elucidation of 
activation of components of the Raf-ERK-MEK and angiogenesis pathways using protein 
microarray technologies developed by the NCI/FDA clinical proteomics program.   
x 
Measurement of the pharmacokinetics of BAY 43-9006 in human patients with prostate cancer. 
x 
Description of the prostate specific antigen (PSA) response rate to therapy with BAY 43-9006. 
2. 
BACKGROUND 
2.1 
Androgen-Independent Prostate Cancer (AIPC) 
Prostate adenocarcinoma is the most common malignancy in American men and the second leading 
cause of cancer related deaths [1, 2].  According to the SEER database, 42% of patients have either 
metastatic disease or will eventually progress following local therapy. Whereas androgen ablation therapy 
is an effective initial modality, androgen independence and progression of disease eventually occurred in 
all patients with metastatic prostate cancer [3, 4].  The utilization of second line hormonal agents is 
generally associated with low response rates, and has no documented survival benefit.   
Chemotherapies have been extensively evaluated in patients with metastatic androgen independent 
prostate cancer (AIPC) since the 1970s.  The initial studies showed low response rates and high toxicities. 
 Recently, however, with the development of new agents targeting prostate cancer both on the cellular and 
molecular level, promising results have been emerging. The agents, including docetaxel, mitoxantrone, 
estramustine, vinblastine and etoposide, either as a single agent or as a combination therapy, have 
produced significant PSA responses in 30-80% of patients with median progression free survival of 3-5 
months [5]. Chemotherapeutic agents also showed benefits in pain control, and/or quality of life, with 
estramustine/docetaxel combination showing the most promise. In our prior trial of thalidomide in a similar 
patient population, the median time to treatment failure was 2.2 months.  However, the benefit in overall 
survival is still unknown.  There is no standard therapy for patients in this population which has been 
shown to have an impact on survival. Therefore, new therapeutic modalities are needed in patients with 
advanced AIPC. 
 
2.2 
BAY 43-9006 (Sorafenib) 
BAY 43-9006 represents a novel class of anticancer agents known as bi-aryl ureas.  It is a potent inhibitor 
of wild-type and mutant b-Raf and c-Raf kinase isoforms in vitro.  In addition, this agent also inhibits p38, 
c-kit, VEGFR-2 and PDGFR-E affecting tumor growth as well as possibly promoting apoptosis by events 
downstream of c-Raf.  At this time, over 500 patients have been treated with this drug with tolerable side 
effects [6].   
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 


  7
Raf/MEK/ERK cascade and the rac and rho pathways [7, 8].  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 [9-15].  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 [10, 11]. 
In Vitro Activity 
The ability of BAY 43-9006 to inhibit a number of kinases was evaluated [6].  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-ȕ (murine) 
0.028 
Flt-3 
0.058 
c-KIT 
0.068 
FGFR-1 
0.580 
p38Į 
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-ȕ 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 


  8
PDGFR-ȕ 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 [6].  In addition, BAY 43-9006 did not inhibit human EGFR or 
Her2 kinases at 10 PM.  Nor were PKC-Į, PKC-ȕ, PKC-Ȗ, 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 PM, 2.0 PM, and 3.1 PM, 
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-Į (r), PKC-ȕ (r), PKC-Ȗ at concentrations as high as 10 μM.  In 
summary, BAY 43-9006 showed 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-ȕ, Flt-3, c-KIT, and 
p38Į (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-ȕ receptor phosphorylation [6]. 
VEGF and PDGF receptors are involved in the mechanism of tumor angiogenesis [16, 17].  PDGF 
receptors may also play a role in patients with chronic myeloproliferative cancers [18].  Flt-3 is important in 
acute myelogenous leukemia [13] and c-Kit plays a critical role in gastrointestinal stromal tumors [19]. 
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. 


  9
 
BAY 43-9006 Demonstrates Broad Spectrum Anti-Tumor Efficacy in 
Preclinical Xenograft Models 
Tumor Type 
Model
Dose (mg/kg/dose 
free base equiv.)1
Percent TGI 
((1-(T/C))*100)
Colon 
HCT-116 
10 
30 
100 
45 
64 
68 
Colon 
DLD-1 
15 
30 
60 
31 
66 
75 
NSCLC 
NCI-H460 
10 
30 
27 
56 
NSCLC 
A549 
30 
60 
60 
68 
Mammary 
MX-1 
30 
60 
51 
67 
Pancreatic 
Mia-PaCa-2 
10 
30 
100 
45 
66 
73 
Ovarian 
SK-OV-3 
10 
30 
100 
58 
64 
81 
1  Compound dosed as 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 [6].  Recent data also indicated that inhibition of c-Raf may promote cell 
death in endothelial cells as a downstream event of VEGFR-2 stimulation [20]. 
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-ȕ. 


 
 10
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 
 
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.  The most common 
dose limiting toxicities (DLTs) in the phase I trials were hand-foot syndrome, fatigue, pain, diarrhea, 
elevated alkaline phosphatase, and abdominal pain/cramping.  DLTs were rarely attriubuted to the 
following:  hypertension weight loss, anorexia, pancreatitis, elevated amylase and lipase without 
pancreatitis,  
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 


 
 11
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. 
 
Pharmacokinetics
Pharmacokinetic studies in humans shows that BAY 43-9006 undergoes metabolism to a few primary 
metabolites, some of which may be active [6].  No data are available at this writing to describe the 
pharmacokinetics of repetitive dosing of BAY 43-9006 in patients.  However, up to 36 hours after a single 
dose, BAY 43-9006 continues to be the predominant species detected.  In vitro liver microsomal 
degradation studies data indicate that BAY 43-90006 is primarily metabolized by CYP 3A4.  Ongoing 
studies are being pursued by the Sponsor to evaluate drug-drug interaction potential of BAY 43-9006 with 
agents that alter function of CYP2C19, CYP2D6, and CYP3A4.  Moderate fat meals do not affect 
bioavailability of BAY 43-9006; it is in fact recommended to be administered with or around meals.  
Approximately 19% of dose is excreted in urine and 76% in feces.   
2.3 
Rationale 
Specific to prostatic adenocarcinomas, strong epithelial staining for Ras oncoproteins has been seen with 
a significant difference in expression levels between normal and tumor cells.  Furthermore, an inverse 
correlation between Ras positivity and degree of differentiation and survival has been reported [21, 22].  
Such findings suggest that functional activation of wild-type Ras might contribute to prostate 
tumorigenesis. 
Bakin and colleagues [23, 24] demonstrated that manipulation of Ras-related signaling affected sensitivity 
to hormonal interventions in vitro.  This pathway is involved in the mediation of responses to a number of 
growth factors as well angiogenic factors.  More recently, Fu and colleagues have been able to 
demonstrate that when Raf kinase inhibitor protein (RKIP) is transfected into C4-2B cells (malignant 
prostatic rat epithelial cells derived from LNCaP cells with a metastatic phenotype), invasion was 
decreased and development of lung metastases in animal models was no longer seen suggesting that this 
pathway is associated with suppression of tumor metastases [25].   
In addition to activity on Raf-associated signaling, BAY 43-9006 has been described to affect human 
VEGFR-2, murine VEGFR-2, murine VEGFR-3, murine PDGFR-ȕ, Flt-3, c-KIT, and p38Į (MAPK family).  
Multiple reports in the available literature report VEGF expression in most prostatic carcinomas [26] and 
expression of VEGFR may relate to migratory and invasive ability.  Furthermore, in vitro models have 
suggested that activation of p38-MAPK active pro-apoptotic pathway activity in prostate cancer [27].  
While the remainder of the targets listed above have not been well characterized in prostate cancer, their 
impact on the angiogenic cascade is of interest in prostate cancer as several groups have proposed 
manipulation of angiogenic signaling as a therapeutic target [28]. 
Given the potential role of the Ras-Raf pathway in metastatic prostate cancer in addition to the known in 
vivo and in vitro activity of the agent, we propose the execution of a phase II trial to measure the efficacy 
of this compound in preventing progression of AIPC. At this time little data exists for this agent in AIPC.  
This study represents the first formal inquiry into this matter. 
 
3. 
PATIENT SELECTION 
3.1 
Eligibility Criteria 
3.1.1 
Patients must have histopathological confirmation of prostate cancer by the Laboratory of 
Pathology of the NCI or Pathology Department of the National Naval Medical Center prior to entering this 
study.  Patients whose pathology specimens are no longer available may be enrolled in the trial if the 
patient has a clinical course consistent with prostate cancer and available documentation from an outside 
pathology laboratory of the diagnosis.  In cases where original tissue blocks or archival biopsy material is 
available, all efforts should be made to have the material forwarded to the research team for use in 
correlative studies. 
3.1.2 
Patients must have metastatic progressive androgen-independent prostate cancer.  There must 


 
 12
be radiographic evidence of disease after primary treatment with either surgery or radiotherapy 
that has continued to progress despite hormonal agents.  Progression requires that a measurable 
lesion is expanding, new lesions have appeared, and/or that PSA is continuing to rise on 
successive measurements. Patients on flutamide must have disease progression at least 4 weeks 
after withdrawal.  Patients on bicalutamide or nilutamide must have progression at least 6 weeks 
after withdrawal.   
3.1.3 
Patients may have had no more than 1 previous cytoxic chemotherapeutic line. 
3.1.4 
Because no dosing or adverse event data are currently available on the use of BAY 43-9006 in 
patients <18 years of age, children are excluded from this study. 
3.1.5 
Patients must have a life expectancy of more than 3 months. 
3.1.6 
Patients must have a performance status of 0 to 2 according to the ECOG criteria. 
3.1.7 
Patient must have adequate organ function as defined below: 
Leukocytes 
>3,000/ȝl 
absolute neutrophil count 
>1,500/ȝl 
Platelets 
>100,000/ȝl 
total bilirubin 
 
1.5 X  institutional upper limits of normal 
AST(SGOT) and ALT(SGPT) 
<2.5 X institutional upper limit of normal 
creatinine 
 
OR 
Creatinine clearance 
1.5 X  institutional upper limits of normal  
 
>60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
 
3.1.8 
Patients must have recovered from any acute toxicity related to prior therapy, including surgery.  
Toxicity should be  grade 1 or returned to baseline. 
3.1.9 
Hormonal profile:  all patients who have not undergone bilateral surgical castration must continue 
suppression of testosterone production by appropriate usage of GnRH agonists. 
3.1.10 Patients must not have other invasive malignancies (within the past two years with the exception 
of non-melanoma skin cancers or non-invasive bladder cancer).  
3.1.11   Patients must be able to understand and sign an informed consent form. 
3.1.12 Concurrent use of bisphosphonates will be allowed for patients with known bone metastases 
3.1.13   Patients who require hematopoietic growth factor support (e.g. epogen, darbepoetin) , NSAIDs, 
and other maintenance medications prior to study entry will be allowed to continue their supportive 
therapies. 
3.1.14   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 inhibitors are known to be teratogenic, men must 
agree to use adequate contraception (abstinence; hormonal or barrier method of birth control) prior to 
study entry and for the duration of study participation. 
 
3.2 
Exclusion Criteria 
3.2.1 
Patients who have had chemotherapy or radiotherapy (including radioisotopes) within 4 weeks (6 
weeks for nitrosoureas or mitomycin C; >3 months for suramin) prior to entering the study or those who 
have not recovered from adverse events due to agents administered more than 4 weeks earlier. 
3.2.2 
Patients may not be receiving any other investigational agents. 
3.2.3 
Patients with known brain metastases are excluded from this clinical trial because of their poor 


 
 13
prognosis and because they often develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events. 
3.2.4 
History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
BAY 43-9006 
3.2.5 
Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements.  
3.2.6 
Hypertension as defined by systolic blood pressure in excess of 170 mmHg or diastolic pressure 
in excess of 100 mmHg.  Patients with a history of hypertension that is well controlled on medication will 
not be excluded.  Patients may not be on either verapamil or diltiazem while on study.  Use of calcium 
channel blocker should be discouraged. 
3.2.7 
Patients with immune deficiency are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.  Therefore, HIV-positive patients receiving combination anti-retroviral 
therapy are excluded from the study because of possible pharmacokinetic interactions with BAY 43-9006. 
 Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when 
indicated. 
3.2.8 
History of bleeding diathesis 
3.2.9 
Patients on therapeutic anticoagulation are at increased risk from bleeding while on BAY 43-9006. 
 Prophylactic anticoagulation (i.e. low dose warfarin) of venous or arterial access devices is allowed 
provided that the requirements for PT, INR or PTT are met:  PT < 1.1 x institutional upper limit of normal; 
INR < 1.1; PTT within the institutional limits of normal.  These requirements will only be made upon those 
patients on warfarin. 
 
3.3 
Inclusion of Women and Minorities 
Men of all races and ethnic groups are eligible for this trial.  Women are excluded by the nature of the 
disease.   
 
3.4 
Baseline evaluation 
3.4.1 
Imaging Studies (Baseline- obtained within one month prior to enrollment):  Technetium-99 Bone 
Scintigraphy, Chest X-ray,  CT scan of chest, abdomen and pelvis  
3.4.2 
Laboratory Evaluation (Baseline- obtained within 16 days prior to enrollment) 
3.4.2.1 Hematological Profile:  CBC with differential and platelet count, PT, aPTT, fibrinogen 
3.4.2.2  Biochemical Profile:  electrolytes, BUN, creatinine, AST, ALT, total bilirubin, calcium, 
phosphorus, albumin, magnesium, uric acid, C-reaction protein, albumin, amylase, lipase, 
testosterone level. 
3.4.2.3 Tumor Marker Profile: PSA (baseline within 7 days prior to enrollment), acid phosphatase 
(if PSA <4 ng/mL, for research purposes only) 
3.4.2.4  Electrocardiogram (performed within 30 days prior to enrollment); Patients with a history 
of myocardial infarction or cardiac arrhythmias will undergo evaluation by cardiology. 
 
3.5 
Patient Registration 
3.5.1 
Authorized physicians or designees must telephone information concerning an eligible candidate 
to the Orkand personnel (Orkand is the current data management contract company for the Center for 
Cancer Research of the NCI) by fax at (301) 480-0757 between the hours of 8:30am and 5:00pm, Monday 
through Friday. 
3.5.2 
At the time of enrollment, eligibility criteria will be queried.  Protocol specific eligibility checklist will 
be developed by the Orkand staff and reviewed by the principal investigator. 


 
 14
3.5.3 
The Orkand personnel are to be called at the time any patient is taken off the study 
 
 
4. 
TREATMENT PLAN 
This study will be executed in a two-stage optimal design as described by Simon et al [29].  In the first 
stage, 22 patients will be enrolled and evaluated for progression.  If 8 patients show disease stability 
beyond 4 months accrual will continue to the full 46 patients.  If among the first 22 patients, 7 or fewer are 
able to be progression free at the 4 month evaluation, then no further patients will be enrolled and the 
study will close to accrual.  Should 18 or more patients remain progression free at 4 months, BAY 43-9006 
will be considered worthy of further development in clinical trials.  If 8-17 patients are progression free at 4 
months, the study set will be considered insufficient.  Under the null hypothesis (30% progression free at 4 
months), the probability of being able to stop accrual after 22 patients have been evaluated at 4 months is 
67%. 
The study was originally designed to have a two-stage design with 22 and then up to a total of 46 patients 
evaluating progression using PSA criteria. The results from the first stage were inadequate to justify 
accrual to the second stage. However, per amendment D, waiver of the stopping rule is requested to allow 
for accrual to the second stage. 
 
4.1 
BAY 43-9006 (Sorafenib) Administration 
At the outset of the study, the patient will be admitted to the inpatient service for a period of approximately 
24 hours to complete research studies including biopsies and PK measurements.  Otherwise, treatment 
will be administered on an outpatient basis.  Reported adverse events and potential risks are described in 
Section 6.  Appropriate dose modifications for BAY 43-9006 are described in Section 5.  No investigational 
or commercial agents or therapies other than those described below may be administered with the intent 
to treat the patient’s malignancy. 
BAY 43-9006 is supplied as 200-mg tablets and is administered orally twice a day. Patients are to swallow 
the tablets whole with approximately 250 ml (8 oz.) of water, each morning and evening (i.e., 12-hourly).  
Tablets may be taken with or without food.  BAY 43-9006 will be given as self-administered oral doses of 
400 mg bid continuously throughout the 28 day cycle.  Patients will be asked to administer the drug at 
approximately 08:00 and 20:00 hours.  Patients will be asked to maintain a diary to document 
consumption of BAY 43-9006 as out lined in section 6 and 12.6.7. 
Patients will be required to have weekly blood pressure monitoring for the first 4 weeks of the study at a 
healthcare facility given the risk of hypertension from BAY 43-9006.  This will be logged into the patient’s 
study diary during the first 4 weeks of treatment. 
4.2 
Supportive Care Guidelines 
4.2.1 
No premedications will be used with the initiation of therapy.   
4.2.2 
Nausea 
Should patients develop persistent nausea, they will be given appropriate antiemetic therapy 
following clinical center guidelines starting with prochlorperazine 10 mg PO/IV q8h prn. 
4.2.3 
Hand-Foot Syndrome 
o 
Treatment with topical emollients (such as Aquaphor) for symptom relief is permitted. 
o 
Topical and/or oral steroids or antihistamine agents may be used.   
o 
Vitamin B6 (pyridoxine; 50 - 150 mg orally each day) may also be used. 
 
4.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
o 
Disease progression 


 
 15
o 
Intercurrent illness that prevents further administration of treatment 
o 
Unacceptable adverse event(s) 
o 
Patient decides to withdraw from the study, or 
o 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
o 
Subject death 
 
5. 
DOSING DELAYS/DOSE MODIFICATIONS 
Toxicities will be described using CTCAE v3.  The following adjustment will only apply if the toxicities 
reported are attributed by the investigator to be related to BAY 43-9006 therapy. 
For Grade 1 toxicity, treatment with BAY 43-9006 will not be interrupted.  For symptoms that last more 
than 7 days and have been found to be intolerable to the patient, the dose of BAY 43-9006 may be 
reduced by 200 mg/day (i.e.200 mg qAM and 400 mg qPM as the initial reduction). 
For Grade 2 toxicity 
For nausea, vomiting and diarrhea, maintain dosing with symptomatic treatment.  The dose of 
BAY 43-9006 may be repeated if emesis occurs within 30 minutes of taking the tablet(s) OR all 
the tablets are seen in the emesis. 
For persistent nausea, vomiting or diarrhea despite symptomatic treatment that remains 
unacceptable (intolerable) to the patient, reduce dose by 200 mg/day (i.e.200 mg qAM and 400 
mg qPM as the initial reduction). 
For other grade 2 toxicities, the dose does not need to be reduced unless side effects become 
intolerable to the patient. 
If patients are receiving 200 mg bid at the time of occurrence/recurrence of toxicity, change the 
schedule of administration to 200 mg qd.  Reductions below this dose/schedule will not be 
allowed. 
Patients with intolerable or limiting toxicity while taking 200 mg qd will be removed from study.  .   
For Grade 3 clinical toxicity, or Grade 3/Grade 4 metabolic/hematologic toxicityHold BAY 43-9006 
and reevaluate the patient at least weekly until toxicity improves to  Grade 1 or pre-treatment 
baseline.  Grade 3 metabolic toxicities which can be corrected to  Grade 1 or pre-treatment 
baseline within 48 hours will not necessitate a dose reduction. For Grade 4 metabolic toxicity or 
Grade 3/4 hematologic toxicity the dose of BAY 43-9006 will be reduced by 200 mg/day. .  
Treatment will be discontinued in patients who experience toxicity  grade 3 or 4 that does not resolve 
to  grade 1 or baseline within 3 weeks. 
If patients are receiving 200 mg bid at the time of occurrence/recurrence of toxicity, change the 
schedule of administration to 200 mg qd.  Reductions below this dose/schedule will not be 
allowed. 
Patients with intolerable or limiting toxicity while taking 200 mg qd will be removed from study. 
For Grade 4 clinical toxicity 
Patients who had clinical grade 4 toxicity (except pulmonary embolism without significant hypoxia 
and hemodynamic instability) will be taken off study permanently.   
5.1  
Hypertension 
Given that hypertension is one of the major toxicities that may be experienced, all patients should 
have blood pressure measured and recorded weekly during the first 4 weeks and as needed, 
thereafter. 
 


 
Grade of Event (CTCAE v.3) 
Management/ Next Dose 
grade 1 
No dose modification 
grade 2 asymptomatic and diastolic 
BP < 110 mm Hg 
Begin (additional) 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; treat patient with anti-
hypertensives and when BAY 43-9006 is restarted, 
reduce dose level as described above* 
2. If diastolic BP not controlled ( 100) on therapy, 
reduce dose again** 
grade 4 
Discontinue protocol therapy 
* May be able to resume full dose later. 
      ** Patients requiring > 2 dose reductions should go off protocol therapy. 
Current CTCAE definitions used by CTEP: 
x 
Grade 1:  asymptomatic, transient (< 24 hours) increase by > 20 mmHg (diastolic) or to 
o 
>150/100 if previously WNL; intervention not indicated                                             
x 
Grade 2:  recurrent or persistent (> 24 hours) or symptomatic increase by > 20 mmHg        
o 
(diastolic) or to > 150/100 if previously WNL; monotherapy may be indicated 
x 
Grade 3:  requiring more than one drug or more intensive therapy than previously 
x 
Grade 4:  life threatening (e.g. hypertensive crisis) 
 
5.1.1  Recommended antihypertensive therapy 
Patients requiring additional antihypertensive therapy while on BAY 43-9006 should be 
started on a beta blocker, diuretic, angiotensin converting enzyme inhibitor (ACE-I) or an 
angiotensin II receptor blocker (ARB).  Doses should be advanced as needed until the 
patient is unable to tolerate the antihypertensive medication due to side effects.  If further 
medication is required a beta-blocker should be initiated and doses advanced. Calcium 
channel blockers should be avoided. 
5.1.2 
For severe hypertension, hypertensive urgency/emergency 
BAY 43-9006 should be held and the patient should be admitted.  An EKG should be 
obtained and, if appropriate, cardiology should be consulted.  Inpatient therapy for 
hypertension should be initiated. 
5.1.3 
Therapy may be continued if the hypertension is successfully controlled with 
additional medication.  However, for hypertension that persists despite additional medical 
therapy or becomes symptomatic, therapy will be held as described above.  If therapy is 
held for 4 weeks, the patient will be taken off of study. 
5.2        GI Perforation (NOS) 
If a patient experiences GI perforation while on study of any grade, patient must be taken 
off the study. 
 
6. 
PHARMACEUTICAL INFORMATION 
6.1 BAY 43-9006 (Sorafenib, NSC 724772, IND 38583)   
6.1.1 
Source:  BAY 43-9006 will be supplied by the Bayer Health Care Corporation and distributed by 
CTEP 
 
 16


 
 17
6.1.2 
Chemical name and identification 
Chemical Name: 4–-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.  
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 p38Į, 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 of Administration: Oral 
Reported Adverse Events and Potential Risks:   
Body as a whole:  
fatigue, flu-like syndromes, fever, arthralgia 
Gastrointestinal:  
diarrhea, pancreatitis, elevated amylase/lipase, abdominal 
pain/cramping, nausea, flatulence, dyspepsia 
Hepatic:
increased bilirubin, ALT, AST, GGT, LDH, and alkaline 
phosphatase 
Metabolic and Nutritional: 
anorexia 
Skin:
hand-foot syndrome, characterized by palmar and plantar 
erythema; rash/desquamation, hypersensitivity reactions, dry 
skin, alopecia, nail changes, vitiligo, itching 
Cardiovascular:  
cardiac arrhythmias 
Other: 
voice changes 
The following adverse events have been reported on trials but with the relationship to BAY 43-9006 still 
undetermined:  arthritis, brain stem stroke, dyspnea, hypertension, increase PT and PTT, and weight loss. 
 
Method of Administration:  
BAY 43-9006 tosylate should be taken with at least 250 mL of water and 
can be given without regards to meals. Food does not appear to have a 


 
 18
clear effect on BAY 43-9006 tosylate pharmacokinetics. 
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, 
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. 
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 drugs received from DCTD using the NCI Drug Accountability Record 
Form (DARF).   BAY 43-9006, as an oral self-administered investigational agent, will be properly 
accounted for, handled, and disposed in accordance with CCR Policy # Clin-1 “Policy on Documenting, 
Handling and Disposing of Oral Investigational Agents that are Self-Administered by NCI CCR patients.”  
The Standard Operating Procedure # Clin-1 “Standard Operating Procedure for Conducting and 
Documenting Drug Accountability for Oral Investigational Agents that are Self Administered by Patients at 
the CCR” identifies all activities associated with drug accountability for orally self administered 
investigational agents.  Study drug may be repackaged by the Clinical Center Pharmacy Dept. and 
dispensed in light-resistant HDPE containers that contain up to a 28-day supply of BAY 43-9006..  
Patients will be instructed to document on a study diary the daily intake of BAY 43-9006, including the time 
the dose is taken, and whether or not any doses are missed.  They will bring the study diary and any 
unused drug to their clinic appointments.  Clinic staff will (1) collect all “old” [i.e., empty bottle(s), partial 
bottle(s) or full bottle(s)] of study drug; (2) perform a capsule count and record the results on the approved 
CCR Pill Count Case Report Form which is to be maintained in the research record; (3) dispense the 
partial and full bottle(s) of BAY 43-9006 to the patient.  Unused study drug is to be returned to the 
research nurse who will dispose of it according to the SOP. 
7. 
CORRELATIVE/SPECIAL STUDIES 
 
7.1 
Tissue analysis for molecular endpoints 
Given the nature of this pharmacologic intervention, characterization of the actual biological manipulation 
will be critical in understanding the biological effects seen following administration.  Tissue samples will be 
analyzed to achieve this goal. 
The collection of correlative studies is designed to characterize a baseline molecular profile as well as a 
treatment-induced molecular profile.  Raf mutational analysis will allow for retrospective analysis of 
responsiveness in the presence or absence of mutations.  Proteomic analysis will provide profiles of 
signaling pathways pre-treatment and on treatment so as to understand how this agent affects a variety of 


 
 19
important signaling cascades associated with its reported molecular targets.  In particular, primary 
endoints address key events in survival, proliferation, and angiogenesis which will affected either directly 
or downstream of Raf or VEGFR/PDGFR targets.  Pharmacokinetic anlaysis will provide insight into 
dosing efficacy as it realtes to both biological activity and clinical response. 
Correlative laboratory studies for this trial will be conducted in the Clinical Pharmacology Section of Dr. 
William D. Figg at the NCI and by Dr. Elise C. Kohn. All patients will have leukocyte collections (by 
standard buffy coat preparation) to evaluate for tumor and gene expression alterations related to drug 
therapy.  Patients with accessible disease will have tumor biopsies before and during treatment for 
molecular analysis described below. 
Tumor Biopsies 
Bone Marrow 
Archival Tissue 
Leukocytes
Proteomic pathway 
analysis 
Proteomic pathway 
analysis 
B-Raf genomic analysis 
Proteomic pathway 
analysis 
B-Raf mutational 
screening 
Cross-validation with 
tumor biopsy 
 
Cross-validation with 
tumor biopsy 
 
7.1.1 
Accessible tumor biopsy 
Biopsies of accessible tumors will be required prior to initiation of therapy and prior to starting 
cycle 2 as described.   Patients should avoid the use of aspirin or non-steroidal anti-
inflammatory drugs for 1 week prior to biopsy to ensure safety.  Accessible tumors will be 
defined as those masses which can be safely accessed by a core needle biopsy while posing 
minimal risk to the patient.  These lesions may be cutaneous or palpable or demonstrable under 
CT or ultrasound guidance.   Determination of accessibility and safety will be made jointly by an 
investigator and a staff member from Special Procedures.  Accessible tumors will be defined as 
those masses which can be safely accessed by a core needle biopsy under CT or ultrasound 
guidance or while posing minimal risk to the patient.  Laser capture microdissection and cell 
lysates will be prepared for protein microarrays with targets as identified below.  Garreth Peters 
(pager 104-4587-7 or 301-402-4622) or Dr. Edwin Posadas (phone 301-451-4982 pager 104-
6563) should be contacted to arrange for sample collection.  Samples should be preserved in 
OCT according to the NCI/FDA clinical proteomics program SOP (appendix B).  Samples should 
be barcoded and stored in liquid nitrogen until the time of preparation for microdissection. 
Biopsy specimens will be used for tissue lysate array analysis in the proteomics laboratory (see 
section 7.2) for signal pathway profiling before and during treatment as well as Raf mutation 
detection via TLA. 
7.1.2. 
Bone marrow biopsy and aspiration 
In addition to attempting to obtain tumor biopsies, attempts will be made to determine effect in 
both bone marrow and in white blood cells.  Bone metastases are a common event in metastatic 
prostate cancer affecting about 80% of patients.  In limited series, bone marrow trephines and 
aspirations were shown to yield metastatic tumor cells in 75% of cases using traditional 
histopathologic techniques [30].  Given the fact that patients often have bone as their sole site of 
metastasis and the relative difficulty of obtaining soft tissue biopsies for direct tumor sampling, 
bone marrow aspiration and biopsy may be a powerful tool in assessing biological response both 
in the tumor and in the tumor microenvironment.  This question will be addressed using protein 
microarrays in conjunction with immunohistochemistry on these samples. 
Marrow cores and aspirate collection will not be mandated, but will be requested of all patients.  In 
addition, given the activity of BAY 43-9006 on angiogenic pathways and receptor tyrosine kinases, 
markers of angiogenesis including VEGFR and PDGFR and associated signals will be 
characterized as well.  These results will be compared to findings obtained for tumor biopsy 
analysis to describe the correlation of these findings. 
Bone marrow specimens should be obtained from the posterior iliac crest when possible.  
Aspiration should precede trephine biopsy collection.  A total of 2-3 ml of marrow will be aspirated 
into a heparainzed syringe with no heparin remaining in the syringe at the time of collection.  The 


 
 20
aspirate should be preserved in 0.5 ml aliquots stored in cyropresevation (Nunc) vials and will be 
stored in the laboratory of Dr. W. Douglas Figg until processing.  The samples should be 
immediately frozen and stored at – 80 C until thawed for analysis.  Biopsy material should be 
collected by a representative of Dr. Figg’s laboratory.  Garreth Peters (pager 104-4587-7 or 301-
402-3622) should be notified for sample collection.  
Trephine biopsies (bone marrow core biopsies) should be immediately preserved in OCT, 
barcoded, and stored in liquid nitrogen until the time of utilization. 
Bone marrow biopsies will be lysed and printed on protein lysate arrays and analyzed as 
described below (section 7.2).     
 
7.1.3 
Leukocyte analysis 
In addition to either direct tumor or bone marrow analysis, leukocytes will be isolated by buffy coat 
and lysed for correlative analysis of the Ras/Raf pathway elements, angiogenic markers, and RTK 
makers using the same protein microarrays proposed above as a surrogate to the bone marrow 
and tumor analysis.  Approximately 10 ml of blood will be drawn using a CPT collection tube 
(Becton Dickinson).  The blood will be centrifuged and the buffy coat layer of white blood cells will 
be removed, washed in cold PBS and pelleted by centrifugation.  The DNA will be processed 
using a column purification technique (Qiagen), or the buffy coat pellet will be frozen for future 
DNA extraction. 
7.1.3 
Archival tissue 
Archival tissue blocks will be collected for genomic DNA extraction for B-Raf mutational analysis 
in the laboratory of Dr. Paul Meltzer.  This process will be streamlined using screening methods 
described in section 7.6. 
 


 
 21
7.2 
Pharmacoproteomic analysis 
7.2.1 
The primary targets of pharmacoproteomic modulation to be measured were defined 
based upon the preclinical signaling data.  They are listed below 
Survival/Proliferation 
Angiogenesis
Apoptosis
Other
AKT 
p-AKT 
eNOS 
p-eNOS 
PARP 
Cleaved-PARP 
PSA 
ERK 1 / 2 
p-ERK 1 / 2 
PDGFRE 
p-PDGFRE 
Caspase 9 
Cleaved 
Caspase-9 
 
Cyclin D1 
 
CD31 
 
Caspase 3 
Cleaved 
Caspase-3 
 
 
7.2.2  
Should additional tissue or TLA arrays be available, the following targets will be 
characterized. These will include but are not limited to the following: 
Survival/Proliferation 
Angiogenesis
Apoptosis
Other
mTOR 
p-mTOR 
D-smooth muscle actin 
p53 
PSMA 
EGFR 
p-EGFR 
Pyk2 
p-Pyk2 
GSK3ß 
p-GSK3ß 
Cytokeratin-1 
Src 
p-Src 
VEGFR-2 
p-bad 
 
NFkB 
p-NFkB 
 
p-Bcl-2 
 
STAT1 
p-STAT1 
 
 
 
TGFa 
 
 
 
 
p38 
Phospho-p38 
 
 
 
Jak1 
pJak1 
 
 
 
IkB 
p-IkB 
 
 
 
IGFR 
 
 
 
 
 
7.2.3. 
Provided that the following antibodies be validated for usage and adequate tissue or TLA 
arrays be available, the following additional targets will be characterized: 
Survival/Proliferation 
Angiogenesis
Apoptosis
PCNA 
DvE3 complex 
Bad 
Fos  
CD34
Annexin V 
Raf 
VEGFR-1
Bcl-2 
Ras 
bFGF
 
CREB 
vWF
 
Rho 
Factor VIII
 
Jun 
pJun 

 
pIkB 

 
 
Any unused tissue collected during the study will be saved for future studies, including 
assessment of the differences in gene expression/protein profiles in pre- and post-treatment using 
cDNA and protein microarray analyses in addition to other genomic and proteomic technologies.  
Consent for such procedures will be procured at the time of study enrollment. 


 
 22
 
7.4  Imaging studies 
Non-invasive imaging has become a standard tool in the clinic to monitor primary and metastatic solid 
tumors.  CT scan and bone scan will be performed on all patients at study entry and after every 2 cycles to 
assess clinical response to BAY 43-9006.   
7.5  Assessment of the pharmacokinetic parameters of BAY 43-9006 
Blood samples will be obtained serially from prior to ingestion until 24 hours post-dose at the following 
time points: immediately pre-dose, and at 0.25, 0.50, 1, 2, 4, 6, 8, 12, and 24 hours after ingestion, and 
then at each clinic visit.  In the event that inpatient admission is not possible, PKs may be done on an 
outpatient basis.  When outpatient PKs are being collected an hour 12 PK will not be required. The Clinical 
Pharmacology Research Core of Dr. William D. Figg will coordinate rapid acquisition and evaluation of 
patient samples.  The pharmacokinetic characteristics of BAY 43-9006 in patients with AIPC will be 
evaluated using the WinNonlin software (Pharsight, Mountain View, CA).  The maximum concentration, 
time to maximum concentration, the area under the curve extrapolated to infinity, and the apparent 
terminal half-life will be calculated.  Pharmacodynamic study will address any correlation in BAY 43-9006 
concentration with disease response and/or toxicities.    
7.6  
B-Raf mutation analysis 
It has recently been found that B-Raf is commonly mutated in human tumors.  To determine if BAY 43-
9006 preferentially inhibits tumors with mutant B-Raf, mutational analysis of B-Raf using the following 
paradigm:  
Initial screening for B-Raf mutation will be executed by protein lysate array analysis.  The most frequently 
observed mutation in B-Raf is the V599E [31] amino acid substitution.  Dr. Meltzer’s group has developed 
a monoclonal antibody specific to this mutation (unpublished data).  Lysate arrays will be optimized with 
this monoclonal antibody and then will be used to assess expression of this BRAF mutation. .  Detection of 
this protein product will prompt allele specific PCR analysis of this region of the tumor genome using a 
recut from the tumor biopsies obtained for the protocol.  No germline analysis will be done.  Additionally, 
once a cohort of responders has been identified, genomic DNA will be extracted from tissue blocks for 
allele specific PCR in the other commonly mutated region, T1769A. 
7.7 
 
Labeling, Storage, and Tracking 
x All labels used must be freezer-proof. 
x Barcode labels will be used in this study.  A sample of the barcode will 
be provided to the processing laboratory by Dr. Figg’s laboratory 
before use because some DNA processing laboratories have 
encountered scanning incompatibility due to inclusion of hidden digits 
in barcode labels.
x Label each collection tube with the following information: 
- unique sample I.D.  
- study I.D. (NCI protocol number,  etc.) 
x All data associated with samples is entered into the Clinical 
Pharmacology Program’s “Patient Sample Database Management 
System” (PSDMS) - Labrador. This is a secure program that can only 
be accessed by authorized users in Dr. Figg’s lab. PSDMS creates a 
unique barcode ID for every sample and sample box which cannot be 
traced back to patients without PSDMS access 


 
 23
x The data recorded for each sample includes the patient ID, name, trial 
name/protocol number, time drawn, cycle time point, dose, material 
type, as well as box and freezer location. There are patient 
demographics that can be obtained to correlate with the samples 
through the PSDMS system.  For each sample, there are associated 
processing notes (i.e., delay in sample processing, storage conditions 
on the ward, etc.).  Bar-coded samples are stored in bar-coded boxes in 
a locked freezer at either -20 or -85qC according to stability 
requirements.  These freezers are located onsite in Dr. Figg’s lab and 
offsite at NCI Frederick Central Repository Services (Fisher 
Bioservices) in Frederick, MD. Samples will be stored until requested 
by the researcher assigned to the protocol (however, those requests 
must come from a member of Dr. Figg’s laboratory with PSDMS 
access/clearance).  All requests are monitored and tracked in the 
PSDMS system. All researchers are required to sign a form stating that 
the samples are only to be used for research purposes associated with 
this trial (as per the IRB approved protocol – that protocol is stored in 
the PSDMS system) and that any unused samples must be returned to 
Dr. Figg’s laboratory.
x After collection, blood samples must be refrigerated (+ 4°C) or frozen 
(see chart below) at the site of collection and transported to the central 
reference laboratory or designated DNA processing laboratory as soon 
as possible.
Option
Storage
Temperatur
e at 
Treatment
Site
Maximum
Duration of 
Storage at 
Treatment
Site
Transport
Temperature
Delivery
Time
1
+ 4°C 
(fridge)
24 hours 
0 - 4°C (ice 
blocks)
24 hours 
2
+ 4°C 
(fridge)
24 hours 
Less than -20°C 
(dry ice) 
24-72
hours
x Samples must not be thawed and then re-frozen at any point. 
Protocol Completion/Sample Destruction
x Once primary research objectives for the protocol are achieved, 
intramural researchers can request access to remaining samples 
providing they have an IRB approved protocol and patient consent. 


 
 24
x Samples, and associated data, will be stored permanently unless the 
patient withdraws consent. If researchers have samples remaining once 
they have completed all studies associated with the protocol, they must 
be returned to Dr. Figg’s laboratory. 
The PI will report destroyed samples to the IRB if samples become unsalvageable 
because of environmental factors (ex. broken freezer or lack of dry ice in a shipping 
container) or if a patient withdraws consent. Samples will also be reported as lost if they 
are lost in transit between facilities or misplaced by a researcher.  Dr. Figg’s laboratory 
will report any freezer problems, lost samples or other problems associated with samples 
to the IRB, the NCI Clinical Director, and the office of the CCR, NCI. 
 
 
 


 
 25
8. 
STUDY CALENDAR 
Schedules shown in the Study Calendar below are provided as an example and should be modified 
as appropriate (+/- 1-2 days to allow for clinic variations around federal holidays). 
Baseline evaluations are to be conducted within 1 week prior to administration 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. 
 
 
 
Pre-
Study 
C1D1 
C1D2-
28 
C2D1 
C3D1 
C4D1 
C5D1 
C6D1 
C7D1 
Q4 
weeks 
Q12 
weeks 
Off 
Study
c 
 
BAY 43-9006 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Concurrent Meds 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Physical exam 
 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Vital signs 
 
X 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Performance status 
 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
CBC w/diff, plts, PT, PTT 
 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum chemistry
b 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
PSA 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
EKG (as indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tumor measurements 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Radiological Evaluation 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
 
Tumor Biopsy OR Bone 
Marrow Biopsy and Aspirate 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other correlative studies 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
a:  BAY 43-9006: Dose as assigned; route/schedule. 
b:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT(AST), SGPT(ALT), sodium, amylase, lipase 
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. 


 
 26
9. 
MEASUREMENT OF EFFECT 
For the purposes of this study, patients should be reevaluated for response every 8 weeks for the first 6 
months of the study.  After 6 months, CT and bone scans should be obtained at least every 3 months to 
monitor disease status while on BAY 43-9006.  In addition to a baseline scan, confirmatory scans should 
also be 4 weeks following initial documentation of objective response. 
9.1 
Definitions 
Response and progression will be evaluated in this study using the new international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [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. 
9.1.1 
Measurable disease
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
9.1.2 
Non-measurable disease
All other lesions (or sites of disease), including small lesions (longest diameter <20 
mm with conventional techniques or <10 mm using spiral CT scan), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all 
non-measurable. 
9.1.3 
Target lesions
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in 
total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis 
of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  A sum of the 
longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD.  The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
9.1.4 
Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline.  Non-target lesions include measurable lesions 
that exceed the maximum numbers per organ or total of all involved organs as well as 
non-measurable lesions.  Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  
9.2 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 
4 weeks before the beginning of the treatment. 
Note: Tumor lesions that are situated in a previously irradiated area might or might 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 


 
 27
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 complete disappearance of superficial lesions usually assessed by clinical examination. 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation has not yet 
been fully and widely validated.  Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may only be available in some centers.  Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation purposes in reference centers. 
However, such techniques may be useful to confirm complete pathological response when biopsies are 
obtained. 
Cytology, Histology.  These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
9.3 
Response Criteria 
9.3.1 
Evaluation of target lesions 
 
Complete Response (CR): Disappearance of all target lesions 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference 
the baseline sum LD 
 
Progressive Disease (PD):  
At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum 
LD recorded since the treatment started or the 
appearance of one or more new lesions 
 
Stable Disease (SD): 
 
 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment 
started 
 
9.3.2 
Evaluation of non-target lesions 


 
 28
 
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. 
 
9.3.3 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria (see section 9.3.1). 


 
 29
 
 
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. 
 
9.4 
Confirmatory Measurement/Duration of Response 
9.4.1 
Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be 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 8 weeks (see 
section 9.3.3). 
9.4.2 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
 


 
 30
9.4.3 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since 
the treatment started.  
9.5 
Biochemical Response Criteria –PSA measurements (PSA Consensus Criteria) (Bubley et al. 
1999) 
9.5.1 
PSA Decline of 50% 
 A decline of PSA of at least 50% (confirmed by a second value at least 4 weeks after the first) 
with no other evidence of disease progression. 
9.5.2.    PSA Progression (all progression dates require to be confirmed by a second value after 
the first no sooner than 4 weeks after the initial measurement) 
A 50% increase in PSA over nadir (confirmed by a second reading four weeks later) in patients 
whose PSA has fallen by at least 50%. PSA increase must be at least 5ng/ml. 
9.5.2.1 A 25% increase in PSA over nadir (confirmed by a second reading) in patients 
whose PSA has not fallen by at least 50%.  PSA increase must be at least 5ng/ml. 
9.5.2.2 A 25% increase in PSA over baseline in patients whose PSA has not decreased.  
PSA increase must be at least 5ng/ml. 
9.5.3 
Time to PSA Progression 
The time between the first day of treatment to the day of PSA progression as described in 9.5.2.   
the day of progression is defined as the first study day when the PSA level meets progression 
criteria (not the day of verification). 
9.5.4  Per amendment D, Biochemical Response Criteria will continue to be measured as a 
primary endpoint, however patients may continue to receive BAY 43-9006 as long as they do not 
have clear evidence of radiographic or clinical progression. 
 
 
9.6 
Progression-Free Survival 
The primary objective of this study is to determine whether BAY 43-9006, when used to treat metastatic 
androgen independent prostate cancer (AIPC), is associated with 50% of patients progression free at 4 
months by PSA and clinical criteria.  Patient monitoring studies and definitions of response are defined 
above.  Please refer to the statistics section for further details. 
Per Amendment D, a secondary objective of this study is to determine whether BAY 43-9006, when used 
to treat metastatic AIPC, is associated with 50% of patients progression free at 4 months by clinical and 
radiographic criteria. The 22 patients treated on the first stage of this protocol will be retrospectively 
evaluated with respect to this secondary endpoint. Please refer to the statistics section for further details. 
 
9.7 
Response Review-  N/A 
 
10. 
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 


 
 31
Events (CTCAE) version 3.0 will be utilized for adverse event reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 3.0.  A 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 3.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/reporting/ctc.html).
 
10.1 
Expedited Adverse Event Reporting 
 
(AE; formerly known as Adverse Drug Reaction) 
Expedited reports are submitted to CTEP via the secure AdEERS application accessed via the CTEP web 
site (https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup) and to the NCI IRB.  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. 
 
10.1.1 Expedited Reporting Guidelines 
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 & 5
2
Grades
4 & 5
2
Unexpected
Expected
 
Unexpected
and
Expected 
Unex-
pected 
Expected 
with  
Hospitali-
zation 
without 
Hospitali-
zation 
with  
Hospitali-
zation 
without 
Hospitali-
zation 
Unex-
pected
Expected
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: 
x 
Grade 4 and Grade 5 unexpected events  
 
AdEERS 10 calendar day report: 
x 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
x 
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 must be reported using expedited reporting regardless of causality.
Attribution to treatment or other cause should be provided. 
 
x 
Expedited AE reporting timelines defined: 
¾ “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. 
¾ “10 calendar days” - A complete AdEERS report on the AE must be submitted within 10 
calendar days of the investigator learning of the event.  
 
x 
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 


 
 32
expedited adverse event reporting exclusions. 
 
x 
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. 
 
x 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
10.1.2 Expedited Adverse Event Reporting Exclusions- N/A 
10.1.3 Secondary AML/MDS 
Investigators are required to report cases of secondary AML/MDS occurring on or following treatment on 
NCI-sponsored chemotherapy protocols using the NCI/CTEP Secondary AML/MDS Report Form.  This
form can be downloaded from the CTEP web site (http://ctep.cancer.gov/reporting/index.html). Second 
malignancies and non-AML/MDS secondary malignancies (e.g., endometrial cancer in a breast cancer 
patient receiving tamoxifen) should NOT be reported via AdEERS but should be submitted as part of the 
study results via routine CDUS reporting. 
 
10.2 
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). 
 
10.3 
CTEP Multicenter Guidelines- N/A 
10.4 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) 
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 ACollaborator(s)@) and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the 
following obligations/guidelines, in addition to the provisions in the AIntellectual Property Option to 
Collaborator@ contained within the terms of award, apply to the use of the 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 or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data.@): 
a. 
NCI must provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NIH, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 


 
 33
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and  
commercialization of its own investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a collaborative agreement will be 
made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate. 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 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: 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 Collaborators 
confidential/ proprietary information. 
 
11. 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Endpoints 
The study was originally designed to have a two-stage design with 22 and then up to a total of 46 patients 
evaluating progression using PSA criteria. The results from the first stage were inadequate to justify 
accrual to the second stage. However, per amendment D, waiver of the stopping rule is requested to allow 
for accrual to the second stage. 
 
The primary objective of this study is to determine whether BAY 43-9006, when used to treat metastatic 
AIPC, is associated with having 50% of patients progression free at 4 months by clinical, radiographic and 
PSA criteria.  The secondary objective of this study is to determine the time to progression measured by 


 
 34
clinical and radiographic criteria. If this is found to be the case, then this agent will be considered 
potentially useful when combined with other anticancer agents to be tested in later trials.  Data from 
previous trials of NCI patients with similar eligibility requirements demonstrated a 2.1 month median 
progression free survival when using thalidomide (n=63) [32].  Median progression free survival on 
ketoconazole alone is expected to be 4 months based on previous trials[33]. Ketoconazole is recognized 
as a standard therapy alterative to cytotoxic chemotherapy in the setting of failure of primary hormonal 
therapy with GnRH agonists and anti-androgen therapy.  The Eastern Cooperative Oncology Group is 
currently sponsoring a phase III clinical trial comparing ketoconazole to the combination of estramustine 
and docetaxel.  Median progression free survival on ketoconazole alone is expected to be 4 months based 
on previous trials [34, 35].  Based on these results, it would be useful to demonstrate whether BAY 43-
9006 is able to induce progression free survival in 50% of patients at the 4 month (approximately day 113 
evaluation) time point. 
The study will be conducted as a two-stage optimal design (Simon 1989)[29]. Using alpha=0.10 and 
beta=0.10 as acceptable error probabilities, the trial will target 50% as the desirable proportion of patients 
who are still without progression by clinical, radiographic and PSA criteria at the 4th monthly evaluation 
(p1=0.50; see section 9.5.1 for details), and will be considered inadequate if only a fraction consistent with 
30% are without progression by the same evaluation time (p0=0.30). 
Initially, 22 patients will be enrolled and evaluated for progression. The enrollment will be 
temporarily halted after the 22nd patient unless we know that 8 patients have passed the 4 month 
point without progression.  If 8 or more of the first 22 patients enrolled on the trial have not 
progressed as defined in Section 9.3 and 9.4 at the 4th evaluation (day 113, approximately), then 
enrollment will continue until 46 patients have been enrolled.  If, among the first 22 patients 
enrolled, 7 or fewer are able to be progression free at the 4 month evaluation, then the original 
design specified that no further patients will be enrolled once such a determination has been 
made. If 18 or more of the total cohort of 46 patients have been found to be progression free at 4 
months, then this will indicate an adequate progression free probability to be worthy of further 
consideration in future trials.  On the other hand, if 8-17 of 46 are progression free at 4 months, 
this will be considered insufficient.  Under the null hypothesis (30% progression free at 4 months), 
the probability of being able to stop accrual after 22 patients have been evaluated at 4 months is 
67%. However, under amendment D, the stopping rule will be waived due to potential benefit 
identified in patients during the first stage, despite failure to meet criteria established for continuing 
accrual. The total set of 46 patients will be evaluated with respect to progression free survival, 
using clinical, radiographic and PSA criteria to primarily focus on 4 month progression free 
survival. In addition, progression free survival evaluated by clinical and radiographic measures 
only will be determined on all evaluable patients from whom this may be determined. 
 
Given the difficulties in interpreting progression free rates in our patients compared to historical data, the 
response rate will be included as a secondary clinical endpoint.   
In addition to evaluation of the proportion progression free at 4 months, the progression free 
survival will also be analyzed via a Kaplan-Meier curve.  This will be done for both progression 
free survival evaluated by clinical, radiographic and PSA criteria, as well as secondarily based 
only on clinical and radiographic criteria. This latter, secondary, evaluation will be based on all 
patients who are able to be assessed by these criteria in either the first (retrospectively) or second 
stage of accrual.  
 
 
11.2 
Sample Size/Accrual Rate 
Based on previous efforts in recruiting patients with this disease onto trials at the NCI, it is anticipated that 
30 patients per year may be able to enroll onto this protocol. Thus, it is expected that accrual to this trial 
can be completed in approximately 1.5 years if all 46 patients are to be enrolled 
 
11.3 
Stratification Factors 


 
 35
There are no stratification factors 
 
11.4 
Analysis of Secondary Endpoints 
Proteomic, PSA, pharmacokinetic, and molecular endpoints will be evaluated on the protocol in all 
available enrolled patients.  These will all be considered exploratory analyses, and will not have their 
statistical results adjusted for multiple comparisons. However, all interesting findings will be carefully 
interpreted as hypothesis generating. 
 
11.5 Reporting and Exclusions 
11.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with BAY 43-9006 
11.5.2 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.  
12. 
HUMAN SUBJECTS PROTECTIONS 
12.1 
Rationale for subject selection 
Subjects treated on this study, will be individuals with metastatic prostate cancer, which has recurred (or 
persisted) after appropriate standard treatment.  Individuals of any race or ethnic group will be eligible for 
this study.  Eligibility assessment will be based solely on the patient’s medical status.  Recruitment of 
patients onto this study, will be through standard CCR mechanisms.  No special recruitment efforts will be 
conducted. 
12.2 
Evaluation of benefits and risks/discomforts 
The potential benefit to a patient that goes onto study, is a reduction in the bulk of their tumor and 
improvement in their bony lesions, which may or may not have favorable impact on symptoms and/or 
survival.  Potential risks include the possible occurrence of any of a range of side effects, that are listed in 
the Consent Document (Please refer to http://ctep.cancer.gov/reporting/adeers.html to review the up-to-
date expected adverse event list for BAY 43-9006).  The procedure for protecting against or minimizing 
risks, will be to medically evaluate patients on a regular basis as described in Section 9. 
12.3 
Risks to patients in relation to anticipated benefits 
12.3.1 For patients with androgen-independent prostate cancer, median survival is in the range 
of 12-18 months.  Potential risks include the possible occurrence of any of a range of side effects 
listed in section 6.  Please refer to http://ctep.cancer.gov/reporting/adeers.html to review the up-to-
date expected adverse event list for BAY 43-9006.   
12.3.2 Risk of serial biopsies: All care will be taken to minimize risks that may be incurred by 
tumor sampling.  However, there are procedure-related risks (such as bleeding, infection and 
visceral injury) that will be explained fully during informed consent. If patients suffer any physical 
injury as a result of the biopsies, immediate medical treatment is available at the NIH’s Clinical 
Center in Bethesda, Maryland.  Although no compensation is available, any injury will be fully 


 
 36
evaluated and treated in keeping with the benefits or care to which patients are entitled under 
applicable regulations. 
12.4 
Consent process 
Patients will meet with an associate or principal investigator on the trial in the Prostate Cancer Clinic, 
during the initial evaluation for this study.  During that meeting, the investigator will inform patients of the 
purpose, alternatives, treatment plan, research objectives and follow-up of this trial.  The investigator will 
then provide a copy of the IRB-approved informed consent document that is included in this protocol.  The 
patient will be allowed to take as much time as he wishes, in deciding whether or not he wishes to 
participate.  If a prolonged period of time expires during the decision making process (several weeks, as 
an example), it may be necessary to reassess the patient for protocol eligibility.  A copy of the signed 
informed consent will be placed in the patient's medical record and the original held in the Protocol Office. 
 
12.5 
All patients must have a signed informed consent form and an on-study (confirmation of eligibility) 
form filled out and signed by a participating investigator before entering on the study. 
12.6 
Patient Records and Quality Assurance 
Quality assurance complete records must be maintained on each patient treated on the protocol.  These 
records should include primary documentation (e.g.: laboratory report slips, X-ray reports, scan reports, 
pathology reports, physicians notes, etc.) which confirm that: 
12.6.1  The patient met all eligibility criteria 
12.6.2   Signed informed consent was obtained prior to treatment 
12.6.3  Treatment was given according to protocol (dated notes about doses given, 
complications, and clinical outcomes). 
12.6.4   Toxicity was assessed according to protocol (laboratory report slips, etc.) 
12.6.5   Response was assessed according to protocol (X-ray, scan, lab reports, date noted on 
clinical assessment, as appropriate). 
12.6.6 Drug Accountability  
The unused BAY 43-9006 (partial bottles, empty bottles, and full bottles) will be returned for drug 
accountability at each clinic visit.  An oral study agent case report form will be used to document 
drug accountability for each patient on this study.  Unused agent, which is not returned to the 
patient for the next dose cycle, will be disposed of according to the Procedure of Disposal of 
Returned Oral agents. 
12.6.7 Patients will use a diary to document daily drug intake and adverse events.                
13. 
Data and Safety Monitoring Plan 
 
A complete CDUS report will be submitted to CTEP on a quarterly basis.  Response data will be on a 
quarterly basis as well. All adverse drug reactions will be reported to the NCI Institutional Review Board 
(IRB) within 10 working days of the date of occurrence. Safety information from patients enrolled onto the 
study will be gathered and reported.  Any unusual toxicity will be explored for possible causative 
mechanisms.  The safety of the repetitive biopsy procedure will also be determined and reported. 
13.1  
Any unanticipated or unknown treatment- or drug-related toxicity(ies) and life-threatening and 
lethal toxicity(ies) will be reported according to the DCT’s Guidelines for Reporting Adverse Drug 
Reactions to the Investigational Drug Branch (301-230-2330; Fax 301-230-0159) within 24 hours, with a 
copy sent to the NCI-IRB.  All fatal events (NCI/CTEP grade V toxicity) will require a written report from the 


 
 37
Principal or Associate Investigator will follow within 10 working days.  A written report, within 10 working 
days, should be sent on CTEP ADR forms to: 
 
 
 
 
Investigational Drug Branch 
 
 
 
 
PO Box 30012 
 
 
 
 
Bethesda, MD 20824 
Clinical Associates and/or senior staff should notify the Principal Investigator at 301-435-8183 (Dr. Dahut), 
Bldg.10, Rm 12N226 of the occurrence of such toxicity.  
13.2
Adverse events listed in section 6 do not require ADEERS reporting except as otherwise 
mandated by the guidelines (e.g., grade 3 with hospitalization, grade 4 or 5).  The occurrence of any new 
toxicity (not in the above list), regardless of grade, and all life threatening events (NCI/CTEP grade IV 
toxicity) will be reported to the Drug Monitor, Investigational Drug Branch, CTEP, and the NCI IRB within 
24 hours.  An ADR form may be required.  The Principal Investigator, Study Coordinator, or an Associate 
Investigator will be responsible for completing the ADR form and for notifying the NCI’s Institutional 
Review Board. 
A summary of the ongoing study will be submitted to the NCI’s Institutional Review Board at 12 month 
intervals and a final report will be sent within six months of study completion at the request of the 
Institutional Review Board using the CTEP study summary form.  The status reported will be submitted 
and presented at upcoming NCI meetings as requested


38 
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Rini, B.I. and E.J. Small, Prostate cancer update. Curr Opin Oncol, 2002. 14(3): p. 286-91. 
3. 
Goktas, S. and E.D. Crawford, Optimal hormonal therapy for advanced prostatic carcinoma. 
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4. 
Klotz, L., Hormone therapy for patients with prostate carcinoma. Cancer, 2000. 88(12 Suppl): p. 
3009-14. 
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Beedassy, A. and G. Cardi, Chemotherapy in advanced prostate cancer. Semin Oncol, 1999. 
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Investigator's Brochure, versions 3 and 4.1. ed. A. Shah, C. Lathia, and K. Heininger. 2003, Bayer 
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Chong, H., H.G. Vikis, and K.L. Guan, Mechanisms of regulating the Raf kinase family. Cell 
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Cohen, Y., et al., BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst, 2003. 95(8): p. 
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Davies, H., et al., Mutations of the BRAF gene in human cancer. Nature, 2002. 417(6892): p. 949-
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Mercer, K.E. and C.A. Pritchard, Raf proteins and cancer: B-Raf is identified as a mutational 
target. Biochim Biophys Acta, 2003. 1653(1): p. 25-40. 
12. 
Pollock, P.M. and P.S. Meltzer, A genome-based strategy uncovers frequent BRAF mutations in 
melanoma. Cancer Cell, 2002. 2(1): p. 5-7. 
13. 
Sawyers, C.L., Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid 
leukemia. Cancer Cell, 2002. 1(5): p. 413-5. 
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Singer, G., et al., Mutations in BRAF and KRAS characterize the development of low-grade 
ovarian serous carcinoma. J Natl Cancer Inst, 2003. 95(6): p. 484-6. 
15. 
Tannapfel, A., et al., Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular 
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16. 
Bergers, G., et al., Benefits of targeting both pericytes and endothelial cells in the tumor 
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Ferrara, N., VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer, 2002. 2(10): p. 
795-803. 
18. 
Apperley, J.F., 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, 
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19. 
Heinrich, M.C., et al., Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the 
treatment of KIT-positive malignancies. J Clin Oncol, 2002. 20(6): p. 1692-703. 
20. 
Alavi, A., et al., Role of Raf in vascular protection from distinct apoptotic stimuli. Science, 2003. 
301(5629): p. 94-6. 
21. 
Bushman, E.C., R.N. Nayak, and W. Bushman, Immunohistochemical staining of ras p21: staining 
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Agnantis, N.J., et al., Comparative immunohistochemical study of ras-p21 oncoprotein in 
adenomatous hyperplasia and adenocarcinoma of the prostate gland. Anticancer Res, 1994. 
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23. 
Bakin, R.E., et al., Constitutive activation of the Ras/mitogen-activated protein kinase signaling 
pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res, 2003. 
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Bakin, R.E., et al., Attenuation of Ras signaling restores androgen sensitivity to hormone-
refractory C4-2 prostate cancer cells. Cancer Res, 2003. 63(8): p. 1975-80. 
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Fu, Z., et al., Effects of raf kinase inhibitor protein expression on suppression of prostate cancer 
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Qi, L., et al., Migration and invasion of human prostate cancer cells is related to expression of 
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Wu, J., K. Haugk, and S.R. Plymate, Activation of pro-apoptotic p38-MAPK pathway in the 
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Nicholson, B. and D. Theodorescu, Angiogenesis and prostate cancer tumor growth. J Cell 
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Brown, R.S., et al., The comparative values of bone marrow aspirate and trephine for obtaining 
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Figg, W.D., et al., A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients 
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Figg, W.D., et al., A randomized, phase II trial of ketoconazole plus alendronate versus 
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Walczak, J.R. and M.A. Carducci, Phase 3 randomized trial evaluating second-line hormonal 
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40 
APPENDIX A 
 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
100 
Normal, no complaints, no evidence of 
disease. 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some 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). 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
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. 
50 
Requires considerable assistance and 
frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 


41 
Appendix B: NCI/FDA Proteomics Program Standard Operating Procedure for Tissue Core 
Collection- Needle Biopsy – Cryopreservation in OCT 
 
Principle:
Core needle biopsies are used to sample tissue from a specific, defined location.  These biopsies may 
consist of normal, pre-malignant and malignant tissue due to the multi-level tissue sample that is obtained. 
 This type of sample is ideal for studying the micro-tumor environment. 
Rapid freezing of the sample is required to prevent degradation of the proteins or RNA.  Optimal Cutting 
Temperature (OCT) compound is an alcohol polymer that is liquid at room temperature and a solid at –
20oC.  This polymer is used to cryo-protect the tissue and provide a medium for cryo-sectioning. 
 
Materials:
Cryomolds  (Sakura Finetek Ca.t # 4728) 
OCT (Sakura Finetek Cat. # 4583) 
Dry ice 
Ultra cold freezer (-700 to -800C)  
Needle: 16 or 18 gauge 
Permanent marker 
Sterile forceps 
Sterile Glass slides 
Aluminum foil or 50ml Falcon tubes 
 
 
Procedure:
1. Prepare all supplies prior to the biopsy procedure to avoid delay once the specimen has been 
obtained. 
2. Label the handle and the front surface of the cryomold with the sample or patient’s identifying 
information. 
3. Perform core needle biopsy. 
4. Pick the core from the biopsy needle onto a sterile glass slide. 
5. Fill cryomold about 1/3 full with OCT.  Place the cryomold in dry ice to partially freeze the OCT.  
The OCT should be jelly-like, not completely frozen. 
6. Carefully lift the core biopsy by both ends with sterile forceps. Do not stretch the biopsy or it 
will break. 
7. Lay the biopsy as straight as possible in the OCT.  Once the sample touches the OCT, you cannot 
reposition it or the sample will break apart. 
8. Quickly add OCT on top of the biopsy, completely covering the sample. 
9. Ensure the sample is level and freeze immediately in dry ice. 
10. Store wrapped in aluminum foil or in a 50ml Falcon tube at –70oC. 
 
Note:  
Do not lay the biopsy on frozen OCT and cover it with liquid OCT.  The OCT will not fuse and will split into 
two sections when cutting the frozen tissue sections. 
 


42 
Frozen Section Slides 
1. Frozen sections for proteomic analysis should be cut at 5-8um on plain, uncoated glass 
microscope slides. 
2. The tissue section should be placed as close as possible to the center of the slide.  Do not place 
the frozen section at the end of the slide. 
3. Two tissue sections from the same biopsy may be placed on the same glass slide if space 
permits. 
4. Do not allow the tissue section to air on the slide.  Freeze immediately on dry ice or at –80oC. 
 
Shipping Slides or Frozen Tissue 
1. Ship slides/tissue in OCT on dry ice Monday through Thursday only.  
2. Tissue should be embedded in OCT prior to shipment.  Refer to procedure steps 5-10. 
3. Seal slide box in a plastic bag with dessicant (such as Drierite crystals).  Seal tissue in a 50ml 
polypropylene Falcon tube, wrap in aluminum foil or place in a plastic bag. 
4. Place dry ice on top of the plastic bag containing the slides/tissue. 
5. Place any special instructions/inventory/shipping documents in the box. 
6. Seal the box with tape.   
7. Ship to: 
 
Ginny Espina 
National Cancer Institute 
9000 Rockville Pike 
Bldg 10 Room B1B53 
Bethesda, MD 20892 
 
301-435-7763 


43 
Appendix C: Cytochrome P450 3A4 Metabolized Drugs 
Substrates
Acetaminophen 
Dapsone 
Levobupivicaine 
Risperidone 
Alfentanil 
Dehydroepiandrostendione 
Lidocaine 
Ritonavir** 
Alosetron 
Delavirdine 
Loratadine 
Salmeterol 
Alprazolam 
Desmethyldiazepam 
Losartan 
Saquinavir 
Amiodarone 
Dexamethasone 
Lovastatin 
Sertindole 
Amitriptyline (minor) 
Dextromethorphan (minor) 
Methadone 
Sertraline 
Amlodipine 
Diazepam (minor) 
Mibefradil 
Sibutramine 
Anastrozole 
Digitoxin 
Miconazole 
Sildenafil citrate  
Androsterone 
Diltiazem 
Midazolam 
Simvastatin 
Antipyrine 
Disopyramide 
Mifepristone 
Sirolimus 
Astemizole 
Docetaxel 
Mirtazapine  
Sufentanil 
Atorvastatin 
Dofetilide (minor) 
Montelukast 
Tacrolimus 
Benzphetamine 
Dolasteron 
Navelbine 
Tamoxifen 
Bepridil 
Donepezil 
Nefazodone 
Temazepam 
Bexarotene 
Doxorubicin 
Nelfinavir 
Teniposide 
Bromazepam 
Doxycycline 
Nevirapine 
Terfenadine 
Bromocriptine 
Dronabinol 
Nicardipine 
Testosterone 
Budesonide 
Enalapril 
Nifedipine 
Tetrahydrocannabinol 
Bupropion (weak) 
Erythromycin 
Niludipine 
Theophylline 
Buspirone 
Estradiol 
Nimodipine 
Tiagabine 
Busulfan 
Ethenyl estradiol 
Nisoldipine 
Tolterodine 
Caffeine 
Ethosuximide 
Nitrendipine 
Toremifene 
Cannabinoids 
Etoposide 
Omeprazole 
(sulfonation) 
Trazodone 
Carbamazepine 
Exemestane 
Ondasetron 
Tertinoin 
Cerivastatin 
Felodipine 
Oral contraceptives 
Triazolam 
Cevimeline  
Fentanyl 
Orphenadrine 
Troglitazone 
Chlorpromazine 
Fexofenadine 
Paclitaxel 
Troleandomycin 
Cimetidine 
Finasteride 
Pantoprazole 
Venlafaxine 
Cisapride 
Fluoxetine 
Pimozide 
Verapamil 
Citalopram 
Flutamide 
Pioglitazone 
Vinblastine 
Clarithromycin 
Glyburide 
Pravastatin 
Vincristine 
Clindamycin 
Granisetron 
Prednisone 
Warfarin 
Clomipramine 
Halofantrine 
Progesterone 
Yohimbine 
Clonazepam 
Hydrocortisone 
Proguanil 
Zaleplon (minor) 
Clozapine 
Hydroxyarginine 
Propafenone 
Zatoestron 
Cocaine 
Ifosfamide 
Quercetin 
Zileuton 
Codeine 
Imipramine 
Quetiapine 
Ziprasidone 
Cortisol 
Indinavir 
Quinidine 
Zolpidem 
Cortisone 
Isradipine 
Quinine 
Zonisamide 
Cyclobenzaprine  
Itraconazole 
Repaglinide 
 
Cyclophosphamide 
Ketoconazole 
Retinoic acid 
 
Cyclosporine 
Lansoprazole (minor) 
Rifampin 
 
Inducers
Carbamazepine 
Nelfinavir 
Primidone 
Sulfadimidine 
Dexamethasone 
Nevirapine 
Progesterone 
Sulfinpyrazone 
Ethosuximide 
Oxcarbazepine 
Rifabutin 
Troglitazone 
Glucocorticoids 
Phenobarbital 
Rifampin 
 
Griseofulvin 
Phenylbutazone 
Rofecoxib (minor) 
 
Nafcillin 
Phenytoin 
St. John’s Wort 
 


44 
Inhibitors
Amiodarone 
Disulfiram 
Mibefradil 
Ranitidine 
Anastrozole 
Entacapone 
Miconazole (moderate) 
Ritonavir** 
Azithromycin 
Erythromycin 
Nefazodone 
Saquinavir 
Cannabinoids 
Ethenyl estradiol 
Nelfinavir 
Sertindole 
Cimetidine 
Fluconazole (weak) 
Nevirapine 
Sertraline 
Clarithromycin 
Fluoxetine 
Norfloxacin 
Troglitazone 
Clotrimazole 
Fluvoxamine 
Norfluoxetine 
Troleandomycin 
Cyclosporine 
Gestodene 
Omeprazole (weak) 
Valproic acid (weak) 
Danazole 
Grapefruit Juice 
Oxiconazole 
Verapamil 
Delavirdine 
Indinavir 
Paroxetine (weak) 
Zarfirlukast 
Dexamethasone 
Isoniazid 
Propoxyphene 
Zileuton 
Dimethyldithiocarbamate 
Itraconazole** 
Quinidine 
 
Diltiazem 
Ketoconazole** 
Quinin 
 
Dirithromycin 
Metronidazole 
Quinupristin and 
dalfopristin 
 
** Contraindications  
From Drug Information Handbook 8th Edition