Conditions: Prostatic Neoplasms
Keywords: Hormones Angiogenesis Markers Tumor Prostate Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 73
Healthy volunteers: no

Brief summary:
This is a Phase II study of docetaxel, bevacizumab, prednisone and thalidomide in patients with androgen independent metastatic prostate cancer who are previously untreated with chemotherapy. The primary objective of this study is to determine if the combination of docetaxel, thalidomide and bevacizumab is able to be associated with a sufficiently high proportion of patients with a prostate-specific antigen (PSA) response to be worthy of further investigation in metastatic prostate cancer. We will also be looking at multiple secondary endpoints. These will include possible pharmacokinetic interactions among the study agents, potential correlation between patient genotype and efficacy of treatment. We will also be looking for circulating tumor cells in blood before and after treatment. Additionally we will be monitoring the tolerability of the regimen and survival duration as endpoints as well. We hope to use this trial to build on the promising results seen in our thalidomide/docetaxel protocol where there was a significant PSA decline and a trend toward survival benefit.

Detailed description:
This is a Phase II study of docetaxel, bevacizumab, prednisone and thalidomide in patients with androgen independent metastatic prostate cancer who are previously untreated with chemotherapy. The primary objective of this study is to determine if the combination of docetaxel, thalidomide and bevacizumab is able to be associated with a sufficiently high proportion of patients with a PSA response to be worthy of further investigation in metastatic prostate cancer. We will also be looking at multiple secondary endpoints. These will include possible pharmacokinetic interactions among the study agents, potential correlation between patient genotype and efficacy of treatment. We will also be looking for circulating endothelial cells in blood before and after treatment. Additionally we will be monitoring the tolerability of the regimen, time to disease progression, and survival duration as endpoints as well. We hope to use this trial to build on the promising results seen in our thalidomide/docetaxel protocol where there was a significant PSA decline and a trend toward survival benefit.

Arms:
arm 1: Docetaxel 75 mg/m\^2 intravenously over 60 minutes on cycle 1 day 1 repeated every 21 days. Thalidomide 200 mg by mouth daily throughout the cycle. Prednisone 10 mg by mouth daily throughout the cycle. Bevacizumab 15 mg/kg intravenously on cycle 1 day 1 every 21 days. arm 2: Docetaxel 75 mg/m\^2 intravenously over 60 minutes and Bevacizumab 15 mg/kg intravenously was given for 2 cycles. After two cycles Prednisone 10 mg by mouth daily and Thalidomide 200 mg by mouth daily was added.

Interventions: intervention 1: Docetaxel intervention 2: Thalidomide intervention 3: Prednisone intervention 4: bevacizumab intervention 5: polymorphism analysis intervention 6: immunoenzyme technique intervention 7: laboratory biomarker analysis intervention 8: pharmacological study
Intervention descriptions: intervention 1: Docetaxel 75 mg/m\^2 intravenously over 60 minutes on cycle 1 day 1 repeated every 21 days. intervention 2: Thalidomide 200 mg by mouth daily throughout the cycle. intervention 3: Prednisone 10 mg by mouth daily throughout the cycle. intervention 4: Bevacizumab 15 mg/kg intravenously on cycle 1 day 1 every 21 days. intervention 5: Two buffy coat tubes (two 7mL blue tiger top tubes) will be obtained and wrapped in foil when the patient enters onto the study. DNA (deoxyribonucleic acid) will be isolated only for the purpose of genotype analysis of enzymes with putative relevance for docetaxel or thalidomide disposition. intervention 6: The PBMC (peripheral blood mononuclear cells) of patients will be analyzed pre-treatment and post cycle 2 for any changes in the function of regulatory T cells. The following analysis will be performed: flow cytometry analysis, CD4 CD25 T cell enrichment, and immunosuppression assay. intervention 7: Serum and urine samples will be collected at baseline and monthly to measure VEGF (vascular endothelial growth factor) levels. intervention 8: Plasma concentrations of docetaxel and thalidomide will be determined to assess interactions between docetaxel (and thalidomide) and the concomitant therapy.The analysis will be performed using a validated method based on liquid chromotography with mass-spectrometric detection.

Protocol document:
Prot_SAP_ICF_000.pdf: 
Amendment
Protocol Number:
04C0257-Q
Principal Investigator: Ravi Madan 
NCI 
GMB 
301.480.7168 
madanr@mail.nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
366512
Protocol Title:
A Phase II Trial of Docetaxel, Thalidomide, Prednisone, and Bevacizumab in Patients with Androgen-Independent Prostate Cancer
SIGNATURES
Principal Investigator (*): 
Ravi Madan - applied signature on 02/09/2017 9:47 AM EST
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
James L Gulley, MD PhD - applied signature on 02/06/2017 3:53 PM EST
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
N/A
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 03/07/2017 7:58 PM EST
Clinical Director:
N/A
CONCURRENCE
OPS Protocol Specialist:
Signature
Print Name
Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and
used solely for those purposes.  Questions may be addressed to the Protrak System Owner.
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
Expedited
DEC Clearance Date:
NA
Protocol Version Date:02/03/2017
Royal Reed 
 
 
            AM Q 
 
 
   03/17/17


Abbreviated Title:  D&T&P&B in AIPC 
Version Date: 2/3/2017 
  
 
 
 
Confidential                                                                                                                                  1 
 
Abbreviated Title: 
D&T&P&B in AIPC 
NCI Protocol #: 
04-C-0257 (Q) 
Version Date: 
2/3/2017 
 
 
A Phase II trial of Docetaxel, Thalidomide, Prednisone and Bevacizumab in 
Patients with Androgen-Independent Prostate Cancer 
 
 
NCI Principal Investigator:  
Ravi A. Madan, MD, GMB, CCR, NCIA-F   
 
National Cancer Institute 
Building 10, Rm. 13N240B  
9000 Rockville Pike 
Bethesda, MD 20892 
Phone: 301-480-7168 
 
Email:  madanr@mail.nih.gov 
 
 
Lead Associate Investigator: 
William D. Figg, PharmD, GMB, CCR, NCIB,E,F 
 
 
NIH Associate Investigators: 
William L. Dahut, MD, GMB, CCR, NCIA-F 
Howard Parnes, MD, DCP, CCR, NCIA-F 
 
 
 
 
 
John Wright, MD, CTEP, NCIA-F 
 
 
 
 
 
Ramaprasad Srinivasan, MD, UOB, CCR, NCIA-F 
 
 
 
 
 
Peter Pinto, MD, UOB, CCR, NCIA-F 
Adam R. Metwalli, MD, UOB, CCR, NCIA-F 
 
 
 
 
 
Helen Owens, RN, GMB, CCR, NCIA,B,E 
Douglas Price, PhD, GMB, CCR, NCIE,F 
 
 
 
 
 
David Kohler, PharmD, CC, NIHA,B 
 
 
 
 
 
Seth Steinberg, OCD, CCR, NCIE,F 
 
 
 
 
 
Peter Choyke, MD, MIP, CCR, NCIA,B,E,F 
 
 
 
 
 
Jane Trepel, DTB, CCR, NCIE,F     
Anna Couvillon, MS, CRNP, GMB, CCR, NCIA-F  
Fatima Karzai, MD, NIMHDA-F 
 
 
 
 
 
  
Referral Contact/ 
 
 
Helen Owens, RN, GMB, CCR, NCIA,B,E  
  
Study Coordinator:                        Telephone:  240-760-6068 
                                                      Email:  helen.owens@nih.gov 
 
 
Non-NIH Associate Investigator:   Philip Arlen, MD, Special Volunteer, CCR, NCIA-F 
 


Abbreviated Title:  D&T&P&B in AIPC 
Version Date: 2/3/2017 
  
 
 
 
Confidential                                                                                                                                  2 
 
Investigator Roles: 
 
A. Obtain information by intervening or interacting with living individuals for research purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
Commercial Agents:    Docetaxel, Prednisone, Thalidomide, Bevacizumab 


Abbreviated Title:  D&T&P&B in AIPC 
Version Date: 2/3/2017 
  
 
 
 
Confidential                                                                                                                                  3 
 
PRÉCIS 
 
This is a Phase II study of docetaxel, bevacizumab, prednisone and thalidomide in 
patients with androgen independent metastatic prostate cancer who are previously 
untreated with chemotherapy. The primary objective of this study is to determine if the 
combination of docetaxel, thalidomide and bevacizumab is able to be associated with a 
sufficiently high proportion of patients with a PSA response to be worthy of further 
investigation in metastatic prostate cancer. We will also be looking at multiple 
secondary endpoints. These will include possible pharmacokinetic interactions among 
the study agents, potential correlation between patient genotype and efficacy of 
treatment. We will also be looking for circulating endothelial cells in blood before and 
after treatment. Additionally, we will be monitoring the tolerability of the regimen, time to 
disease progression, and survival duration as endpoints as well. We hope to use this 
trial to build on the promising results seen in our thalidomide/docetaxel protocol where 
there was a significant PSA decline and a trend toward survival benefit.


Abbreviated Title:  D&T&P&B in AIPC 
Version Date: 2/3/2017 
Confidential                                                                                                                                    4 
 
Treatment Schema: 
 
Cycle Number: ________________ 
 
Study Schedule for patients in the original protocol 
Day 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
1 
Dex. 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
T 
 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Do 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
B 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
P 
 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
E 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dex -  Dexamethasone 4 mg. PO 12 and 1 hour pre and 12 hours post-docetaxel infusion 
T     -  Thalidomide 200 mg. PO daily throughout cycle  
Do   -  Docetaxel 75 mg/m2   IV  
B    -  Bevacizumab 15 mg/kg IV 
P   -  Prednisone 10 mg PO daily throughout cycle 
E –  
Enoxaparin 1 mg/kg SQ daily 
 
 
 
 
 
 


Abbreviated Title:  D&T&P&B in AIPC 
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Confidential                                                                                                                                  5 
 
Study Schedule for patients enrolled in the expansion cohort 
Day 
 
Cycle1  
Day 1 
Cycle1,  
Day 21 
Cycle 2, Day 
1 
Cycle 2, 
Day 21 
>Cycle 3, Day 
1 
>Cycle 3, 
Day 2-20 
>Cycle 3, Day 
21 
Dex. 
 
X 
X 
X 
X 
X 
 
X 
T 
 
 
 
 
 
X 
X 
X 
Do 
 
X 
 
X 
 
X 
 
 
B 
 
X 
 
X 
 
X 
 
 
P 
 
 
 
 
 
X 
X 
X 
E 
 
 
 
 
X 
X 
X 
 
 
Dex -  Dexamethasone 4 mg. PO 12 and 1 hour pre and 12 hours post-docetaxel infusion 
T     -  Thalidomide 200 mg. PO daily throughout cycle  
Do   -  Docetaxel 75 mg/m2   IV  
B    -  Bevacizumab 15 mg/kg IV 
P   -  Prednisone 10 mg PO daily throughout cycle 
E –  
Enoxaparin 1 mg/kg SQ daily 
 


Abbreviated Title:  D&T&P&B in AIPC 
Version Date: 2/3/2017 
Confidential                                                                                                                                    6 
 
TABLE OF CONTENTS 
PRÉCIS ......................................................................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................................... 6 
1 
OBJECTIVES ....................................................................................................................................... 8 
1.1 
PRIMARY OBJECTIVES..................................................................................................................... 8 
1.2 
SECONDARY OBJECTIVES ............................................................................................................... 8 
2 
BACKGROUND ................................................................................................................................... 8 
2.1 
STUDY DISEASE ............................................................................................................................. 8 
2.2 
DOCETAXEL ................................................................................................................................... 9 
2.3 
PREDNISONE ............................................................................................................................... 10 
2.4 
THALIDOMIDE ............................................................................................................................... 10 
2.5 
BEVACIZUMAB (RHUMAB) ............................................................................................................. 11 
2.6 
RATIONALE FOR COMBINATORIAL THERAPY .................................................................................... 15 
2.7 
CORRELATIVE STUDIES ................................................................................................................ 19 
2.8 
CONCLUSION ............................................................................................................................... 20 
3 
PATIENT SELECTION ...................................................................................................................... 21 
3.1 
ELIGIBILITY CRITERIA ................................................................................................................... 21 
3.2 
EXCLUSION CRITERIA ................................................................................................................... 22 
3.3 
INCLUSION OF WOMEN AND MINORITIES ........................................................................................ 23 
3.4 
ON-STUDY RESEARCH EVALUATION.............................................................................................. 23 
3.5 
PATIENT REGISTRATION ............................................................................................................... 24 
4 
TREATMENT PLAN........................................................................................................................... 25 
4.1 
STUDY DESIGN ............................................................................................................................ 25 
4.2 
AGENT ADMINISTRATION .............................................................................................................. 26 
4.3 
TREATMENT MODIFICATIONS ........................................................................................................ 27 
4.4 
PHARMACOKINETIC AND CORRELATIVE STUDIES ............................................................................ 30 
4.5 
PROTOCOL EVALUATION ............................................................................................................... 35 
4.6 
CONCURRENT THERAPIES ............................................................................................................ 36 
4.7 
SURGICAL GUIDELINES ................................................................................................................. 36 
4.8 
RADIATION THERAPY GUIDELINES ................................................................................................. 36 
4.9 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA ............................. 36 
5 
SUPPORTIVE CARE ......................................................................................................................... 37 
6 
DATA COLLECTION AND EVALUATION ........................................................................................ 38 
6.1 
DATA COLLECTION (PATIENTS RECORDS AND QUALITY ASSURANCE) ............................................. 38 
6.2 
RESPONSE CRITERIA .................................................................................................................... 39 
6.3 
TOXICITY CRITERIA ...................................................................................................................... 43 
6.4 
STATISTICAL CONSIDERATIONS ..................................................................................................... 43 
6.5 
MULTI-INSTITUTIONAL GUIDELINES ................................................................................................ 46 
7 
HUMAN SUBJECTS PROTECTIONS ............................................................................................... 46 
7.1 
RATIONALE FOR SUBJECT SELECTION ........................................................................................... 46 
7.2 
PARTICIPATION OF CHILDREN ....................................................................................................... 46 
7.3 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS .................................................................... 46 
7.4 
RISKS/BENEFITS ANALYSIS ........................................................................................................... 47 
7.5 
CONSENT PROCESS AND DOCUMENTATION ................................................................................... 47 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .................. 47 
8.1 
DEFINITIONS ................................................................................................................................ 47 


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8.2 
NCI-IRB AND NCI CLINICAL DIRECTOR REPORTING ...................................................................... 50 
8.3 
DATA AND SAFETY MONITORING PLAN .......................................................................................... 50 
9 
PHARMACEUTICAL INFORMATION ............................................................................................... 51 
9.1 
DOCETAXEL (DOCETAXEL-AVENTIS PHARMACEUTICAL, INC.; BRIDGEWATER, NJ)) ................... 51 
9.2 
THALIDOMIDE (THALOMID – CELGENE CORPORATION, WARREN, NJ) .............................................. 54 
9.3 
PREDNISONE ............................................................................................................................... 55 
9.4 
BEVACIZUMAB (AVASTIN – GENENTECH BIOONCOLOGY, SOUTH SAN FRANCISCO, CA) ................... 56 
9.5 
OTHER AGENTS ........................................................................................................................... 59 
10 
COLLABORATIVE AGREEMENTS .................................................................................................. 60 
10.1 
AGREEMENT TYPE ....................................................................................................................... 60 
11 
REFERENCES ................................................................................................................................... 61 
12 
APPENDIX A: AGENTS METABOLISED THROUGH CYP450 SUBSTRATES ............................... 64 
TABLE OF TABLES 
 
Table 1:  Phase II Clinical Trials .................................................................................... 12 
Table 2:  Adequate Organ and Marrow Function .......................................................... 22 
Table 3:  Bevacizumab and Venous Thrombosis .......................................................... 28 
Table 4:  Thalidomide and Venous Thrombosis ............................................................ 28 
Table 5:  Bevacizumab and Proteinuria ......................................................................... 29 
Table 6:  Evaluation of Best Overall Response ............................................................. 41 
Table 7:  Bevacizumab Excipients ................................................................................ 57 
 
TABLE OF FIGURES 
 
Figure 1:  Concentrations of angiogenic factors in different cell lines vs. treatment with 
thalidomide and analogues ........................................................................................... 17 
Figure 2:  Microvessel count of various cell lines after treatment with thalidomide and 
analogues. ..................................................................................................................... 18 
 
 
 


Abbreviated Title:  D&T&P&B in AIPC 
Version Date: 2/3/2017 
Confidential                                                                                                                                    8 
 
1 
OBJECTIVES  
1.1 PRIMARY OBJECTIVES 
• The primary objective of this study is to determine if the combination of 
docetaxel, thalidomide, prednisone and bevacizumab is able to be associated 
with a sufficiently high proportion of patients with a PSA response to be 
worthy of further investigation in metastatic prostate cancer. 
• The primary endpoint of the expansion cohort is to determine if docetaxel and 
bevacizumab cause immunologic changes that would not be considered to be 
compatible with concomitant therapeutic vaccination. The changes will be 
assessed through measuring regulatory T-cell (Treg) percentage and 
function, lymphocyte function, myeloid suppressor cells, and mixed 
lymphocyte reaction.  
1.2 SECONDARY OBJECTIVES 
• To evaluate time to disease progression and survival duration of those 
patients treated.  Time to progression will be evaluated in two ways.  First by 
using Bubley criteria and secondarily by clinical and radiographic criteria 
without the use of PSA.   
• To compare the PSA-elevation only group with the patients having both PSA-
elevation and clinical or radiographic progression 
• To characterize the pharmacokinetics of both docetaxel and thalidomide and 
determine if any pharmacodynamic relationships exist between plasma 
concentrations of either agent and clinical activity or toxicity 
• To determine the existence of and quantification of circulating endothelial 
cells before and after drug administration 
• To analyze the patients’ genotype with regard to cytochrome P450 2C19 
polymorphism and correlate that with pharmacokinetics and efficacy 
• To evaluate the usefulness of dynamic MRI to monitor the progression of 
bony and soft tissue disease in metastatic prostate cancer 
• To determine whether there are changes in the molecular markers of 
angiogenesis (including, but not limited to serum and urine VEGF) before and 
after administration of docetaxel, prednisone, thalidomide and bevacizumab 
• To evaluate the toxicity profile of this combination 
2 
BACKGROUND 
2.1 STUDY DISEASE 
Metastatic prostate cancer is a leading cause of death from cancer in men. Though 
initially responsive to hormone therapy, it eventually progresses in almost all patients. 
For this reason there has been a search for novel agents to use in the treatment of 
androgen independent prostate cancer. Antiangiogenesis is a relatively new antitumor 
strategy that has been employed in the treatments of many malignancies.  


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Confidential                                                                                                                                  9 
 
Historically, chemotherapy was not considered to have significant activity in metastatic 
androgen independent prostate cancer (AIPC).  However, this view changed within the 
past 10 years due in part to the availability of prostate-specific antigen (PSA) 
measurements to monitor tumor burden.  Estramustine, a tubulin-targeting drug, when 
combined with agents such as etoposide, vinblastine or paclitaxel, can induce 
responses in patients with AIPC (25-27). Docetaxel, both as a single agent and in 
combination with estramustine has activity as well. However, while it seems that 
chemotherapy, either as a single agent or in combination, may lead to clinical 
responses, reduction in PSA measurements, pain control, and/or improved quality of 
life, to date, no benefit in overall survival has been shown. 
2.2 DOCETAXEL 
Docetaxel is a semisynthetic taxane with potent antitumor activity in a variety of 
malignancies. Its mechanism in prostate cancer is thought to be two-fold. First it acts as 
a microtubule stabilizer by binding preferentially to Beta-tubulin, leading to assembly of 
microtubules without GTP and other various cofactors. This leads to static 
polymerization, which disrupts the normal mitotic process, causing cell arrest in G2M 
phase, which ultimately leads to apoptosis (1). A second mechanism involves the bcl-2 
gene. Bcl-2 is an oncogene that enhances tumor activity via inhibition of apoptosis. 
There have been several clinical and experimental studies that have shown that 
overexpression of bcl-2 in prostate cancer leads to chemotherapy and androgen 
resistance as well as protection from apoptosis (2, 3). During the G2/M cell cycle 
interface, bcl-2 is normally temporarily phosphorylated to facilitate mitosis. Docetaxel 
has been shown to induce continuous bcl-2 phosphorylation, which leads to the loss of 
its normal antiapoptotic properties (4). 
Based on this preclinical data, there has been much investigation in the use of 
docetaxel both as a single agent and as part of combination therapy in patients with 
androgen independent prostate cancer (AIPC). Several phase II studies used single 
agent docetaxel every three weeks at 75 mg/m2 and demonstrated a PSA decrease of 
at least 50% in 38-46% of patients with AIPC (5, 6).  
Two recent phase III trials of docetaxel combination therapy in 1006 patients with AIPC 
were presented at the most recent meeting of the American Society of Clinical Oncology 
(ASCO). Eisenberger et al. conducted a three arm trial of prednisone (5 mg bid) plus 
either a) docetaxel (75 mg/m2 q 3 wk x 10 cycles) b) docetaxel (30 mg/m2 q wk for 5/6 
weeks x 5 cycles) or c) mitoxantrone (12 mg/m2 q 3 wk x 10 cycles). Results showed 
that the combination of daily prednisone plus docetaxel given every 3 weeks had a 
statistically significant improvement in survival (18.9 vs. 16.5 mos.) and PSA response 
(45% vs. 32 %) over prednisone plus mitoxantrone. While the prednisone plus weekly 
docetaxel had comparable PSA benefit, the survival benefit was less and not 
statistically significant. Petrylak et al. conducted SWOG 99-16, a phase III study of 770 
men with AIPC randomized to either docetaxel (60-70 mg/m2 q 3 weeks) plus 
estramustine (280 mg d 1-5 q 3 wk) versus mitoxantrone (12-14 mg/m2 q 3 wk) plus 
daily prednisone (5 mg po bid). Results showed that the docetaxel and estramustine 
arm was superior to the mitoxantrone and prednisone arm in median survival (18 vs. 15 
mos) as well as several other meaningful endpoints.  


Abbreviated Title:  D&T&P&B in AIPC 
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Confidential                                                                                                                                  10 
 
These larger randomized studies were the first to demonstrate survival benefit in men 
with AIPC and strongly encourage further trials using these and other docetaxel 
combinations in this disease. 
2.3 PREDNISONE 
Prednisone, a glucocorticoid has been shown to have significant palliative activity in 
patients with androgen-independent prostate cancer.  A previous study was done in 
patients with androgen-independent prostate cancer that were given prednisone alone.  
Patients received 10 mg orally twice a day.  Of the 29 patients, 48% of patients had a > 
25% PSA decline, 34% had a PSA decline > 50% and 14% experienced a PSA decline 
of > 75%.  The average PSA declined in this study population was 33%.  Average 
progression free survival was 2.8 months (7). 
2.4 THALIDOMIDE 
Thalidomide, a glutamic acid derivative, is a potent teratogen that causes dysmelia 
(stunted limb growth) in humans (8).  It was marketed in Europe as a nonbarbiturate 
sedative but was withdrawn 30 years ago because of its teratogenic effects.  It has been 
postulated that thalidomide-induced limb defects were secondary to an inhibition of 
blood vessel growth in the developing fetal limb buds.  In 1994, D’Amato et al 
demonstrated that thalidomide inhibited bFGF-induced angiogenesis (9).  Bauer et al 
subsequently determined that a metabolite of thalidomide was responsible for this 
antiangiogenic activity (10).  Thalidomide was later shown to inhibit the growth of V2 
carcinoma and Lewis lung carcinoma in animal models by antiangiogenic mechanisms 
(11). As angiogenesis appears to play a prominent role in the development, growth and 
metastasis of prostate cancer (24-29), there have been considerable efforts to 
investigate the use of antiangiogenic agents such as thalidomide with cytotoxic 
chemotherapy drugs in this particular malignancy.   
A recent phase II trial randomized 75 chemotherapy naïve AIPC patients to receive 30-
mg/m2 weekly docetaxel for 3 consecutive weeks followed by a 1-week rest period; or 
docetaxel at the same dose and schedule plus thalidomide 200 mg orally each day. The 
patients were enrolled in a 2:1 randomization scheme with 50 patients receiving 
combination therapy and 25 receiving docetaxel alone. Both regimens were well 
tolerated with only mild toxicities. It should be noted that there was a significant amount 
of thromboembolism seen in the initial group of patients receiving combination therapy. 
However, subsequent patients in the combination group were given prophylactic 
anticoagulation and no further thromboembolic events occurred. Measurement of the 
angiogenic markers VEGF and bFGF showed no significant changes between pre and 
post treatment levels in either the combination or docetaxel-alone group. After a follow-
up period of 26.4 months, the percentage of patients with a greater than 50% decline of 
PSA was higher in the combination group (51% vs. 37% in the single agent docetaxel 
group). Median progression-free survival was 5.9 months in the combination arm and 
3.7 months in the docetaxel arm. The median survival in the docetaxel group was 14.7 
months and 28.9 months in the combined group. The primary objective of the study was 
to determine whether the combination of thalidomide and docetaxel can produce a 
sufficiently high clinical response rate to warrant further investigation in patients with  


Abbreviated Title:  D&T&P&B in AIPC 
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Confidential                                                                                                                                  11 
 
androgen independent prostate cancer. It should be noted that though the study was 
not powered to detect a survival difference, the addition of thalidomide nearly doubled 
the median survival in patients with metastatic AIPC (12, 12a).  
This study represented an exciting step in the movement to combine traditional 
cytotoxic chemotherapy and antiangiogenic therapy. Significant improvement in the 
major clinical endpoints (PSA decline and progression-free survival) was demonstrated, 
as was a strong trend toward an improvement in overall survival. 
Recently there has been significant interest in combinations of cytotoxic and 
antiangiogenic agents. A recent multi-center Phase III trial randomized 800 patients with 
metastatic colorectal cancer to bevacizumab, a VEGF inhibitor, plus 5FU/ 
Leucovorin/CPT-11 or placebo plus 5FU/Leucovorin/CPT-11. The results showed that 
the arm that included bevacizumab had increased overall survival, progression-free 
survival, response rate and duration of response (13). As previously mentioned, 
prostate cancer seems to utilize angiogenesis in its growth and metastasis, it is 
therefore logical to include an antiangiogenic agent like thalidomide which has proven 
antiangiogenic effects, in the treatment of AIPC. Additionally, thalidomide has 
demonstrated very promising activity when combined with docetaxel alone in the 
treatment of AIPC. 
2.5 BEVACIZUMAB (RHUMAB) 
Background:  Bevacizumab (rhuMAb) is a recombinant humanized anti-VEGF 
monoclonal antibody composed of human IgG1 framework regions and antigen-binding 
complementarity-determining regions from a murine monoclonal antibody (muMAb 
VEGF A.4.6.1) which blocks the binding of human VEGF to its receptors. Approximately 
93% of the amino acid sequence, including most of the antibody framework, is derived 
from human IgG1, and ~7% of the sequence is derived from the murine antibody.  
Preclinical data: In cynomolgus monkeys, twice weekly IV treatments with bevacizumab 
(doses of 2, 10 and 50 mg/kg) for 4, 13 or 26 weeks were well tolerated, with no overt 
signs of acute toxicity (14, 15). Animals with open growth plates showed physeal 
dysplasia as well as focal to diffuse chondroid necrosis and linear fissuring of the 
cartilaginous growth plate. Females treated with 10-50mg/kg twice weekly had 
decreased ovarian and uterine weights, which were associated with absence of corpora 
lutea. These findings were expected, considering the known role of VEGF in formation 
of the corpora lutea and of the growing bone (16). A further study using a similar 
treatment regimen, in the recovery period the physeal dysplasia and ovarian and uterine 
changes induced by rhuMAb VEGF were partially reversible. No antibodies against 
bevacizumab were detected. 
Phase I Clinical studies: 
Two phase I studies have been performed. Study AVF0737g 
was a dose escalation trial of single and multiple intravenous (IV) administration of 
rhuMAb in patients with advanced malignancies. Five dose levels were evaluated (0.1, 
0.3, 1.0, 3.0, and 10mg/kg). rhuMAb VEGF was administered as a 90-minute infusion 
on days 0, 28, 35 and 42 (17). Study AVF0761g evaluated multiple doses of rhuMAb 
VEGF 3 mg/kg weekly for up to 8 weeks in combination with one of three cytotoxic 
chemotherapy regimens (5-fluorouracil/leucovorin, carboplatin/paclitaxel, or 


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doxorubicin) in subjects with advanced solid malignancies (18). rhuMAb VEGF was 
administered as eight weekly doses of 3mg/kg. 
In both studies, rhuMAb VEGF appeared to be well tolerated. In study AVF0737g, 3 of 
25 patients treated experienced tumor-related hemorrhagic events, possibly related to 
the administration of rhuMAb VEGF. In two cases the event was considered serious: an 
intracranial hemorrhage (at an occult cerebral metastasis) in a patient with 
hepatocellular carcinoma and bleeding at the tumor site in a 38-year-old woman with a 
slowly progressing sarcoma of the thigh. No patient in AVF0761g reported serious 
bleeding. No dose limiting toxicity was reached in either study. No antibodies to rhuMAb 
VEGF were detected after therapy in either study. Three subjects from each study 
subsequently enrolled in the extension study. 
Pharmacokinetics: In study AVF0737g, the pharmacokinetics of rhuMAb VEGF 
appeared to be linear for doses ≥ 1mg/kg with a half-life of approximately 15 days. 
Comparable pharmacokinetic data was seen in study AVF0761g. Co-administration of 
rhuMAb and cytotoxic chemotherapy did not appear to result in a change in the 
systemic concentration of the cytotoxic agents. 
Phase II Clinical Studies:  There are 4 Phase II Clinical Trials that have been conducted 
or still accruing patients (see below). 
Table 1:  Phase II Clinical Trials 
Study 
Population 
Study Treatment 
rhuMAb VEGF 
Dosing Regimen 
AVF0757g 
Stage IIIB or IV 
non-small cell 
lung cancer 
Carboplatin/paclit
axel ± rhuMAb 
VEGF 
7.5mg or 15mg/kg 
every 3 weeks 
until disease 
progression 
AVF0780g 
Metastatic 
colorectal cancer 
5-FU/leucovorin 
± rhuMAb VEGF 
5mg or 10mg/kg 
every other week 
until disease 
progression 
AVF0776g 
Relapsed 
metastatic breast 
cancer 
Single-agent 
rhuMAb 
VEGF 
3,10 or 20 mg/kg 
every other week 
over a 168-day 
treatment period 
or until disease 
progression 
AVF0775g 
Hormone-
refractory prostate 
cancer 
Single-agent 
rhuMAb 
VEGF 
10mg/kg every 
other week over a 
168-day treatment 
period or until 
disease 
progression 
 
In Study AVF0780g, patients with metastatic colon cancer were treated with either 5-
FU/leucovorin (500mg/m2 5-FU and 500mg/m2 leucovorin administered weekly for six 


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weeks, with courses repeated every eight weeks) alone or in combination with rhuMAb 
VEGF 5mg/kg or 10mg/kg every two weeks. Response rates were 17%, 40% (p=. 03) 
and 24% (p=. 23), respectively. A prolonged time to disease progression was seen in 
patients treated with rhuMAb VEGF 5mg/kg in combination with chemotherapy (9.0 
months p=. 005) compared with those who received rhuMAb VEGF 10mg/kg (7.2 
months p= .217) or chemotherapy alone (5.2 months).  
The anti-VEGF antibody Bevacizumab (rhuMAb) was evaluated as a single agent in 
several malignancies including AIPC (18, 19). In a Phase II trial 15 patients with AIPC 
were treated with 10 mg/kg every 14 days. Results of the study showed that though the 
drug was tolerated well, there were no significant objective responses. Picus et al. is 
conducting an ongoing CALGB trial looking at the use of bevacizumab, estramustine 
and docetaxel in 79 patients with AIPC. Early results show that 53% of patients had a 
PR and 65% of patients had a >50% decrease in PSA in those patients with sufficient 
data to analyze. This regimen was well tolerated, though there was some increase in 
thrombosis (20).  This trial is using 15 mg/kg of bevacizumab every 3 weeks.    
Toxicities:  Life threatening toxicities seen in clinical trials to date with rhuMAb VEGF 
have included hemorrhage and thrombosis. Less severe toxicities have included 
proteinuria, hypertension, fever, chills, rash, headache, infection, epistaxis and mouth 
ulceration. 
 
a) Hemorrhage:  Life threatening hemorrhage was seen in a Phase I trial (AVF0737g) 
in the form of an intracranial hemorrhage (at an occult cerebral metastasis) in a 
patient with hepatocellular carcinoma and in the Phase II study (AVF0757g) in the 
form of massive hemoptysis or hematemesis. There were 6 life-threatening 
hemorrhages among 66 patients receiving rhuMAb VEGF-treated patients of which 
four of these events were fatal. An analysis of possible risk factors for life-
threatening bleeding identified squamous cell histology as a risk factor (4 of 6 
bleeds occurred in patients with squamous cell histology whereas only 13 of 66 
rhuMAb VEGF-treated patients had squamous histology). A number of 
investigations were performed on two of the patients with pulmonary hemorrhage 
and in eight patients in AVF0780g receiving rhuMAb VEGF including platelet count, 
prothrombin time, activated prothrombin time, fibrinogen, bleeding time, euglobulin 
clot lysis, d-dimer, alpha2-antiplasmin, PFA-100 (a platelet function assay) and 
these were all within normal range (Novotny,W. Genentech Inc personal 
communication).  
b) Thrombosis:  In Study AVF0780g in metastatic colorectal cancer, venous and 
arterial thrombosis were seen more frequently than in patients treated with rhuMAb 
VEGF plus 5-FU/leucovorin than in patients treated with 5-FU/leucovorin alone: 3 of 
35 patients in the control arm, 9 of 35 patients in the 5mg/kg rhuMAb VEGF arm 
and 4 of 32 patients in the 10mg/kg rhuMAb VEGF arm. One event was fatal (a 
pulmonary embolism in the 10mg/kg arm) and three events required study 
discontinuation (a pulmonary embolism and a superior mesenteric vein occlusion in 
the 5mg/kg arm and a cerebrovascular event in the 10mg/kg arm). Cancer patients 
are known to be at high risk for thromboembolism owing to a number of factors 


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including intrinsic tumor pro-coagulant activity, immobilization, indwelling catheters 
and the pro-thrombotic effects of chemotherapy. The incidence of thrombosis 
among patients with breast cancer receiving chemotherapy is approximately 5-10% 
being higher in patients on tamoxifen and in patients with metastatic disease (22). In 
the first 59 patients with metastatic breast cancer treated with rhuMAb VEGF 
monotherapy, two patients have developed a subclavian/axillary deep venous 
thrombosis on the side of the indwelling central line. 
c) Hypertension:  Hypertension has been seen in all rhuMAb VEGF clinical trials to 
date. There has been one reported case of hypertensive encephalopathy in a 
patient receiving 3mg/kg of rhuMAb VEGF on Study AVF0776g. In addition, 12 
other patients have developed either new hypertension (7 patients) or worsening 
existing hypertension (5 patients) for which 10 of these patients required medical 
therapy (3 patients in 3mg/kg rhuMAb arm [n=18] and 7 in the 10mg/kg [n=41], no 
data available from 20mg/kg arm). 
After 10 weeks of treatment, the mean change in blood pressure for all subjects 
compared with baseline was as follows (mean systolic change/mean diastolic 
change); 3mg/kg rhuMAb VEGF +10.5mmHg/+8.5mmHg and 10mg/kg rhuMAb 
VEGF +18.5mmHg/+8.2mmHg. In Study AVF0780g (colorectal cancer), using NCI-
CTC Grade 3 or 4 events, there were four events in the control arm (n=35), four 
events between 2 patients in the 5mg/kg rhuMAb VEGF (n=35) and nine-events 
among 5 subjects in the 10mg/kg rhuMAb VEGF (n=32). The most commonly used 
therapies to treat this hypertension have been angiotensin converting enzyme 
inhibitors and calcium channel blockers. 
VEGF has been shown to induce nitric oxide-mediated vasodilatation and 
hypotension (23). In a recent study, VEGF has been shown to govern endothelial 
nitric oxide synthase expression via a KDR/flk-1 receptor and protein kinase C 
signaling pathway, which suggests a possible mechanism for rhuMAb VEGF (24). 
d) Proteinuria:  Proteinuria by dipstick analysis has been seen in all rhuMAb VEGF 
clinical trials and has ranged in severity from clinically silent trace proteinuria to 
nephrotic syndrome. In study AVF0776g, 8 of 59 subjects treated with 3mg/kg or 
10mg/kg have developed some degree of proteinuria (detected by dipstick) during 
the study to date. Three of these patients have also developed hypertension. Two 
patients were discontinued from study because of proteinuria; one patient (10mg/kg 
arm) had >2.5g/24 hr which decreased to 0.7mg/24 hr within 4 weeks with a normal 
serum creatinine and a second patient in the 20mg/kg arm who developed 
>5g/24hr. Another patient (3mg/kg arm) developed hypertensive encephalopathy, 
which was followed by the development of nephrotic syndrome (5g/24hr). This 
patient died of progressive disease soon thereafter and renal biopsy was not 
performed. 
A recent study has shown that VEGF mediates glomerular repair, which suggested 
a possible mechanism for rhuMAb VEGF-associated proteinuria (24). 
e) Congestive Heart Failure:  Two patients with metastatic breast cancer in study 
AVF0776g who had been treated previously with doxorubicin developed congestive 


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heart failure while on rhuMAb VEGF, one patient after one year at 10 mg/kg and the 
second patient after two doses at 20 mg/kg. 
f) Dyspnea: In study AVF2107g, an ongoing trial with bevacizumab with 
5FU/leucovorin in metastatic colon cancer, one patient on this study developed 
dyspnea and pneumonitis requiring intubation eleven days after receiving her fifth 
infusion of bevacizumab with irinotecan and 5-FU.  Two other patients on this study 
also developed grade IV respiratory failure felt to be related to end-of-life events 
and not directly related to the drug.  In study AVF0757g, for stage IIIb and IV non-
small cell lung cancer, 3 patients had grade IV dyspnea events, the etiology of 
which is unclear but at least partially attributable to their underlying disease.  No 
other grade IV dyspnea events were reported in other trials.  
2.6 RATIONALE FOR COMBINATORIAL THERAPY 
We have shown that the combination of docetaxel and thalidomide is clinically 
promising in androgen independent prostate cancer (improvement in response rate and 
trend towards improvement in overall survival).  However it is important to have a 
molecular rationale in adding bevacizumab to this combination.  In microarray 
experiments using thalidomide and thalidomide analogs (the analogs are similar to the 
active metabolite of thalidomide) multiple angiogenesis factors are down regulated 
(KIF5A, TTK, etc), but not VEGF.   VEGF expression was not altered in xenograft 
experiments using these analogs, however PDGF was significant reduced.  The CALGB 
has published data to suggest that an elevation in VEGF is a poor prognosis factor in 
prostate cancer and the reduction of VEGF results in a survival advantage. We believe 
that by combining the anti-VEGF activity of bevacizumab with the anti-angiogenic 
activity of thalidomide (against multiple targets but not VEGF) we will have effectively 
suppressed all of the important angiogenic factors.  This approach will begin to test the 
hypothesis that the blockade of multiple factors in angiogenic is the most effective anti-
tumor strategy.  
VEGF, VEGFB or VEGFC were not de-regulated by any of the analogs or thalidomide in 
either PC3 or 22Rv1 xenografts or HUVECs in vitro, though other genes related to 
angiogenesis were.  Thalidomide down- regulated anti- apoptotic proteins such as the 
NFkB activator TNFSF11 as well as the endothelial cell- specific protein BIRC8, which 
protects cells from shear stress- induced apoptosis via caspase regulation. Other genes 
in this dataset have roles in cellular respiration (NDUFC1), detoxification of superoxides 
in blood vessels (SOD3) and peroxides (CAT), interleukin-2 signaling (IL2RG) and 
cellular vitamin A homeostasis (RBP1).  These results strongly suggest that thalidomide 
in particular promotes endothelial cell death by reducing the levels of various transcripts 
that have housekeeping functions in the endothelial cell. Catalase (CAT), which is 
activated by IGF-1R-mediated anti-apoptotic signaling via caspase-3 inhibition in a PI-3 
kinase- dependent manner, has an anti- apoptotic function. Interestingly, various 
proteins of significance in neurobiology were down- regulated specifically in 
thalidomide- treated HUVECs.  
PC3 and 22Rv1 tumors differentially expressed VEGF, PDGF-AA and bFGF proteins 
(Fig. 1, A, B and C).  Neither the analogues nor thalidomide significantly altered VEGF 
levels in PC3 or 22Rv1 tumors compared to the vehicle control (Fig. 1A).  Interestingly, 


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PDGF-AA levels were significantly reduced by 82%, 67%, and 58% in PC3 tumors 
treated with CPS45, CPS49 (both thalidomide analogues) and thalidomide, respectively 
(Fig. 1B).  All the analogues and thalidomide had no significant effects on 22Rv1 tumor 
PDGF-AA levels (Fig. 1B).  PC3 and 22Rv1 tumor bFGF levels were unchanged by the 
analogues and thalidomide (Fig. 1C). Microvessel density was decreased by 64% in 
PC3 tumors treated with CPS49 (Fig. 2).  In 22Rv1 tumors, CPS45 and CPS49 reduced 
microvessel density by 60% and 53%, respectively (Fig. 2).  CPS11 and thalidomide did 
not affect microvessel density in PC3 and 22Rv1 tumors compared to the vehicle 
control (Fig. 2). 


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Figure 1:  Concentrations of angiogenic factors in different cell lines vs. treatment 
with thalidomide and analogues 
 
 
 


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Figure 2:  Microvessel count of various cell lines after treatment with thalidomide 
and analogues. 
 
In our recent phase II trial we randomized 75 chemotherapy naïve AIPC patients to 
receive 30-mg/m2 weekly docetaxel for 3 consecutive weeks followed by a 1-week rest 
period; or docetaxel at the same dose and schedule plus thalidomide 200 mg orally 
each day. After a follow-up period of 26.4 months, the percentage of patients with a 
greater than 50% decline of PSA was higher in the combination group (51% vs. 37% in 
the single agent docetaxel group). The median survival in the docetaxel group was 14.7 
months and 28.9 months in the combined group. Both regimens were well tolerated with 
only mild toxicities. Though this study was not powered to detect a survival difference, 
the addition of thalidomide nearly doubled the median survival in patients with 
metastatic AIPC (30).  


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Picus et al combined docetaxel and estramustine with the anti-VEGF antibody 
bevacizumab in a phase II study of 79 patients with AIPC (21). The rationale for this 
study was in part based on the evidence that patients with AIPC treated with suramin 
who had lower baseline VEGF levels showed an increase in overall survival compared 
to those with higher baseline VEGF levels (17 vs. 10 mos. p= .024). In the same study, 
patients who had at least a 15% reduction of VEGF levels form their baseline also had 
increased survival advantage (28). 
In the study by Picus, patients received docetaxel (70 mg/m2 every 21 days), 
estramustine (280 mg on day 1-5) and bevacizumab (15 mg/kg) over a 21- day cycle. 
Preliminary analysis showed that 65% of patients had a PSA decline of ≥ 50% and that 
53% of patients had a partial response in their measurable disease. While the regimen 
was fairly well tolerated, there was an increase in thrombotic events. Based on these 
promising results, a phase III trial is being planned, though estramustine will be 
substituted for by prednisone to improve on the toxicity profile.  Thus both the 
docetaxel/thalidomide and the docetaxel/bevacizumab combinations have significant 
activity in prostate cancer, presumably through targeting different angiogenic factors. 
2.7 CORRELATIVE STUDIES 
Plasma concentrations of docetaxel will be determined to assess interactions between 
docetaxel and the concomitant therapy. Plasma concentrations of thalidomide will be 
determined to assess a possible interaction between thalidomide and the concomitant 
therapy. Single nucleotide polymorphisms (SNPs) in genes that play an important role in 
elimination pathways for docetaxel (in the CYP3A4 and CYP3A5 genes) and 
thalidomide (CYP2C19) will be evaluated.  
 
rhuMAb VEGF has been shown to recognize all isoforms of VEGF-A and is specific for 
VEGF-A; it fails to recognize other peptide growth factors tested including fibroblast 
growth factor, epidermal growth factor and platelet-derived growth factor. 
Multiparametric flow cytometric analysis for identification of circulating epithelial tumor 
cells on the basis of forward and side scatter profiles coupled to expression of human 
epithelial antigen and absence of CD45 expression will be performed. These studies will 
be done for research purposes. We will collect both serum and urine samples at 
baseline and monthly to measure vascular endothelial growth factor (VEGF) levels. 
 
Dynamic magnetic resonance imaging (MRI) with high temporal resolution permits 
noninvasive assessment of extravasation of extracellular paramagnetic contrast agents 
such as gadolinium (Gd)-chelates and thus permits an in vivo assessment of tumor 
vascularity and vascular permeability. Knopp et al used high temporal resolution 
imaging and quantification of the contrast enhancement using pharmacokinetic 
assessing the intensity of enhancement (amplitude), redistribution rate constant (kep) 
and the elimination rate constant (kel) in a study comparing the vasculature of 
undetermined breast lesions including both benign and malignant breast tumors (33). 
Tissue vascular density was assessed using CD31 and expression of VEGF determined 
using immunohistochemistry. Using correlative analysis of histology, vascular density 
and expression of VEGF, the study showed significantly faster exchange rates in 


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malignant lesions compared to benign breast lesions, distinct differences between 
histologic subtypes and a significant dependence of enhancement kinetics on VEGF 
expression. Thus the pathophysiologic basis for the difference in contrast enhancement 
patterns of tumors detectable by MRI is mainly due to vascular permeability, which 
leads to more characteristic differences than vascular density. This same technique has 
been used to assess changes in tumor vasculature during primary chemotherapy for 
breast cancer. Response to therapy has been correlated with a deceleration of the rate 
of tumor contrast enhancement characteristics (33). Thus, MRI assessment of tumors 
may provide a suitable non-invasive way of monitoring the effects of anti-angiogenesis 
therapy. 
 
 Primary Functional Angiogenesis Parameter 
 
Kep, the redistribution constant of contrast between the plasma and the extracellular 
space is our fourth primary parameter. This pharmacokinetic parameter, Kep (min-1) is 
directly affected by changes in the microvascular properties and is directly related to 
permeability. It has the highest reproducibility of the pharmacodynamic parameters and 
a variability of less than 10%. The other two parameters; intensity of enhancement 
(amplitude) and the elimination rate constant (kel) will be measured in an exploratory 
fashion. 
 
Microvessel density counting is a method of studying angiogenesis. 
Immunohistochemical staining of the tumor sample with monoclonal antibodies to the 
endothelial cell antigen CD31 are used. The histological sections are scanned areas of 
greatest vessel density “hot spots” and the individual microvessels in these areas as 
delineated by the stained endothelial cells are counted. The microvessel count is 
associated with the inherent problem that the regions of most active angiogenesis may 
be distributed irregularly throughout the tumor. The examination of multiple tumor 
sections and multiple areas within a section together with an automated counting 
system may help to diminish this problem.  To assess microvascular density, we will 
obtain baseline tumor biopsies. 
2.8 CONCLUSION 
Though this would be the first trial to combine bevacizumab, thalidomide and docetaxel 
in prostate cancer, thalidomide and bevacizumab have been combined in multiple 
myeloma with acceptable toxicity (personal communication, unpublished data). We 
believe that the combination of bevacizumab, thalidomide and docetaxel has the 
potential to make a significant impact in the disease. We believe that if this trial is 
successful, a larger randomized trial through the cooperative groups with survival as an 
endpoint would be warranted.  


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3 
PATIENT SELECTION 
3.1 ELIGIBILITY CRITERIA 
3.1.1 Androgen-independent metastatic adenocarcinoma of the prostate defined as 
progressive metastatic disease (see 3.1.3) while on GnRH agonists or 
postsurgical castration 
3.1.2 Histopathological documentation of prostate cancer confirmed in the NCI 
Laboratory of Pathology at the National Institutes of Health, the Pathology 
Department at Walter Reed Medical Center, or the Pathology Department at 
National Naval Medical Center, prior to starting this study.  In addition, patients 
whose slides are lost or unavailable will be eligible for the study if they provide 
documentation of prostate cancer and if they meet criteria of clinically 
progressive prostate cancer as outlined in section 3.1.3. 
3.1.3 Clinically progressive prostate cancer documented prior to entry.  Progression 
must be documented by at least one of the following parameters 
3.1.3.1 Two consecutively rising PSA levels.  The first rising PSA must be a minimum 
of one week from a reference value.  It is recognized that PSA fluctuations are 
such that the confirmatory PSA value might be less than the previous one.  In 
these cases, that patient would still be eligible provided the next PSA was 
greater than the first rising PSA value.  Patients must have PSA > 5.0. 
3.1.3.2 At least one new lesion on bone scans. 
3.1.3.3 Progressive measurable disease. 
3.1.4 Patients must have undergone bilateral surgical castration or must continue on 
GNRH agonist. 
3.1.5 Those patients receiving an anti-androgen agent and are entering the trial due to 
a rise in PSA must demonstrate a continued rise in PSA 4 weeks after stopping 
flutamide and 6 weeks after stopping bicalutamide or nilutamide. 
3.1.6 Patients may not have received any chemotherapy for metastatic prostate cancer 
3.1.7 Age > 18 years 
3.1.8 ECOG performance status < 2 
3.1.9 Life expectancy of greater than 3 months 


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3.1.10 Patients must have adequate organ and marrow function as defined below: 
Table 2:  Adequate Organ and Marrow Function 
 
 Laboratory 
Test 
 
Required value 
Leukocytes 
>3,000/μl 
Absolute neutrophil count 
>1,500/μl 
Platelets 
>100,000/μl 
Hemoglobin 
> 8.0 g/L – transfusions acceptable 
Total bilirubin 
≤1.5 X institutional upper 
limits of normal, or < 3 mg/dl 
in a subject with Gilbert 
Syndrome 
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  
 
> 40 mL/min/1.73 m2 for patients with 
creatinine levels above institutional 
normal. 
 
3.1.11 Recovered from any toxicity from surgery or radiotherapy 
3.1.12 Must be willing to travel from their home to the NIH for follow-up visits 
3.1.13 Able and willing to follow instructions and conform to protocol. 
3.1.14 Patients may have had no other active malignancy within the past 2 years with 
the exception of non-melanoma skin cancer and superficial bladder carcinoma. 
3.1.15 No history of myocardial infarction within the past 6 months, uncontrolled CHF or 
uncontrolled angina pectoris 
3.1.16 Patients must agree to use adequate contraception (abstinence; hormonal or 
barrier method of birth control) for the study and at least 2 months after 
completion. 
3.1.17 Ability to understand and the willingness to sign a written informed consent 
document. 
3.2 EXCLUSION CRITERIA 
3.2.1 Present clinical signs or symptoms of brain and/or leptomeningeal metastases 
confirmed by CT or MRI brain scan.  
3.2.2 Uncontrolled, intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure (AHA Class II or worse), unstable 


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angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements 
3.2.3 Persistent systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 
mmHg. 
3.2.4 HIV-positive patients receiving combination anti-retroviral therapy are excluded 
from the study because of possible pharmacokinetic interactions with docetaxel, 
bevacizumab, and/or the combination 
3.2.5 Proteinuria, as demonstrated by a UPC ratio  ≥ 1.0 at screening, required to be 
assessed if urine dipstick is > 1+. 
Urine protein should be screened by urine analysis for Urine Protein Creatinine 
(UPC) ratio.  For UPC ratio > 0.5, 24-hour urine protein should be obtained and 
the level should be <1000 mg for patient enrollment. Note: UPC ratio of spot 
urine is an estimation of the 24 urine protein excretion – a UPC ratio of 1 is 
roughly equivalent to a 24-hour urine protein of 1 gm.  UPC ratio is calculated 
using one of the following formulas: 
- [urine protein]/[urine creatinine] – if both protein and creatinine are 
reported in mg/dL 
- [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported 
in mmol/L 
3.2.6 Therapeutic anticoagulation with coumadin, heparins, or heparinoids. 
3.2.7 Greater than Grade 2 peripheral neuropathy at baseline 
3.2.8 History of transient ischemic attacks (TIA) or cerebrovascular accident (CVA) 
within the past 2 years. 
3.2.9  History of allergic reaction to docetaxel, prednisone, thalidomide and/or 
bevacizumab or related products. 
3.2.10 Patients who are on concurrent investigational agent(s) 
3.2.11 Patients who are unable to ingest oral medication. 
3.3 INCLUSION OF WOMEN AND MINORITIES 
Men of all races and ethnic groups are eligible for this trial.  Every effort will be made to 
recruit minorities in this study.  Women are ineligible for this study. 
3.4 ON-STUDY RESEARCH EVALUATION 
3.4.1 Complete history and physical examination (including height, weight, and ECOG 
performance score) with documentation of 1) measurable disease, 2) narcotic 
use and pain assessment and 3) prior therapies (hormonal, surgical, 


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radiotherapeutic, and cytotoxic) will be conducted prior to starting therapy.  A 
complete medication history will be obtained prior to starting, including over the 
counter medications, homeopathic remedies, vitamins, and alternative therapies. 
3.4.2 Imaging Studies (baseline) – Within 4 weeks prior to enrollment 
3.4.2.1 Technetium-99 Bone Scintigraphy 
3.4.2.2 Chest X-ray, CT scan of chest, abdomen and pelvis 
3.4.2.3 MRI* *A selected number of patients will undergo dynamic MRI as outlined in 
section 4.5.3.2 
3.4.3 Laboratory evaluation [baseline is to be obtained within 16 days prior to 
enrollment] 
3.4.3.1 Hematological Profile: CBC with differential and platelet count, prothrombin 
time, activated partial thromboplastin time 
3.4.3.2 Biochemical Profile: electrolytes, BUN, creatinine, glucose, AST, ALT, bilirubin, 
calcium, phosphorous, albumin, magnesium, alkaline phosphatase 
3.4.3.3 Urine analysis 
3.4.4 Tumor Marker Profile 
3.4.4.1 PSA (within 7 days prior to enrollment) 
3.4.4.2 Acid phosphatase (if PSA <4ng/mL, for research purposes only) 
3.4.5 Testosterone level (baseline only, should be obtained within 8 weeks prior to day 
1); no required for patients with prior bilateral orchiectomy 
3.5 PATIENT REGISTRATION 
Authorized staff must register an eligible candidate with NCI Central Registration Office 
(CRO) within 24 hours of signing consent.  A registration Eligibility Checklist from the 
web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed 
and sent via encrypted email to:  NCI Central Registration Office (HOIS) 
ncicentralregistration-l@mail.nih.gov.  After confirmation of eligibility at Central 
Registration Office, CRO staff will call pharmacy to advise them of the acceptance of 
the patient on the protocol prior to the release of any investigational agents Verification 
of Registration will be forwarded electronically via e-mail to the research team. A 
recorder is available during non-working hours.  


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4 
TREATMENT PLAN 
4.1 STUDY DESIGN 
This is an open label, phase II trial of up to 60 patients who will receive docetaxel 
75mg/m2 IV over 60 minutes on cycle 1 day 1, repeated every 21 days (i.e. a 3-week 
cycle), plus bevacizumab 15mg/kg cycle 1 day 1, repeated every 21 days, thalidomide 
200 mg orally each day at bedtime plus prednisone 10 mg orally every day.  All patients 
will receive 4 mg of oral dexamethasone, 12 hours before, 1 hour before and 12 hours 
after docetaxel treatment.  If a patient misses a pretreatment dose of dexamethasone, 
he may receive dexamethasone 8 mg intravenously prior to docetaxel plus 
dexamethasone 4 mg orally 12 h after docetaxel administration. If a patient develops 
grade 3 or 4 neutropenia, pegfilgrastim will be given as described in section 4.3.1.1 to 
reduce risk of febrile neutropenia and facilitate full dose delivery of the chemotherapy. 
After the completion of the initially planned enrollment of 60 patients, fifteen additional 
patients will be enrolled in an expansion cohort (Ex-Cohort) for studying the effects of 
docetaxel and bevacizumab on the immune system in patients with metastatic AIPC as 
a prelude to a possible clinical trial of the triplet of docetaxel, bevacizumab, and 
vaccine. These patients will receive docetaxel 75 mg/m2 IV over 60 minutes on cycle 1 
day 1, repeated every 21 days, plus bevacizumab 15 mg IV on day 1, repeated every 
21 days, for a total 2 cycles. Use of dexamethasone and pegfilgrastim will be same as 
described above. After Cycle 2 and since cycle 3, patients will resume the original 
treatment regimen with the four drugs, administered as described above, plus the 
initiation of prophylactic enoxaparin at 1 mg/kg sq daily beginning on cycle 3, day 1. 
Treatment will continue until disease progression or unacceptable toxicities.  If patients 
have disease progression or unacceptable toxicities after cycle 2, they will be taken off 
the study and they will not be replaced. 
Patients will be evaluated by a physician and have their PSA checked every 3 weeks.  
PSA will be measured by the Hybritech Tandem-R (San Diego, CA) assay.  This assay 
is used at the National Institutes of Health and the vast majority of laboratories 
nationally.  If our patients have a PSA drawn at an outside laboratory, we will attempt to 
verify that this particular assay is used, if it is/was not, we will repeat the test at the NIH. 
Radiographic studies (CT scans of the chest, abdomen, and pelvis, Technetium-99m 
bone scintigraphy) will be performed at baseline, after second cycle and then every 3 
cycles. For the patients enrolled in Ex-Cohort, disease progression prior to the end of 
cycle 5 (after three cycles of treatment with the combination of docetaxel, bevacizumab, 
thalidomide, and prednisone) will not be used to remove patients from study. If patients 
have radiographic progression on restaging prior to Cycle 3, then these scans will serve 
as baseline scans for the rest of the study. If there is no significant toxicity or evidence 
of disease progression (as defined below) therapy will continue. For patients who simply 
have PSA elevations, treatment can continue till they have clinical or radiographic 
disease progression, unacceptable toxicities, or voluntary withdrawal from the protocol. 
In addition, patients who had not undergone bilateral orchiectomy will continue to 
receive medical castration with a LHRH agonist (leuprolide or goserelin acetate). 


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4.2 AGENT ADMINISTRATION 
4.2.1 Docetaxel Administration 
Docetaxel 75mg/m2 will be administered intravenously over 60 minutes on cycle 1 day 1 
and repeated every 21 days (i.e. a 3-week cycle).  All patients will receive 4 mg of 
dexamethasone orally 12 hours and 1 hour prior to docetaxel, and then 12 hours after 
docetaxel.  Patients who have excessive dexamethasone-induced toxicity (defined as 
Grade III toxicity in the CTCAE 3.0 felt to be caused by dexamethasone) may have their 
doses altered to a single 8 mg intravenously dose of dexamethasone prior to docetaxel 
administration. 
4.2.2 Bevacizumab Administration 
Bevacizumab 15 mg/kg diluted in 0.9% Sodium Chloride Injection, USP, to a total 
volume of 100 ml. Administration will be as an intravenous infusion over 30-90 minutes 
every 21 days (see below).  
The initial bevacizumab dose will be delivered as an IV infusion over 90 ± 10 minutes. If 
the first infusion is tolerated without infusion-associated adverse events (fevers and/or 
chills), the second infusion maybe delivered over 60 ± 10 minutes. If the 60 minute 
infusion is well tolerated, all subsequent infusions maybe delivered over 30 ± 10 
minutes.  
If a patient experiences an infusion-associated adverse event, subsequent infusions will 
be given over the shortest period that was well tolerated. The patient may be 
premedicated for the next bevacizumab infusion. 
4.2.3 Thalidomide Administration 
Patients will receive their first dose of thalidomide 200 mg orally on day 1 and will 
continue this dose daily throughout the cycle. For patients enrolled in Ex-cohort, 
thalidomide will not be started until Day 1 of cycle 3 and will continue this dose daily 
while patients remain in the trial. 
4.2.4 Prednisone Administration 
Patients will receive their first dose of prednisone 10 mg orally on day 1 and 
will continue this dose daily throughout the cycle. For patients enrolled in Ex-
cohort, prednisone will not be started until Day 1 of cycle 3 and will continue 
this dose daily while patients remain in the trial. 
4.2.5 Enoxaparin Administration 
Patients will receive 1 mg/kg of enoxaparin sq daily beginning on day 1. For patients 
enrolled in Ex-cohort, enoxaparin will not be started until Day 1 of cycle 3 and will 
continue while patients remain in the trial. 


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4.3 TREATMENT MODIFICATIONS 
4.3.1 Dose reduction will be according to the following rules 
4.3.1.1 Dose modifications for docetaxel 
Administration of docetaxel will be withheld on a treatment day for the occurrence of 
dose-limiting toxicity (DLT) defined as grade 3 or 4 hematologic toxicities or non-
hematologic toxicity ≥ grade 3.  Patients should have an ANC ≥1500 cells/mm3, a 
platelet count ≥ 75,000 cells/mm3 (grade 1 hematologic toxicity) and resolution of any 
non-hematologic toxicity to < grade 1 or baseline in order to initiate another treatment 
cycle of docetaxel. It should be noted that no platelet transfusions would be allowed 
within 7 days prior to docetaxel administration.  
For febrile neutropenia developed within a prior cycle and resolved before next cycle, 
docetaxel can be continued at a dosage decreased by 25% during future cycles and 
pegfilgrastim will be given to prevent future episodes. For patients who had either grade 
3 or 4 neutropenia during a cycle, docetaxel treatment will continue at 100% dosages 
thereafter with the addition of pegfilgrastim; however, docetaxel dosage will be 
decreased by 25% if patients supported with pegfilgrastim continue to experience grade 
4 neutropenia or febrile neutropenia.  
     
For grade 3 constipation or fatigue, treatment can resume with a 25% dose reduction 
after resolution of toxicity to < grade 2.   The occurrence of DLT or a delay of > 2 weeks 
in initiating a new treatment cycle for the recovery of docetaxel-induced toxicities would 
result in a docetaxel dose reduction of 25%. In patients whose Grade III fatigue and/or 
constipation are felt to be caused by thalidomide; then docetaxel need not be held or 
reduced. Patients will be allowed to continue docetaxel treatment at successively 
reduced doses as long as they do not have progressive disease, regardless of the time 
required for recovery from ADEs.  For dose-limiting toxicities related to docetaxel, it 
should be noted that thalidomide, bevacizumab and prednisone should not be 
interrupted. 
4.3.1.2 Dose modifications for bevacizumab 
Bevacizumab will be discontinued for the following toxicities: Development of proteinuria 
>2g /24 hr; Development of Grade 4 hypertension (hypertensive crisis); Development of 
Grade 4 symptomatic venous thrombosis, not including catheter related thrombi; 
Development of a non-healing wound; Development of > Grade 3 hemorrhagic event. 


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Bevacizumab treatment modifications based on venous thrombosis: 
 
Table 3:  Bevacizumab and Venous Thrombosis 
CTCAE Grade  
Action to be Taken  
Grade 3 or asymptomatic 
/minimally symptomatic Grade 4 
• Hold Bevacizumab treatment. If the 
planned duration of full-dose 
anticoagulation is < 2 weeks, 
Bevacizumab should be held until the 
full-dose anticoagulation period is over.  
• If the planned duration of full-dose 
anticoagulation is > 2 weeks, 
Bevacizumab may be resumed if either: 
the thrombosis has resolved OR during 
full-dose anticoagulation IF all of the 
criteria below are met:  
o The subject must not have 
pathological conditions that carry 
high risk of bleeding (e.g. tumor 
involving major vessels or other 
conditions)  
o The subject must not have had 
hemorrhagic events while on study  
o The subject must be on stable 
doses of heparin or have an in-
range INR (usually 2-3) on a stable 
dose of warfarin prior to restarting 
Bevacizumab 
o If thromboemboli worsen/recur upon 
resumption of study therapy, 
discontinue Bevacizumab 
  
Grade 4 Symptomatic 
Discontinue Bevacizumab 
 
Table 4:  Thalidomide and Venous Thrombosis 
Thalidomide treatment modifications based on venous thrombosis: 
CTCAE Grade  
Action to be Taken  
Grade 3 or asymptomatic 
/minimally symptomatic Grade 4 
• Hold Thalidomide treatment. If the 
planned duration of full-dose 
anticoagulation is < 2 weeks, 
Thalidomide should be held until the 
full-dose anticoagulation period is over.  
• If the planned duration of full-dose 
anticoagulation is > 2 weeks, 
Thalidomide may be resumed during 
full-dose anticoagulation IF all of the 
criteria below are met:  


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CTCAE Grade  
Action to be Taken  
o The subject must not have 
pathological conditions that carry 
high risk of bleeding (e.g. tumor 
involving major vessels or other 
conditions)  
o The subject must not have had 
hemorrhagic events while on study  
o The subject must be on stable 
doses of heparin or have an in-
range INR (usually 2-3) on a stable 
dose of warfarin prior to restarting 
Thalidomide  
o If thromboemboli worsen/recur upon 
resumption of study therapy, 
discontinue Thalidomide 
 
Grade 4 Symptomatic 
Discontinue Thalidomide 
 
Bevacizumab treatment modifications based on proteinuria: 
Table 5:  Bevacizumab and Proteinuria 
Urine Dipstick 
Further evaluation 
Bevacizumab dose modification 
Negative 
None 
Continue bevacizumab 
Trace 
None 
Continue bevacizumab 
1+ 
None 
Continue bevacizumab. 
2+ or > 2+   
24-hour urine 
Hold bevacizumab, treatment based 
on 24-hour urine protein 
 Urine protein 
Further evaluation 
Bevacizumab 
<2000mg 
None 
Resume or continue bevacizumab 
> 2000mg  
24-hr urine before 
subsequent doses 
Hold bevacizumab until 24-hr urine 
protein < 2000 mg 
 
 
In addition to the toxicities listed above, bevacizumab will be discontinued if there is 
persistent (≥3 weeks) NCI-CTG Grade 3 or 4 adverse events or any other significant 
adverse event that compromises the subjects’ ability to participate in the study. 
4.3.1.3 Dose modification for thalidomide 
Doses may be reduced by 50 mg to 100 mg at a time, to alleviate side effects quickly, 
with slow escalation back to upper limit of tolerability. Patients with any grade III or IV 
nonhematological toxicity felt to be caused by thalidomide will have their thalidomide 
held. Thalidomide will be resumed with a dose reduction of 50 % when toxicity returns 
to the patients’ baseline or is < grade I. Patients who develop ≥ grade 2 peripheral 
neuropathy should have their thalidomide dose withheld until toxicity resolves to < grade 
1, at which point thalidomide may be restarted at a 50% dose reduction.  Patients who 
develop recurrence of ≥ grade 2 peripheral neuropathy at a decreased dose or whose 


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toxicity fails to resolve to < grade 1 will discontinue taking thalidomide. Thalidomide 
should be discontinued if a skin rash occurs and only resumed following appropriate 
clinical evaluation.  If the rash is exfoliative, purpuric, bullous or if Stevens-Johnson 
Syndrome or toxic epidermal necrolysis is suspected, thalidomide should not be 
resumed.  For dose-limiting toxicities related to thalidomide, it should be noted that 
docetaxel and bevacizumab should not be interrupted. 
4.3.2 As this trial allows patients to receive treatment indefinitely, patients may have 
the doses of any or all drugs (docetaxel, bevacizumab, thalidomide and 
prednisone) temporarily withheld, and potentially resume treatment as long as 
they do not fulfill the off-study criteria outlined in section 4.9. 
 
Patients may also have those FDA-approved drugs administered at their local 
health care facilities other than the NIH with their own oncologists who agree to 
treat them under the investigational physician’s guidance. 
Although the treatment is planned every 21 days as a cycle, patients may have 
their treatments administrated about or after 21 days in order to accommodate 
their travel, hospitalization, variations in clinical availability due to holidays, or other 
unpredictable personal or family situations. Every effort will be made to minimize 
delay from their planned cycles and/or staging evaluations. Continuation of the 
treatment will be decided at the investigational physicians’ discretion for the best 
benefits of patients with no deviations from the protocol.      
4.3.3 Patients who develop deep vein thrombosis will continue on docetaxel and 
prednisone, receive appropriate medical care and have thalidomide and 
bevacizumab managed as described above.”  This reflects our experience from 
our docetaxel/thalidomide versus docetaxel alone trial in a similar patient 
population, where those patients in the docetaxel alone arm had no episodes of 
thrombosis. 
4.4 PHARMACOKINETIC AND CORRELATIVE STUDIES 
Research blood and urine collection described in this section are optional. 
4.4.1 Pharmacokinetic Analysis 
4.4.1.1 Pharmacokinetics of docetaxel 
Plasma concentrations of docetaxel will be determined to assess interactions between 
docetaxel and the concomitant therapy.  Venous blood samples will be collected in a 7-
mL sodium heparin (green top) tube pre-dose on cycle 1 day 1, 5 minutes before the 
end of infusion, and 15, and 30 minutes, and 1, 2, 4, 8, and 24 hours after the end 
infusion.  Sampling will also be repeated cycle 2, day 1.  A heparin-lock should be 
placed in the opposite arm from the docetaxel infusion in order to facilitate sample 
collection.  The samples will be analyzed by the Clinical Pharmacology Research Core, 
Clinical Center, Building 10, Room 5A01, Telephone: 240-760-6190.  The analysis will 
be performed using a validated method based on liquid chromatography with mass-


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spectrometric detection.  Concentration-time profiles in each individual patient will be 
performed using non-compartmental in the software package WinNonlin. 
4.4.1.2 Pharmacokinetics of thalidomide 
Plasma concentrations of thalidomide will be determined to assess a possible 
interaction between thalidomide and the concomitant therapy.  This analysis will be 
performed in the same samples obtained for the purpose of docetaxel pharmacokinetic 
analysis. The samples will be analysed by the Clinical Pharmacology Research Core, 
Clinical Center, Building 10, Room 5A01, Telephone: 240-760-6190.  The analysis will 
be performed using a validated method based on liquid chromatography with ultraviolet 
detection.  Concentration-time profiles in each individual patient will be performed using 
non-compartmental in the software package WinNonlin. 
4.4.1.3 Pharmacokinetic collections in the expansion cohort 
No pharmacokinetic sampling will be collected for patients enrolled onto the Ex-cohort.   
4.4.2 Genotyping of Patients 
Single nucleotide polymorphisms (SNPs) in genes that play an important role in 
elimination pathways for docetaxel (in the CYP3A4 and CYP3A5 genes) and 
thalidomide (CYP2C19) will be evaluated.  For this purpose two buffy coat tubes (two 7 
mL blue tiger top tubes) will be obtained, and wrapped in foil when the patient enters 
onto the study.  DNA will be isolated only for the purpose of genotype analysis of 
enzymes with putative relevance for docetaxel or thalidomide disposition. The 
genotyping will be performed on a research basis in the Clinical Pharmacology 
Research Core (Bldg. 10 Room 5A01; William Figg, Pharm.D.). 
4.4.3 Molecular Analysis 
Patients will undergo venipuncture of approximately 25-30 cc of blood in green-top 
(heparinized) tubes prior to initial treatment and after cycle 2 and 5 of treatment. 
Selected patients will undergo bone marrow biopsy.  We will collect these samples for 
molecular analysis and estimation of circulating endothelial cells. These samples will be 
sent to the laboratory of Jane Trepel located in Building 10 Room 12N218. The samples 
will undergo testing which will include multiparametric flow cytometric analysis for 
identification of circulating epithelial tumor cells on the basis of forward and side scatter 
profiles coupled to expression of human epithelial antigen and absence of CD45 
expression. These studies will be done for research purposes. 
4.4.4 Angiogenesis Markers 
We will collect both serum and urine samples at baseline and monthly to measure 
vascular endothelial growth factor (VEGF) levels.  These studies will be done by the 
Molecular Pharmacology Section of the Clinical Pharmacology Research Core, under 
the direction of Dr. Figg. 
Serum and plasma research samples (2 green top, 2 blue tiger top, and 2 red top 7 mls 
each on ice), send to Dr. Figg, Bldg 10, Rm 5A01; tel 240-760-6190.  Blood collected in 
the course of this research project may be banked and used in the future to investigate 


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new scientific questions related to this study.  However, this research may only be done 
if the risks of the new questions were covered in the consent document.  If new risks are 
associated with the research (e.g. analysis of germ line genetic mutations), the principal 
investigator must amend the protocol and obtain informed consent from all research 
subjects. 
Urine Profile  
Research spot urine samples should be collected in a clean catch container (approx. 30 
ml) prior to first treatment cycle and after second treatment cycle and sent to Dr. Figg, 
Bldg. 10, Rm 5A01; tel 240-760-6190 via messenger on ice and STAT. Twenty-four 
hour urine samples may be collected to assess urinary elimination of parent compound. 
These tests will be done for research purposes. 
4.4.5 Baseline and Follow-Up Biopsy of Accessible Tumors 
A baseline biopsy of accessible tumor tissue will be obtained prior to starting treatment 
as well as after 2-3 cycles of treatment if it can be performed with minimal risk of 
complications from the procedure.  The location of this tissue may be an abnormally 
enlarged lymph node, mass or an unresected, non-irradiated prostate or radiated 
prostate that has a significant abnormality on either physical exam or imaging studies.  
However, patients can still participate in the trial even if they refuse to have the biopsy.  
Punch, percutaneous core, fine needle or laparoscopic techniques will be used for 
tumor biopsy. Anticoagulation will be held as is clinically indicated for biopsy. The 
Molecular Pharmacology Section of Dr. William D. Figg will coordinate rapid acquisition 
and evaluation of patient samples. The samples will be processed by Dr. Mike Buck in 
the NCI Laboratory of Pathology according to a routine MOCRU protocol.  Tissue 
acquisition form will be included if applicable.   
4.4.6 Immune Cellular and Molecular Studies    
4.4.6.1 Regulatory T-cell Assay 
The PBMC of patients enrolled onto the Ex-cohort will be analyzed pre-treatment and 
post-cycle 2 for any changes in the function of regulatory T cells.  Six green tops and 2 
SST's (a total of ~56 mL blood for these collections) will be collected pre-chemotherapy 
and post-cycle 2 (pre the introduction of prednisone /thalidomide). These samples will 
be sent to the laboratory of Dr. Jeffrey Schlom, Ph.D, Head of Laboratory of Tumor 
Immunology and biology, for the analyses as described below. 
 
Flow Cytometry Analysis 
To determine the regulatory T-cell phenotype, three color flow cytometry analysis 
will be performed on PBMCs. Cells will be resuspended in staining buffer 
(phosphate-buffered saline containing 3% fetal bovine serum) and stained for 30 
minutes at 4°C with the combination of following antibodies: PerCP-Cy5.5-
conjugated anti-CD4 and phycoerythrin (PE)-conjugated anti-CD25; (all 
purchased from BD Pharmingen, San Diego, CA). After that, FoxP3 intra-cellular 
staining will be performed on the cells stained with anti-CD4 and anti-CD25. They 
will be fixed and permeabilyzed using a fix/perm kit (eBioscience, San Diego, 


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CA) according to the manufacturer’s manual, and will be labeled with FITC-
conjugated anti-Foxp3 antibody (PCH101 clone) or its isotype control antibody 
(eBioscience). Flow cytometry will be performed on a Becton Dickinson LSRII 
(BD Biosciences), 1 x 105 cells will be acquired and data will be analyzed using 
FlowJo software (BD Biosciences). To determine the percentage of Tregs, 
lymphocytes will be gated by plotting forward vs. side scatter followed by gating 
on CD4 positive population.  Then, CD25high and Foxp3 positive population will 
be gated. CD25high population will be separated from CD25low on the basis of the 
level of CD25 expression in CD4- T cells, as previously described. 
 
CD4+ CD25high T-cell Enrichment 
CD4+CD25high T cells will be enriched using Miltenyi CD4+CD25+ regulatory T cell 
isolation kit (Miltenyi Biotec, Auburn, CA) with modifications to the manufacturer's 
instructions. In order to achieve a consistently high CD4+ purity rate, the amount 
of CD4 antibodies, antibiotin MicroBeads, as previously described. After CD4+ T 
cells will be negatively enriched, it will be performed a positive selection for 
CD25+ cells. The CD25+ fraction will be collected by eluting cells twice through a 
magnetic separation (LS) column to further enrich for CD4+CD25high T cells. 
 
Immunosuppression Assay 
CD4+CD25- T cells (5 x 104 cells/well) will be cultured alone or cocultured with 
CD4+CD25high T cells (5 x 104 cells/well) on three different ratios with 1 µg/ml 
anti-CD3 antibody (OKT3; eBioscience) in the presence of irradiated (3500 Rad) 
T-depleted PBMCs (2.5 x 105 cells/well) in a 96-well flat-bottom plate at 37°C and 
5% CO2. All cells will be cultured in medium RPMI 1640 (Mediatech, Inc., 
Herndon, VA) supplemented with 10% heat-inactivated human AB serum (Gemini 
Bio-Products, Woodland, CA); 100 units/ml penicillin and 100µg/ml streptomycin 
(Mediatech, Inc.); 2 mM L-glutamine (Mediatech, Inc.). Proliferation will be 
assessed by [3H]thymidine (1 µCi [0.037 MBq] per well) (Perkin-Elmer, Boston, 
MA)  incorporation pulsed on day 4 and quantified 18 hours later using a liquid 
scintillation counter (Wallac, Gaithersburg, MD). All experiments will be 
performed in triplicate. 
 
4.4.6.2 Phenotypic and Functional Analysis of Human Dendritic Cells Derived from 
Peripheral Blood Mononuclear Cells 
Generation of Dendritic cells from Peripheral Blood Mononuclear Cells  
PBMCs will be obtained from heparinized blood. PBMCs will be separated using 
lymphocyte separation medium gradient (Organon Teknika, Durham, NC). DCs will be 
prepared using a modification of the procedure described by Sallusto and Lanzavecchia. 
PBMCs (1.5 x 108) were resuspended in AIM-V medium containing 2 mmol/L glutamine, 
50µg/mL streptomycin, and 10µg/mL gentamycin (Invitrogen Life Technologies) and 
allowed to adhere to a T-150 flask (Corning Costar Corp., Cambridge, MA). After 2 
hours at 37°C, the nonadherent cells will be removed with a gentle rinse. The adherent 
cells were cultured for 6 to 7 days in AIM-V medium containing 100 ng/mL of 
recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) and 


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20 ng/mL of recombinant human interleukin 4 (rhIL-4). The culture medium will be 
replenished every 3 days 
 
Immunophenotyping of Dendritic Cells 
DC generated from PMBC will be analyzed for cell surface markers by flow cytometry 
using a Becton Dickinson LSR2 flow cytometer. Multiple-color flow cytometric analysis 
will be performed on DCs by using the following antibody combinations: anti-CD80-
FITC, anti-CD83-PE, anti-MHC class II-APC, anti-CD58-Cy7, anti-MHC Class I-PerCP 
Antibodies will be purchased from BD Biosciences (San Jose, CA). Staining will be 
conducted simultaneously for 1 hour at 4°C, cells will then be washed thrice with cold 
Ca2+- and Mg2+-free PBS, resuspended in the same buffer, and immediately analyzed 
 
Mixed Lymphocyte Responses (MLR) 
The Dendritic cells (DC) generated from the patients will be analyzed for their ability to 
stimulate proliferation in an allo-MLR assay. Peripheral blood mononuclear cells 
(PMBC) will be isolated from two different normal healthy donors. The two different 
samples will be mixed in a 96-well flat-bottomed microtiter plate at a concentration of 1 x 
105 cells/well with 1:1 ratio. DCs are added at a concentration of 5% and 10% of the 
total cell concentration. Control wells contained 105 of each sample alone and mixed 
cells with no DC added. Cells will be incubated for 5 days at 37o C in 5% CO2.  After 
incubation, 1 µCi of radiolabeled [3 H] thymidine will be added to each well, and the plate 
will be incubated for an additional 18 h. After the final incubation period, the cells will be 
harvested and counted for radioactivity.   
 
Immunophenotyping of Myeloid Dendritic Cells and Plasmacytoid Dendritic 
cells 
PMBC will be analyzed for cell surface markers by flow cytometry using a Becton 
Dickinson LSR2 flow cytometer.  Multiple-color flow cytometric analysis will be 
performed on DCs by using the following antibody combinations: anti-CD11c, anti-
CD14, anti-CD1a, anti-CD123, anti-BDCA2. Antibodies will be purchased from BD 
Biosciences (San Jose, CA). Staining will be conducted simultaneously for 1 hour at 
4°C, cells will then be washed thrice with cold Ca2+- and Mg2+-free PBS, resuspended in 
the same buffer, and immediately analyzed 
 
Phenotyping peripheral myeloid-derived suppressor cells 
Phenotypically, Myeloid-derived suppressor cells are identified as 
CD34+CD33+CD13+CD15- cells. PBMC will be analyzed flow cytometry. Antibodies 
used will be FITC-CD34, APC-CD33, PE-CD13 and PerCP-CD15. Data acquisition and 
analysis will be performed using LSR-2 flow cytometer (BD BioSciences) and BD 
FACSDiVa software (BD BioSciences). 
4.4.7 Prediction of bone metastasis risk in mCRPC 
A nomogram to predict which men with CRPC were at high risk for developing bone 
metastasis was developed using men from the Centers for Prostate Disease Research 
through Walter Reed National Military Medical Center who were on androgen 
deprivation therapy with castrate testosterone.  In this population it was found that PSA 


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nadir on androgen deprivation therapy, PSA doubling time and a novel metric, Alkaline 
Phosphatase Velocity (APV) predicted bone metastasis-free survival. The patients used 
to develop the nomogram had not been treated with chemotherapy and had no 
evidence of bone metastases. 
An evaluation of patient records of the subjects enrolled on this protocol through BTRIS, 
using the identical analysis, is planned.  Subjects in this protocol differ from the original 
cohort used to develop the nomogram in that these patients had evidence of bone 
metastases upon enrollment.  We plan to determine whether the APV metric is still valid 
in this different cohort of patients.  If the APV metric proves to be valid in this 
independent analysis and a similar nomogram to the original can be created, we intend 
to validate the new nomogram on a different set of patients in order to determine 
whether alkaline phosphatase velocity is independent of PSADT and whether it predicts 
progression of bone metastasis and/or overall Survival and/or other evidence of 
progression of disease. 
4.5 PROTOCOL EVALUATION 
4.5.1 History and physical examination (including weight and ECOG performance 
status) each clinic visit, as well as height at the first visit.  History and PE do not 
need to be included in the electronic database.  However, weight will be included 
in the electronic database.  Patients will be seen and examined on or about day 
21, and then every 3 weeks by a physician in the NCI outpatient clinic (weight, 
and ECOG performance status if changed, should be included in the database).  
Patients will undergo imaging evaluation (CT and bone scan as discussed in 
section 4.5.3.1) 2 months after start of study and every 3 months thereafter. 
4.5.2 Laboratory Evaluation 
4.5.2.1 Hematological profile (every cycle) 
4.5.2.2 PSA (every cycle) 
4.5.2.3 Acute care panel (every cycle) – to include hepatic panel and LDH 
4.5.2.4 Mineral panel (calcium, phosphorus, albumin, magnesium) every cycle 
4.5.2.5 Urinalysis (every cycle).  A patient found to have 2+ or greater proteinuria on 
urinalysis must have a 24-hour urine collection 
4.5.3 Radiographic evaluation 
4.5.3.1 CT scan and bone scan will be performed after 2 cycles after start of trial and 
every 3 cycles thereafter during the first year.  Patients remaining on-study after 
a year will have CT scans and bone scans performed when patient has signs of 
clinical progression at physician’s discretion. 


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4.5.3.2 MRI 
We will conduct an observational pilot study utilizing dynamic MRI to evaluate the tumor 
response in a cohort of patients on study. As this imaging technique has not been well 
studied in prostate cancer (particularly in the evaluation of bony disease), we are 
hopeful it will provide information about changes in tumor vascularity prior to a clinical 
response. We will acquire dynamic MRI scans on at least 10 study patients at baseline 
and at 3-month intervals.  Target lesions in the bone or soft tissues will be identified 
from the patient’s CT scan.  Dynamic MRI will be performed after the intravenous 
administration of 0.1mmol/kg of Gadolinium chelate.  If after the first ten patients 
dynamic MRI results do not appear to predict clinical response dynamic MRI will NOT 
be performed on the remaining patients in the study.  If, however, dynamic MRI results 
correlate with clinical response in at least 5 of the first 10 patients evaluated, this 
examination will be extended to the remainder of the study population.  Dynamic MRI 
will be reported in the following manner:  Pharmacokinetic parameters A and kep will be 
generated from time signal curves.  Additionally, initial slope, peak, and washout and 
area under the curve (AUC90) will be evaluated.  Data will be displayed by cluster 
analysis and by average value over the entire tumor   Dynamic MRI will not necessarily 
be used as criteria for progression. If a patient chooses not to undergo MRI evaluation 
he may still proceed on protocol. 
4.6 CONCURRENT THERAPIES 
A medication history including complementary and alternative medications, herbal and 
nutritional products, and dietary supplements should be reviewed at the initial screening 
visit and at each clinic visit to assure that no agents have been introduced that may 
interact with experimental treatment. 
 
All patients will be instructed to consult a member of the study team prior to 
commencing any other medications (including over the counter agents).   
 
Patients who have not undergone surgical castration should be maintained on an LHRH 
agonist. 
4.7 SURGICAL GUIDELINES 
There are no surgical guidelines in this protocol. 
4.8 RADIATION THERAPY GUIDELINES 
There are no radiation therapy guidelines in this protocol. 
4.9 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to documenting removal from protocol therapy, effort must be made to have all 
subjects complete a safety visit approximately 30 days following the last dose of study 
therapy. 
4.9.1 Criteria for removal from protocol therapy 
• 
Completion of protocol therapy 


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• 
Disease progression as evidenced by radiographic progression, either in RECIST 
measurement or new lesions on CT or bone scans, or clinical progression 
• 
Patient request 
• 
Best medical judgment of the Principal Investigator or a physician in the list of 
Associate Investigators 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable (intolerable) adverse event(s) defined as a grade 3 or 4 toxicity that is 
probably or likely related to protocol therapy that persists for ≥ 21 days. 
4.9.2 Post Treatment Evaluation 
Once the patient is no longer receiving treatment (as per section 4.9.1), he may receive 
follow-up calls to monitor his well-being and progress. The phone calls will likely be 
annual though no specific guidelines shall be set.  
4.9.3 Off Study Criteria 
The patient will be considered off study upon either: 
a) Patient’s death 
b) Patient’s decision to no longer participate in post treatment follow-up 
4.9.4 Off-Study Procedure 
 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken 
off-study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed 
and sent via encrypted email to:  NCI Central Registration Office (HOIS) 
ncicentralregistration-l@mail.nih.gov. 
 
5 
SUPPORTIVE CARE 
Anti-emetic treatment and secondary prophylaxis may be given as needed, but should 
NOT include the agent aprepitant.  
Agent-specific expected adverse events are listed in Section 9.  The supportive 
treatment plan for these adverse events is discussed in detail in Section 4. Pegfilgrastim 
6 mg will be administrated subcutaneously 24 hours post-docetaxel infusion for patients 
with indications as described in section 4.3.1.1. Other supportive care will be provided in 
accordance with good medical care and consistent with standard care for the 
individual’s type of cancer.  Supportive care will continue until patient care can resume 
with primary medical doctors. 
 
Transfusions of red blood cells (RBCs) will be allowed as clinically required. 
 


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6 
DATA COLLECTION AND EVALUATION 
6.1 DATA COLLECTION (PATIENTS RECORDS AND QUALITY ASSURANCE) 
 
The PI will be responsible for overseeing entry of data into an in-house password 
protected electronic system and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts.  All data obtained during the 
conduct of the protocol will be kept in secure network drives or in approved alternative 
sites that comply with NIH security standards. Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject 
participant. 
 
End of study procedures: Data will be stored according to HHS, FDA regulations, and 
NIH Intramural Records Retention Schedule as applicable.  
 
Loss or destruction of data: Should we become aware that a major breech in our plan 
to protect subject confidentiality and trial data has occurred, the IRB will be notified.  
 
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, physician notes, etc.) which 
confirm that: 
6.1.1 The patient met all eligibility criteria 
6.1.2 Signed informed consent was obtained prior to treatment 
6.1.3 Treatment was given according to protocol (dated notes about doses given, 
complications, and clinical outcomes) 
6.1.4 Toxicity was assessed according to protocol (laboratory report slips, etc) 
6.1.5 Response was assessed according to protocol (X-ray, scan, lab reports, date 
noted on clinical assessment, as appropriate) 
6.1.6 Drug Accountability 
The unused thalidomide and prednisone (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 drug supplies that are not returned to the patient 
for the next dose cycle will be disposed of according to the Procedure of Disposal 
of Returned Oral Agents. 
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6.2 RESPONSE CRITERIA 
6.2.1 Biochemical response – PSA measurements (PSA Consensus Criteria) (31) 
6.2.1.1 PSA Decline > 50% 
6.2.1.2 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 
6.2.1.3 PSA Progression (all progression dates require to be confirmed by a second 
value after the first) 
6.2.1.3.1 A 50% increase in PSA over nadir (confirmed by a second reading 4 weeks 
later) in patients whose PSA has fallen by at least 50%.  PSA increase must 
be at least 5 ng/ml. 
6.2.1.3.2 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 5 
ng/mL. 
6.2.1.4 A 25% increase in PSA over baseline in patients whose PSA has not 
decreased.  PSA increase must be at least 5 ng/mL. 
6.2.2 Time to PSA Progression 
6.2.2.1 The time between the first day of treatment to the day of PSA progression as 
described in 6.2.1.2. 
6.2.3 Measuring of Soft Tissue Disease 
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 (32).  Changes in only the largest diameter (uni-dimensional measurement) 
of the tumor lesions are used in the RECIST criteria. 
6.2.3.1 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 
 


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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. 
6.2.3.2 Evaluation of Non-Target Lesions 
 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
 
Incomplete Response 
 
Stable Disease (SD):  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
 
6.2.3.2.1 Although a clear progression of a “non-target” lesion 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.) 
6.2.3.2.2 If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response 
6.2.3.3 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 
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Table 6:  Evaluation of Best Overall Response 
 
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 
 
6.2.3.4 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.  
6.2.3.5 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 lesions be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
6.2.4 Confirmatory Measurement/Duration of Response 
6.2.4.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed 4 weeks after the criteria for 
response are first met. 
6.2.4.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are 
met or 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 time treatment started). 


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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. 
6.2.5 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). 
6.2.6 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. 
6.2.7 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 to characterize the objective tumor 
response. 
6.2.8 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.  
6.2.9 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 
 
6.2.10  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 
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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 
6.2.11 Methods of Measurement 
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.  
 
CT and MRI - CT and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment. For this study helical Multi-
detector CT will be performed with cuts of 5mm in slice thickness for chest, abdomen 
and pelvis lesions and 2-3mm thickness for head and neck lesions. 
6.3 TOXICITY CRITERIA 
The study will use the NCI Common Toxicity Criteria (CTCAE) 3.0 for grading toxicity 
and adverse events.  A copy of the CTCAE can be downloaded from the CTEP 
homepage (http://ctep.cancer.gov).  All treatment areas should have access to a copy of 
the CTCAE 3.0. 
6.4 STATISTICAL CONSIDERATIONS 
The primary objective of this trial is to determine if the combination of docetaxel, 
bevacizumab, prednisone, and thalidomide is able to be associated with a sufficiently 
high proportion of patients with a PSA response and be worthy of further investigation in 
metastatic prostate cancer.  The toxicity of this combination will also be evaluated, and 
if unacceptably high, will result in modification to the treatment regimen.  As a 
secondary endpoint, survival duration will be evaluated. 
 
Data from the recently conducted NCI trial of thalidomide and docetaxel in the same 
intended patient population indicated that approximately 50% of patients (25/49) were 
able to achieve a PSA decline of greater than 50% while undergoing treatment.  An 
ongoing study has indicated that bevacizumab in combination with docetaxel and 
estramustine have resulted in a 53% PR and a 65% decrease of at least 50% in PSA.  
The CALGB is planning a large phase III trial based on this data.  Prednisone will be 
substituted for estramustine due to toxicity concerns. 
 
The trial will be conducted using a two-stage MinMax design (Simon Controlled Clinical 
Trials 1989 10:1-10) with the undesirably low response proportion of 65% (p0=0.65) and 
targeting an improvement to 80% with a PSA response (p1=0.80). With alpha=0.10 and 
beta=0.10, the trial will initially enroll 33 patients and evaluate until PSA decline can be 
definitively determined. Per section 6.2.1, this may require several months in some 
patients.  
 
If no more than 22 of 33 patients have an eventual PSA decline of >50%, then no 
further patients will be accrued. If 23 or more of 33 are able to have a PSA decline of 
>50%, then accrual to a total of 60 patients will take place as soon as this can be 
determined. It is quite possible that accrual may need to be halted for an extended 
period of time while this is being determined. If so, patients otherwise eligible for this 


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trial will be enrolled onto other available studies until this trial is able to resume 
enrollment.  
 
Provided that enrollment to 60 is permitted, if 23 to 43 of 60 have a PSA decline of 
>50%, then this will not be considered sufficient for further investigation. However, if 
44+/60 have this response, then this will warrant investigation in a subsequent trial. 
Under the null hypothesis (65% proportion with 50% PSA decline), the probability of 
early termination of this trial is 64%. 
 
Toxicity is also an important parameter to evaluate in this trial. Based on previous data, 
it would be considered problematic, balancing the nature of the disease and the toxicity, 
if the true fraction of patients who received adequate anti-coagulation and developed 
grade III thrombosis or grade III hemorrhage could be greater than one-third. It is 
expected that 90-95% of patients or greater on this trial will be able to receive adequate 
anti-coagulation.  Monitoring for this toxicity will be taking place during the initial 33 
patient enrollment stage of the trial. It will be assumed that 30-33 patients will receive 
adequate anti-coagulation from among the first 33 on study. Should greater than 4 
adequately anti-coagulated patients in the first protocol stage experience a grade III 
thrombosis or grade III hemorrhage, then the trial will be amended with appropriately 
reduced doses of agents, as soon as this occurs, in order to limit this from happening on 
the remaining patients. This bound of 4 patients was selected since the upper 95% 
confidence interval about 4/33 is 25.6%, and is 26.4% for 4/32, 27.1% for 4/31 and 
28.0% for 4/30-any of which would be marginally tolerable with respect to this outcome. 
Higher fractions (5 or more patients with thrombosis anytime in the first stage of accrual) 
would not be.  
 
It would also be desirable if the overall toxicity profile with this combination were 
equivalent to that of thalidomide plus docetaxel. Provided the data are available from 
the other trial, for each type of toxicity which has 5 or more patients with a maximal 
grade of 2 or higher on either trial, we will compare the distribution of maximal toxicity 
grades per patient noted between this study and the thalidomide plus docetaxel study, 
using a Cochran-Armitage trend test, and will report the results for these comparisons. 
Any such individual toxicity comparisons noted with p<0.05, without adjustment for 
multiple comparisons, will be identified as being statistically significant, and will be taken 
into consideration when determining the role of the three drug combination in future 
studies.  
 
In addition, survival will be evaluated, using Kaplan-Meier curves, as a secondary 
endpoint of this trial. No formal comparison will be undertaken with other results, but 
informal comparisons to the survival probabilities on the trial of thalidomide and 
docetaxel or other studies may be undertaken. 
 
It is expected that accrual to this trial can be completed in 20 months if the current 
accrual rate of 3 similar patients per month or more is maintained. 
 


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Statistical considerations for patients enrolled in the expansion cohort are as 
follow:  
 
The primary endpoint of this 15 patient expansion is to determine if docetaxel and 
bevacizumab cause immunologic changes that would not be considered to be 
compatible with concomitant therapeutic vaccination.  Four primary immunologic 
evaluations will be performed for assessment, and the results from these four will be 
used to decide if an individual patient has immunologic changes that are not compatible 
with concomitant vaccine in the following manner.   
 
Regulatory T-cell (Treg) percentage 
The percent of Treg’s will be analyzed comparing baseline levels with levels after 6 
weeks of therapy.  Based on our previous study (Yokokawa et al, Clin Ca Res 2008) the 
Treg percent of 5.2 is at the 95th percentile.  The following will be used to suggest that 
the docetaxel / bevacizumab combination may not be compatible with concomitant 
vaccine: 
For patients with a baseline Treg <5.2% an absolute increase of ≥5% to a level >8% 
For patients with a baseline Treg ≥5.2% an absolute increase of ≥5% 
 
Treg Functional Assay 
If a patient has an increase in Treg identified above but a decrease in Treg function 
following 6 weeks of docetaxel / bevacizumab, then that data will not be used to suggest 
that the docetaxel / bevacizumab combination may not be compatible with concomitant 
vaccine. 
Lymphocyte Function 
The potential for CD4 and CD8 stimulation will be analyzed comparing baseline levels 
with levels after 6 weeks of therapy.  If there is a decrease in stimulation index of >3 
with both CD4 and CD8 assays, this will be used to suggest that the docetaxel / 
bevacizumab combination may not be compatible with concomitant vaccine. 
  
Mixed Lymphocyte Reaction (MLR) 
The ability of dendritic cells to present antigen will be analyzed comparing baseline 
levels with levels after 6 weeks of therapy.  If there is a decrease in stimulation index of 
>3, this will be used to suggest that the docetaxel / bevacizumab combination may not 
be compatible with concomitant vaccine.  Due to the time consuming nature of making 
DC for this assay, it will be performed in selected individuals. 
 
Myeloid Suppressor Cells 
Phenotypic analysis by flow cytometry will be used to assess levels of myeloid 
suppressor cells.  The results will be descriptive and not used to make a decision about 
the primary endpoint. 
 
Individual Scoring of Compatibility 
Each patient will be scored as to concomitant vaccine compatibility or not. If data are 
available for Treg and lymphocyte function only, both would have to suggest that the 
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having immunologic changes not compatible with concomitant vaccine.  If data are 
available for Treg, lymphocyte function and MLR then all 3 would have to suggest that 
the combination may not be compatible with concomitant vaccine to rule any patient as 
having immunologic changes not compatible with concomitant vaccine.   
 
Statistical Analysis 
With results of immunologic assays from 15 patients, if 4 or more patients are 
considered to have immunologic changes not compatible with concomitant vaccine, and 
if the true probability of any individual having such a problem were 10%, there would be 
a 5.6% probability of having 4 or more patients with these immune problems. On the 
other hand, if the true probability of any individual having such a problem were 35%, 
there would be an 82.7% probability of having 4 or more patients with these problems. 
Thus, observance of 4 or more patients out of 15 who are considered to have 
immunologic changes not compatible with concomitant vaccine would indicate an 
excessively high true probability, consistent with 35%, of having these problems, as 
opposed to having a rate consistent with 10% (which would be tolerable). If 3 or fewer 
patients are considered to have immunologic changes not compatible with concomitant 
vaccine, this is more consistent with a 10% rate than a 35% rate, and thus would be 
tolerable. 
6.5 MULTI-INSTITUTIONAL GUIDELINES 
This is not relevant to this protocol as it is being conducted at a single institution. 
7 
HUMAN SUBJECTS PROTECTIONS 
7.1 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. 
7.2 PARTICIPATION OF CHILDREN 
Children will not be eligible for this protocol. 
7.3 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, which are listed in the Consent Document. The procedure 
for protecting against or minimizing risks will be to medically evaluate patients on a 
regular basis as described in Section 4.5. 
If there is no existing DPA, all patients > 18 years old will be offered the opportunity to 
assign a substitute decision maker on the “NIH Advance Directive for Health Care and 


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Medical Research Participation” form, so that another person can make decisions about 
their medical care if they become incapacitated or cognitively impaired.  
7.4 RISKS/BENEFITS ANALYSIS 
For patients with androgen independent prostate cancer, median survival is in the range 
of 12-18 months. The agents administered in this trial have shown activity against 
prostate cancer in vitro and in vivo.  Potential risks include the possible occurrence of 
any of a range of side effects listed in the consent document.  
7.5 CONSENT PROCESS AND DOCUMENTATION 
Patients will meet with an attending physician in the Prostate Cancer Clinic, during the 
initial evaluation for this study.  During that meeting, the attending physician will provide 
verbal informed consent regarding this study, as well as provide a copy of the 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. 
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. 
 
Reconsent for this study may be obtained via telephone according to the following 
procedure:  the informed consent document will be sent to the subject.  An explanation 
of the changes in the study will be provided over the telephone after the subject has had 
the opportunity to read the consent form.  The subject will sign and date the informed 
consent. A witness to the subject’s signature will sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator 
who will sign and date the consent form with the date the consent was obtained  via 
telephone.   
 
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the 
consenting investigator and a copy of the informed consent document and note will be 
kept in the subject’s research record. 
 
8 
 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
8.1 DEFINITIONS 
8.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs 
during the course of the clinical trial associated with the use of a drug in humans, 
whether or not the event is considered related to the treatment or clinically significant. 
For this study, AEs will include events reported by the patient, as well as clinically 
significant abnormal findings on physical examination or laboratory evaluation. A new 


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illness, symptom, sign or clinically significant laboratory abnormality or worsening of a 
pre-existing condition or abnormality is considered an AE.  All AEs must be recorded on 
the AE case report form. 
 
All AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of at least possibly related to 
the agent/intervention should be recorded and reported as per section 8.2.  
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms  
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including 
hospitalization.  
• Is judged by the investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the test 
drug and about the patient’s outcome. 
8.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
8.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. "Unexpected”, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of 
the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
8.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a 
Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or 
others. 


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8.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of 
the investigator or the sponsor, it results in any of the following: 
 
• Death, 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition, including rising PSA that has progressed 
as defined in Section 6.2.1.2, or potentially serious harm to research subjects or 
others. 
8.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
8.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in 
the view of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that had it occurred in a more severe form, 
might have caused death. 
8.1.8 Protocol Deviation (NIH Definition)  
Any change, divergence, or departure from the IRB-approved research protocol.  
8.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program 
(HRPP) policies, IRB requirements, or regulatory requirements for the protection of 
human research subjects. 
8.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research 
protocol and informed consent document; Investigator’s Brochure or other 
study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 


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• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
8.2 NCI-IRB AND NCI CLINICAL DIRECTOR REPORTING 
8.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and 
Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical 
Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
8.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely 
related to the research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
 
NOTE: Grade 1 events are not required to be reported.  
8.3 DATA AND SAFETY MONITORING PLAN 
8.3.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis weekly when patients are being 
actively treated on the trial to discuss each patient. Decisions about dose level 
enrollment and dose escalation if applicable will be made based on the toxicity data 
from prior patients.  
 
All data will be collected in a timely manner and reviewed by the principal investigator or 
a lead associate investigator. Adverse events will be reported as required above. Any 
safety concerns, new information that might affect either the ethical and or scientific 
conduct of the trial, or protocol deviations will be immediately reported to the IRB using 
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The principal investigator will review adverse event and response data on each patient 
to ensure safety and data accuracy. The principal investigator will personally conduct or 
supervise the investigation and provide appropriate delegation of responsibilities to 
other members of the research staff.  
9 
PHARMACEUTICAL INFORMATION 
9.1 DOCETAXEL (DOCETAXEL-AVENTIS PHARMACEUTICAL, INC.; BRIDGEWATER, NJ) 
9.1.1 Chemical formula:  
[2aR-[2aa,4b,4ab,6b,9a(aR*,bS*),11a,12a,12aa,12ba]]-12b-(acetyloxy)-12-
(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,6,11-
trihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca 
[3,4]benz[1,2-b]-oxet-9-yl b-[[(1,1-dimethylethoxy)carbonyl]-amino]-a-
hydroxybenzenepropanoate, trihydrate. 
C43H53NO14· 3H2O 
Molecular weight of 861.9 Daltons 
Synonyms: RP56976. 
9.1.2 Availability: The drug will be purchased from commercial sources by the Clinical 
Center pharmacy. 
9.1.3 Formulation: 
Docetaxel is supplied in single-dose vials as a sterile, non-pyrogenic, non-
aqueous, clear yellow to brownish-yellow viscous solution and is 
packaged with a sterile, non-pyrogenic, diluent in single-use vials.  Both 
the Docetaxel® for Injection Concentrate and the diluent vials contain 
excess volume to compensate for fluid lost during product preparation. 
 
 
The commercial drug product is available in packages containing either: 
 
 
[1] 
Docetaxel (anhydrous) 80 mg in 2 mL polysorbate 80 (2080 mg).  
The diluent vial contains 6 mL 13% (w/w) in Water for Injection. 
 
 
OVERFILL: Docetaxel® for Injection Concentrate vial overfilled to 
94.4 mg docetaxel/2.36 mL 
 
 
 
Diluent vial overfilled to 6.96–7.70 mL.  Approximate 
extractable volume = 7.1 mL. 
 
[2] 
Docetaxel (anhydrous) 20 mg in 0.5 mL polysorbate 80 (520 mg). 
The diluent vial contains 1.5 mL 13% (w/w) in Water for Injection. 
 
 
OVERFILL: Docetaxel® for Injection Concentrate vial is overfilled to 
23.6 mg docetaxel/0.59 mL 
 
 
 
Diluent vial overfilled to 1.88–2.08 mL.  Approximate 
extractable volume = 1.8 mL. 


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9.1.4 Preparation 
Docetaxel® for Injection Concentrate requires TWO dilutions prior to 
administration. 
 
•  Preparing the “INITIAL DILUTED SOLUTION” (10 mg docetaxel/mL)1 
 
 
[1] 
Before proceeding, inspect the vial containing Docetaxel® for 
Injection Concentrate solution for clarity. 
 
[2] 
After removing vials from refrigeration, allow them to stand at room 
temperature for approximately five minutes. 
 
[3] 
Partially invert a vial containing diluent, aseptically withdraw the 
ENTIRE CONTENTS (including overfill) of the vial into a syringe, and 
transfer the solution to a vial containing docetaxel. 
 
[4] 
The INITIAL DILUTED SOLUTION should be clear; however, there may be 
some foam on top of the solution due to the polysorbate 80.  Allow 
the solution to stand for a few minutes to allow any foam to dissipate.  
It is not required that all foam dissipate prior to continuing the 
preparation process.  The INITIAL DILUTED SOLUTION may be used 
immediately or stored either in the refrigerator or at room temperature 
for a maximum of 8 hours. 
 
•   Preparing “DOCETAXEL INFUSION SOLUTION”1 
 
[1] 
With a syringe, aseptically withdraw the required amount of docetaxel 
INITIAL DILUTED SOLUTION (10 mg/mL) and inject it into a non-
polyvinylchloride bag containing an appropriate amount 
of 5% Dextrose, or 0.9% Sodium Chloride Injection, USP, to produce 
a final concentration between 0.3–0.74 mg docetaxel/mL. 
 
 
Do not exceed a concentration > 0.74 mg docetaxel/mL. 
 
[2] 
Thoroughly mix the INFUSION SOLUTION by repeatedly inverting the 
drug container. 
 
[3] 
Visually inspect the INFUSION SOLUTION for particulate matter or 
discoloration.  If the solution is not clear or appears to have 
precipitation, it should be discarded. 
 
Docetaxel must not come into contact with polyvinylchloride (PVC) 
equipment or devices during solution preparation or administration.  
Docetaxel should be prepared in polypropylene- or polyolefin-lined drug 
product containers and administered using polyethylene-lined 
administration sets1; e.g., ALARIS™ LOW SORBING SET #2264-0500 
(non-PVC, polyethylene-lined fluid pathway, with integral 0.2 µm 
polysulfone filter [Alaris Medical Systems; San Diego, CA]). 
9.1.5 Stability 
DOCETAXEL INFUSION SOLUTION (in either 0.9% NS or D5%W), if stored 
between 2°–25°C (36°–77°F) is stable for four hours and should be used 
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9.1.6 Storage 
Store between 2°–25°C (36°–77°F).  Retain in the original package to 
protect from bright light.  Freezing does not adversely affect the product.1 
9.1.7 Dosage and Administration 
9.1.7.1 Premedication 
All patients will receive dexamethasone 4 mg 12 and 1 h prior to docetaxel 
administration and 12 hours post-docetaxel to reduce the incidence and severity of fluid 
retention and the severity of hypersensitivity reactions. 
9.1.7.2 Administration 
Docetaxel 75 mg/m2 will be administered as an intravenous infusion over one hour on 
scheduled days per section 4.2.1. 
9.1.8 Drug Interaction 
Docetaxel and dexamethasone are metabolized by the cytochrome P450 (CYP) 
enzyme, CYP3A4.  Many other drugs and herbal and nutritional supplements are 
similarly metabolized, and may in addition, perturb docetaxel and dexamethasone 
metabolism by inhibiting or inducing the enzyme. Whenever possible we will take efforts 
to limit patients from being on such medications while receiving treatment on protocol 
Enzyme induction may hasten docetaxel and dexamethasone clearance; CYP3A4 
inhibition may delay clearance.  Both enzyme induction and inhibition alter the 
pharmacokinetic behavior of drugs that are substrates for CYP enzymes, and 
consequently, their pharmacodynamic effects, potentially compromising the benefit of 
treatment and exacerbating toxicity. 
 
Docetaxel and dexamethasone likewise may alter the pharmacokinetics and 
pharmacodynamic effects of other drugs metabolized by CYP3A4.  Caregivers may 
circumspectly permit continuation of treatment with CYP3A4 substrate drugs for patients 
on this study after gaining the approval of a medically responsible investigator. 
 
Contact a medically-responsible study investigator about patient volunteers who are 
receiving treatment before study enrollment and to discuss using any of the drugs listed 
in Appendix A for patients on study. 
9.1.9 Toxicities 
 
COMMON 
• 
Leukopenia 
• 
Neutropenia 
• 
Anemia 
• 
Alopecia 
• 
Asthenia 
• 
Neurosensory deficits 


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• 
Fluid retention 
• 
Nausea 
• 
Vomiting 
 
SERIOUS 
• 
Myelosuppression 
• 
Thrombocytopenia 
• 
Neutropenia 
• 
Hypersensitivity reaction 
• 
Skin toxicity 
 
Please see package insert for additional toxicities. 
9.2 THALIDOMIDE (THALOMID – CELGENE CORPORATION, WARREN, NJ) 
The drug will be purchased from commercial sources by the Clinical Center pharmacy. 
The S.T.E.P.S program will be adhered to in dispensing this agent.  
Briefly, the S.T.E.P.S program requires that the patient be adequately counseled 
regarding the potential risks of thalidomide prior to the start of drug administration 
(either via consent form or in-person counseling. It also requires that the physician, 
patient and pharmacy register with a central agency and that all three contact this 
agency each month prior to when drug is dispensed to monitor effects of the agent.  
9.2.1 Treatment Regimen  
Thalidomide will be given orally to patients at a dose of 200 mg every evening 
throughout the cycle. 
9.2.2 Other names: Thalomid 
9.2.3 Molecular Formula C13 O4 N2 H9 
9.2.4 Molecular weight: 
243 Daltons 
9.2.5 Formulation: Supplied as 50 mg or 200 mg hard gelatin capsules 
9.2.6 Storage: 
Store at room temperature. 
9.2.7 Stability: 
Shelf life surveillance studies are ongoing. 
9.2.8 Route of Administration: 
Oral 
9.2.9 Toxicities 
COMMON 
Sedation 
Headache  
Constipation 


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Diarrhea 
Nausea  
Mucosal dryness,  
Photosensitivity 
Rash 
Weight gain 
Mood changes (including depression-like symptoms) 
SERIOUS 
Birth defects 
Neuropathy 
 
Stevens-Johnson syndrome 
 
Toxic epidermal necrolysis 
 
Seizures 
 
Hypertension 
 
Neutropenia 
Renal toxicity (particularly in patients receiving bisphosphonate therapy) 
Hypocalcemia (particularly in patients receiving bisphosphonate therapy)  
 
Please refer to package insert for additional toxicities. 
9.3 PREDNISONE 
9.3.1 Chemical formula: 17a, 32-Dihydroxy-1,4-pregnadiene-       3,11,20-trione 
Chemical Formula: C21H26O5 Molecular weight of 358.4 
9.3.2 Classification: Glucocoticorticoids 
9.3.3 Mechanism of Action:  Multiple mechanisms leading to anti-inflammatory and 
immune suppression outcomes 
9.3.4 How supplied: Prednisone is supplied as a tablet or suspension.  We will use 
commercially available 5 mg tablets for this study. 
9.3.5 Storage:  Prednisone should be stored in original containers at room 
temperature, out of direct sunlight. 
Stability:  Prednisone tablets are stable for three years from date of 
manufacture 
9.3.6 Route of administration: Oral 
9.3.7 Toxicities: Anemia, eosinopenia, leukocytosis, lymphopenia, thrombocytopenia, 
leukocytosis, hypertensive crisis, hypertension, psychosis, schizophrenic 
psychosis, extrapyramidal effects, pseudotumor cerebri, hyperglycemia, 
hyperuricemia, hypercalcemia, adrenal suppression, Cushing’s syndrome, 
porphyria, lipid abnormalities, hypokalemia, peptic ulcers, pancreatitis, abdominal 


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pain, nephrotoxicity, proteinuria, cataracts, papilledema, acne, osteonecrosis, 
osteoporosis, myopathy, and superinfections. 
9.3.8 Availability: Prednisone will be obtained from commercial stock purchased by the 
NIH CC Pharmacy Department. 
9.4 BEVACIZUMAB (AVASTIN – GENENTECH BIOONCOLOGY, SOUTH SAN FRANCISCO, CA) 
9.4.1 Chemical name and identification: 
Recombinant humanized monoclonal anti-VEGF antibody  
(rhuMAB VEGF) 
9.4.2 Classification: Recombinant humanized monoclonal antibody 
9.4.3 Mechanism of Action: Inhibition of vascular endothelial growth factor (VEGF) 
resulting in inhibition of angiogenesis. 
 
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.  
9.4.4 How Supplied: Bevacizumab will be provided by Genentech, BioOncology under 
the Umbrella CRADA 2407. (Copy of CRADA attached) 
9.4.4.1  Information and Supply.  NCI will provide updated quarterly forecasts of 
amounts of Bevacizumab anticipated to be required for ongoing and pending 
mutually agreeable studies, as well as quarterly study accrual updates to 
enable Genentech BioOncology to adequately plan for timely delivery of 
Bevacizumab 
9.4.4.2 Registration of Clinical Trials.  NCI represents that all applicable clinical 
research conducted under this CRADA will be registered, and the results of 
such clinical research will also be posted on the www.ClinicalTrials.gov web site 
in accordance with the requirements set forth in 42 U.S.C. § 282(j).   
9.4.4.3 Access, review and receipt of Identifiable Private Information.  Genentech 
BioOncology’s access to and review of Identifiable Private Information shall be 
only for on-site quality auditing. Genentech BioOncology will receive Identifiable 
Private Information only if necessary for purposes of satisfying its or its Affiliates 
FDA or other health authorities' reporting requirements, and for Genentech 
BioOncology and Affiliates’ internal research purposes directly related to 
regulatory filings related to Bevacizumab.  Genentech BioOncology and 
Affiliate(s) are prohibited from access, review, receipt, or use of such 
information for other purposes.  All IRB approved Protocols and informed 
consent documents related to this CRADA will clearly describe this 
practice.  NCI will ensure that the Protocol and the informed consent clearly 
state (i) the existence of the Genentech BioOncology; (ii) the Genentech 


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BioOncology’s and its Affiliate(s)’ access to Identifiable Private Information; and 
(iii) the extent to which confidentiality will be maintained.  For clinical Protocol(s) 
involving a Third Party, the other party's access, review, receipt, or use of 
Identifiable Private Information shall be subject to the same limitations as 
described in this section 9.4.4.3. 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile 
solution for intravenous infusion. The commercial product is supplied in 
preservative-free, single-use vials containing 100 mg/4 mL and 400 mg/16 mL 
of bevacizumab at a uniform concentration of 25 mg/mL. 
The commercial products also contain the following excipients: 
 
Table 7:  Bevacizumab Excipients 
Excipients Content 
Avastin® Formulations 
100-mg 
400-mg 
α,α-trehalose dihydrate 
240 mg 
960 mg 
sodium phosphate (monobasic, 
monohydrate) 
23.2 mg 
92.8 mg 
sodium phosphate (dibasic, anhydrous) 
4.8 mg 
19.2 mg 
polysorbate 20 
1.6 mg 
6.4 mg 
Water for Injection, USP 
 
Preparation:  Bevacizumab must be stored under refrigeration at 2°–8°C (36°–
46°F) and protected from light.  Store in the original overwrap carton until the 
product is used.  Do not freeze the product. Do not shake bevacizumab during 
handling or preparation for clinical use. 
 
An amount of bevacizumab needed to prepare a dose of 15 mg/kg (patient’s 
body weight) should be withdrawn from one or more vials and diluted in a total 
volume of 0.9% Sodium Chloride Injection, USP, (qs.) 100 mL. 
9.4.5 Storage: Bevacizumab must be stored under refrigeration at 2°–8°C (36°–46°F) 
and protected from light.  Store in the original overwrap carton until the product is 
used.  Do not freeze the product. Do not shake bevacizumab during handling or 
preparation for clinical use. 
9.4.6 Stability:  Intact vials bear the manufacturer’s expiration dating and are stable 
until that date if stored at 2°–8°C.  Partially used vials should be discarded 
because the product does not contain an antimicrobial preservative.  
 
Bevacizumab should be diluted ONLY with 0.9% Sodium Chloride Injection, 
USP (0.9%NS).  Diluted bevacizumab solutions are stable in both 
polyvinylchloride (PVC) and polyolefin containers. 
 
No significant changes were observed in protein concentration, pH, turbidity, 
or potency after bevacizumab dilution with 0.9%NS to concentrations of 0.9, 
2.25, 3, 6.6, 7.5, and 16.5 mg/mL and storage for 24 hours in commercial PVC 
and polyolefin containers at 30°C.  No changes were observed with respect to 
protein concentration, turbidity, or potency for the undiluted drug product 


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(25 mg/mL) and after bevacizumab dilution with 0.9%NS to 1 mg/mL and 
12.5 mg/mL and storage for 24 hours in non-PVC, polyolefin bags at 5°C 
(41°F) and 30°C (86°F). [DRKohler personal communication with Genentech 
Medical Communications; 04/13/04] 
9.4.7 Route of Administration:  Intravenous 
9.4.8 Reported Adverse Events and Potential Risks: 
Serious Adverse Events 
 
 
Hypertension 
 
Thrombosis/embolism 
 
Fever (in the absence of neutropenia, where neutropenia is defined as 
absolute granulocyte count <1.0x10e9/L) 
 
Rigors, chills 
 
Rash/desquamation 
 
Stomatitis/pharyngitis (oral/pharyngeal mucositis) 
 
CNS hemorrhage/bleeding 
 
Epistaxis 
 
Hematemesis 
 
Hemoptysis 
 
Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia 
 
Infection without neutropenia 
 
Headache 
 
Proteinuria 
 
Dyspnea 
 
Delayed wound healing – although wound healing was delayed in animal 
studies, this effect has not been seen in humans 
 
Rare  
 
Reversible and marked elevations of liver function tests (total bilirubin 
and/or transaminase and alkaline phosphatase) have been rarely reported 
when bevacizumab is used in combination with chemotherapy or 
concurrently with other drugs that are potentially hepatotoxic.  The 
mechanism of such hepatic toxicities is unclear.  It is possible that in rare 
occasions, bevacizumab may potentiate the liver side effect of a 
concurrent medication, although it is unclear at this time whether 
bevacizumab alone can cause LFT derangement. 
 
Bowel perforation and bowel anastomotic dehiscence have been reported 
in clinical trials using bevacizumab alone or in combination with 


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chemotherapy.  Although these events were likely related to co-existing 
factors such as tumor involvement, chemotherapy, recent invasive 
procedures or bowel inflammation, contribution of bevacizumab to these 
events cannot be excluded at this time.  Partial delay in wound healing 
has been demonstrated in animal models treated with anti-VEGF 
antibodies and it is possible that bevacizumab may delay or compromise 
wound healing in patients. 
9.4.9 Method of Administration:  bevacizumab will be administered intravenously 
through a secondary IV set piggybacked above the infusion control device 
(pump) into a primary IV set containing 0.9% NS.  When the bevacizumab drug 
product container is empty, 0.9% NS from the primary line should be used to 
flush the secondary set to complete bevacizumab delivery.  0.9% NS infusion 
should be continued to flush the primary IV set with a volume of fluid at least 
equal to the tubing priming volume, thus insuring complete drug delivery.  Note 
that this flush is not included in the infusion times below. 
The initial dose should be administered over a minimum of 90 minutes.  If no 
adverse reactions occur, the second dose should be administered over a 
minimum of 60 minutes.  Again, if no adverse reactions occur, the third and 
subsequent doses should be administered over a minimum of 30 minutes.  If 
infusion-related adverse reactions occur, subsequent infusions should be 
administered over the shortest period that was well tolerated. 
9.5 OTHER AGENTS 
9.5.1 Pegfilgrastim (Neulasta™, Amgen Inc., Thousand Oaks, CA) 
9.5.1.1 Chemical Name and Identification: 
A covalent conjugate of recombinant methionyl human granulocyte 
colony stimulating factor (Filgrastim) and monomethoxypolyethylene 
glycol 
Average molecular weight: ~ 39 kilo-Daltons 
9.5.1.2 Classification: 
Colony stimulating factors acting on hematopoietic cells 
9.5.1.3 Mechanism of Action: 
Binding to a specific cell surface receptor thereby stimulating myeloid 
proliferation, differentiation, commitment, and end cell functional 
activation 
9.5.1.4 How Supplied: 
In 0.6 mL prefilled syringes for subcutaneous (SC) injection containing 6 
mg pegfilgrastim in a sterile, clear, colorless, preservative-free solution 
(pH 4.0).  The manufacturer’s product (Neulasta®; Amgen) is intended 


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for a single use and comes with a fixed 27 Gauge 1/2-inch needle and 
an UltraSafe® Needle Guard 
9.5.1.5 Storage: 
Stored refrigerated at 2° to 8°C (36° to 46°F) and kept in carton to 
protect from light until time of use. Shaking should be avoided. 
9.5.1.6 Stability: 
Intact syringes bear the manufacturer’s expiration dating and are stable 
until that date if stored at 2°–8°C.  The syringes may be allowed to reach 
room temperature for a maximum of 48 hours but should be protected 
from light. If left at room temperature for more than 48 hours or 
discoloration or particulates are observed in the product, it should be 
discarded. 
9.5.1.7 Route of Administration: 
Subcutaneous (SC) injection of 6 mg/0.6 mL administered once per 
chemotherapy cycle approximately 24 hours after docetaxel 
administration. 
9.5.1.8 Reported Adverse Events and Potential Risks 
COMMON 
Bone pain 
Reversible elevations in LDH, alkaline phosphatase, and uric acid 
SERIOUS, but very rare: (with filgrastim, the parent compound of 
pegfilgrastim) 
Adult respiratory distress syndrome (ARDS) 
Allergic-type reactions (anaphylaxis, skin rash, and urticaria) 
Splenic rupture 
9.5.2 For any agents not specifically mentioned above, please refer to the commercial 
product’s package insert for information on all commercial pharmaceutical agents 
used in this trial. 
10 COLLABORATIVE AGREEMENTS 
10.1 AGREEMENT TYPE 
Avastin is supplied to NCI under a CRADA with Genentech.   


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12. Figg WD, Arlen P, Gulley J, et al.  A randomized phase II trial of docetaxel 
(docetaxel) plus thalidomide in androgen-independed prostate cancer.  Semin 
Oncol 2001;28:62-6. 
12a. Dahut WD, Gulley J, Arlen PM, et al. Randomized phase II trial of docetaxel 
plus thalidomide in androgen-independent prostate cancer. Jrnl Clin Onc 
2004; 22: 2532-2539 
13. Hurwitz J, Fehrenbacher L, Cartwright T, et al.  Bevacizumab prolongs 
survival in first-line colorectal cancer: results of a phase III trial of 
bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, 
leucovorin) as first-line therapy in subjects with metastatic colorectal cancer. 
Proc Am Soc Clin Oncol 2003: abs 3646. 
14. Christian B.  26-Week intravenous toxicity study with rhuMAB VEGF in 
cynomolgus monkeys with a 12 week recovery.  Genentech Report 
1999:South San Fransico. P. 97-194. 


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15. Ryan AM, Epler DB, Hagler KE, Bruner RH, Thomford PJ et al.  Preclinical 
safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal 
antibody.  Toxicol Pathol 1999;27’78-86. 
16. Ferrara N, Chen H, Savis-Smyth T, Gerber P, Nguyen TN, et al.  Vascular 
endothelial growth factor is essential for corpus luteum angiogenesis.  Nat 
Med 1998;4:336-340. 
17. Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Novotny W, et al.  Phase I 
safety and pharmacokinetic study of recombinant human anti-vascular 
endothelial growth factor in patients with advanced cancer.  J Clin Oncol 
2001;19:843-850. 
18. Margolin K, Gordon MS, Holmgren E, Gaudreault J, Novotny W, et al.  Phase 
Ib trial of intravenous recombinant humanized monoclonal antibody to 
vascular endothelial growth factor in combination with chemotherapy in 
patients with advanced cancer: pharmacologic and long-term safety data.  J 
Clin Oncol 2001;19:851-856. 
19. Reese DM, Fratesi P, Corry M.  A phase II trial of humanized anti-vascular 
endothelial growth factor antibody for the treatment of androgen-independent 
prostate cancer. The Prostate J 2001; 3(2):65-70. 
20. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, 
et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth 
factor antibody for metastatic renal cancer. N Engl J Med 2003; 349:427-434 
21. Picus J, Halabi B, Rini N, Vogelzang N, Wheng Y, Kaplan E,et al. The use of 
bevacizumab with docetaxel and estramustine in hormone refractory prostate 
cancer: Initial results of CALGB 90006. Proc Am Soc Clin Oncol 2003: abst 
1578 
22. Levine MN.  Prevention of thrombotic disorders in cancer patients undergoing 
chemotherapy.  Throm Haemost 1997;78:133-136. 
23. Yang R, Thomas GR, bunting S, Ko A, Ferrar N, et al.  Effects of vascular 
endothelial growth factor on hemodynamics and cardia performance.  J 
Cardiovasc Pharmacol 1996;27:838-844. 
24. Ostendorf T, Kanter U, Eitner F, Loos A, Reagele H, et al.  VEGF(165) 
mediates glomerular endothelial repair.  J Clin Invest 1999;104:913-923. 
25. Hudes GR, Greenberg R, Krigel RL, et al.  Phase II study of estramustine and 
vinblastine, two microtubule inhibitors in hormone refractory prostate cancer.  
J Clin Oncol 1992;10:1754-1761. 
26. Pienta KL, Redman BG, Bamdekar R, et al.  A phase II trial of oral 
estramustine and oral etoposide in formone refractory prostate cancer. 
27. Hudes GR, Nathan F, Khater C, et al.  Phase II trial o 96-hour paclitaxel plus 
oral estramustine phosphate in metastatic hormone-refractory prostate 
cancer.  J Clin Oncol 1997;15:3156-3163. 
28. Bok PA, Halabi S, Fei DT, et al.  Vascular endothelial growth factor and basic 
fibroblast growth factor urine levels as predictors of outcome in hormone-
refractory prostate cancer patients: a Cancer and Leukemia Group B study.  
Canc Res 2001;61:2533-2536 


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29. Crawford ED, Eisenberger MA, McCleod DG, et al.  A controlled trial of 
leuprolide with and without flutamide in prostate carcinoma.  N Engl J Med 
1989;321:419-24. 
30. Goktas S, Crawford ED.  Optimal hormonal therapy for advanced prostatic 
carcinoma.  Semin Oncol 1999;26:162-73 
31. Bubley GJ, Carducci M, Dahut W, Dawson N, et al.  Eligibility and response 
guidelines for phase II clinical trials in androgen-independent prostate cancer: 
recommendations from the Prostate-Specific Antigen Working Group.  J Clin 
Oncol 1999;17:3461-7. 
32. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, et al.  New guidelines to 
evaluate the response to treatment in solid tumors.  European Organization 
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2000;92:205-16. 
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Pathophysiologic basis of contrast enhancement in breast tumors. J.Magn 
Reson.Imaging 1999;10:260-6. 
 


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Version Date: 2/3/2017 
  
 
 
 
Confidential                                                                                                                                  64 
 
12 APPENDIX A: AGENTS METABOLISED THROUGH CYP450 SUBSTRATES 
Acetaminophen 
Dapsone 
Levobupivicaine 
Risperidone 
Alfentanil 
Dehydroepiandroste
ndione 
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 
Tetrahydrocannabin
ol 
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 


Abbreviated Title:  D&T&P&B in AIPC 
Version Date: 2/3/2017 
  
 
 
 
Confidential                                                                                                                                  65 
 
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 
 
 
 
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 
Dimethyldithiocarbamat
e 
Itraconazole** 
Quinidine 
 
Diltiazem 
Ketoconazole** 
Quinine** 
 
Dirithromycin 
Metronidazole 
Quinupristin and 
dalfopristin 
 
 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
04-C-0257 
PRINCIPAL INVESTIGATOR: 
Ravi Madan, M.D. 
STUDY TITLE:  
A Phase II Trial of Docetaxel, Thalidomide, Prednisone and Bevacizumab in Patients 
with Androgen-Independent Prostate Cancer 
Continuing Review Approved by the IRB on 02/06/17 
Amendment Approved by the IRB on 03/07/17 (Q) 
Date posted to web: 03/18/17 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional. 
Why is this study being done?  
This study involves your voluntary participation in a research protocol.  The purpose of this 
research is to determine if a specific treatment regimen is effective for prostate cancer patients.  
Each treatment will be given in a 21-day cycle. Your treatment regimen will consist of 4 
anticancer agents.  The first is docetaxel (a type of chemotherapy), which will be given through a 
vein over 60 minutes on the first day of each cycle.  The second will be prednisone (a steroid 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 2 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
agent), which will be taken by mouth on every day of the cycle.  The third is thalidomide (an 
agent that may inhibit new blood vessel growth) is a tablet that will be taken by mouth every 
evening throughout the cycle.  The fourth is bevacizumab (another agent thought to inhibit new 
blood vessel growth will be given through a vein on the first day of each 21day cycle.  We know 
that all of these agents have been used successfully in treating patients with prostate cancer 
(when used alone or in together with other agents), and we have reason to believe that these 
anticancer effects can be increased by giving them in this specific combination. 
We are also attempting to understand how these drugs work and what side effects commonly 
occur when they are combined.  All four drugs are approved by the U.S. Food and Drug 
Administration (FDA). Docetaxel is an anti-cancer drug used in the treatment of many types of 
cancer.  Prednisone is a steroid that has been used safely in the treatment of many cancerous and 
noncancerous diseases.  Thalidomide was initially developed as a sedative, but was found to 
cause birth defects in the children born to women who received the drug during pregnancy.  
Thalidomide is FDA-approved to treat a form of leprosy, but recently has shown an ability to 
block the development of new blood vessels (technically, this is called inhibiting angiogenesis).  
In prior clinical trials in patients with prostate cancer at the NCI, some patients had a clinical 
benefit (improvement in pain and a lowering of their PSA) after taking thalidomide, either by 
itself or together with docetaxel.  Bevacizumab is a man-made antibody that blocks the 
development and growth of new blood vessels and has been shown to be effective and safe in the 
treatment of many types of cancer including colorectal, breast and prostate.  Bevacizumab will 
be provided to the study by the company Genentech, Incorporated.  There have also been studies 
that demonstrate that the combination of docetaxel and prednisone increases survival for patients 
with prostate cancer.  We hope that the combination of these four drugs will provide even greater 
benefit than that provided by taking any of the drugs individually or as part of a two or three-
drug combination.  The experimental treatment in this clinical trial will be done on an outpatient 
basis whenever possible. 
It is possible that some of the prostate cancer cells in your body may still grow if exposed to the 
male hormone testosterone.  Thus your testosterone must be suppressed either surgically 
(removal of the testicles) or medically with injections (shot) of an LHRH agonist drug 
(leuprolide or goserelin) that are repeated approximately every three months. 
Why are you being asked to take part in this study? 
Your doctors have told you that you have advanced prostate cancer that is not responding to 
hormonal therapy.  Your doctors have told you that although "standard" treatment can be 
administered to you, there is no known curative option for your cancer.  For this reason, we are 
offering you experimental treatment on this research study.  Although we hope that this 
experimental therapy may be of benefit to you and that your tumor will shrink, there is no 
guarantee that your tumor will respond.  Benefit cannot be promised, nor can the chance of 
benefit be accurately predicted. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 3 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
How many people will take part in this study?  
75 people will take part in this trial at NIH. 
Description of Research Study 
What will happen if you take part in this research study?   
You should understand that this study involves research.  Eligibility criteria are routinely used to 
assure that it is medically appropriate for patient candidates to participate and that they have the 
carefully defined medical condition as outlined by the study protocol.  For your own well being, 
as well as to ensure that the results of this study can be useful to making treatment decisions 
regarding other patients with similar diseases, it is important that no exceptions be made to these 
criteria for admission to the study. 
Before you begin the study 
Before receiving any form of treatment, you will be evaluated in the outpatient clinic to see if 
you are eligible for this experimental therapy.  This evaluation may take up to 2 weeks and will 
be done on an outpatient basis.  Some studies for determining the extent of spread of your cancer 
may be done for the first time or repeated if necessary (e.g., CT scans).  In addition, blood and 
urine studies will be needed to determine if the experimental treatment can be safely 
administered to you.  We will collect approximately 170 milliliters of blood (11 tablespoonfuls) 
from you during the first month of treatment, and then approximately 90 milliliters (6 
tablespoonfuls) after 2 months of treatment and 60 milliliters (4 tablespoons) during all other 
months.  We will also collect approximately 30 milliliters of urine at the initiation of your 
treatment.  The collected blood and urine will be used to monitor the effects of the treatment on 
your body, study the concentration of drug in your body and look for other experimental factors 
associated with your cancer. 
There is also a possibility that you will be asked to undergo a dynamic magnetic resonance 
imaging (MRI) test as part of this study.  This is a radiological test that requires you to lie in an 
imaging machine for approximately one hour.  This will help us determine how useful this test is 
for following the progress of disease and response to treatment in patients with prostate cancer. 
We will ask patients to undergo a tumor biopsy before the initial treatment and after 2-3 cycles 
of treatment.  Examples of potential sites of biopsies are an abnormally enlarged lymph node or 
an unresected, nonirradiated prostate or radiated prostate with a significant abnormality on either 
physical exam or imaging studies. The purpose of the biopsies will be to evaluate the effect of 
these drugs on blood vessel growth and development and markers of cell death in the tumor.  
This will only be done in participants who can safely undergo the procedure.  The biopsy will be 
performed at the NIH. A separate consent form will be provided to you that describes the biopsy 
procedure.  Please note, your decision to refuse this biopsy will not prevent you from joining the 
study. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 4 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Selected patients will be asked to undergo biopsy of their bone marrow to look for the presence 
of cancer.  Once again, your decision to refuse this biopsy will not prevent you from joining the 
study 
The research treatment that you will receive will consist of docetaxel, bevacizumab, thalidomide, 
and prednisone. 
During the study 
On this regimen, treatment cycles are 3 weeks in duration.  You will take one dose of 
thalidomide every day throughout the cycle.  You will receive an intravenous infusion of 
Docetaxel at a dose of 75 mg/m2 on the first day of each cycle. In association with receiving 
docetaxel, we will ask you to take 3 doses of dexamethasone (a steroid agent), one at 12 hours 
before docetaxel, a second dose just 1 hour before docetaxel, and a third dose 12 hours after you 
receive docetaxel.  Docetaxel may cause fluid retention (edema) in some patients and 
dexamethasone helps to prevent this.  On the first day of each cycle you will also receive an 
intravenous infusion of bevacizumab at a dose of 15 mg/kg.  You will also begin taking 
prednisone by mouth at a dose of 10 mg on the first day of each cycle but you will continue to 
take it daily throughout the cycle.  You will also start taking thalidomide by mouth at a dose of 
200 mg on the first evening of each cycle and it too will be taken daily throughout each cycle.  
So while the docetaxel and bevacizumab will be given every 21 days by intravenous infusion, the 
prednisone and thalidomide will be taken every day by mouth.  You will also be asked to give 
yourself or have a caregiver give you, a daily injection of enoxaparin, a blood –thinning drug, 
because both bevacizumab and thalidomide have been shown to increase the risk of blood clot 
formation. 
If you are enrolled in the expansion cohort of the trial, you will only receive docetaxel at a dose 
75 mg/m2 and an intravenous infusion of bevacizumab at a dose of 15 mg/kg one the first day of 
a 21-day cycle for a total of 2 cycles. The other three medicines as mentioned above, including 
thalidomide, prednisone, and enoxaparin will not be started until the beginning of cycle 3. In 
other words, your treatment will be same as that described in the paragraph above and the 
treatment will continue until your disease has shown evidence of progression or you could not 
tolerate the treatment due to considerable unwanted side effects. It is important that you begin to 
use the blood-thinning drug enoxaparin daily from the day that you receive thalidomide.      
Throughout your treatment it will be very important to keep us informed about any new 
symptoms from either your disease or any of the drugs.  You will come to the NIH clinical center 
to be seen one day of each three week cycle.  We will repeat some of the studies approximately 
every 3 months (e.g., bone scan and/or CT scan) to determine if your cancer has responded.  If 
there are no severe signs of toxicity or if your cancer has not progressed, we will continue to give 
you treatment. This is especially important for possibly maximizing potential benefits from the 
treatment. Although a significant PSA rise from the lowest value after your treatment is 
traditionally thought to be an early sign of disease progression, there has not had clear evidence 
showing that the PSA progression is well correlated with clinical progression of your disease. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 5 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Therefore, the therapy regimen will continue till you have clear evidence of progression in those 
scans, develop clinical progression signs, or unable to tolerate the therapy.  Your experimental 
treatment is designed to be given in an outpatient setting (with the exception of the very start of 
treatment where you may spend two nights in the Clinical Center Hospital).  The experimental 
therapy could last for longer than 6 months, depending on whether you are gaining benefit and 
not experiencing side effects.  After 6 cycles of therapy (approximately 6 months) you will 
receive a monthly chest x-ray in conjunction with your follow-up visit.  The purpose for doing so 
is to monitor whether there is any evidence of fluid collecting around the lining of your lungs, a 
side effect that has been found in some persons who received docetaxel for periods of 6 months 
or greater which may or may not be associated with symptoms. 
Birth Control 
Birth control measures must be used by all participants or their sexual partners who have child-
bearing potential for at least one month before beginning thalidomide therapy, during 
thalidomide therapy, and for at least 1 month after stopping thalidomide therapy.  Thalidomide 
causes severe birth defects in unborn babies if females who are pregnant take it.  The risk of 
thalidomide causing damage to the embryo is as great as 50% for females taking thalidomide 
during a time that is estimated to range from 35-50 days after their last menstrual period.  It is 
not known whether thalidomide may cause birth defects if it is taken after the sensitive period, 
however, even a single dose of thalidomide may cause birth defects. 
Birth defects observed in babies who were exposed to thalidomide before birth include absent or 
abnormal legs and arms; spinal cord defects; cleft lip or palate; absent or abnormal external ear; 
heart, kidney, and genital abnormalities; and abnormal formation of the digestive system, 
including blockage of necessary openings.  Thalidomide has also been associated with autism in 
the children born to females who received it during pregnancy. 
Because of the severity of these abnormalities, and the fact that it is not known if thalidomide is 
present in male ejaculate (semen), it is extremely important that pregnancies do not occur in your 
sexual partner while you are taking thalidomide. 
Therefore, you must be counseled about the possibility that thalidomide may be present in 
semen.  You must use a latex condom every time you have sexual intercourse with a woman 
during therapy and for 4 weeks after discontinuing thalidomide, even if you have had a 
vasectomy.  You should recognize that no method of birth control besides abstinence provides 
100% protection from pregnancy. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 6 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
We are asking you to participate in this study.  All of the drugs previously have been safely 
given to human patients.  Although we have considerable information about potential side effects 
you may develop, the combination of docetaxel bevacizumab, thalidomide and prednisone have 
not been administered together.  Thus, we cannot accurately predict the side effects that you may 
experience.  For that reason, you will be monitored closely while you are receiving the 
experimental treatment for any evidence of the earliest stages of toxicity so that appropriate 
intervention can be done. 
It is extremely important after starting to take the experimental treatment that you notify us 
before starting to take any new medications that your local doctors may have prescribed, or that 
you can purchase without a prescription.  Docetaxel can have a very negative interaction with 
several other drugs.  Thus, you should notify us before you start any new medical treatments and 
before beginning to use any herbal or nutritional supplements. 
The side effects that have been associated with docetaxel include:  Bone marrow depression, the 
result of which is anemia (low red cell count) that occasionally may cause you to require a blood 
transfusion; a decrease in the number of your white blood cells resulting in an increased risk of 
infection; a low platelet count, which may cause you to be at increased risk of bleeding; nausea 
and vomiting; changes in finger and toe nail growth; diarrhea; hair loss; and sterility.   
Pegfilgrastim (neulasta), a medication which can increase the number of neutrophils (white cells 
that fight infection), will be given to you approximately 24 hours after docetaxel administration 
in every future cycle if your total neutrophils within a cycle are less than 1000. Pegfilgrastim is 
given as an injection (shot) under the skin.  This is done to reduce the increased risk of infection 
which may occur with decreased neutrophils. The common side effects of pegfilgrastim include 
bone pain, reversible elevations in some laboratory testes such as LDH, alkaline phosphatase, 
and uric acid. Rare but serious side effects have also been reported with filgrastim, the parent 
compound of pegfilgrastim, which are adult respiratory distress syndrome (ARDS), allergic-type 
reactions such as anaphylaxis, skin rash, and urticaria, or splenic rupture.  
Shortness of breath and eye tearing have been reported with docetaxel.  In addition, docetaxel 
may cause fluid retention, numbness and tingling of hands and feet, and hypersensitivity 
reactions consisting of skin rash, wheezing, and occasionally a decrease in blood pressure.  To 
minimize the chances of such a reaction, you will receive dexamethasone pills to take orally 
before and after treatment with docetaxel. 
Rarely, a group of symptoms may occur with docetaxel therapy which include a blister-like rash, 
which may be severe; fever; inflammation of the eyes; redness, swelling, and painful sores on the 
lips and in the mouth.  If you have this group of symptoms, it is likely you will need intravenous 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 7 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
(IV) fluids and medicines, and you may need to be hospitalized.  If you have ever had radiation 
treatments, redness and soreness may develop in the treated areas. 
The most common complications associated with thalidomide include:  fatigue, sleepiness, 
constipation, damage to nerves, swelling and/or redness in the face, legs and arms, hair loss, 
fever, reduced function of the thyroid gland, mood changes, dry mouth, itching, depression, 
hypersensitivity reactions, decreased white blood cell counts, decreased platelet counts, 
increased blood sugar, high or low blood pressure, abnormal heart rhythm, abnormal heart rate, 
inflammation of the pancreas, blurry vision and nausea.  Most of these side effects resolve on 
their own or after thalidomide has been discontinued.  Damage to the nerves may cause 
numbness, ataxia, fainting, tingling or shooting pains.  Rarely, weakness to the extremities has 
been observed.  In most cases the nerve damage has lessened or gone away after thalidomide is 
discontinued; however there is a chance of permanent nerve damage. 
Thalidomide may cause decreased function of the thyroid gland through an effect of the drug on 
a portion of the brain called the hypothalamus, which helps to regulate thyroid gland function.  
You may be required to take medication to treat this condition and it may be permanent. 
Thalidomide may also increase your risk of developing blood clots.  Blood clots are potentially 
serious because they may interfere with blood circulation or may dislodge and cause problems 
elsewhere. For this reason you will be required to inject under the skin a medication called 
enoxaparin that will prevent blood clots from forming by ‘thinning’ your blood. Though the use 
of enoxaparin may increase your risk of bleeding complications such as bleeding from your 
digestive tract, gums, nose, urinary tract or even life-threatening bleeding (because of the 
medications blood-thinning properties), we believe this medication is necessary and provides 
overall benefit to you. 
Bevacizumab is a relatively new agent that has been investigated in all phases of clinical study.  
The common side effects seen with this agent are high blood pressure, weakness, nose bleeds, a 
mild increase of blood or protein in urine and fatigue.  Uncommon side effects seen include 
fever, diarrhea, nausea, pain, blood clot formation, decreased white blood cell count and bleeding 
from mouth and gums.  Rare side effects seen are chest pain, formation of a hole in your 
intestinal wall, bleeding into the lungs or brain and life threatening blood clots (including clots to 
the lungs). 
Since bevacizumab and thalidomide together may also increase your risk for developing blood 
clots, enoxaparin will be injected daily as previously discussed.  Though the use of enoxaparin 
will increase your risk of bleeding complications as well as the fact that we are combining it with 
bevacizumab, we believe this medication is necessary and provides overall benefit to you.  If any 
of the following symptoms occur:  sudden onset of swelling to one leg that may or may not be 
accompanied by leg pain (calf or thigh), chest pain, or shortness of breath, if you experience 
these symptoms seek immediate medical attention. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 8 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
There may be changes in your blood chemistries and other blood values related to this treatment, 
many of these changes are mild and you will not experience symptoms.  Rarely patients may 
experience elevated liver function tests.  Any significant changes in your blood values will be 
discussed with you. 
There is a possibility that the combination of bevacizumab and thalidomide may increase the risk 
of developing osteonecrosis of the jaw in patients who have received past treatment or continue 
to receive treatment with intravenous bisphosphanates.  Zoledronic acid (Zometa) is a 
bisphosphonate commonly used for the prevention of fractures in prostate cancer patients with 
bone involvement.  Osteonecrosis of the jaw occurs when the jaw fails to heal after minor 
trauma, such as a tooth extraction; this can be a debilitating condition if not recognized and 
treated early.  For this reason we recommend you have a dental exam before beginning treatment 
and periodically throughout the study.   
In the previous study with bevacizumab (Avastin) two study patients experienced aortic 
dissection.  There is a possibility that Bevacizumab may possibly increase the likelihood of the 
development of an aortic dissection. 
Aortic dissection is a medical emergency.  The aorta is the major artery that carries blood from 
the heart to the rest of the body; aortic dissection occurs when the inner layer of the aorta’s artery 
wall splits open (dissects).   Aortic dissection may cause sudden chest pain often described as 
very severe and tearing.  The pain may be localized to the front or back of the chest.  Typically 
the pain moves as the dissection gets worse.  If you experience these symptoms seek immediate 
medical attention. 
High blood pressure is the most common factor predisposing the aorta to dissection.  
Bevacizumab can cause an increase in blood pressure.   We will aggressively monitor your blood 
pressure at clinic visits and also ask you to continue management of your blood pressure with 
your regular physician.  Additionally, we review a CT scan of your chest every nine weeks as 
part of your cancer restaging; this scan may also help us detect aortic dissection.  Aortic 
dissection can be treatable with either surgery or medical management when found in the early 
stages. 
It is not possible to accurately predict all of the side effects of docetaxel, bevacizumab, 
thalidomide and prednisone when given together.  We will be watching your physical condition 
and laboratory tests very closely while you are on this study.  Any significant new findings that 
relate to your treatment will be discussed with you. 
Alternative Approaches or Treatments 
It has been explained to you that you have prostate cancer that has come back despite hormonal 
treatment and that Docetaxel and prednisone is the standard treatment for your cancer at this 
time.  Other treatment alternatives which can be considered for you now include:  1) other forms 
of commercially available drugs, chemotherapy or additional hormone-based treatments, 2) other 
forms of experimental drugs or hormonal treatments, 3) radiation therapy to the tumor that is 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 9 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
limited to certain areas to relieve symptoms, and 4) you may also elect to receive no treatment 
for your cancer now, but to wait until symptoms or complications develop and receive supportive 
care or other therapies at that time in order to lessen or eliminate symptoms. 
Please talk to your doctor about these and other options. 
Potential Benefits of Participation 
Are there benefits to taking part in this study? 
This is a phase 2 study, which means we are trying to determine if the experimental drug 
combination is effective for the treatment of prostate cancer. 
Individual benefit cannot be promised, nor can the chance of benefit be accurately predicted.  It 
is possible that you may experience some, all, or none of the side effects described above.  It is 
also possible that the combination of drugs may produce some unanticipated side effects.  For 
that reason, you will be monitored closely while you are receiving the experimental treatment for 
any signs which might signal the earliest stages of toxicity so that appropriate intervention can be 
done. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 10 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
• Qualified representatives from Genentech, the pharmaceutical company who produces 
Bevacizumab. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Genentech or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 11 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
The National Institutes of Health and the research team for this study are using Bevacizumab 
developed by Genentech through a joint study with your researchers and the company.  This 
means it is possible that the results of this study could lead to payments to NIH scientists and to 
the NIH.  By law, government scientists are required to receive such payments for their 
inventions.  You will not receive any money from the development of Bevacizumab.  
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 12 of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Ravi Madan, M. D.; Building 10 CRC, Room 13N240B, Telephone:  301-
480-7168.  You may also call the Clinical Center Patient Representative at 301-496-2626. If you 
have any questions about the use of your specimens or data for future research studies, you may 
also contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 04-C-0257 
CONTINUATION: page 13 of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM FEBRUARY 06, 2017 THROUGH FEBRUARY 05, 2018.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name