A Phase I/II Trial of Concurrent Chemohormonal Therapy Using Enzalutamide (MDV-3100) and Cabazitaxel in Patients With Metastatic Castration Resistant Prostate Cancer
Phase: PHASE1
Conditions: Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Cancer AJCC v7
Sponsor: OHSU Knight Cancer Institute

i 
 
ClinicalTrials.gov ID NCT02522715 
Oregon Health & Science University 
OHSU Knight Cancer Institute OHSU 
IRB Protocol #: 11227 PCCTC 
Protocol #: c15-148 
 
A Phase I/II Trial of Concurrent Chemohormonal Therapy Using 
Enzalutamide (MDV-3100) and Cabazitaxel in Patients with Metastatic 
Castration Resistant Prostate Cancer 
 
Coordinating Center: 
Oregon Health & Science University 
Prostate Cancer Clinical Trials Consortium, LLC 
(PCCTC) 
 
Principal Investigator: 
Julie Graff, MD 
3485 SW Bond Ave 
MC: OC14P 
Portland, OR 97239 
503-220-8262 x 55688 
 
 
Co-Investigators: 
Tomasz Beer, MD  
3485 SW Bond Ave 
MC: OC14P 
Portland, OR 97239 
 
Chris Ryan, MD  
Jeremy Cetnar, MD  
Nagendra Tirumali, MD 
Jacqueline Vuky, MD 
George Thomas, MD  
(same address as above) 
 
 
Protocol Version Date:  
09/25/19

ii 
 
Outside Co-Investigators 
Heather H. Cheng, MD, PhD 
Evan Y. Yu, MD 
Celestia S. Higano, MD 
Andrew Hsieh, MD 
Elahe Mostaghel, MD, PhD 
R. Bruce Montgomery, MD 
Peter S. Nelson, MD Michael 
T. Schweizer, MD 
 
Seattle Cancer Care Alliance 
825 Eastlake Ave East 
Mailstop: G4-830 
Seattle, Washington 98109 
United States 
 
Statistician: 
Yiyi Chen, PhD 
3181 Sam Jackson Park Road, CR 145 
Portland, OR 97239-3098 
503-346-0790 
 
 
 
 
 
 
Final Protocol Date: 
5/27/2015 
Protocol Revision Dates: 
Amendment 1: 07/25/16 
 
Amendment 2: 02/22/18 
 
Amendment 3: 09/25/19 
 

3 
 
SCHEMA 
 
 
We propose a single-arm Phase II study design with a Phase I dose de-escalation 
component to identify safe dosing of concurrent cabazitaxel (with prednisone) and 
enzalutamide. All safety data will be reviewed by the Principal Investigators and an 
independent data safety monitoring committee at Oregon Health & Science University. 
Toxicity requiring therapy discontinuation or dose reduction will be the event of interest 
(a pragmatic endpoint that measures the viability of a regimen) in the Phase I portion. If 
≥2 such events are reported in the initial 6 patients, the dose of cabazitaxel will be 
reduced by 20% to 20 mg/m2 IV q3 weeks thereafter. There will not be dose reductions 
for enzalutamide. The endpoint for the Phase II portion is percent of patients whose 
PSAs decrease by ≥90%. 
A total of 39 study subjects will be treated as part of this study, including the first 3-12 
subjects in the dose-finding component. 
To understand the biological effects of the treatment, and to evaluate for potential 
prognostic biomarkers, we will collect correlative biospecimens. Metastatic tumor 
biopsies will be obtained prior to first treatment. Sites where prior radiation has been 
administered for metastatic disease will be avoided. Patients will be offered the option of 
a second biopsy at the time of progression. If they consent, all attempts will be made to 
biopsy the same lesion as was sampled for the first biopsy. Blood will also be collected 
pre- and post-treatment for evaluation of circulating tumor cells and other circulating 
markers, such as microRNAs. 
Serum PSA will be checked on day 1 of each cycle. Restaging CT and bone scans will 
be performed every 12 weeks 7 days. 

4 
 
TABLE OF CONTENTS 
1. OBJECTIVES .............................................................................................................1 
2. BACKGROUND 
2.1 
Disease State: Metastatic, castration resistant prostate cancer .......................1 
2.2 
Study Agents: Cabazitaxel, Enzalutamide ........................................................1 
2.3 
Other Agents: Prednisone, G-CSF or GM-CSF ................................................2 
2.4 
Rationale ..........................................................................................................2 
3. PATIENT SELECTION 
3.1 
Inclusion Criteria...............................................................................................3 
3.2 
Exclusion Criteria .............................................................................................4 
4. TREATMENT PLAN 
4.1 
Agent Administration ........................................................................................5 
4.1.1 Study Agents: Cabazitaxel, Enzalutamide .............................................5 
4.1.2 Other agent: Prednisone .......................................................................5 
4.2 
Supportive Care Guidelines (G-CSF or GM-CSF) ............................................6 
4.3 
Duration of Therapy ..........................................................................................6 
5. DOSING DELAYS/DOSE MODIFICATIONS 
5.1 
Study Agents: Cabazitaxel, Enzalutamide ........................................................7 
5.2 
Other Agent: Prednisone, Denosumab, Bisphosphonates ................................7 
6. AGENT FORMULATION AND PROCUREMENT 
6.1 
Agent Accountability .........................................................................................7 
6.2 
Study Agents: Cabazitaxel, Enzalutamide ...................................................... 15 
6.3 
Commercial Agents: Prednisone, G-CSF or GM-CSF .................................... 18 
 
7. CORRELATIVE/SPECIAL STUDIES 
7.1 
Correlative studies………………………………………………………………….19 
7.2 
Pharmacokinetic studies 
………………………………………………………..20 
 
8. STUDY PROCEDURES AND SCHEDULE OF EVENTS 
8.1 
Subject Registration ....................................................................................... 20 
8.2 
Baseline Screening ........................................................................................ 21 
8.3 
Phase I Details ............................................................................................... 21 
8.4 
Study Visits .................................................................................................... 23 
8.5 
Follow-up ....................................................................................................... 24 
8.6 
Early Termination ........................................................................................... 24 
8.7 
Schedule of Events ........................................................................................ 25 

9. MEASUREMENT OF EFFECT 
9.1 
Definitions ............................................................................................................... 27 
9.2 
Guidelines for Evaluation of Measurable Disease ..........................................29 
9.3 
Response Criteria...........................................................................................29 
9.4 
Confirmatory Measurement/Duration of Response ........................................31 
9.5 
Progression-Free Survival ..............................................................................32 
10. ETHICAL AND REGULATORY REQUIREMENTS 
10.1 Protocol Review .............................................................................................32 
10.2 Informed Consent ...........................................................................................32 
10.3 Changes to Protocol .......................................................................................32 
10.4 
Maintenance of Records ................................................................................33 
10.5 
Safety Evaluation ...........................................................................................33 
10.6 
OHSU Safety Reporting .................................................................................34 
10.7 
Astellas Reporting ..........................................................................................34 
10.8 
Sanofi Reporting ............................................................................................35 
10.9 
Roles and Responsibilities .............................................................................36 
10.10 OHSU Knight Cancer Institute Data and Safety Monitoring Plan ....................37 
10.11 Inclusion of Women, Minorities and Children .................................................38 
11. STATISTICAL CONSIDERATIONS 
11.1 Study Design ...................................................................................................39 
11.2 Primary and Secondary Endpoints ..................................................................39 
11.3 Analysis Population .........................................................................................40 
11.4 Statistical Analysis Plan ..................................................................................40 
11.5 Sample Size and Power ..................................................................................40 
11.6 Early Stopping Rule ........................................................................................40 
REFERENCES ........................................................................................................................ 41 
 
 
APPENDICES 
 
APPENDIX A: Performance Status Criteria 
APPENDIX B: CTCAE v4.0 
APPENDIX C: List of Potent CYP3A Inhibitors 
APPENDIX D: List of Inducers by CYP3A Isoenzymes 
APPENDIX E: KNOWN SUBSTRATES OF CYP 2C19, 2C8, 2C9, 3A4 
APPENDIX F: Suggestions of protocols of intra-venous hydration for CT-scan with contrast 
APPENDIX G: Handling of fresh biopsy specimen (to be sent to OHSU) 
APPENDIX H: Handling of blood samples (to be sent to OHSU) 
APPENDIX I: Procedure for collection of fresh biopsy tissue (to be sent to FHCRC/UW) 
APPENDIX J:  Procedure for collection and processing of circulating blood markers (to be sent to 
FHCRC/UW) 
APPENDIX K: Procedure for collection and processing of PK samples 
APPENDIX L: PCCTC SAE Report Form 
APPENDIX M: Storage and Disposition of data and specimens 

1 
 
1. OBJECTIVES 
 
1.1. 
Primary Objectives 
o To determine the safety and tolerability of combination treatment with enzalutamide and 
cabazitaxel (as determined by percent dose limiting toxicities (DLT), where DLT < 17% 
is consistent with it being a tolerable combination). 
o To determine the efficacy of treatment with the hormonal agent enzalutamide and the 
chemotherapy cabazitaxel in combination in men with metastatic CRPC (as determined 
by percent of patients achieving ≥90% PSA declines following initiation of treatment). 
There will be a subgroup analysis according to prior abiraterone exposure. 
 
1.2. 
Secondary Objectives 
The secondary objective will be to further define the anticancer effect and safety profile of the 
combination of enzalutamide and cabazitaxel. 
o Collect toxicity data (description of adverse events) 
o Determine PSA response (percent of patients who achieve ≥50% PSA decline and 
≥30% PSA decline) 
o Examine PK data of cabazitaxel to characterize enzalutamide and cabazitaxel 
pharmacokinetic blood levels 
o Determine tumor response by RECIST 1.1 for measurable disease and Prostate Cancer 
Working Group 2 criteria for non-measurable (bone) disease 
o Determine overall survival 
 
1.3 
Exploratory Objectives 
There are still many unknowns regarding molecular determinants of response and 
resistance to cabazitaxel and enzalutamide. We will attempt to better define them using the following 
techniques and markers. 
o To determine baseline (and at progression) biological tumor characteristics to evaluate 
for possible biomarkers indicative or predictive of response. 
- 
Apoptosis by cleaved caspase 3 
- 
Androgen signaling axis (including but not limited to: androgen receptor 
expression, androgen receptor splice variants, and intratumoral androgen levels) 
- 
Glucocorticoid receptor 
o To collect circulating tumor cells (CTCs) and determine the degree to which tumor 
characteristics (delineated above) are shared by the CTCs. 
o To collect plasma and serum pre-treatment and at progression for assessment of 
circulating microRNAs and other circulating markers. 
o To collect buffy coat to evaluate for steroid transporters. 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
Metastatic, castration resistant prostate cancer (mCRPC) is prostate cancer that no 
longer responds to castration alone, either surgically or chemically, and which has spread 
to organs outside of the prostate as seen on an imaging study, such as bone scan or CT 
scan. It is also the final disease state in prostate cancer and invariably fatal. There are 
several new agents that prolong survival in mCRPC, but none that cure it. The benefit of 
using these agents in combination, rather than sequentially, is unknown. We seek to better 

2 
 
understand the effect of combining enzalutamide and cabazitaxel. If it looks especially 
promising, this will lead to a phase III study examining the combination of these agents 
versus sequential use. 
 
2.2 
Study Agents 
Recently the CHAARTED study results were released. This study showed that the 
combination of androgen suppression therapy and docetaxel in treatment naïve metastatic 
prostate cancer prolonged survival relative to androgen suppression therapy alone. This is 
one example of how combining therapies may be effective. 
 
Cabazitaxel is a cytotoxic chemotherapeutic currently FDA-approved for metastatic CRPC 
after prior treatment with docetaxel chemotherapy. The Phase III TROPIC trial showed 
efficacy in metastatic CRPC with a 2.4 month survival benefit over mitoxantrone in the post- 
docetaxel line setting.1 
The approved dose is 25 mg/m2 IV every 3 weeks. A known toxicity of cabazitaxel is 
myelosuppression, including neutropenia, and it is frequently given with growth factor 
support, i.e. G-CSF or GM-CSF. However, cabazitaxel is considered safe and effective. 
 
Enzalutamide is a hormonal agent that is also FDA-approved for metastatic CRPC after 
prior docetaxel chemotherapy. It acts as a specific inhibitor of the androgen receptor at 
multiple steps in the androgen-signaling pathway.2  In preclinical studies, enzalutamide 
exerts anti-proliferative activity on prostate cancer cells that exhibit amplification of the 
androgen receptor. The Phase III AFFIRM study confirms that enzalutamide improves 
median survival in post-docetaxel metastatic CRPC patients by 4.8 months.3 In addition, 
there is a randomized, phase III clinical trial that evaluated its efficacy in the pre- 
chemotherapy setting (PREVAIL).Treatment with enzalutamide resulted in a 30% reduction 
in the risk of death (HR 0.7) and an 81% reduction in the risk of radiographic disease 
progression or death (HR 0.19). Both of these differences were unambiguously statistically 
significant. Complete results will be presented at an upcoming scientific meeting. 
Enzalutamide is not recommended in patients with a risk of seizure because seizure was 
observed in the phase I study.2 In AFFIRM, which excluded patients with a history of 
seizure there was a <1% rate of seizure. In retrospect, those who did have a seizure had 
underlying conditions that should have excluded them from the study (brain metastatic 
disease) or they were treated with drugs that lowered the seizure threshold (intravenous 
lidocaine). 
 
2.3 
Other Agents. 
 
Prednisone is an oral corticosteroid given with cabazitaxel for its anticancer effect. Once 
the final cycle of cabazitaxel is completed, the prednisone can be tapered off. One 
suggested regimen would be to decrease it from 5 mg twice daily to 5 mg once daily for 2 
weeks and then off. 
 
Growth factor support (G-CSF or GM-CSF) minimizes neutropenia after (and induced by) 
chemotherapy. 
Both of these agents will be used in conjunction with cabazitaxel and enzalutamide. 
 
2.4 
Rationale 
Castration resistant prostate cancer is the final disease state and an invariably fatal form of 
prostate cancer. While great strides have been made in developing new agents for 

3 
 
metastatic CRPC, response rates and duration have remained modest, and men ultimately 
succumb to their disease. In the past three years, five additional agents that extend survival 
have been approved for this disease. These agents include an immunotherapy (sipuleucel- 
T), a second-line chemotherapeutic agent (cabazitaxel), a radiopharmaceutical (radium- 
223) and two hormonally active agents (abiraterone and enzalutamide). Thus, the 
management of advanced prostate cancer has been both enhanced and complicated by 
the rapid emergence of at least five new agents that can lengthen survival: enzalutamide, 
abiraterone, sipuleucel-T, cabazitaxel, radium-223. 
 
Historically, combined chemo-hormonal therapy has not improved outcomes for patients 
with prostate cancer, but earlier trials were hindered by lack of efficacious chemotherapy 
and weaker hormonal agents. In this study, we aim to determine if potential synergistic 
effects between two newer and more effective agents can be identified and exploited for 
therapeutic effect, and to obtain correlative biological information that may offer predictive 
and response value. 
 
 
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
3.1.1 Men 18 years or older with metastatic CRPC  
 
3.1.2 Willing to provide a tumor sample via biopsy from a metastatic site of disease to 
be collected at screening if safe and feasible per discretion of treating 
investigator. Adequate archival metastatic tissue can be used, if available, in 
lieu of baseline biopsy if done when patient had CRPC. Patients without a site 
amenable to biopsy and lack of archival tissue may still join the study. 
 
3.1.3 Evidence of prostate cancer progression by any of the following criteria: radiographic 
or PSA criteria, or symptomatic progression related to prostate cancer. (See section 
9.1.2 for details.) 
 
3.1.3 Castrate testosterone levels (<50 ng/dL) achieved by orchiectomy or maintenance on 
a LHRH agonist or antagonist. 
 
3.1.4 Histologic confirmation of original prostate cancer diagnosis per institutional 
standard. Life expectancy of greater than 6 months. 
 
3.1.5 ECOG performance status of 0 or 1. 
 
3.1.6 Patients must have normal organ and marrow function as defined below: 
- 
leukocytes 
>3,000/mm3 
- 
absolute neutrophil count  >1,500/mm3 
- 
platelets 
>100,000/mm3 
- 
total bilirubin 
within normal institutional limits (or <2X the upper limit 
of normal in those with Gilbert’s disease) 
- 
AST(SGOT)/ALT(SGPT) 
<1.5 X institutional upper limit of normal 
- 
creatinine 
     less than the institutional 

4 
 
upper limit of normal 
- 
creatinine clearance* 
>45 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal 

5 
 
*Web link to be used to estimate glomerular filtration rate (GFR) using the CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration) 
formula.http://www.qxmd.com/calculate-online/nephrology/ckd-epi-egfr 
 
3.1.7 Subject agrees to use a double barrier method of birth control during the course of 
study treatment period with enzalutamide and/or cabazitaxel treatment and for at 
least 3 months after the study is discontinued. 
 A double-barrier method of contraception involves the use of a condom in 
combination with 1 of the following: contraceptive sponge, diaphragm, or cervical 
ring with spermicidal gel or foam. 
 Subject who has had a vasectomy at least 6 months prior to starting study 
treatment period and those whose female sexual partner(s) are more than 55 
years of age and postmenopausal for at least 2 years or surgically sterile (tubal 
ligation, hysterectomy, or bilateral oophorectomy) agree to use at least a 
condom. 
 
3.1.8 Ability to understand, and the willingness to sign, a written informed consent 
document, as well as comply with study requirements. 
 
3.1.9 Must have appropriate wash out (> 6 half-lives) of androgen receptor antagonists, 5α 
reductase inhibitors or ketoconazole prior to the start of cycle 1. If the agent is not in 
the table below, the washout should be 2 weeks. 
 
Drug 
Approximate Half-Life 
Washout Period 
Required 
Bicalutamide 
6 days 
36 days 
Flutamide 
6 hours 
36 hours 
Nilutamide 
4 days 
24 days 
Finasteride 
8 hours 
48 hours 
Aminoglutethamide 
15 hours 
4 days 
Ketoconazole 
8 hours 
48 hours 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Prior chemotherapy for mCRPC prostate cancer. Chemotherapy given 
neoadjuvantly, adjuvantly, or for hormone sensitive metastatic disease is permitted 
as long as the cancer did not progress on chemotherapy AND >6 months have 
elapsed. 
 
3.2.2 Patients may not have received any other investigational agents within the last 14 
days at the time of treatment start. 
 
3.2.3 Patients may not have received enzalutamide or ARN-509 (another androgen 
receptor antagonist) in the past. 
 
3.2.4 Patients may not have received cabazitaxel in the past. 

6 
 
3.2.5 Subject has clinical signs suggestive of high or imminent risks for pathological 
fracture, spinal cord compression and/or cauda equina syndrome. 
 
3.2.6 History of severe hypersensitivity reaction (≥grade 3) to docetaxel, polysorbate 80 
containing drugs, or any of the capsule components of enzalutamide, including 
Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene. 
 
3.2.7 Concurrent or planned treatment with strong inhibitors or strong inducers of 
cytochrome P450 3A4/5. (A one-week wash-out period is necessary for patients who 
are already on these treatments, see Appendices C and D.) 
 
3.2.8 Uncontrolled, intercurrent illness including, but not limited to, ongoing or active 
infection, uncontrolled diabetes, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.2.9 Subject has a history of seizure or any condition that may predispose to seizure 
including, but not limited to, underlying brain injury, stroke in the past 6 months, 
primary brain tumors, brain metastases, prior seizures. 
 
3.2.11 Subject has a history of unexplained loss of consciousness or transient ischemic 
attack within 12 months of treatment start. 
 
3.2.12 Subject is unwilling to stop using herbal supplements that can affect the PSA, such 
as saw palmetto or PC-SPES. 
 
3.2.13 Subject has another active malignancy other than non-melanomatous skin cancer 
(unless it is metastatic) or superficial bladder cancer. 
 
3.2.14 Must not have a gastrointestinal condition that would interfere with absorption. 
 
3.2.15 Subjects may not be on other therapies that affect hormone levels, such as 
estrogens, testosterones, ketoconazole during this study. However, megestrol for 
hot flashes is permitted. 
 
 
4. TREATMENT PLAN 
 
4.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent 
to treat the patient's malignancy. Supportive treatments, such as zolendronic acid or 
denosumab, may be continued if the subject is on them at the time of study entry. 
 
4.1.1  Study Agents 
 
During treatment with cabazitaxel + enzalutamide, one cycle is 21 days. 
 
During treatment with enzalutamide monotherapy (after 6-10 cycles of cabazitaxel) 

6 
 
one cycle is 28 days. 
 
Cabazitaxel 25 mg/m2 IV every 21 days. This study has a dose de-escalation 
portion, so the dose may be decreased to cabazitaxel 20 mg/m2 IV every 21 days in 
the Phase I portion if it proves too toxic in combination with enzalutamide. In the 
event that the combination of cabazitaxel 20 mg/m2 IV with enzalutamide 160 mg is 
too toxic in the phase I portion, the study will be terminated. 
o Premedication with an antihistamine (dexchlorpheniramine 5 mg or 
diphenhydramine 25 mg), a corticosteroid (dexamethasone 8 mg or 
equivalent), and H2 antagonist (ranitidine 50 mg) given 30 minutes 
before the cabazitaxel or per institutional standard of care. 
o Subjects will also receive prednisone 5 mg PO twice daily with 
cabazitaxel or per institutional standard of care. 
 
Enzalutamide 160 mg PO once daily. 
o A minimum of 6 subjects will participate in the PK portion of this study. 
They will begin taking enzalutamide on day 2 of cycle 1 and continue 
taking it daily for the rest of cycle 1. On day 1 of cycle 2, they will not 
take their enzalutamide until they are instructed to take it in the infusion 
unit when they receive their cabazitaxel. However, on all other days, 
these patients will take their enzalutamide at home. 
o All subjects who are not part of the PK portion of this study will take 
their enzalutamide at home starting on day 1 of cycle 1 and continuing 
every day of all subsequent cycles. Enzalutamide may be taken with or 
without food, but should be taken either with food or without food 
consistently. 
 
 
 
 
4.2 
Supportive Care Guidelines 
 
Subcutaneous G-CSF or GM-CSF is mandated for each cycle as a safety 
precaution, and should be given 24-48 hours after each cabazitaxel dose. Brand of 
G-CSF or GM-CSF will be up to the treating physician. 
 
4.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment with cabazitaxel may 
continue for 6-10 cycles, or until one of the following criteria applies: 
 
 Disease progression (see 9.1.2), 
 
 Intercurrent illness that prevents further administration of treatment, 
 
 Unacceptable adverse event(s), 
 
 Subject decides to withdraw from the study, or 
 
 General or specific changes in the subject's condition render the patient 

7 
 
unacceptable for further treatment in the judgment of the investigator. 
 
The enzalutamide may be continued after the 6-10 cycles of cabazitaxel are given and may 
be discontinued for one of the events outlined above. 
 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1 Study Agents 
 
There will not be dose reductions for enzalutamide. 
 
Cabazitaxel may be dose reduced for a subject who experiences the toxicities outlined in 
section 6.2.1. It is important to note that the dose will only be reduced to 20 mg/m2. If  
further dose reductions are required, the subject will be removed from the study. 
 
Also, DLTs identified in the first two cycles of treatment of the Phase I portion of the study 
will inform the dose of cabazitaxel in the phase II portion of the study. The same toxicities in 
the phase II portion of the study will only affect the dose of that individual subject. In the 
case that 8 or more patients in the Phase II portion of the study experience DLTs, the study 
will be stopped early (see section 11.6). 
 
5.2 Other Agents 
 
Prednisone may be discontinued for the onset or exacerbation of diabetes mellitus, 
hypertension, gastrointestinal ulceration or bleeding, severe neurological side effects, or 
other serious adverse events that the Investigator considers to be a contraindication to 
continuing steroids. Prednisone may be reinstituted with the resolution of the adverse event 
at the discretion of the Investigator. The reason for altering the dose or discontinuing 
prednisone should be documented on the CRF. Prednisone may also be tapered off after 
the final cycle of cabazitaxel in all patients. 
 
Bisphosphonate or Denosumab Usage 
Subjects who are on a bisphosphonate or denosumab should be on a steady dose for at 
least four weeks prior to day 1 of the study. Zoledronic acid and denosumab can be added 
after cycle 2.  
 
 
6. AGENT FORMULATION AND PROCUREMENT 
 
 
6.1 
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a 
careful record of the inventory and disposition of the study agent. 

8 
 
6.2 
Study Agents: 
 
6.2.1 Cabazitaxel 
 
Availability: Cabazitaxel is supplied to investigators by Sanofi for study purposes. 
 
Product description: 
Cabazitaxel is supplied for parenteral administration as a sterile, non-pyrogenic non- 
aqueous solution contained in a 15 mL clear glass vial closed with a rubber closure. 
The closure is crimped to the vial with an aluminum cap covered with a light green 
plastic flip-off cap. The solution is clear and yellowish to brownish-yellow. Each vial 
contains 60 mg of cabazitaxel, expressed on anhydrous and solvent-free basis, per 1.5 
mL of solution. 
 
The fill volume has been established to include an overfill [i.e., 1.5 mL (nominal 
volume) + 0.33 mL]. This overfill was determined to ensure that a 10 mg/mL 
(corresponding to 60 mg/mL) concentration is obtained in the premix and that 60 mg 
dose can be extracted. This must be done with the entire contents [i.e., 4.5 mL 
(nominal volume) + 1.17 mL) of the solvent for dilution for cabazitaxel. 
 
Solvent vial: 
 
The solvent used for the preparation of the premix is a sterile, non-pyrogenic solution 
containing a 13 % w/w ratio of ethanol 95 % in water for injection. This solution is 
contained in a 15 mL clear type I glass vial closed with a rubber closure. The closure is 
crimped to the vial with either an aluminum cap covered with a light grey plastic flip-off 
cap or a gold-color aluminum cap covered with a colorless plastic flip off cap. The 
solution is a clear colorless liquid. 
 
Each vial is overfilled to ensure that a 10 mg/mL concentration is obtained in the 
Premix and that 60 mg dose can be extracted. [i.e., 4.5 mL (nominal volume) + 1.17 
mL] 
 
Excipients: 
Polysorbate 80 from vegetable origin, for the drug product vial. 
Water for injection and ethanol for the solvent vial. 
 
Storage conditions: 
Vials should be stored according to their labeling and kept in their kit until use. 
 
Solution preparation 
Cabazitaxel drug products should be administered only by intravenous route. 
It is supplied as a kit containing one single-use vial of cabazitaxel concentrate for 
solution for infusion and one single vial of solvent for dilution. The administration of the 
product requires two dilutions prior to administration. 
 
This pharmaceutical dosage form is a concentrate for solution for infusion and must be 
diluted before administration. First the dosage form is diluted with the solvent supplied 

9 
 
(preparation of the “cabazitaxel premix solution”). Then this premix solution must be 
diluted in an infusion vehicle (preparation of the “cabazitaxel infusion solution”). Each 
cabazitaxel vial and each corresponding solvent vial are overfilled to ensure that a 60 
mg dose can be withdrawn after the preparation of the premix. 
 
 Preparation of cabazitaxel premix solution under aseptic conditions: 
Use one solvent vial per each vial of cabazitaxel concentrate. 
Withdraw, under aseptic conditions, the entire contents of the solvent vial and inject it 
into the corresponding vial of cabazitaxel concentrate. Gently mix the reconstituted 
solution by repeated inversions for at least 45 seconds until obtaining clear and 
homogenous solution. Do not shake. Let the premix solution stand for a few minutes 
at room temperature to allow foam to dissipate. The solution is homogeneous and 
contains no visible particulate matter. It is normal for foam to persist after this time 
period. 
 
In order to compensate for liquid loss during preparation and to ensure that the 
cabazitaxel initial diluted solution (premix) can be prepared at the concentration of 10 
mg/mL and that a nominal volume of at least 6 mL can be withdrawn from the premix 
vial, the cabazitaxel 60 mg/1.5 mL concentrate vials are filled with a 22% overfill (total 
fill volume 1.83 mL) and the diluent vials with a 26% overfill (total fill volume 5.67 mL). 
 
The concentration of 10 mg/mL in the premix [60mg/1.5 mL (concentrate) + 4.5 mL 
(diluent)] can be calculated as follows taking into account the overfilling: 73.2mg/ 1.83 
ml (22 % overfill concentrate) + 5.49 mL (overfill diluent *) = 10 mg/mL 
 
Thus, the preparation obtained ensures a minimal extractable volume of the premix 
solution of 6 mL corresponding to a concentration of 10 mg/mL of cabazitaxel 
corresponding to 60mg/6 mL. 
 
 
 Preparation of cabazitaxel infusion solution under aseptic conditions: 
 
WARNING: Since foam is normally present, the required dose must be accurately 
adjusted using a graduated syringe. 
 
Withdraw, under aseptic conditions, the volume of the premix solution containing 10 
mg/mL of cabazitaxel that corresponds to the required dose (mg) and inject the 
required premix volume into a 125 to 500 mL infusion container (either 5 % glucose 
solution for injection or 0.9 % sodium chloride solution for injection). Mix the content of 
the infusion container manually by gently inverting the bag or bottle. The concentration 
of the infusion should be between 0.10 mg/mL and 0.26 mg/mL (based on Maximum 
Tolerated Dose of 30 mg/m² and a Body Surface Area of 2.1 m²). 
 
 Infusion conditions: 
 
The recommended infusion duration is one hour. The infusion solution should be used 
within 8 hours at ambient temperature (including the one hour infusion time) or within a 
total of 24 hours if refrigerated (including the one hour infusion time).The infusion 
solution should be administered at room temperature under normal lighting conditions. 

10 
 
 Do not use PVC infusion containers for cabazitaxel preparation and 
administration. 
 Do not use polyurethane infusion sets for cabazitaxel preparation and 
administration. 
 
Glass bottles could also be used. 
 
Use an in-line filter of 0.22 μm nominal pore size (also referred to as 0.2 μm) 
during cabazitaxel administration. 
 
 
 Shelf life: 
 
Cabazitaxel premix solution 
Premix solution should be used immediately after preparation and within 1 hour at 
ambient temperature. 
 
Cabazitaxel infusion solution 
The infusion solution is stable for 8 hours at ambient conditions (including the 1 hour 
infusion time) or a total of 24 hours if refrigerated, from preparation to end of infusion. 
 
 
 Recommendation for the safe handling: 
 
Cabazitaxel is an antineoplastic agent and, like other potentially toxic compounds, 
caution should be exercised in handling and preparing cabazitaxel solutions. The use 
of gloves is recommended. If cabazitaxel concentrate, premix solution or infusion 
solution should come into contact with skin, wash immediately and thoroughly with 
soap and water. If cabazitaxel concentrate, premix solution, or infusion solution should 
come into contact with mucous membranes, wash immediately and thoroughly with 
water. 
 
Dosing Regimen: 
 
On Day 1 of each cycle, patients will receive cabazitaxel at a dose of 25 mg/m², 
administered by IV route in 1 hour, unless the Phase I portion identifies the 20 mg/m2 
dose as the safe dose. 
 
Cycle length for cabazitaxel is 21 days. New cycles of therapy may not begin until 
Absolute Neutrophil Count (ANC) ≥1500/mm3, platelet count ≥75,000/mm3, and non- 
hematologic toxicities (except alopecia) have recovered to baseline. A maximum of 3 
weeks delay is allowed between 2 treatment cycles. Patients should come off 
treatment if treatment delay is more than 3 weeks. 
 
At least 30 minutes prior to each administration of cabazitaxel, patients will be 
administered IV premedication including: 
 
- An antihistamine (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or 
equivalent). In case of IV antihistamine other than promethazine is not being available, 
local practice should be followed. 

11 
 
- Corticosteroid (dexamethasone 8 mg or equivalent) 
- H2 antagonist (ranitidine or equivalent). 
- Antiemetic prophylaxis is recommended and can be given orally or intravenously if 
necessary. 
 
Primary prophylaxis with Granulocyte Colony-Stimulating Factor (G-CSF) or GM-CSF 
will be given to all patients. 
 
 
Dose modifications and dose delay: See Section 5. 
 
 
Expected adverse events: 
Hematological toxicity 
 
The dose of cabazitaxel will be modified in case of hematologic toxicity. Dose 
modifications are summarized in Table1 
 
Table 1 - Dose modifications for hematological toxicity 
 
 
Toxicity 
Grade 2 
Grade 3 
Grade 4 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
Febrile neutopenia 
or neutopenic 
infection 
 
 
 
 
 
Thrombocytopenia 
If not recovered 
on D21, delay** 
next infusion until 
recovery to grade 
≤1 (ANC 
≥1,500cells/mm3). 
- 1st episode: No 
dose reduction 
required. 
- 2nd episode; 
reduce by 1 dose 
level 
 
 
Not applicable 
 
 
Delay** next 
infusion until 
recovery to grade 
≤1 (platelets 
≥75,000/mm3). 
No dose 
reduction 
required. 
No dose reduction if isolated and duration ≤7 
days. 
If duration more than 7 days or not recovered on 
D21 
Delay** next infusion until ANC 
≥1,500cells/mm3and: 
- 1st episode: reduce the dose. 
- 2nd episode: withdraw from study treatment. 
 
 
 
 
Delay** next infusion until recovery and ANC 
≥1,500cells/mm3and: 
- 1st episode: reduce the dose, see Section 5. 
- 2nd episode: withdraw from study treatment 
Delay** infusion until platelets ≥75,000/mm3. If 
grade 3 without delay, no dose reduction required. 
If grade 4 with or without delay, or grade 3 with 
delay 
- 1st episode: Reduce dose by 1 dose level. 
- 2nd episode: Withdraw from study treatment in 
case of recurrence 
 
 
** maximum of 3 weeks delay, otherwise the subject will come off study 

12 
 
Blood counts will be performed in case of fever or infection. Cabazitaxel should not be 
given to patients with neutrophil counts <1,500 cells/mm3. 
Deaths due to sepsis following severe neutropenia have been reported in patients 
treated with cabazitaxel. Neutropenic complications should be managed promptly with 
antibiotic support. Infections concomitant with grade 3-4 neutropenia should be 
reported with the term “neutropenic infection” in the eCRF. 
No dose modification will be made for anemia; patients will be supported appropriately 
by the treating physician (the investigator can refer to ASCO guidelines). 
 
 
Allergy (Anaphylactic and Hypersensitivity reactions) 
 
Hypersensitivity reactions that occur despite premedication are very likely to occur 
within a few minutes of start of the first or second infusion of cabazitaxel. Therefore, 
during at least the first 10 minutes of the first and second infusions, careful evaluation 
of general sense of well-being, blood pressure and heart rate will be performed so that 
immediate intervention can occur. 
 
Facilities equipment and medications (i.e., antihistamine, corticosteroids, aminophylline 
and epinephrine) for resuscitation must be immediately available. If a reaction occurs, 
the medically indicated treatment for a given symptom will be instituted (e.g., 
epinephrine in case of anaphylactic shock, aminophylline in case of bronchospasm, 
etc). In addition, it is recommended to take the measures listed below: 
 
 
Mild: localized cutaneous reaction, 
such as: pruritus, flushing, rash. 
o Consider decreasing the rate of infusion until 
recovery of symptoms, stay at bedside 
o Complete cabazitaxel infusion at the initial 
planned rate. 
Moderate: Generalized pruritus, 
more severe flushing or rash, mild 
dyspnea, hypotension with systolic 
B.P. >80 mmHg 
o Stop cabazitaxel infusion 
o Give IV diphenhydramine 50 mg and/or IV 
dexamethasone 10 mg 
o Once all signs and/or symptoms of 
hypersensitivity reaction disappear, cabazitaxel 
may be reinfused within 24 hours from the 
interruption, if medically appropriate, and 
whenever possible. 
o Re-administer premedication regimen as 
described in Section 8.6 when cabazitaxel is 
reinfused more than 3 hours after the 
interruption 
o Administer cabazitaxel over 2 hours for all 
subsequent infusions 
Severe: bronchospasm, 
generalized urticaria, hypotension 
with systolic B.P. ≤80 mmHg, 
angioedema. 
o Stop cabazitaxel infusion 
o Give IV diphenhydramine 50 mg and/or IV 
dexamethasone 10 mg 
o Add epinephrine** or bronchodilators and/or IV 
plasma expanders if indicated 
o Hospitalize if needed 
o Withdraw patient from study; no further exposure 
to cabazitaxel. 

13 
 
 
 
 
 
Nausea/Vomiting 
A prophylactic anti-emetic treatment should be given to the patients during all cycles. 
The use of prochlorperazine is recommended. More aggressive anti-emetic prophylaxis 
(i.e., ondansetron, etc.) should be given to the patient who has experienced grade ≥3 
nausea/vomiting in a preceding cycle. If, despite the appropriate medication, grade ≥3 
nausea/vomiting still occur, reduce the dose of cabazitaxel. If, despite dose reduction 
and prophylaxis, nausea/vomiting still occur at grade ≥3, the patient should be 
withdrawn from treatment with cabazitaxel. This is considered a DLT. 
 
Stomatitis 
If grade 3 stomatitis occurs, cabazitaxel should be withheld until resolution to grade ≤1. 
Treatment may then be resumed, but the dose of cabazitaxel should be reduced for all 
subsequent doses. In case of grade 4 stomatitis, the patient will be withdrawn from 
treatment with cabazitaxel. This is considered a DLT. 
 
Diarrhea 
No prophylactic treatment for diarrhea is recommended in Cycle 1. However, following 
the first episode of diarrhea, the patient should be treated with rehydration 
or antidiarrheal medications as needed. In case of grade ≥ 3 diarrhea or persisting 
diarrhea despite appropriate medication, fluid and electrolytes replacement, delay 
treatment until improvement or resolution, then reduce the dose. If despite dose 
reduction, diarrhea still occurs at grade ≥3, the patient will be withdrawn from treatment 
with cabazitaxel. If grade ≥3 diarrhea persists despite adequate antidiarrheal treatment, 
it is considered a DLT. 
 
Other GI toxicity 
Gastrointestinal (GI) haemorrhage and perforation, ileus, colitis, including fatal 
outcome, have been reported in patients treated with cabazitaxel. Caution is advised 
with treatment of patients most at risk of developing gastrointestinal complications: 
those with neutropenia, the elderly, concomitant use of NSAIDs, anti-platelet therapy or 
anti-coagulants, and patients with prior history of pelvic radiotherapy, gastrointestinal 
disease, such as ulceration and GI bleeding. Symptoms such as abdominal pain and 
tenderness, fever, persistent constipation, diarrhea, with or without neutropenia, may 
be early manifestations of serious gastrointestinal toxicity and should be evaluated and 
treated promptly. Cabazitaxel treatment discontinuation may be necessary. 
 
Hematuria 
An imbalance in the incidence of hematuria was observed in the Phase III study in 
second line mCRPC (EFC6193). More hematuria was reported in cabazitaxel arm 
versus mitoxantrone arm (62 patients/16.7% versus 14 patients/3.8%). In cabazitaxel 
arm, no clear possible explanation such as local infection/obstruction/progression, or 
anticoagulation/aspirin therapy, or thrombocytopenia was found for 21 patients. 
Therefore, in case of hematuria with no clear possible explanation every effort should 
be undertaken to document the cause (e.g., urine cultures, urinary tract ultrasound, 
and if no cause identified cystoscopy with or without biopsy). 
Anaphylaxis(Grade 4 reaction) 
Withdraw treatment (DLT) 

14 
 
Kidney function 
 Consider nephrologist advice in case of creatinine increase by at least 2 x ULN 
from baseline value or eGFR (according to CKD-EPI formula) decrease by 50%. 
Cabazitaxel or enzalutamide would only be held for a calculated creatinine 
clearance less than 45 ml/min. Web link to be used to estimate glomerular 
filtration rate (GFR) using the CKD-EPI (Chronic Kidney Disease Epidemiology 
Collaboration) formula.http://www.qxmd.com/calculate-  
online/nephrology/ckd-epi-egfr. This is not considered a DLT. 
 Recommend IV hydration for CT scan with contrast in case of eGFR< 60 ml/min 
and to provide some examples of hydration protocol in Appendices (see 
Appendix E). 
 In case of renal function impairment, make every effort to identify the cause and 
report the cause as an adverse event. The existing renal function should be 
considered in the grading of the event. If no cause is identified (no diagnostic), 
report eGFR decrease as an adverse event. 
 Creatinine and eGFR should be assessed until recovery or stabilization. 
 
 
Liver toxicity 
In case of increase of SGOT(AST) and/or SGPT(ALT) >2.5 x ULN or bilirubin to >ULN, 
delay cabazitaxel treatment for up to 2 weeks until SGOT(AST) and/or SGPT(ALT) 
returned to ≤2.5 x ULN and bilirubin to ≤ULN. If the subject was treated with 25 mg/m2, 
resume treatment at the reduced dose of cabazitaxel 20mg/m2. If the subject was 
receiving the 20mg/m2 dose of cabazitaxel, he will be removed from the study. 
 
Peripheral neuropathy 
Dose modification should be performed as follows: 
 Grade ≤1: No change 
 Grade 2: Retreat with reduced dose 
 Grade 3: Patient will be withdrawn from treatment with cabazitaxel, and it is 
considered a DLT. 
 
Other Toxic Effects 
For ≥ grade 3 toxicities except fatigue, local reaction, fluid retention, anemia and other 
toxicities that merely are uncomfortable but do not cause serious morbidity to patients, 
chemotherapy should be held for a maximum of 3 weeks from the planned date of 
reinfusion until resolution to ≤ grade 1, then reinstituted, if medically appropriate. A 
dose reduction of subsequent doses will be left to the investigator’s judgment. These 
patients will be withdrawn from study treatment if >1 dose reductions are needed. Any 
measures such as frozen gloves or socks or scalp cooling cap to prevent nail toxicity or 
alopecia are left to the investigator’s judgment. 
 
Concomitant Medication 
Concurrent treatment with strong inhibitors and strong inducers of cytochrome P450 
3A4 is not permitted. For patients who were receiving treatment with such agents, a 2- 
week washout period is required prior to cycle 1 day 1. Concurrent participation in 
another clinical trial or treatment with any other anti-cancer therapy is also not 
permitted. The Investigator may prescribe any other concomitant medications as 

15 
 
deemed necessary. The Investigator should look in Appendix E to see if the patient is 
on drugs metabolized by CYP 2C19, 2C8, 2C9 or 3A4. If this is the case, and the 
patient is on a drug with a narrow therapeutic index (shown in the table in bold), then 
the patient will need careful observation on the study. 
 
Adverse event relationship to treatment 
Investigators are required to assess if there is a reasonable causal relationship with the 
study drug/treatment regimen administered for each reported AE. “Reasonable causal 
relationship” means that, in the Investigators best clinical judgment, there are 
facts/evidence or arguments to suggest a causal relationship. Possible answers are 
‘Yes’ or ‘No'. 
 
All Serious Adverse Events (SAEs) must be transmitted within 1 working day of the 
Investigator’s awareness or identification of the event. They need to be transmitted to 
PCCTC and Oregon Health & Science University. The PCCTC SAE Report form will be 
used for reporting (see appendix K). 
 
 
6.2.2 Enzalutamide (formerly known as MDV3100) 
 
Availability: Agent Provided by Medivation/Astellas until the final patient is off of study 
drug. 
 
Product description: Enzalutamide is a white to off white solid. It is insoluble in water 
and no salts are formed from ~ pH 2 to 10. Enzalutamide drug product is formulated in 
a Labrasol solution containing antioxidants (butylated hydroxytoluene and butylated 
hydroxyanisole) and filled into gelatin capsules. Capsules are filled to contain 40 mg of 
active pharmaceutical ingredient and are provided in high-density polyethylene bottles 
with child-resistant induction seal closure. 
 
Packaging and Labeling 
All medication used in this study will be prepared, packaged, and labeled under the 
responsibility of a qualified person at Astellas US Technologies, Inc. (AUST) in 
accordance with AUST Standard Operating Procedures (SOPs), Good Manufacturing 
Practice (GMP) guidelines, ICH GCP guidelines, and applicable local laws/regulations. 
 
Information presented on the label for investigational product will comply with 
applicable local regulations. 
 
Site pharmacist or medically qualified staff will dispense the study treatment to each 
subject in accordance with this protocol. 
 
Solution preparation: Not applicable. 
 
Storage requirements: Enzalutamide should be stored in a secure location with 
limited access at 77°F (25°C), with excursions permitted to 59°F to 86°F (15°C to 
30°C). Bottles will be labeled with the study protocol number, medication or bottle 
number, contents, directions for use, storage directions, clinical trial statement, and the 
sponsor. Subjects will be instructed to store study drug at room temperature out of the 
reach of children. 

16 
 
Route of administration: Oral; four tablets comprise one dose. 
 
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug 
deliveries from the sponsor are received by a responsible person (e.g. pharmacist), 
and that 
o such deliveries are recorded 
o study drug is handled and stored safely and properly 
o study drug is only dispensed to study subjects in accordance with the protocol 
o any unused study drug is returned to the sponsor or standard procedures for the 
alternative disposition of unused study drug are followed 
 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist/designee. Study drug accountability throughout the study must 
be documented. The following guidelines are therefore pertinent: 
o 
The investigator agrees not to supply study drugs to any persons except the 
subjects in this study. 
o 
The investigator/pharmacist/designee will keep the study drugs in a pharmacy or 
other locked and secure storage facility under controlled storage conditions, 
accessible only to those authorized by the investigator to dispense these test 
drugs. 
o 
Inventory and to record the results of this inventory on the Drug Accountability. A 
study drug inventory will be maintained by the investigator/pharmacist/designee. 
The inventory will include details of material received and a clear record of when 
they were dispensed and to which subject. 
o 
At the conclusion or termination of this study, the 
investigator/pharmacist/designee agrees to conduct a final drug supply record. It 
must be possible to reconcile delivery records with those of used and returned 
medication. Any discrepancies must be accounted for. Appropriate forms of 
deliveries and returns must be signed by the person responsible. 
o 
Used or unused study drug may be destroyed at the study center according to 
standard institutional procedures after drug accountability has been conducted by 
the Sponsor or representative, only if agreed upon by the Sponsor. A copy of the 
standard institutional procedure for destroying investigational drugs will be 
provided to the Sponsor or designee upon request. Unused study drug not 
destroyed at the site must be returned to the Sponsor or designee at the end of 
the study or upon expiration. 
 
Expected adverse events: 
Enzalutamide was examined in a Phase III placebo-controlled study in 1199 men with 
metastatic CRPC previously treated with docetaxel chemotherapy. It was generally well 
tolerated. 
 
Adverse events in men treated with enzalutamide 160 mg by mouth daily with an incidence 
of at least 5% and by at least 2% greater than those who received placebo are summarized 
below. 
 
fatigue (33.6% v 29.1%) 
 
diarrhea (21.4% v 17.5%) 
 
hot flash (20.3% v 10.3%) 

17 
 
 musculoskeletal pain (13.6% v 10.0%) 
 
headache (11.6% v 5.5%) 
 
insomnia (8.6% v 6.0%) 
 
anxiety (6.4% vs. 4.0%) 
 hypertension (6.1% v 2.8%) 
 nasopharyngitis (5.1% v 3.0%) 
 
Adverse events reported less than 5% but may be associated with enzalutamide after 
careful assessment of the adverse events include the following. 
falls (4.0% vs.1.3%) 
dry skin (3.6% vs. 1.3%) 
pruritus (3.5% vs. 1.3%) 
 
A greater proportion of patients in the enzalutamide-treated group (4.1% vs. 1.8%) 
reporting the following adverse event terms: memory impairment, cognitive disorder, 
amnesia, disturbance of attention, and dementia. In addition, event terms related to 
hallucination (visual hallucination, tactile hallucination, hallucination) were reported more 
frequently in the enzalutamide-treated group (1.6% vs. 0.3%). 
 
Serious events that occurred at a ≥0.5% absolute difference in event frequency and more 
frequently in the enzalutamide arm than the placebo arm included spinal cord compression 
(6.0% vs. 3.8%), bone pain (1.5% vs. 1.0%), metastatic pain (1.5% vs. 0.8%), pathological 
fracture (1.5% vs. 0.5%), urinary tract infection (0.9% vs. 0.3%), and cauda equina 
syndrome (0.8% vs. 0.0%). 
 
Seizure is a known potential toxicity of enzalutamide. In vitro studies have shown that 
MDV3100 and its metabolite M2 bind to the GABA-gated chloride channel with IC50 values 
of 1.2 μg/mL and 3.3 μg/mL, respectively and in a cell-based assay inhibit the channel’s 
activity with IC50values of 1.4 μg/mL and 1.07 μg/mL, respectively. Some compounds that 
inhibit the GABA gated chloride channel are associated with seizures [Foster, 2011]. 
 
In the first clinical study of enzalutamide (S-3100-1-01), a dose-escalation study in men 
with castration-resistant prostate cancer with and without prior exposure to chemotherapy, 
the following doses were evaluated: 30, 60, 150, 240, 360, 480 (as 240 mg twice per day 
[BID]), and 600 (as 300 mg BID) mg/day. Three patients were reported to have dose- 
limiting toxicities of seizure, one each at doses of 360, 480, and 600 mg/day. The results of 
this study led to the selection of the clinical dose of MDV3100 of 160 mg/day. 
 
As of the database cut-off date for the respective unblinded or open-label studies reported 
in the Investigator’s Brochure, 7 patients out of a total of 1100 patients (0.6%) exposed to 
enzalutamide at a dose of 160 mg/day have reported a seizure during the enzalutamide 
treatment emergent adverse event reporting period. These include one patient each in 
studies 9785-CL-0007 and 9785-CL-0321, and 5 patients in the CRPC2 study. Two 
additional patients have been identified by the Sponsor to have experienced adverse events 
that may have been seizures, including one case reported by the Investigator as      
syncope (CRPC2) and the other reported as a transient ischemic attack with an abnormal 
electroencephalogram (CRPC-MDA-1). As of the data cut-off date, treatment with 
enzalutamide at a daily dose of 160 mg is associated with a 0.6-0.8% risk of seizure in men 
with late-stage castration-resistant prostate cancer. Taking into account information from 

18 
 
ongoing blinded studies and events occurring after the database cut-off date, the range for 
seizure risk is unchanged. No seizures have been reported in the blinded placebo- 
controlled Phase 3 study MDV3100-03 (PREVAIL) with over 1300 patients enrolled 
(randomized 1:1 to enzalutamide 160 mg/day or placebo). One additional patient in the 
CRPC2 study has been reported to have had a seizure after the safety data cut-off date, 
and one additional patient in an ongoing blinded study (9785-CL-0222) has also reported a 
seizure. 
 
6.3 
Commercial Agents 
 
Prednisone 
Prednisone is a corticosteroid given twice daily in this trial during cabazitaxel treatment. It is 
commercially available. There is no preparation required. The patients will receive a 
prescription for this agent, which they will fill at their outpatient pharmacy. We will provide 
information on it to the patient within the consent form. They will also receive written 
information with their prescription. It should be stored away from heat, light, and moisture at 
room temperature. 
 
Expected adverse events: 
Prednisone should be administered with fluids and food to decrease the risk of 
gastrointestinal complications. Prednisone can exacerbate diabetes mellitus, hypertension, 
and chronic and acute infections. Prednisone can mask symptoms of infections. 
 
Other toxicities include: 
a. 
Cardiovascular: fluid retention (common), hypertension, congestive heart failure 
b. 
Gastrointestinal (GI): pain and/or ulcerations anywhere in the GI tract (common), 
weight gain (common), increased thirst, pancreatitis (rare) 
c. 
Infections: increased risk of acute and chronic infections (common) 
d. 
Metabolic: diabetes mellitus, fluid and electrolyte disturbances 
e. 
Musculoskeletal: weakness (common), decrease in muscle mass (common), 
osteoporosis 
f. 
Neurological: mood swings (common), depression, insomnia (common), dizziness, 
headache, confusion (rare), excitement (rare), psychosis (rare), seizures (rare) 
g. 
Ophthalmological: visual changes 
h. 
Urological: increased frequency of urination 
 
G-CSF or GM-CSF 
G-CSF and GM-CSF are commercially available growth factors (brand per institution). Must 
be given 24-48 hours after the cabazitaxel for each cycle. Dose, ingredients and packaging 
will be different according to the brand. Refer to the package insert for this information as 
well as “standard” preparation instructions. 
 
Expected adverse events: 
G-CSF: Common side effects include headache, loss of appetite, irritation at injection site, 
fluid retention, flu like symptoms, bone pain, diarrhea and/or constipation. Occasional side 
effects include rash, fever, hair loss, dizziness, weakness, indigestion, sore throat, fatigue, 
liver function abnormalities, and/or splenomegaly. 
 
GM-CSF: Common side effects with GM-CSF are lightheadedness, flushing, tachycardia 
and hypotension with the first dose; diarrhea; local reaction at the injection site (redness, 

19 
 
swelling, tenderness); weakness and fatigue. Some may have mild flu-like syndrome (fever, 
headache, generalized aches and pains) or swelling in the hands or feet. Rarely (<1%), 
there may be a “capillary leak syndrome” or blood clots. 
 
 
7. 
CORRELATIVE/SPECIAL STUDIES 
 
7.1 Correlative Studies 
 
Tumor Biopsies 
Metastatic tumor biopsies will be obtained prior to first treatment, unless not safe and 
feasible. Sites where prior radiation has been administered for metastatic disease will be 
avoided. Soft tissue sites are preferred over bone sites. Patients will be offered the option of 
a second biopsy at the time of progression. If they consent, all attempts will be made to 
biopsy the same lesion as was sampled for the first biopsy. See Appendices F-I for details 
on specimen handling. 
 
The correlative science and biopsy endpoints will be considered exploratory and will 
therefore be described without formal statistical hypotheses. However, they are a critical 
piece of this trial and will provide important hypothesis-generating biological evidence that 
can be further studied and validated in later trials. 
 
Optional tumor biopsy at progression: During treatment, tumors change at a DNA level, and 
these changes can be reflected in their phenotype. The pre- and post-treatment biopsies 
will be interrogated to see if there are changes in the androgen signaling access and 
glucocorticoid receptor. If there are changes between the first and second biopsy, we will be 
able to hypothesize about how resistance may have arisen and how we might target 
cancers better in the future. This is optional, but encouraged. 
 
i. Baseline tumor biopsy (and optional tumor biopsy at progression) to assess cytotoxic  
effects and androgen axis. Biopsies will be obtained with imaging-guidance and 
undergo pathology review at the participating site to ensure presence of tumor. For 
PCR-based assays (AR expression, splice variants), we estimate a minimum of ~3,000- 
5,000 cells would be needed. For each core, the participating site will perform H&E to 
determine presence of tumor. All cores with presence of tumor will be prioritized for 
analysis as per below: 
o 
Core #1 (FFPE): IHC staining for expression of AR, PTEN, glucocorticoid 
receptor; add caspase-3 for apoptosis at biopsies taken at progression (not 
baseline). Please see Appendix G for FFPE processing and shipping details.  
Core #2, 4, 6 (Frozen): Evaluate AR copy number, AR splice variants, SLCO 
transport genes5, and CYP17 lyase levels by RT-PCR6. Also measure 
testosterone, dihydrotestosterone and DHEA levels by mass spectroscopy. 
Finally, measure TMPRSS2-ERG by FISH. 
 
Please see Appendix I for fresh frozen biopsy tissue processing and shipping 
details. 
 
Core #3, 5 (FFPE): Next Generation Sequencing on Ion Torrent (using a Solid 
Tumor Panel). Please see Appendix G for FFPE processing and shipping details. 
 
This will require minimum 10% of tumor. 

20 
 
 
We will try to enrich for tumor selection by performing methyl green 
staining (in order to only remove tumor cells). However, in instances 
where we cannot easily separate tumor from normal, then we need at 
least 10% of the biopsy to consist of tumor. 
 
ii. Evaluation of circulating blood markers. To be drawn at baseline and progression. 
o 
Evaluate prostate cancer-associated miRNAs7, cell-free tumor DNA, and host 
genetic factors from plasma or serum prior to treatment and at end of treatment 
(time of resistance). See Appendix J. 
 7.5-10 mls of blood (i.e. 1 red top serum tube) 
 7.5-10 mls of blood (i.e. 1 purple top EDTA tube) 
 7.5-10 mls of blood (i.e. 1 tan/black top Streck Cell-Free DNA BCT tube) 
 Buffy coat (no extra tube required; can be taken off of purple top tube) 
 
iii. Molecular characterization of circulating tumor cells 
o 
Enumerate circulating tumor cells (CTCs)8,9 (Drawn at baseline and progression) 
o 
Interrogate molecular features of CTCs: 
 
CTCs will be isolated using an immunodensity cell isolation system (Stem 
Cell Technologies, Vancouver, BC). The assay is optimized for enrichment 
of CTCs by the negative depletion of WBCs and RBCs. 15-20 mls of blood 
(i.e. 2 purple-top EDTA tubes with 7.5-10 mls) will be needed for the 
proposed CTC analysis. If the samples cannot be shipped the same day 
as the collection, use CellSave tubes instead of EDTA tubes. See 
Appendix H. 
 
7.2 Pharmacokinetic Studies 
 
Cabazitaxel: Patient evaluations will be performed to assess the pharmacokinetic 
parameters of cabazitaxel with and without concomitant enzalutamide treatment for a 
minimum of 6 subjects. Serial post-cabazitaxel whole blood samples (2 mL) will be 
collected at time points during Cycle 1 and Cycle 2 (after 21 days of enzalutamide) to 
measure post-infusion plasma concentrations of cabazitaxel. Samples will be drawn pre- 
cabazitaxel infusion shortly before the start of the infusion (Cycle 2 only), and after the start 
of the 1-hour cabazitaxel infusion at 0.5-hour, 1-hour (coinciding with the end of the 
infusion), 1.5-hour, 2-hour, 4-hour, 8-hour and 24-hour time points. See Appendix J. 
 
 
8. 
STUDY PROCEDURES AND SCHEDULE OF EVENTS 
 
8.1 
Subject Registration (Local and Multicenter) 
 
Written informed consent will be obtained from all patients participating in this trial, as stated 
in the Informed Consent section of the Code of Federal Regulations, Title 21, Part 50. If a 
patient’s signature cannot be obtained, the investigator must ensure that the informed 
consent is signed by the patients legally authorized representative. Documentation of the 
consent process and a copy of the signed consent shall be maintained in the patient’s 
medical record. 
 
The PCCTC will manage subject registration on behalf of OHSU through Caisis EDC, the 
PCCTC Clinical Data Management System (CDMS). To initiate enrollment, the investigator 

21 
 
will verify eligibility according to all inclusion and exclusion criteria. All eligible subjects must 
be centrally registered through PCCTC. To complete the registration process, the study site 
must email the signed completed study-specific eligibility checklist, all source documents 
verifying eligibility, any supporting documents, and the signed informed consent to PCCTC at 
pcctc@mskcc.org. Once the enrollment packet is received and reviewed at PCCTC and if 
eligibility is confirmed, the subject will be enrolled in PCCTC Caisis EDC. 
 
 
Each site must maintain a log of all subjects who sign informed consents. The log must also 
document an explanation for exclusion due to screen failure. Subjects who are enrolled on 
study will be assigned a site and protocol specific subject number. Participating sites are 
required to retain, in a confidential manner, sufficient information on each subject so that the 
subject may be contacted should the need arise. Sub-sites should submit their logs to OHSU 
monthly. 
 
 
 
8.2 
Baseline Screening 
Baseline screening evaluations are to be conducted within 4 weeks prior to start of 
protocol therapy. Scans must be done within 4 weeks prior to the start of therapy. 
 
 A biopsy should be performed at this time, if safe and feasible. The preferred site of 
the biopsy is unradiated soft tissue. Unradiated bone is the second choice. 
 Screening labs include: 
o CBC with differential: white blood cells count (WBC), red blood cell count (RBC), 
hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), , 
platelet count (UNVPLT), neutrophils (NEUTP), lymphocytes (LYMP), 
monocytes (MONP), eosinophils (EOSP), basophils (BASOP). 
o Chemistry Panel (sodium (NA), potassium (K), chloride (CL), bicarbonate (CO2), 
blood urea nitrogen (BUN), creatinine (CREAT), glucose (GLU), calcium (CA), , 
o Liver Function Tests (aspartate transaminase (AST), alanine transaminase 
(ALT), total protein (TP), albumin (ALB), total bilirubin (TBILI), alkaline 
phosphatase (ALK) 
o LDH 
o PSA 
o Testosterone (TEST) 
 Radiographic examinations include: CT scan chest/abdomen/pelvis with contrast 
(preferred) or MRI chest/abdomen/pelvis and nuclear medicine bone scan. 
 EKG 
 Review of past medical history 
 Physical exam 
 Medications 
 Height and weight 
 Collection of circulating blood markers 
 Collection of circulating tumor cells 
 
8.3 
Phase I Details 
 
An initial 3-12 study subjects will be treated with cabazitaxel at 25 mg/m2 on day 1 and 
enzalutamide 160 mg daily every 21 days (starting on day 2 of cycle 1 for those in the PK 

22 
 
studies or day 1 of cycle 1 for all others). These subjects will be permitted to continue on 
cabazitaxel and enzalutamide until progression and will be included in the final analysis of 
efficacy. Depending on the number of DLTs in these initial patients, we may move on to the 
Phase II portion of the study or study cabazitaxel at 20 mg/m2 with enzalutamide 160 mg per 
day. See below for details. 
 
The rationale for starting at current FDA approved doses of both agents with a dose de- 
escalation design is below: 
 
The product label for cabazitaxel (JEVTANA USPI) states the following: “Though no formal 
drug interaction trials have been conducted for JEVTANA, the concomitant administration of 
strong CYP3A inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital) is expected to decrease cabazitaxel concentrations. Therefore, co- 
administration with strong CYP3A inducers should be avoided.” 
 
The product label for enzalutamide (XTANDI USPI) states the following: “Enzalutamide is a 
strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady 
state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin 
(CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with 
narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), 
CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, 
as enzalutamide may decrease their exposure.” 
 
Based on these labels, concomitant use of enzalutamide with cabazitaxel could theoretically 
lead to decreased exposure to cabazitaxel. 
 
In addition, the Phase I enzalutamide-docetaxel study was presented at GU ASCO 2013. In 
22 patients, it was shown that enzalutamide did not have significant effects on the PK of 
docetaxel and that the toxicity profile of docetaxel was not altered.10 
 
In the phase I portion, DLT will be assessed during the first 2 cycles of treatment. Further 
dosing with cabazitaxel will be determined by the review committee consisting of participating 
investigators and an independent review committee using the following measures (standard 
3+3 design): 
 If 0 of the first 3 patients experience a DLT, we will cease the dose finding part of the 
trial and continue with the cabazitaxel 25 mg/m2 dose for the entire trial. 
 If ≥2 of the first 3 patients experience a DLT, cabazitaxel will be reduced 20% to 20 
mg/m2 thereafter. 
 If 1 of the first 3 patients experiences a DLT, 3 additional patients will be treated (total of 
6) with cabazitaxel 25 mg/m2. 
• 
If ≥2 of 6 patients experience DLT, cabazitaxel will be reduced 20% to 20 mg/m2 
thereafter for the rest of the trial. 
 If we need to use the dose-reduced cabazitaxel (20 mg /m2), we will review the side 
effects of the next 3-6 subjects for DLTs during the first two cycles. If there are no DLTs, 
we will move forward with the trial. If there is ≥2 DLT, we will terminate the study. If  
there is 1 DLT, we will examine the next 3 subjects. If there are any other DLTs, we will 
terminate the study. If not, we will move forward with the study. 

23 
 
 No lower dose levels will be tested. If the combination of full dose enzalutamide and 
cabazitaxel 20 mg/m2 proves intolerable, we will conclude that the two drugs cannot be 
combined safely and the study would not continue further. 
 
Treatment will continue at the determined concurrent dosing on a 21-day cycle for 6-10 cycles 
of cabazitaxel and enzalutamide. Patients may then continue enzalutamide monotherapy on a 
28-day cycle until progression or limiting toxicity. 
 
Definition of DLT in the phase I portion of this study. 
Toxicity will be evaluated according to the NCI CTCAE, Version 4.0. 
These criteria are available online. See Appendix B. 
 
DLT will be defined as any of the following events that are considered by the investigator to be 
related to therapy with cabazitaxel in combination with enzalutamide. 
 
1. 
Grade 3 neutropenia associated with coincident fever (where fever is defined as an oral 
temperature ≥ 38.5 degrees Celsius) 
2. 
Grade ≥3 neutropenia that lasts >7 days or has not recovered by day 1 of the next cycle 
3. 
Grade 3-4 thrombocytopenia with clinically significant bleeding 
4. 
Delay in the initiation of the subsequent cycle of therapy by more than 21 days due to 
treatment-related toxicity 
5. 
Grade ≥3 nausea and vomiting despite optimal antiemetic therapy (5-hydroxytryptamine 
3 (5-HT3) serotonin receptor antagonist 
6. 
Grade ≥3 diarrhea despite optimal supportive therapy with loperamide 
7. 
Grade ≥3 stomatitis 
8. 
Grade ≥4 anaphylaxis 
9. 
Grade ≥3 neuropathy 
10. 
Seizure 
 
Although DLTs may occur at any point during treatment, only DLTs occurring during cycles 1 
and 2 of treatment during the phase I portion of this study will necessarily influence decisions 
regarding dose de-escalation. DLTs in cycle 3 and beyond will not influence dose decisions. 
Patients experiencing DLTs during cycles 1 or 2 of the phase I portion of the study may 
continue on the study providing they are deriving clinical benefit and will have their dose of 
cabazitaxel decreased no more than one level. 
 
Patients will be monitored during all cycles of therapy for treatment-related toxicities. AEs that 
require dose reductions after the first two cycles will not be considered DLTs. 
 
8.4 
Study Visits (Day 1 of each cycle, +/- 3 days) 
For all participants' weeks 1-30, the following will be performed every 3 weeks during treatment 
with cabazitaxel (first 10 cycles): 
 Physical exam 
 Concomitant medications 
 CBC with differential: 
o During the first cycle, the CBC with differential will be completed weekly. 
 Chemistry panel 
 Liver function tests 
 LDH (collected for the first 10 cycles only) 
 PSA 

24 
 
 Assessment of adverse events 
 
For all participants in the PK portion (3-12 possible participants, minimum 6): 
All of the above, plus PK measurements: 
 Serial post-cabazitaxel whole blood samples (2 mL) will be collected at the following 
time points during Cycle 1: after the start of the 1-hour cabazitaxel infusion at 0.5-hour 
+/- 5 minutes, 1-hour (coinciding with the end of the infusion) +/- 15 minutes, 1.5-hour  
+/- 15 minutes, 2-hour  +/- 15 minutes, 4-hour  +/- 15 minutes, 8-hour  +/- 15 minutes 
and 24- hour +/- 60 minutes time points (prior to initiation of enzalutamide). 
 At Cycle 2, serial blood samples will be drawn pre-cabazitaxel infusion shortly before 
the start of the infusion, after the start of the 1-hour cabazitaxel infusion at 0.5-hour  +/- 
5 minutes, 1- hour (coinciding with the end of the infusion) +/- 15 minutes, 1.5-hour  +/- 
15 minutes, 2-hour  +/- 15 minutes, 4-hour  +/- 15 minutes, 8-hour  +/- 15 minutes and 
24- hour time points  +/- 60 minutes. 
 Note that for all subjects in the PK portion, enzalutamide starts on day 2 of cycle 1. 
 
For all participants in the phase I portion (3-12 possible participants): 
 Assessment of dose limiting toxicities at each cycle in the DLT period. 
 
For all participants weeks 30+, the following will be performed every 4 weeks (±3 days): 
 Physical exam 
 Concomitant medications 
 CBC with differential 
 Chemistry panel 
 Liver function tests 
 PSA 
 Assessment of adverse events 
 
For all participants weeks 1 until end of study: 
 Imaging studies every 12 weeks (± 7 days)  (CT scan chest/abdomen/pelvis with 
contrast (preferred) or MRI chest/abdomen/pelvis and nuclear medicine bone scan) 
 Toxicities and adverse experiences will be assessed at each visit using the NCI 
Common Toxicity Criteria for Adverse Events v4.0 (CTCAE, see appendix B). 
 
 
8.5 
Follow-up 
 
End of Study Visit (28 (±7) days after last dose for safety follow up for monitoring toxicity for 
study drug) 
 Physical exam 
 CBC with differential 
 Chemistry panel 
 Liver function tests 
 PSA 
 Collection of circulating blood markers 
 Circulating tumor cells 
 Optional tumor biopsy 
 Phone calls every 6 months for up to 5 years after study to assess survival. 
8.6 
Early Termination (Termination from the study other than progression of disease) 

25 
 
Voluntary subject withdrawal 

26 
 
Investigator’s decision that is in the patient’s best interest to withdrawal 
Noncompliance 
Significant protocol violation 
For any reason, at the Sponsor or Investigator discretion 

27 
 
8.7 
Schedule of Events 
 
 
 
Pre- 
Study 
Wk 
1 
C1 
Wk 
4 
C2 
Wk 
7 
C3 
Wk 
10 
C4 
Wk 
13 
C5 
Wk 
16 
C6 
Wk 
19 
C7 
Wk 
22 
C8 
Wk 
25 
C9 
Wk 
28 
C10 
Change to 
4-Week 
Cycles 
End of 
Studyf 
Off 
Study 
(Every 6 
months)d 
Window (days) 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
Cabazitaxel, day 1 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A  
 
 
Enzalutamide, days 1-21  
Be 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
 
 
Prednisone, daily 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
X 
X ------------------------------------------------------------------------------------------------ X 
 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Vital signs 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC w/diff, plts 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry panela 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Circulating blood markers 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Circulating Tumor Cells 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Testosterone 
X 
Pharmacokinetic Studiesh 
Xh 
Xh 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
(safety) 
 
X ------------------------------------------------------------------------------------------------ X 
X 
 
Tumor measurements by 
Radiographic evaluation 
(CT or MRI 
Chest/Abd/Pel and Whole 
body bone scan) 
 
X 
Tumor measurements are repeated every 12 weeks (±7 days). Documentation 
(radiologic) must be provided for subjects removed from study for progressive 
disease. 
 
Xc 
 
Tumor Biopsyb 
X 
 
X 
 
Survival assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: Cabazitaxel: Dose as assigned; given day 1 (+/- 2 working days) of each cycle 
B: Enzalutamide: 160 mg by mouth daily, throughout cycle 
a: Albumin (ALB), alkaline phosphatase (ALK), total bilirubin (TBILI), bicarbonate (CO2), BUN, calcium (CA), chloride (CL), creatinine (CREAT), glucose 
(GLU), LDH, potassium (K), total protein (TP), (AST), (ALT), sodium (NA). LDH is collected for the first 10 cycles only. 
b: Screening biopsy to be performed if safe and feasible. End of study biopsy  is optional, but encouraged. See Section 7.1 
c: Off-study evaluation.  Two bone scans taken 6-12 weeks apart must be used to document progressive disease if the patient is removed from study for this 
reason in order to account for flare phenomenon. CT scan and MRI progression does not require confirmation 
d: For up to 5 years per subject, not study close 
e: For the patients in the PK analysis, enzalutamide starts day 2 of cycle 1. For all others, it begins on day 1 of cycle 1.  
f:  Visit occurs 28 (+/- 7) days after the last dose of study medication. 
g: Weekly CBC with differential for cycle 1 
h: For patients in the PK portion only (minimum 6). Serial post-cabazitaxel whole blood samples (2 mL) will be collected at Cycle 1 after the start of the 1- 
hour cabazitaxel infusion at 0.5-hour +/- 5 minutes, 1-hour (coinciding with the end of the infusion) +/- 15 minutes, 1.5-hour+/- 15 minutes, 2-hour +/- 15 
minutes, 4-hour +/- 15 minutes, 8-hour +/- 15 minutes and 24-hour +/- 60 minutes time(prior to initiation of enzalutamide). At Cycle 2, samples will be 
drawn pre-cabazitaxel infusion shortly before the start of the infusion, after the start of the 1-hour cabazitaxel infusion at 0.5-hour +/- 5 minutes, 1-hour 
+/- 15 minutes (coinciding with the end of the infusion), 1.5-hour +/- 15 minutes, 2-hour +/- 15 minutes, 4-hour +/- 15 minutes, 8-hour +/- 15 minutes  and 
24-hour +/- 60 minutes time points. 

29 
 
9. MEASUREMENT OF EFFECT 
 
For the purposes of this study, subjects should be reevaluated for PSA response every 3 
weeks during the first 28 weeks (during the period of combined treatment with 
cabazitaxel/prednisone plus enzalutamide). After the first 28 weeks, if a patient continues to 
do well without disease progression and proceeds to enzalutamide monotherapy, the PSA 
level will be assessed every 4 weeks. Imaging studies with a bone scan and CT scan will be 
done at baseline and every 12 weeks during the study. If a CT scan is not possible, an   
MRI of the chest/abdomen/pelvis can be substituted. The Prostate Cancer Working Group  
2 (PCWG2) Guidelines will be used to assess stable disease, response and progression of 
disease. 
 
9.1. 
Definitions 
 
9.1.1 PSA Definitions 
PSA progression: PSA increase of ≥ 25% and at least 2 ng/mL from baseline or 
nadir PSA achieved, confirmed by a second measurement at least three weeks 
later. 
PSA nadir: Lowest PSA reached that was confirmed by a second equal or lower 
measurement. 
PSA response: As recommended by the PCWG2 definitions. We will not apply a 
strict definition for PSA response, but we will report 90%, 50% and 30% 
levels of individual decline from baseline. The primary endpoint is the proportion 
of patients with a PSA reduction ≥ 90%. Waterfall plots will be used to describe 
PSA changes while on study. 
Maximum percentage of PSA reduction in each patient. Percentage of PSA 
reduction will be defined as [1 - (lowest PSA attained on study)/(PSA at study 
entry)] x 100. This formula only applies to PSAs that have decreased, and not 
those that have remained constant, i.e. the same as the baseline measurement. 
 
9.1.2 Definition of Disease Progression 
 
The patient may continue on study treatment as long as the patient has not 
progressed by ANY of the following measures: 
 
 
Progression by modified RECIST using PCWG2 criteria for target lymph 
nodes and/or visceral disease. 
 
Development of 2 or more new lesions on bone scan. 
(If investigator believes bone scan changes may represent a healing flare, 
new lesions should be confirmed by repeat bone scan 6-12 weeks later – 
PCWG2 approach will be used to bone scan assessments). 
 
Clinical progression, i.e., increasing pain that requires radiation therapy to 
a bone lesion or the addition or increase in narcotic pain medications. 
 
Time to PSA progression is a secondary endpoint and not alone a reason 
to come off study. For this, PSA progression is defined as a 25% or more PSA 

30 
 
rise from baseline or nadir, whichever is lower. (A confirmatory PSA in 3 weeks 
must be drawn to account for flare responses.) 
 
 
9.1.3 Summary of PCWG2 definitions on metastatic disease 
 The PCWG2 definitions use modified RECIST. 
 Measurable lesions are visceral or extranodal lesions that are ≥1 cm in 
one direction. Lymph nodes are measurable lesions if they are ≥2 cm in 
one direction. Tumor in the prostate may also be used as a measurable 
lesion. 
 Non-measurable lesions are those lesions that do not meet the size 
criteria given above. Other non-measurable lesions are cysts, 
leptomeningeal disease, ascites, pleural/pericardial effusions and 
lymphangitis cutis/pulmonis. 
 Bone lesions will not be considered measurable lesions. For bone lesions, 
a minimum of two new lesions must be seen on bone scan to be 
determined progression of disease. Any lesion on bone scan suspected to 
be flare or inflammation, another study (such as CT or MRI scan) should 
be done to document the presence of a new lesion. Bone scan 
interpretation will follow PCWG2 recommendations. 
 All measurable and non-measurable lesions should be measured at 
Screening and at the defined tumor assessment time points. Extra 
assessments may be performed, as clinically indicated, if there is a 
suspicion of progression. 
 
9.1.4 Measurable disease 
 
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
9.1.5 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. 
 
For bone lesions, a minimum of two new lesions must be seen on bone scan to be 
determined progression of disease. Any lesion on bone scan suspected to be flare 
or inflammation, another study (such as CT or MRI scan) should be done to 
document the presence of a new lesion. Bone scan interpretation will follow 
PCWG2 recommendations. 

31 
 
9.1.6 Target lesions 
 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in 
total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis 
of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). A sum of the 
longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
 
9.1.7 Non-target lesions 
 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Non-target lesions include measurable lesions 
that exceed the maximum numbers per organ or total of all involved organs as well 
as non-measurable lesions.  Measurements of these lesions are not required but the 
presence or absence of each should be noted throughout follow-up. 
 
9.2 
Guidelines for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the antitumor effect of a treatment. 
 
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or 
less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and 
pelvis. Head and neck tumors and those of extremities usually require specific protocols. 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
9.3 
Response Criteria 
 
9.3.1 Evaluation of target lesions 
 
Complete Response (CR): Disappearance of all target lesions 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the 

32 
 
baseline sum LD 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD 
recorded since the treatment started or the appearance 
of one or more new lesions 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the 
smallest sum LD since the treatment started 
 
9.3.2 Evaluation of non-target lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances the opinion of the treating physician should prevail, and the 
progression status should be confirmed at a later time by the review panel (or study 
chair). 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
9.3.3 Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria (see section 9.3.1). 

33 
 
 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
 Overall 
Response 
 
 
CR 
CR 
No 
CR 
 
CR 
 Incomplete 
response/SD 
No 
PR 
 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
 
Note: 
 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.” Every effort should be made to 
document the objective progression, even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) 
before confirming the complete response status. 
 
9.4 
Confirmatory Measurement/Duration of Response 
 
9.4.1 Confirmation 
 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed at least 4 weeks after 
the criteria for response are first met. 
 
9.4.2 Duration of overall response 
 
The duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 

34 
 
9.4.3 Duration of Stable Disease 
 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since 
the treatment started. 
 
9.5 
Progression-Free Survival 
 
Progression-Free survival is defined as the number of weeks from study entry to the time of 
confirmed progression, which is defined here. 
 
 Progression by RECIST using PCWG2 criteria for target lymph nodes and/or visceral 
disease. 
 Development of 2 or more new lesions on bone scan. 
(If investigator believes bone scan changes may represent a healing flare, new lesions 
should be confirmed by repeat bone scan 6-12 weeks later – PCWG2 approach will be 
used to review bone scan assessments). 
 Clinical progression, e.g., increasing pain that requires radiation therapy to a bone 
lesion or the addition or increase in narcotic pain medications. 
 
 
 
10 ETHICAL AND REGULATORY REQUIREMENTS 
 
10.1 Protocol Review 
 
The protocol and informed consent form for this study must be reviewed and approved in 
writing by the OHSU Knight Cancer Institute (CI) Clinical Research Review Committee 
(CRRC), PCCTC and appropriate Institutional Review Board (IRB) prior to any patient 
being registered on this study. 
 
 
10.2 Informed Consent 
 
Written informed consent will be obtained from all patients, or the legally authorized 
representative of the patient, participating in this trial, as stated in the Informed Consent 
section of the Code of Federal Regulations, Title 21, Part 50. If a patients signature cannot 
be obtained, and for all patients under the age of 18, the investigator must ensure that the 
informed consent is signed by the patients legally authorized representative. 
Documentation of the consent process and a copy of the signed consent shall be 
maintained in the patient’s medical record. Privacy will be maintained by reviewing patient 
specific information in a private room. Data will be stored as described in 10.4. 
 
10.3 Changes to Protocol 
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment signed by the Principal Investigator and approved by the CRRC, PCCTC and 
IRB, before the revision or amendment may be implemented. The only circumstance in 
which the amendment may be initiated without regulatory approval is for a change 
necessary to eliminate an apparent and immediate hazard to the patient. In that event, the 

35 
 
investigator must notify the CRRC and IRB in writing within 10 working days after the 
implementation. 
 
10.4 
Maintenance of Records 
 
If the investigator relocates or for any reason withdraws from the study, the study records 
must be transferred to an agreed upon designee, such as another institution, another 
investigator, or to OHSU Knight Cancer Institute Clinical Research Management. Records 
must be maintained according to sponsor or FDA requirements. 
 
Hard copies will be kept in a locked room on a floor that requires a badge to access (Center 
for Health & Healing, floor 14). Electronic information will be kept on a secured drive. 
Patient specimens will be stored in the same fashion as hard copies. They will be labeled 
with an identifier that does not contain protected health information. 
 
 
10. 5  Safety Evaluation 
 
10.5.1 Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment (ICH E2A). 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 
 
An adverse event will be recorded and followed from treatment administration to 30 
days post treatment or resolution. 
 
10.5.2 Expected Adverse Events 
Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. An adverse event can be considered expected when it 
appears in the current adverse event list, the Investigator’s Brochure, the package insert 
or is included in the informed consent document as a potential risk. For Cabazitaxel, 
Reported Safety Information (RSI) for expectedness of adverse events will be the 
Investigator Brochure (IB). 
 
10.5.3 Unexpected Adverse Events 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational 
medicinal product) (ICH E2A). 
 
Contact the Principal Investigator and PCCTC to confirm unexpected adverse events 
when necessary. 
 
10.5.4 Serious Adverse Event (SAE) 
An SAE/ADR as defined in the Code of Federal Regulations (21CFR312.32) is any 
event that: 

36 
 
 Results in death, 
 Is life threatening, (Note: the term “life-threatening” refers to an event/reaction in which 
the patient was at risk of death at the time of the event/reaction; it does not refer to an 
event/ reaction which hypothetically might have caused death if it were more severe), 
 Requires inpatient hospitalization or results in prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 
 Is a medically important event or reaction. Medical and scientific judgment should be 
exercised in deciding whether other situations should be considered serious, such as 
important medical events that might not be immediately life-threatening or result in 
death or hospitalization, but might jeopardize the patient or might require intervention to 
prevent one of the other outcomes listed in the definition above. 
 
Related Adverse Event, i.e. Adverse Drug Reaction (ADR): There is a reasonable 
possibility according to the IST/ISS sponsor that the product may have caused the event. 
 
Unexpected Adverse Drug Reaction: An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information (e.g., Investigator's Brochure for an 
unapproved investigational product or package insert/summary of product characteristics 
for an approved product). An expected ADR with a fatal outcome should be considered 
unexpected unless the local/regional product labeling specifically states that the ADR might 
be associated with a fatal outcome. 
 
 
10.6 
OHSU Safety Reporting 
All SAEs will be reported to PCCTC and OHSU Principal Investigator Julie Graff. PCCTC 
will report SAEs to the OHSU IRB according to the policies, procedures and guidelines 
posted on the OHSU IRB web site: http://www.ohsu.edu/research/rda/irb/policies.shtml. 
SAEs should be reported to PCCTC and Principal Investigator Julie Graff within 24 hours of 
knowledge via email (pcctc@mskcc.org; graffj@ohsu.edu). The PCCTC SAE Report form 
(Appendix K) must be completed and emailed to the PCCTC within 5 working days of 
knowledge of the event. Copies of the report documents will be kept in the study regulatory 
binder. 
SAEs are submitted through OHSU e-IRB and will be reviewed by OHSU Knight Cancer 
Institute and IRB. Monthly accumulative reports will be generated by PCCTC, reviewed by 
a DSMC Oncologist and forwarded to the CRRC. 
 
If applicable, PCCTC will report SAEs to the FDA using the PCCTC SAE Report form. 
When the serious adverse event is reported to the FDA, copies of the PCCTC SAE Report 
form and supporting materials will be submitted to the OHSU IRB and the OHSU Drug 
Information Service. A copy of the PCCTC SAE Report form and supporting materials will 
be kept on file in the study regulatory binder. 
 
10.7 
Astellas Safety Reporting 
 
All serious adverse events, as defined above, need to be reported to the PCCTC via email 

37 
 
(pcctc@mskcc.org) and OHSU Principal Investigator, Julie Graff, MD, within 24 hours. She 
can be reached at 503-220-8262 x 55688; paged through the OHSU operator at 503-494- 
9000; or, emailed at graffj@ohsu.edu. 
 
PCCTC will report the SAE to Astellas as instructed below. 
 
The SAE documentation, including the PCCTC SAE Report Form and available source 
records should be emailed or faxed to: Astellas Pharma Global Development – United 
States 
 
Email: Safety-us@us.astellas.com 
Fax number: (847) 317-1241 
 
The following minimum information is required: 
• Study number/IIT regulatory identifier 
• Subject number, sex and age 
• The date of report 
• A description of the SAE (event, seriousness of the event) 
• Causal relationship to the study drug 
 
Follow-up information for the event should be sent promptly (within 7 days) as 
necessary. 
 
10.8 
Sanofi Safety Reporting 
 
As in the case of the Astellas reporting, Sanofi reporting will be done by the PCCTC. All 
serious events, as defined above, need to be reported to Sanofi by PCCTC. 
 
The PCCTC must report the following information in English to the Sanofi group entity 
Pharmacovigilance contact: 
1. Routine transmission of: 
All Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI), if 
any. These events must be transmitted within 24 hours of the Investigator’s awareness 
or identification of the event. 
Results of any relevant complementary exams performed to obtain the final diagnosis of 
any SAE (e.g., hospital discharge summary, autopsy, consultation) will be made 
available to Sanofi group entity upon request. 
 
2. Other events or periodic reports (e.g. Development Safety Update Report (DSUR)), 
submitted to Regulatory Authority must be transmitted at the time of submission. 
 
3. Other significant safety issues or findings in a study pertaining to safety of product 
must be transmitted within 1 working day to the Sanofi GPE. (e.g., Data Safety 
Monitoring Board recommendations). 
 
4. The study report of any IST/ISS must contain a section describing safety review and 
conclusion. 

38 
 
5. The reference safety information to be used by the IST/ISS sponsor for evaluation of 
expectedness of adverse events shall be the Investigator Brochure. 
 
 
SANOFI GROUP ENTITY PHARMACOVIGILANCE CONTACT 
 
Fax/email of SAE Reports to Sanofi: 
 
IST/ISS Investigators will notify sanofi via fax or email, attention Sanofi Pharmacovigilance (PV): 
 
Fax: 908-203-7783 
E-mail: USPVmailbox@sanofi-aventis.com. 
 
 
10.9 
Roles and Responsibilities 
 
Sponsor Investigator 
The Sponsor Investigator is responsible for performing the following tasks: 
 Responsibility for the overall conduct of the study at all participating sites and for 
monitoring the progress of the study 
 Ensuring that the study will be performed in compliance with all applicable local and 
international laws and regulations including without limitation ICH E6 guidelines for 
Good Clinical Practice 
 Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 
 Reviewing data from all participating sites 
 
PCCTC 
The PCCTC is responsible for performing the following tasks: 
 Ensuring that IRB approval has been obtained at each participating site prior to the first 
patient registration at that site, and maintaining copies of IRB approvals and required 
regulatory documents from each site 
 Managing subject registration 
 Developing and maintaining Clinical Data Management documents and procedures 
 CRF development, setup of study database, and subsequent design changes 
 Participating in review of content of the CRF against the protocol requirements 
 EDC system administration (user/site accounts setup, maintenance and revocation) 
 Data review, cleaning, query management and resolution 
 Establishing procedures for documentation, reporting and submitting of AE’s and SAE’s 
to the PCCTC 
 Reviewing Serious Adverse Events (SAEs) 
 Ensuring submission of required expedited and periodic reports to the appropriate 
Health Authority (HA), the Ethics Committee and investigators of each country 
participating in the IST/ISS (based on applicable regulations) 
 Providing any “Dear Investigator Letter” (DIL) for new safety finding received from 
Sanofi group entity to the investigators and Ethics Committee in each country 
participating in the study 
 Training participating sites on EDC 
 Collecting and compiling data from each participating site 
 Data reviewing from all participating sites 

39 
 
 Facilitating monitoring visits by securing selected source documents and research 
records from participating sites for review, or by on-site monitoring at participating sites 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
 Following the protocol as written, the guidelines of Good Clinical Practice (GCP), and 
applicable Standard Operating Procedures (SOPs) 
 Registering all patients with the PCCTC by submitting the eligibility checklist, supporting 
source documentation, and signed informed consent promptly 
 Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol 
 Maintaining regulatory binders on site and providing copies of all required documents to 
the PCCTC 
 Collecting and submitting data according to the schedule specified by the protocol 
 Responding to queries in a timely manner 
 
 
10.10 OHSU Knight Cancer Institute Data and Safety Monitoring Plan 
 
In addition to complete study and pharmacy files, complete records must be maintained on 
each patient treated on this protocol. Study specific Electronic Case Report Forms (eCRFs) 
will document safety and treatment outcomes for safety monitoring and data analysis. All 
study data will be entered into PCCTC Caisis EDC via standardized eCRFs in accordance 
with the CDMS study calendar, using single data entry with a secure access account. The 
Clinical Research Coordinator (CRC) will complete the eCRFs as soon as possible upon 
completion of the study visit; the Investigator will review and approve the completed  
eCRFs. OHSU Knight Cancer Institute (CI), CRM shared resource is responsible for 
ensuring that all member investigators and affiliate investigators conduct clinical research 
studies in compliance with local IRB standards, FDA regulations and NIH policies. The 
Data and Safety Monitoring Committee (DSMC) is responsible for conducting Quality 
Assurance audits on CI approved protocols according to the Data and Safety Monitoring 
Plan policies and procedures http://ohsucancer.com/crm.  PCCTC will generate audit 
reports and provide to Principal Investigator Julie Graff for submission to the DSMC. 
 
Regularly scheduled registration reports will be generated by the PCCTC to monitor subject 
accruals and the completeness of registration data. Routine data quality reports will be 
generated to assess missing data and inconsistencies. Accrual rates and the extent and 
accuracy of evaluations and follow-up will be monitored periodically throughout the study 
period, and potential problems will be brought to the attention of the Principal Investigator 
for discussion and action. 
Each site participating in the accrual of participants to this protocol will be monitored by the 
PCCTC on behalf of the OHSU Knight CI DSMC audit team. Visits will be performed at 
least once a year, for protocol and regulatory compliance, data verification and source 
documentation. Newly approved studies may be monitored any time after enrollment. 
Monitoring visits may be accomplished in one of two ways: (1) sending source documents 
and research records for selected patients from participating sites to the PCCTC for review, 
or (2) on-site monitoring of selected patient records at participating sites. 
Visits will usually be determined by participant accrual numbers and rate of accrual, but can 
also be prompted by reported SAEs or request of sponsor investigator. 

40 
 
Monitoring will be conducted at least once shortly after initiation of subject recruitment at a 
site, annually during the study (or more frequently if indicated based on the approved 
Monitoring Plan), and at the end or closeout of the trial. The number of subjects reviewed 
will be determined by available time and the complexity of the protocol. 
 
The visit will include a review of source documentation to evaluate compliance for: 
 
 Informed consent documents and procedures 
 Adherence to eligibility criteria 
 Protocol defined treatment 
 Required baseline, on study and follow-up protocol testing 
 IRB  documents  (submitted  amendments,  annual  continuing  review  reports, 
SAEs) 
 eCRF completion 
 
All clinical work conducted under this protocol is subject to Good Clinical Practice (GCP) 
guidelines. This includes inspection of study-related records by the lead site, sponsor, its 
designee, or health authority representatives at any time. 
Audits may be conducted by the lead site at any time and will be facilitated by the PCCTC. 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1 Study Design 
 
This is a Phase I/II clinical trial to determine the dose for cabazitaxel (choose between 25 
mg/m2 and 20 mg/m2) when combined with enzalutamide and to assess the treatment effect 
of the study drugs in men with metastatic CRPC. 
 
The Phase I stage of the study is composed of 3-12 patients. The trial will proceed to Phase II 
stage at the dose of 25 mg/m2 if 0/3 or 0-1/6 patients receiving 25 mg/m2 had DLT. The dose 
de-escalation will happen if ≥2/3 or ≥2/6 patients receiving 25 mg/m2 had DLT. The trial will 
proceed to Phase II stage at the dose of 20 mg/m2 if 0/3 or 1/6 patients receiving 20 mg/m2 
had DLT. Otherwise, the trial will not proceed to Phase II stage. Since DLTs within the first 2 
cycles are used for dose consideration, those who receive less than 2 cycles, and did not have 
a DLT, will not be used for dose consideration. The requirement for moving on to the Phase II 
portion requires adequate evaluable patients. For example, at least 3 evaluable patients (i.e. 
those who have received at least 2 cycles) are needed if there are no DLTs at full dose prior to 
moving on to the phase II portion. Efficacy will be assessed for all subjects in the Phase I 
stage, and those who received the same dosage as was given to patients in phase II stage will 
be included for efficacy analysis as well. 
 
The Phase II stage will assess both efficacy (reflected by PSA change) and toxicity (reflected 
by the percentage of patients who had DLT). However, the definition of DLT differs slightly for 
Phase I stage and Phase II stage (see section 8.3 for more details). 
 
We anticipate a low dropout rate because we have low dropout rates in other studies and have 
very motivated patients, and we will not replace patients who drop out. 

41 
 
11.2 Primary and Secondary Endpoints 
 
11.2.1 
Primary Endpoints: 
DLT, as defined in Section 8 
PSA response 1, defined as ≥90% PSA decline from baseline. This analysis will 
be performed when the final patient has PSA progression, where the final patient 
refers to the final patient to have a PSA progression, not the last patient enrolled. 
 
11.2.2 
Secondary Endpoints 
Adverse events will be collected continuously 
PSA response 2, defined as ≥50% PSA decline from baseline. Will be 
determined when the primary endpoint is analyzed. 
PSA response 3, defined as ≥30% PSA decline from baseline. Will be 
determined when the primary endpoint is analyzed. 
PK measurements 
Overall survival 
 
11.3 Analysis Population 
 
Patients with metastatic CRPC. In the phase I portion, only patients receiving 2 or more cycles 
will be evaluable for DLT. In the phase I and II portions, patients who receive at least one cycle 
will be evaluable for safety and efficacy outcomes. 
 
11.4 Statistical Analysis Plan 
 
Descriptive statistical analysis will be conducted for all primary and secondary endpoints. The 
proportion estimate will be reported with 95% confidence interval using exact method. One- 
sample binomial test will be used to assess whether the proportion of response 1 is 
significantly different from 0.25. As an exploratory subgroup analysis, the various PSA 
response rates will be estimated in two subgroups that either received prior abiraterone or had 
not received prior abiraterone. The median overall survival will be estimated with 95% 
confidence interval (if available). Kaplan-Meier plot will be used to graphically illustrate the 
overall survival distribution. 
 
Individual and mean plasma concentration data will be plotted over time for cabazitaxel alone 
(Day 1, Cycle 1) and for cabazitaxel co-administered with enzalutamide (Day 1, Cycle 2). 
Non-compartmental PK analysis will be performed on individual concentration-time data to 
calculate PK parameters, including, but not limited to Cmax, AUC0-tlast, AUC0-∞, and half-life, 
for cabazitaxel administered alone or co-administered with enzalutamide. Descriptive 
statistics will be presented for plasma PK parameters. 
 
11.5 Sample size and Power 
 
As stated in Section 11.1, we expect to include 3-12 patients to the Phase I stage of the 
study. Based on the dose de-escalation rules specified in the protocol, we could have at least 
33 subjects who receive same dosage as determined for phase II stage, if the trial is not 
stopped early for excessive toxicity. For the efficacy analysis, we take into account existing 
data on rates of PSA decline in similar patient populations from earlier randomized control 
trials. Treatment with 160 mg of enzalutamide daily resulted in 24.8% of patients achieving a 
≥90% PSA decline in the post-docetaxel setting, as demonstrated in the Phase III AFFIRM 

42 
 
trial.11 Based on these results, the null hypothesis to be tested is that 25% of patients will 
achieve a ≥90% reduction in serum PSA, and the alternative assumption is that 50% of 
patients will achieve at least a 90% reduction in serum PSA. A total of 33 subjects will achieve 
82% power using one sample binomial method for a 2-sided alpha of 0.05. That means we will 
have at least 82% power for efficacy analysis, with higher potential in power depending on the 
findings in the phase I stage. 
 
 
11.6 Early Stopping Rule 
 
The trial will be terminated at Phase I stage if none of the two doses of cabazitaxel is 
determined to be adequately safe (see more details in Section 11.1). However, as the trial 
may proceed to Phase II stage with only 3-12 patients in the phase I stage, we propose an 
interim analysis for safety in the middle of Phase II study. The trial will be stopped due to 
safety consideration if ≥8 patients in the first 20 patients in the Phase II cohort had a DLT as 
defined in Section 8.3. This stopping rule will ensure that the trial be stopped early at 87% 
chance if the probability of having DLT is 50%. On the other hand, if the combination of drugs 
is safe (with chance of DLT = 20%), there is only 3% chance that the trial will be stopped 
early. 

43 
 
REFERENCES 
 
1. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for 
metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised 
open-label trial. Lancet 2010;376:1147-54. 
 
2. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant 
prostate cancer: a phase 1-2 study. Lancet 2010;375:1437-46. 
 
3. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after 
chemotherapy. The New England journal of medicine 2012;367:1187-97. 
 
4. Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate 
demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior 
ketoconazole therapy. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2010;28:1481-8. 
 
5. Wright JL, Kwon EM, Ostrander EA, et al. Expression of SLCO transport genes in castration- 
resistant prostate cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate 
cancer outcomes. Cancer epidemiology, biomarkers & prevention : a publication of the American 
Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 
2011;20:619-27. 
 
6. Mostaghel EA, Marck BT, Plymate SR, et al. Resistance to CYP17A1 inhibition with abiraterone in 
castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice 
variants. Clinical cancer research : an official journal of the American Association for Cancer 
Research 2011;17:5913-25. 
 
7. Mitchell PS, Parkin RK, Kroh EM. Circulating microRNAs as stable blood-based markers for 
cancer detection. Proceedings of the National Academy of Sciences of the United States of America 
2008;105:10513-8. 
 
8. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from 
treatment in metastatic castration-resistant prostate cancer. Clinical cancer research : an official 
journal of the American Association for Cancer Research 2008;14:6302-9. 
 
9. Goodman OB, Jr., Symanowski JT, Loudyi A, Fink LM, Ward DC, Vogelzang NJ. Circulating tumor 
cells as a predictive biomarker in patients with hormone-sensitive prostate cancer. Clinical 
genitourinary cancer 2011;9:31-8. 
 
10. Flemming MT, Rathkopf DE, Gibbons J, et al. Enzalutamide in combination with docetaxel in men 
with prostate cancer (PC): Preliminary results from a phase I study. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2013;Suppl 6:abstr 63. 

44 
 
11. Scher HI, Fizazi K, Saad F, et al. Effect of MDV3100, an androgen receptor signaling inhibitor 
(ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III 
AFFIRM study. Journal of Clinical Oncology 2012;30:LBA1. 

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

B 
 
APPENDIX B 
 
 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
 
 
Toxicities and adverse events will be assessed using the NCI Common Toxicity Criteria for Adverse 
Events v4.0 (CTCAE). Since CTEP has standardized the CTCAE, the NCI does not require the 
inclusion of the CTCAE within the protocol document. A copy can be downloaded from the CTEP 
home page http://ctep.cancer.gov/reporting/ctc.html 

APPENDIX C: LIST OF POTENT CYP3A INHIBITORS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c 

D 
 
APPENDIX D: LIST OF INDUCERS BY CYP3A ISOENZYMES 
 
 
 
 
Amobarbital 
Carbamazepine 
Dexamethasone 
Efavirenz 
Modafinil 
Nevirapine 
Norethindrone 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Primidone 
Rifabulin 
Rifampin 
Rifampicin 
Rifapentin 
Ritonavir 
Secobarbital 
St John's Wort 
Troglitazone 
 
 
Referenced using University of Washington database (May 207) 

E 
 
APPENDIX E: KNOWN SUBSTRATES OF CYP 2C19, 2C8, 2C9, 3A4 
 
Comprehensive list of agents known to be substrates of CYP 2C19 
Generic name 
Trade name 
Amiodarone Hydrochloride 
Cordarone, Cordarone IV, Pacerone 
Amitriptyline Hydrochloride 
Clordiazepoxide/ Amitriptyline 
Elavil, Vanatrip 
Limbitrol, Limbitrol DS 
Aprepitant 
Emend 
Atomoxetine Hydrochloride 
Strattera 
Azelastine Hydrochloride 
Astelin, Astelin Ready-Spray, Optivar 
Bortezomib 
Velcade 
Bupivacaine Hydrochloride 
Marcaine HCl, Marcaine Spinal, Sensorcaine, 
Sensorcaine-MPF 
Carisoprodol 
Soma, Vanadom 
Cilostazol 
Pletal 
Citalopram Hydrobromide 
Celexa 
Clomipramine Hydrochloride 
Anafranil 
Clozapine 
Clozaril, FazaClo 
Cyclophosphamide 
Cytoxan, Cytoxan Lyophilized, Neosar 
Dapsone 
Aczone 
Desogestrel/ Ethinyl Estradiol 
Apri, Cesia, Cyclessa, Desogen, Ortho-Cept, 
Solia, Velivet, Reclipsen 
Dextromethorphan Hydrobromide 
 
 
Dextromethorphan Hydrobromide/ 
Guaifenesin/Potassium   Guaiacolsulfonate 
Robitussin, Pediacare, Vicks 44 Cough Relief, 
Creomulsion, Dexalone, Hold DM, Babee Cof 
Syrup, Benylin Pediatric Formula 
Humibid DM 
Diazepam 
Diastat, Diastat Pediatric, Diazepam Intensol, 
Valium 
Diclofenac Potassium 
Diclofenac Sodium 
Diclofenac Sodium/Misoprostol 
Cataflam 
Solaraze, Voltaren, Voltaren-XR 
Arthrotec 
Escitalopram Oxalate 
Lexapro 
Esomeprazole Magnesium 
Esomeprazole Sodium 
Nexium 
Nexium I.V. 
Estradiol 
Alora, Climara, Esclim, Estrace, Estraderm, 
Estrasorb, Estring, EstroGel 
Estrogens, conjugated 
A/synthetic 
Cenestin 
Estrogens, conjugated 
Equine 
Premarin 
Fluoxetine Hydrochloride 
Fluoxetine Hydrochloride/Olanzapine 
Prozac, Prozac Weekly, Sarafem, Rapiflux 
Symbyax 

 
Formoterol Fumarate 
Budesonide/Formoterol 
Foradil Aerolizer 
Symbicort 
Fosphenytoin Sodium 
Cerebyx 
Ibuprofen 
Advil, Motrin, A-G Profen, Addaprin, Bufen, 
Genpril, Haltran, I-Prin 
Ifosfamide 
Ifex 
Imatinib Mesylate 
Gleevec 
Imipramine Hydrochloride 
Imipramine Pamoate 
Tofranil 
Tofranil-PM 
Indomethacin 
Indocin, Indocin SR 
Lansoprazole 
Lansoprazole/Naproxen 
Prevacid, Prevacid I.V., Prevacid SoluTab 
Prevacid NapraPAC 
Meperidine Hydrochloride 
Demerol, Meperitab 
Mephenytoin 
Mesantoin 
Mephobarbital 
Mebaral 
Methadone Hydrochloride 
Dolophine, Methadone HCl Intensol, Methadose 
Methsuximide 
Celontin Kapseals 
Hydrochlorothiazide/ Metoprolol 
Succinate 
Metoprolol Succinate 
Metoprolol Tartrate 
Dutoprol 
 
Toprol-XL 
Lopressor 
Nelfinavir Mesylate 
Viracept 
Nicotine 
Nicotine Polacrilex 
Habitrol, Nicoderm CQ, Nicotrol, Nicotrol 
NSCommit, Nicorette, Nicorelief 
Nilutamide 
Nilandron 
Nortriptyline Hydrochloride 
Aventyl, Pamelor 
Omeprazole 
Omeprazole/Sodium Bicarbonate 
Prilosec, Prilosec OTC 
Zegerid 
Pantoprazole Sodium 
Protonix 
Pentamidine Isethionate 
Nebupent, Pentam 
Perphenazine 
Trilafon 
Phenobarbital Sodium 
Luminal 
Phenytoin 
Dilantin, Dilantin Kapseals, Dilantin Infatabs, 
Dilantin-125, Phenytek 
Progesterone 
Crinone, Prochieve, Prometrium, Progestasert, 
Gesterol 50 
Atovaquone/Proguanil Hydrochloride 
Malarone, Malarone Pediatric 
Propofol 
Diprivan 
Propranolol Hydrochloride 
Inderal, Inderal LA, InnoPran XL, Propranolol 
HCl Intensol 
Quinine 
Formula Q 
Rabeprazole Sodium 
Aciphex 
Ranitidine Hydrochloride 
Zantac, Zantac 150, Zantac 150 Efferdose, Zantac 
25, Zantac 300, Zantac 75, Taladine 
Sertraline Hydrochloride 
Zoloft 
 
F 

 
Testosterone 
Androderm, Androgel, Striant, Testim, Testro AQ 
Thioridazine Hydrochloride 
Mellaril 
TOLBUTamide 
Tol-Tab 
Tolterodine Tartrate 
Detrol, Detrol LA 
Trimethadione 
Tridione 
Trimipramine Maleate 
Surmontil 
Valproic acid 
Depakene 
Venlafaxine Hydrochloride 
Effexor, Effexor-XR 
Voriconazole 
Vfend, Vfend I.V. 
Warfarin Sodium 
Coumadin, Jantoven 
Abacavir Sulfate/Lamivudine/ 
Zidovudine 
Lamivudine/ Zidovudine 
Zidovudine 
Trizivir 
 
Combivir 
Retrovir 
Zolpidem Tartrate 
Ambien, Ambien CR 
Zonisamide 
Zonegran 
 Bolded agents are narrow therapeutic index agents due to individual drug therapeutic 
concentrations or the serious nature of their therapeutic use. Please note that other agents should 
still be reviewed with the prescribing physician as their therapeutic effect may be diminished in a 
clinically significant manner. 
 
Known Substrates of 2C8: Generic name (Brand name): Drugs with a narrow therapeutic index 
are in BOLD font. 
Acenocoumarol (Sintrom) 
Amiodarone (Cordarone, Cordarone IV, Pacerone) 
Dasabuvir (Exviera) 
Paclitaxel (Taxol) 
Pioglitazone (Actos) 
Repaglinide (Prandin) 
Rosiglitazone (Avandia) 
Tretinoin (Retin - A, Avita, Renova) 
 
Known Substrates of 2C9: Generic name (Brand name): Drugs with a narrow therapeutic index 
are in BOLD fold. 
Bosentan (Tracleer) 
Carvedilol (Coreg) 
Celecoxib (Celebrex) 
Dapsone (Aczone) 
Fluoxetine (Prozac, Prozac Weekly, Sarafem, Rapiflux) 
Fluvastatin (Lescol, Lescol XL) 
Fosphenytoin (Cerebyx) 
Fospropofol (Lusedra) 
Glimepiride (Amaryl) 
Glipizide (Glucotrol) 
Ketamine (Ketalar) 
Losartan (Cozaar) 
Mestranol (Necon 1/50, Norinyl 1+50, Ortho-Novum 1/50) 
Montelukast (Singulair) 
 
G 

Nateglinide (Starlix) 
Paclitaxel (Taxol) 
Phenytoin (Dilantin) 
Propofol (Diprivan) 
Sulfadizine (Silvadene) 
Sulfamethoxazole (Bactrim, Septra) 
Tamoxifen (Nolvadex, Soltamox) 
Tolbutamide (Tol-Tab) 
Torsemide (Demadex) 
Trimethoprim (Bactrim) 
Voriconazole (Vfend, Vfend I.V.) 
Warfarin (Coumadin, Jantoven) 
Zafirlukast (Accolate) 
 
Known Substrates of 3A4: Generic name (Brand name): Drugs with a narrow therapeutic index 
are in BOLD fold. 
Alfentanil (Alfenta, Rapifen) 
Alfuzosin (Uroxatral) 
Alprazolam (Xanax, Xanax XR, Niravam) 
Ambrisentan (Letairis) 
Amiodarone (Cordarone, Cordarone IV, Pacerone) 
Amlodipine (Norvasc) 
Aprepitant (Emend) 
Aripiprazole (Abilify) 
Armodafinil (Nuvigil) 
Atazanavir (Reyataz) 
Atorvastatin (Lipitor) 
Benzphetamine (Didrex) 
Bisoprolol (Zebeta) 
Bortezomib (Velcade) 
Bosentan (Tracleer) 
Bromazepam (Lectopam, Lexotan, Lexilium, Lexaurin, Brazepam, Rekotnil, Bromaze, Somalium, Lexotanil) 
Bromocriptine (Cycloset) 
Budesonide (Entocort EC, Uceris, Symbicort, Rhinocort Aqua) 
Buprenorphine (Butrans, Buprenex) 
Buspirone (Buspar)  
Busulfan (Myleran, Busulfex) 
Carbamazepine (Tegretol, Equetro) 
Chlordiazepoxide (Limbitrol, Limbitrol DS) 
Chloroquine (Aralen) 
Chlorpheniramine (Chlor-Tabs, Aller-Chlor) 
Ciclesonide (Alvesco, Omnaris) 
Cilostazol (Pletal) 
Cisapride (Propulsid) 
Citalopram (Celexa) 
Clarithromycin (Biaxin) 
Clobazam (Onfi) 
Clonazepam (Klonopin) 
Clorazepate (Tranxene, Novo-Clopate) 
Cobicistat (Tybost) 
H 

Cocaine 
Colchicine (Colcrys) 
Conivaptan (Vaprisol) 
Cyclophosphamide (Cytoxan, Cytoxan Lyophilized, Neosar) 
Cyclosporine (Sandimmune) 
Dantrolene (Dantrium) 
Dapsone (Aczone) 
Darifenacin (Enablex) 
Darunavir (Prezista) 
Dasantinib (Sprycel) 
Delavirdine (Rescriptor) 
Dexamethasone (Decadron, Ozurdex, Baycadron) 
Dexlansoprazole (Kapidex, Dexilant) 
Diazepam (Diastat, Diastat Pediatric, Diazepam Intensol, Valium) 
Dihydroergotamine (Migranal) 
Diltiazem (Cardizen) 
Disopyramide (Norpace, Rythmodan) 
Docetaxel (Taxotere) 
Doxorubicin (Adriamycin, Doxil) 
Efavirenz (Sustiva, Stocrin, Efavir) 
Eletriptan (Relpax) 
Eplerenone (Inspra) 
Ergoloid mesylates (Hydergine) 
Ergonazine 
Ergotamine (Ergomar) 
Erlotinib (Tarceva) 
Erythromycin (Ery-tab, Ilotycin, Eryc, Akne-mycin, T-Stat, Ery, Erythra-Derm) 
Escitalopram (Lexapro) 
Esomeprazole (Nexium) 
Estradiol (Alora, Climara, Esclim, Estrace, Estraderm, Estrasorb, Estring, EstroGel) 
Estrogens (Apri, Cesia, Cyclessa, Desogen, Cenestin, Ortho-Cept, Premarin Solia, Velivet, Reclipsen) 
Estropipate (Ogen) 
Eszopiclone (Lunesta) 
Ethinyl estradiol (Apri, Reclipsen, Kariva, Azurette, Yaz, Yasmin, Ocella, Gianvi, Beyaz, Safyral Zovia, 
Demulen, Zovia 1/35, Kelnor 1/35, Nuva ring) 
Ethosuximide (Zarontin) 
Etoposide (Toposar, VePesid, Etopophos) 
Exemestane (Aromasin) 
Felbamate (Felbatol) 
Felodipine (Plendil) 
Fentanyl (Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis, Instanyl, Abstral Lazanda) 
Flunisolide (Aerobid, Aerospan, Nasarel, Aerobid-M) 
Flurazepam (Dalmane, Dalmadorm) 
Flutamide (Eulexin, Flutamin, Cytomid, Chimax, Drogenil) 
Fluticasone (Flonase) 
Fosamprenavir (Lexiva) 
Fosaprepitant (Emend) 
Gefitinib (Iressa) 
Haloperidol (Haldol) 
Ifosfamide (Ifex) 
I 

Imatinib (Gleevec) 
Indinavir (Crixivan) 
Irinotecan (Camptosar) 
Isosorbide dinitrate and mononitrate (Monoket) 
Isradipine (DynaCirc, Prescal) 
Itraconazole (Sporanox, Onmel) 
Ixabepilone (Ixempra) 
Ketamine (Ketalar) 
Ketoconazole (Nizoral, Xolegel, Extina) 
Lansoprazole (Prevacid, Prevacid I.V., Prevacid SoluTab) 
Lapatinib (Tykerb) 
Levonorgestrel (Mirena) 
Lidocaine (Xylocaine, Recticare, Solarcaine, Xylocaine-MPF, Anecream) 
Lopinavir (component of Kaletra) 
Losartan (Cozaar) 
Lovastatin (Mevacor) 
Marviroc (Selzentry) 
Medroxyprogesterone (Depo-Provera, Provera) 
Mefloquine (Lariam) 
Mestranol (Nelova 1/50 M, Necon 1/50, Ortho-Novum 1/50, Genora 1/50) 
Methadone (Dolophine, Methadone HCl Intensol, Methadose) 
Methylergonovine (Methergine) 
Methylprednisolone (Medrol, A-Methapred, Hybrisil, Depo-Medrol, Solu-Medrol) 
Micronazole (Zeasorb, Micatin, Oravig, Monistat-derm, Azolen, Conazol) 
Midazolam (Dormicum, Hypnovel, Versed) 
Mirtazapine (Avanza, Axit, Mirtaz, Mirtazon, Remeron, Zispin) 
Modafinil (Provigil) 
Montelukast (Singulair) 
Nateglinide (Starlix) 
Nefazodone (Dutonin, Nefadar, Serzone) 
Nelfinavir (Viracept) 
Nevirapine (Viramune) 
Nicardipine (Cardene) 
Nifedipine (Adalat CC, Procardia) 
Nilotinib (Tasigna) 
Nimodipine (Nimotop) 
Nisoldipine (Sular) 
Norethindrone (Aygensin, Jolivette, Miconor, Errin, Heather) 
Norgestrel (Cryselle 28, Lo/Ovral-28, Low-Ogestrel, Ogestrel-28) 
Omeprazole (Prilosec, Prilosec OTC, Zegerid) 
Ondansetron (Zofran, Zuplenz) 
Paclitaxel (Taxol, Onxal, Abraxane) 
Paricalcitol (Zemplar) 
Paritaprevir (found in Viekira Pak) 
Pazopanib (Votrient) 
Pimozide (Orap) 
Primaquine (generic only) 
Progesterone (Crinone, Prochieve, Prometrium, Progestasert, Gesterol 50) 
Quazepam (Doral, Dormalin) 
Quetiapine (Seroquel, Seroquel XR) 
J 

K 
 
Quinidine (Quin-G, Cardioquin, Quinora, Quinidex Extentabs, Quinaglute Dura-Tabs, Quin-Release) 
Quinine (Formula Q) 
Rabeprazole (Aciphex) 
Ranolazine (Ranexa) 
Repaglinide (Prandin) 
Rifabutin (Mycobutin) 
Ritonavir (Norvir) 
Salmeterol (Serevent) 
Saquinavir (Invirase, Fortovase) 
Sibutramine (Meridia) 
Sildenafil (Viagra) 
Simvastatin (Zocor) 
Sirolimus (Rapamune) 
Solifenacin (Vesicare) 
Spiramycin (Rovamycine) 
Sufentanil (Sufenta) 
Sunitinib (Sutent) 
Tacrolimus (Protopic, Hecoria) 
Tadalafil (Adcirca, Cialis) 
Tamoxifen (Nolvadex, Soltamox) 
Tamsulosin (Flomax) 
Telithromycin (Ketek) 
Temsirolimus (Torisel) 
Teniposide (Vumon) 
Tetracycline (Acnecycline, Dyabetex, Diabecline, Tetra-abc) 
Theophylline (Respbid, Slo-Bid, Theo-24) 
Tiagabine (Gabitril) 
Ticlopidine (Ticlid) 
Tinidazole (Tindamax) 
Tipranavir (Aptivus) 
Tolterodine (Detrol, Detrol LA) 
Toremifene (Fareston) 
Tramadol (Ultram, Conzip, Rybix ODT, and Ultram ER) 
Trazodone (Oleptro) 
Triazolam (Apo-Triazo, Halcion, Hypam, and Trilam) 
Trimethoprim (Proloprim, Primsol) 
Trimipramine (Surmontil, Rhotrimine, Stangyl) 
Vardenafil (Levitra) 
Venlafaxine (Effexor, Effexor-XR) 
Verapamil (Calan, Verelan, Verelan PM, Isoptin, Covera-HS) 
Vinblastine (Alkaban-AQ, Velban) 
Vincristine (Oncovin) 
Vinorelbine (Navelbine) 
Zolpidem (Ambien, Ambien CR) 
Zonisamide (Zonegran) 
Zopiclone (Zimovane and Imovane) 

L 
 
Appendix F Suggestions of protocols of intra-venous hydration for CT-scan 
with contrast (1), (2) 
 
Intra-venous hydration at the time of CT-scan with contrast is recommended when creatinine 
clearance <60 mL/min. 
Step 1: identify the population at risk: 
- all patients with an eGFR<60 ml/min/1.73 m³, 
- especially in diabetic and cardiovascular patients with eGFR<60 ml/min/1.73m². 
(PS: eGRF is the estimated GFR from the EPI formula). 
Step 2: stop NSAID the day before and the day of the radiocontrast examination and make sure 
that the patient is well hydrated (eventually diuretics "on hold" and additional fluid intake is advised 
- if medically possible) 
Step 3 (advisable, not obligatory): the day before and the day of the radiocontrast examination, 
the patient is taking acetylcysteine 600 mg x 2 orally 
Step 4: (write down for your radiologist to) use the lowest possible volume of (iso-/low-osmolar) 
radiocontrast. 
Step 5: before the contrast examination IV fluid is started; oral hydration is not sufficient. 
A/ Radiocontrast kidney injury prevention with isotonic NaCl 0.9%: 
Prehydratation: IV NaCl 0.9% at 1 ml/kg/h during 12h before radiocontrast and during the 
radiocontrast examination 
Posthydratation: continue IV same NaCl 0.9% at 1 ml/kg/h during 12h. 
 
OR 
 
B/ Radiocontrast kidney injury prevention with isotonic NaHCO3: 
Prehydratation: prepare IV 850 ml GLU 5% + 150 mEq NaHCO3 and infuse at 3.5 ml/kg/h during 
1h before radiocontrast and during the radiocontrast examination. 
Posthydratation: IV same preparation 850 ml GLU 5% + 150 mEq NaHCO3 at 1 ml/kg/h during 6h. 
 
OR 
C/ Alternative scheme in case of "URGENT - Emergency" radiocontrast administration: IV NaCl 
0.9% at 3 ml/kg/h during 1 h before and during the radiocontrast examination; continue IV NaCl 
0.9% for 6-12h at 1 ml/kg/h after the radiocontrast examination. (PS: 6 h post only in patients in 
whom a sustained volume expansion is not possible). 
 
 
(1) Weisbord S., Palevsky P. Prevention of contrast-induced nephropathy with volume expansion. 
Clin J Am SocNephrol. 2008;3:273-80. 
(2) KDIGO guidelines on contrast media induced AKI (To be published in 2011) 

M 
 
A P P E N D I X G : F R E S H T U M O R B I O P S Y I N F O R M A L I N ( t o b e s e n t t o O H S U ) 
 
Supplies and Materials 
 
 Requisition form 
 One “Fresh tumor biopsy in formalin” label 
 One container of 10% neutral-buffered formalin 
 One container of 70% ethanol 
 
Sample Preparation, Collection and Processing 
 
1. Fill out the requisition form. 
2. Place the "Fresh tumor biopsy in formalin" label on the 10% neutral-buffered formalin 
container. 
3. Collect the core needle biopsy per institutional procedure. Cores #1, 3 and 5 to be combined 
and placed in single container. 
 
4. Immediately dispense (within one minute of being taken) the core needle biopsy into the 
container with 20-30 ml of 10% neutral-buffered formalin. The date and time taken must also 
be recorded so that the total fixation time can be assessed. Please record the date/time of 
biopsy, total fixation time, biopsy location, and primary tumor details on the requisition form. 
5. Allow the biopsy to incubate in the 10% formalin container at room temperature for 16-24 
hours. 
6. Transfer the biopsy to aliquot with 70% ethanol (20-30 ml) to be stored at room temperature 
and shipped to the Histopathology Shared Resource of the Knight Cancer Institute/OHSU. 
Do not ship on Friday. 
 
Shipping of Formalin-fixed biopsies 
Shipping address: 
 
Attn: Joscelyn Zarceno/Jenny Miller 
Histopathology Shared Resource 
Knight Cancer Institute 
Oregon Health and Science University 
Marquam Plaza 
2525 SW 3rd Ave, Room 235 
Portland, OR 97201 
Telephone: (503) 494-9631 
Fax: (503) 494-9649 

N 
 
A P P E N D I X H : C I R C U L A T I N G T U M O R C E L L S ( t o b e s e n t t o O H S U * ) 
COLLECTION OF BLOOD SAMPLES 
At each time point, the blood sample will be drawn in  a  Rarecyte collection tube. Samples will 
then be processed as described below, labeled and shipped same day. 
 
Rarecyte Tube (for CTC) Collection 
In each tube, at least 7.5 mL of peripheral blood will be collected. It is essential that the tubes 
are filled completely in order to be processed for CTC. After collection, the tube must be 
inverted eight times to prevent clotting and then can be stored at room temperature. Rarecyte 
collection tubes will be provided by OHSU.  
 
 
**It is essential that both sets of tubes are filled as instructed and shipped at room temperature on the 
same day.  
 
**Note: DO NOT SPIN OR FREEZE THE TUBES 
SHIPPING OF BLOOD SAMPLES 
Shipping reservations must be made to allow delivery within 24 hours, prior to 2:00 PM next day. The 
blood samples should be shipped on the same day of the collection to the Prostate Cancer 
Program at OHSU for processing. 
 
Do not ship on Friday. Samples must remain at room temperature, do not ship with cold packs.  
 
Shipping address: 
 
Attn: Prostate Program 
Knight Cancer Institute 
3485 SW Bond Ave  
MC: OC14P 
Portland, OR 97239 
Telephone: (503) 418-3397 
Fax: (503) 418-9381 

APPENDIX I: PROCEDURE FOR COLLECTION OF FRESH BIOPSY TISSUE (to be sent to 
FHCRC/UW) 
 
Materials Needed: 
MATERIAL 
NUMBER/AMT 
VENDOR 
CAT# 
Sterile Tweezers 
(Forceps) 
2 
Fisher 
84011182 
Tissue Tek 
standard-size 
Cryomolds 
1 PER BIOPSY 
(Prepare 6 per 
Procedure; plan to 
use 5) 
Fisher 
NC9511236 
Tissue Tek OCT 
1 bottle 
Fisher 
14-373-65 
Insulated metal 
bucket 
1 
 
 
Isopentane or 2- 
methyl-isobutane 
1 liter 
 
 
Dry ice 
As needed 
 
 
Liquid nitrogen (if 
available) 
1 container 
 
 
70% alcohol (prep 
pads) 
As needed 
 
 
Blue pads and 
Markers 
As needed 
Fisher 
507105 
NC9319816 
-80C Freezer 
 
 
 
Sterile saline 
1-2 bottles 
 
 
Pre-filled 
specimen 
container (20ml 
container) with 
10% neutral- 
buffered formalin 
(10ml formalin) 
1 
Dynamic 
Diagnostics 
 
1.7 ml Posi-Click 
tube (Denville) 
3 
Fisher 
C2170 
Gloves (non- 
sterile) 
1 box 
 
 
Biohazard sharps 
container 
1 
 
 
 
PRE-BIOPSY LABELING 
 
Research staff should communicate with the Interventional Radiology team in advance of the biopsy 
to ensure that requested specimens are collected according to SOP. 
 
1. Prepare the Posi-click tubes and label 2, 4 and 6. This helps in identifying which biopsy core was 
taken 2nd, 4th and 6th. Having tubes pre-labeled and ready is preferred. 
2. Prepare and label specimen containers for formalin and label 1, 3 and 5. 
3. Label tubes and cryomolds with the following information: 
-Biopsy date 
 
O 

P 
 
-Specimen ID (format: CABENZ--STUDY ID#) 
-Biopsy type (core #, Fresh or Frozen) 
-Soft tissue or Bone  
PREPARATION 
Arrive at biopsy collection site at least 15 minutes ahead of scheduled time to allow for sufficient time 
to set up lab supplies. 
 
Bring the following: 
 2 Sterile tweezers (forceps) 
 8 Tissue Tek standard-size cryomolds 
 1 Bottle Tissue Tek OCT media 
 1 Insulated metal bucket 
 Isopentane or 2-methyl-isobutane 
 Dry ice 
 70% alcohol (prep pads) 
 Blue pads and markers 
 3 pre-chilled 1.7 ml Posi-Click tube (Denville) 
 1 Posi-Click tube holder 
 1 Pre-filled specimen container (20ml container) with 10% neutral-buffered formalin (10ml 
formalin) 
 2 styrofoam containers 
 
1. Isopentane conducts heat very rapidly and avoids freeze artifacts. Isopentane must be pre-cooled 
to liquid nitrogen (preferred) or dry-ice temperature. 
-If liquid nitrogen is not available, fill Styrofoam container or ice bucket ¾ full with dry ice. Place 
steel container with isopentane on the dry ice and allow temperature to equilibrate. Pour 200- 
400ml of isopentane into a steel container. 
-If isopentane cannot be used due to regulations, dry ice can be used. 
-If using liquid nitrogen: pour liquid nitrogen into an insulated bucket or Styrofoam container 
that can accommodate both the liquid nitrogen and the steel container. Slowly place (lower) 
the steel container containing isopentane into the liquid nitrogen and allow the temperature to 
equilibrate. 
2. In a 2nd Styrofoam box with dry ice, place the Posi-click tubes on the ice, preferably in a small Posi- 
click tube holder (this makes it easier to see the tubes on dry ice). This is to pre-chill the tubes. 
3. Place both Styrofoam boxes on a cart for easy transport to the biopsy. 
TUMOR NEEDLE BIOPSY COLLECTION 
While the biopsy is taking place, record the following information on the requisition form: 
 CABENZ—Study ID# 
 Needle type, size (gauge and length) 
 Specimen # 
 Time biopsy snap-frozen on dry ice and/or time biopsy frozen in OCT 
RECORD TIMES USING MILITARY TIME (24-hr designation), e.g., 16:15 to indicate 4:15p 

Q 
 
COLLECTION OF BIOPSIES AND FLASH FREEZING 
 
1. Transfer freshly collected needle biopsy with sterile needle or forceps at one end, and touch the 
opposite end of the biopsy to the 1.7-ml pre-chilled, pre-labeled tube #2. The tissue should 
immediately attach to the tube, allowing it to be placed into the tube while easily releasing the 
forceps. This should be done within 15-20 seconds. 
2. Place tubes into chilled isopentane or dry ice, each core should be collected into an individual tube. 
Dispose of needles/forceps into the appropriate biohazard waste container. 
3. Repeat for each separate frozen biopsy. 
 
FLASH FREEZING (should be done within 20-30 min of biopsy collection) 
 
1. Add a drop of Tissue Tek OCT medium into the pre-labeled cryomolds 
2. Hold and remove the freshly collected frozen core needle biopsy tissue from the tubes with sterile 
forceps at one end and touch the opposite end of the tissue to the cryomold and push the biopsy to 
the bottom of the cassette with forceps.  Make sure biopsy is as flat as possible using the forceps. 
3. Fill cryomold with OCT media, ensuring no air bubbles are present. 
4. Place the filled cassette into the chilled isopentane and make sure it is submerged and the 
cryomold is completely frozen and turns white. This should be done within 15-20 seconds. 
5. Once frozen, place cryomold cassettes on dry ice for transport. 
6. Repeat procedure for each separate, frozen biopsy. 
7. Record time to OCT freeze for each pass. 
8. Pour used isopentane back into bottle using a funnel. Do not overfill. 
SAMPLE STORAGE AND INVENTORY 
1. Transfer cryopreserved biopsy specimens to a -80C freezer. Complete sample 
storage/location/inventory log and store until shipping. 
2. Record time of return to specimen storage in -80C and location of sample. 
3. Note any deviations from this protocol. 
 
Samples will be shipped to the University of Washington (see address below): 
 
Univ of Wash 
1959 NE Pacific St 
HSB I-340 
Seattle, WA 98195 
Attn: Lori Kollath 

APPENDIX J: PROCEDURE FOR COLLECTION AND PROCESSING OF CIRCULATING BLOOD 
MARKERS (to be sent to FHCRC/UW) 
 
All sample collection tubes must be stored at room temperature prior to use. 
 
MATERIAL 
NUMBER/AMOUNT VENDOR 
CAT# 
Red top tube 
(serum) 
1 
BD 
BD REF 366430 
Purple top plasma 
tube (EDTA) 
1 
BD 
BD REF 366643 
Streck tube 
1 
Streck.com 
218962 
Cryovials for 
transfer of 
samples from 
EDTA, serum, 
Streck tubes 
 
Per site 
Per site 
Disposable 
transfer pipets 
 
Per site 
Per site 
Sample ID labels 
for EDTA, serum, 
Streck and 
cryovials 
 
Labels will be sent 
out 
Label will be sent 
out 
 
PREPARATION 
1. Label red top tube, EDTA and Streck tubes with appropriate sample ID labels 
2. Check expiration date on all tubes 
3. Prepare subject for venipuncture 
4. Draw red top first, then EDTA tube and Streck tube. 
5. Gently invert red tube, EDTA and Streck tubes 8-10 times and place EDTA tube on ice or at 4C. 
For the Streck tube, leave at room temperature (between 6 and 37 degrees Celsius). 
 
SERUM PROCESSING (red top). Must be performed within 4 hours of draw 
1. Centrifuge 15 minutes at 1600xg force, 4C. 
2. Use sterile pipette, place equal volume serum into each of 2 mL microfuge tubes 
3. Place pre-printed ID labels on microtubes as quickly as possible. 
4. Immediately place microtubes into a freezer box at -80C for eventual shipment. 
 
PLASMA/BUFFY COAT PROCESSING (purple top). Must be performed within 4 hours of draw 
1. EDTA plasma is obtained from whole blood collected in purple top vacutainer tubes containing 
EDTA. Ensure a full 10 ml draw. 
2. Invert tubes 8-10 times after draw. 
3. Centrifuge sample for 15 minutes at 1600xg force, 4C. 
4. Using sterile pipette, place equal volume of plasma into each of 2 microfuge tubes. Remove plasma 
slowly and carefully, so as not to disrupt the layer of white blood cells (leave at least 0.5 cm 
residual plasma). 
5. Immediately place microtubes into a freezer box at -80C for eventual shipment. 
6. Buffy coat is removed from the purple top EDTA tube after the plasma aliquots are removed. 
7. Use a transfer pipet to harvest the buffy coat by removing the buffy/white layer between the plasma 
and the cell pellet. Place into a freezer vial with screw cap and O-rings. 
8. Red cell pellet can be discarded. 
R 

S 
 
9. Immediately place vials into a freezer box at -80C for eventual shipment. 
Samples will be shipped to the University of Washington (see address below): 
Univ of Wash 
1959 NE Pacific St 
HSB I-340 
Seattle, WA 98195 
Attn: Lori Kollath 

T 
 
APPENDIX K: Procedures for Collection & Processing of PK specimens 
 
Blood samples will be collected in heparinized tubes (lithium heparinate). 
 
The samples will be centrifuged within 30 min at approximately 3,000 RPMs for 15 min. 
 
The plasma will be removed, placed into polypropylene tubes, labeled, frozen, and stored at −20 °C 
until analysis. 
 
Studies will be done by Covance. (2202 Ellis Road, Durham, NC 27703 c/o Chris Barringer). 
However, OHSU will batch the samples and send them to Covance. 
 
Samples will be shipped to the Prostate Cancer Program at OHSU and batched prior to shipping to 
Covance. 
 
 
Prostate Program  
3485 SW Bond Ave  
MC: OC14P 
Portland, OR 97239 
 

U 
 
Click here to enter text. 
Click here to enter text. 
APPENDIX L: PCCTC SAE Report Form 
 
 
SERIOUS ADVERSE EVENT REPORTING FORM 
 
 
 
 
SUBJECT INFORMATION 
*Subject Identifier (Study ID) 
*Sex  ☒ Male 
Weight 
 
*Age at Time of Event 
□ lb ☐ kg 
 
SERIOUS ADVERSE EVENT 
*CTCAE Term 
*Start Date 
*Grade 
*Type (check all that apply) 
□ Death 
 
 
*End Date 
 
 
□ Disability or Permanent Damage 
 
 
OR ☐ ongoing 
□ Life-threatening 
☐ Congenital Anomaly/Birth Defect 
□ Hospitalization 
☐ Other Medically Important Condition 
 
 
 
 
 
*Outcome 
□ Recovered/Resolved 
☐ Not Recovered/Not Resolved 
☐ Fatal 
□ Recovering/Resolving ☐ Recovered/Resolved sequelae ☐ Unknown 
 
RELEVANT TESTS/LABORATORY DATA 
Date mm/dd/yyyy 
Test 
Result 
Unit 
Notes 
Click here to enter text. 
*Protocol Title 
Click here to enter text. 
Click here to enter text. 
Click here to enter text. 
Click here to enter a date. 
Click here to enter text. 
Click here to enter a date. 
*Event # 
*PCCTC Protocol # 
*Site Name 
*Date of Report 
□Initial Report 
*Site Protocol # 
□Follow-up Report 
*Reported By 
*Date of Original Report 
*Event Description 
Click here to enter text. 
Click here to enter a date. 
Click here to enter a date. 
 
Click here to enter text. 
Click here to enter a date.  
 Click here to enter text.  

U 
 
Click here to enter a 
date. 
 
 
 
 
Click here to enter a 
 
 
 
 

V 
 
 
date. 
 
 
 
 
Click here to enter a 
date. 
 
 
 
 
 
OTHER RELEVANT HISTORY 
Disease/surgical 
procedure/etc. 
Start Date 
mm/dd/yyyy 
Continuing 
Y/N/U 
End Date 
mm/dd/yyyy 
Comments 
 
Click here to enter a 
date. 
 
Click here to enter a 
date. 
 
 
Click here to enter a 
date. 
 
Click here to enter a 
date. 
 
 
Click here to enter a 
date. 
 
Click here to enter a 
date. 
 
 
 
SUSPECT PRODUCT(S) 
 
*Name 
Relationship 
to Study 
Treatment 
Action Taken 
Dose Frequenc 
y 
Route Start Date 
mm/dd/yyyy 
Last Date 
Prior to SAE 
mm/dd/yyy 
y 
 
☐Unrelated 
☐Drug withdrawn 
 
 
 
Click here to 
Click here to 
☐Unlikely 
☐Dose reduced 
enter a date. 
enter a 
☐Possibly 
☐Dose Increased 
date. 
☐Probably 
☐Dose not changed 
☐Definite 
☐Unknown 
☐Not applicable 
 
☐Unrelated 
☐Drug withdrawn 
 
 
 
Click here to 
Click here to 
☐Unlikely 
☐Dose reduced 
enter a date. 
enter a 
☐Possibly 
☐Dose Increased 
date. 
☐Probably 
☐Dose not changed 
☐Definite 
☐Unknown 
☐Not applicable 
 
☐Unrelated 
☐Drug withdrawn 
 
 
 
Click here to 
Click here to 
☐Unlikely 
☐Dose reduced 
enter a date. 
enter a 
☐Possibly 
☐Dose Increased 
date. 
☐Probably 
☐Dose not changed 
☐Definite 
☐Unknown 
☐Not applicable 
 
 
CONCOMITTANT MEDICAL PRODUCT(S) 
Name 
Start Date 
mm/dd/yyyy 
Last Date Prior to SAE 
mm/dd/yyyy 
 
Click here to enter a date. 
Click here to enter a date. 
 
Click here to enter a date. 
Click here to enter a date. 
 
Click here to enter a date. 
Click here to enter a date. 

W 
 
INVESTIGATOR NAME AND SIGNATURE 
*Investigator Name 
*Investigator Signature 
*Date Signed 
mm/dd/yy 
Click here to enter a date. 
Click here to enter text. 

X 
 
APPENDIX M: Storage and Disposition of data and specimens 
 
During the study, data and specimens will be maintained by the study staff. Specimens will be stored 
in the program clinical research office, in either a locked room or locked cabinet, on an access 
restricted floor. Study data will be maintained on access protected, OHSU network servers. Only staff 
and investigators who are listed as approved study staff with the IRB will be able to access 
specimens or data. When samples are transferred to testing locations outside of the main storage 
location, a chain of custody form will be used to document the transfer. If there is sample remaining 
after the analysis, it will be either transferred back to the principal investigator or destroyed. Either 
action will be documented. 
 
Samples will be coded with a study subject ID and collection date. The investigators and primary 
study staff will have access to the key to the code, which will not contain PHI. 
 
Upon completion of the planned analyses in this protocol, all data and remaining specimens will be 
transferred into the re 
(OHSU IRB 2816). At 
requests, and release 
Database 
sample 
 
 
Describe how and where data/specimens will be stored and describe the final disposition of the 
data/specimens. Include: 
The location of data/specimens, who will have access to the data/specimens, and how 
access will be controlled. 
Method of coding data/specimens, if applicable. Include a process to protect/maintain the 
key to the code and limit access to the key. Coding data does not make it anon 
Plans for final disposition of the data/specimens, including release to a repository (either as 
part of this protocol or into another protocol) or plan to destroy at the end of study. 
Describe the process and requirements for requesting and releasing data/specimens. 
pository, “Master Protocol for Cancer Research Specimen Bank and
that time, repository practices will be followed for access restriction, 
of data or specimens.