Conditions: Metastatic Castration-resistant Prostate Cancer
Keywords: Enzalutamide Metastatic Castration-resistant Prostate Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 67
Healthy volunteers: no

Brief summary:
This research study is evaluating a drug called enzalutamide in metastatic castration resistant prostate cancer. Enzalutamide is already FDA approved for metastatic castration resistant prostate cancer after treatment with chemotherapy.

The purpose of this study is to analyze features of tumor specimens sampled prior to therapy and at disease progression to determine why patients respond or stop responding to treatment with Enzalutamide.

Prior chemotherapy is not a requirement of this trial.

Detailed description:
After the screening procedures confirm that the patient is able to participate in the study,

* The patient will have the first of two required prostate biopsies prior to starting study treatment.
* The patient will be given a prescription for study drug and a study drug-dosing diary for each treatment cycle. Each treatment cycle lasts 28 days (4 weeks), during which time the patient will be taking the study drug once daily. The diary will also include special instructions for taking the study drug. The study drug (enzalutamide) should be taken orally (by mouth) at home.

On Day 1 of each cycle (+/- 4 days), the following procedures will be performed in clinic:

* A medical history.
* A Physical examination
* Performance status
* Blood tests (2-3 tablespoons).
* The patient will be asked about medications they are currently taking, including over-the counter medications, herbal remedies, vitamins, and supplements.
* The patient will be asked about any disease-related symptoms they are experiencing.
* The patient will receive a new supply and the medication diary will be reviewed.

Every 12 weeks (+/-1 week) the following procedures will be performed in clinic:

* Blood tests. A small sample of the patient's blood (about 1-2 tablespoons) will be collected. This blood will be collected for specialized laboratory tests.
* A (CT) scan of the patient's chest and a CT or MRI scan of abdomen, and pelvis and a bone scan will be performed every 12 weeks (+/- 1 week) while the patient is on active treatment. If your baseline CT of the patient's chest does not show disease, the investigator may not asked for this to be repeated.

End of Study Visit in clinic:

* A medical history.
* A physical examination
* Performance status
* Blood tests (2-3 tablespoons)
* The patient will be asked about any disease-related symptoms If the patient completed at least 4 cycles of enzalutamide, the patient will undergo a second of two required biopsies.

Arms:
arm 1: Administration: 160 mg orally once daily with a 28-day cycle. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason.

Dosing: 160 mg orally taken once daily as four 40 mg capsules.

Interventions: intervention 1: Enzalutamide
Intervention descriptions: intervention 1: Enzalutamide, formerly known as MDV3100, is a rationally-designed second generation AR inhibitor which functions by blocking several steps in the AR signaling cascade. Enzalutamide competitively binds the AR with great potency. Additionally, enzalutamide inhibits nuclear translocation of activated AR and inhibits the association of activated AR with DNA.

Protocol document:
Prot_SAP_000.pdf: 
TITLE: Phase II trial of enzalutamide for castrate-resistant prostate cancer (CRPC) with 
correlative assessment of androgen receptor (AR) signaling and whole-exome and 
transcriptome sequencing 
 
 
NCT Number: NCT01942837 
 
 
Protocol Version Date: April 04, 2019 


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Protocol Version Date: April 4, 2019 
 
Local Protocol #: 13-301  
 
 
Title: Phase II trial of enzalutamide for castrate-resistant prostate cancer (CRPC) with 
correlative assessment of androgen receptor (AR) signaling and whole-exome and 
transcriptome sequencing  
 
 
Sponsor-Investigator: 
 
  
  
  
  
  
 
                                                                    
 
 
Co-Principal Investigators:   
 
 
 
 
Coordinating Center:  
Dana-Farber Cancer Institute  
  
  
 
Agent(s):   
Enzalutamide (IND # 74563) 
IND/IDE held by: Medivation Inc.   
Drugs, Biologics, Devices Provided by: Medivation Inc. 


Enzalutamide for Castration-Resistant Prostate Cancer  
 
 
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ABBREVIATIONS 
 
Activation Function – AF  
Adverse event – AE  
Alanine transaminase – ALT   
American Society of Anesthesiologists – ASA  
ANC – Absolute neutrophil count  
Androgen deprivation therapy – ADT  
Androgen Receptor – AR 
Androgen Response Element – ARE  
Area under the concentration-time curve – AUC  
Aspartate transaminase – AST   
Blood Urea Nitrogen – BUN  
Cancer Therapy Evaluation Program – CTEP  
Case Report Form – CRF  
Castration resistant prostate cancer – CRPC 
Circulating Tumor Cells – CTCs  
Code of Federal Regulations – CFR  
Complete response – CR 
Partial response – PR  
Computed tomography – CT  
Confidence interval – CI 
Ligand binding domain – LBD 
Dana-Farber Cancer Institute – DFCI 
Dana-Farber/Harvard Cancer Center – DF/HCC  
Dana-Farber/Partners Cancer Care – DF/PCC  
Data Safety and Monitoring Committee – DSMC  
Dehydroepiandrosterone – DHEA  
Dehydroepiandrosterone-sulfate – DHEA-S  
Deoxyribonucleic acid – DNA  
Diastolic blood pressure – DBP  
Dihydrotestosterone – DHT  
DNA binding domain – DBD  
Eastern Cooperative Oncology Group – ECOG  
Echocardiogram – ECHO  
Electrocardiogram – EKG   
Fluoro-dihydrotestosterone-positron emission tomography – FHDT-PET  
Food and Drug Administration – FDA  
Good Clinical Practice – GCP  
Half-life – t1/2 
Hazard ratio – HR 
Health Insurance Portability and Accountability Act – HIPAA  
Heat Shock Protein – HSP  
Hematoxylin and eosin – H&E 
Human immunodeficiency virus – HIV  
Immunohistochemistry – IHC  


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Institutional Review Board – IRB  
International Normalized Ratio – INR  
Investigational New Drug – IND  
Laser capture microdissection – LCM  
Liver function test – LFT 
Luteinizing hormone-releasing hormone – LHRH  
Magnetic Resonance Imaging – MRI  
Maximum plasma concentration – Cmax   
Messenger RNA – mRNA 
Systolic blood pressure – SBP  
Minimum plasma concentration – Cmin 
Multi Gated Acquisition Scan – MUGA  
National Cancer Institute Common Terminology Criteria for Adverse Events – NCI CTCAE 
New York Heart Association – NYHA  
Not Reached – NR  
N-Terminal Domain – NTD 
Office of Data Quality- ODQ  
Office for Human Research Studies – OHRS  
Overall survival – OS  
Partial thromboplastin time – PTT  
Positron emission tomography – PET  
Principal Investigator – PI  
Progression free survival – PFS  
Progressive disease – PD 
Prostate specific antigen – PSA 
Prostate Cancer Working Group – PCWG  
Prothrombin time – PT 
Response Evaluation Criteria In Solid Tumors – RECIST  
Reverse transcription polymerase chain reaction – RT-PCR  
Ribonucleic acid – RNA  
Serious adverse event – SAE  
Single-nucleotide polymorphism – SNP  
Skeletal Related Event – SRE  
Single-photon emission computed tomography - SPECT 
Stable disease – SD  
Time to PSA Progression – TTPP  
Unknown – UN  
Upper limit of normal – ULN 
WBC – White blood cell count  


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SCHEMA 
 
 
 
 
 
 
 
 
 
1. Population: Metastatic CRPC patients.  
 
2. Treatment: Participants will be treated with enzalutamide in 28-day cycles. Participants 
will be continued on the study until symptomatic or radiographic progression.   
 
3. Planned Enrollment: 66 participants across multiple sites. 
 
4. Study Duration: 
a. Enrollment – one year.  
b. Sample collection and analysis – two years.  
c. Final report – 3-6 months after the end of data collection.  
 
5. Data Safety Monitoring Committee (DSMP)/Safety Review: Quarterly. 
Symptomatic or 
Radiographic 
Progression 
Metastatic 
CRPC 
Pre-Treatment 
Tumor Biopsy  
Enzalutamide 
until 
Progression   
Tumor 
Biopsy at 
Progression 


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TABLE OF CONTENTS 
1. 
OBJECTIVES .................................................................................................................................................... 1 
1.1 
Study Design .................................................................................................................................................... 1 
1.2 
Primary Objectives .......................................................................................................................................... 1 
1.3 
Secondary Objectives ...................................................................................................................................... 1 
1.4 
Exploratory Objectives .................................................................................................................................... 2 
2. 
BACKGROUND ................................................................................................................................................ 3 
2.1 
Study Agent(s) ................................................................................................................................................. 3 
2.2 
Study Disease .................................................................................................................................................. 6 
2.3 
Rationale ......................................................................................................................................................... 6 
2.4 
Correlative Studies Background...................................................................................................................... 7 
3. 
PARTICIPANT SELECTION .......................................................................................................................... 8 
3.1 
Eligibility Criteria ........................................................................................................................................... 8 
3.2 
Exclusion Criteria ......................................................................................................................................... 10 
3.3 
Inclusion of Minorities and Other Underrepresented Populations ............................................................... 12 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 12 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ......................................................................... 12 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ..................................................................... 12 
4.3 
General Guidelines for Other Participating Institutions ............................................................................... 12 
4.4 
Registration Process for Other Participating Institutions ............................................................................. 13 
5. 
TREATMENT PLAN ...................................................................................................................................... 14 
5.1 
Pre-treatment Criteria ................................................................................................................................. 14 
5.2 Agent Administration ................................................................................................................................... 15 
5.3 
General Concomitant Medications and Supportive Care Guidelines ........................................................... 15 
5.4 
Duration of Therapy .................................................................................................................................... 18 
5.5 
Duration of Follow-Up ................................................................................................................................ 18 
5.6 
Criteria for Removal from Study ................................................................................................................. 18 
6. 
6EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................. 19 
6.1 
Anticipated Toxicities .................................................................................................................................... 19 
6.2 
Toxicity Management/Dose Modifications/Delays ........................................................................................ 21 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 22 
7.1 
Enzalutamide ................................................................................................................................................. 22 
Pharmacy Storage Requirements ............................................................................................................................... 23 
8. 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 25 


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8.1 
Statistical Data Analysis ............................................................................................................................... 25 
9. 
STUDY CALENDAR ...................................................................................................................................... 27 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 29 
10.1 Antitumor Effect– Solid Tumors .................................................................................................................... 29 
10.2 Other Response Parameters .......................................................................................................................... 36 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 37 
11.1 Definitions ..................................................................................................................................................... 37 
11.2 Procedures for AE and SAE Recording and Reporting ................................................................................. 38 
11.3 Reporting Requirements ................................................................................................................................ 39 
11.4 Reporting to the Study Sponsor ..................................................................................................................... 39 
11.5 Reporting to the IRBs .................................................................................................................................... 40 
11.6 Reporting to the FDA .................................................................................................................................... 41 
11.7 Reporting to Hospital Risk Management....................................................................................................... 41 
11.8 Monitoring of Adverse Events and Period of Observation ............................................................................ 41 
12. 
DATA AND SAFETY MONITORING .......................................................................................................... 41 
12.1 Data Reporting .............................................................................................................................................. 41 
12.2 Safety Meetings ............................................................................................................................................. 42 
12.3 Monitoring ..................................................................................................................................................... 42 
13. 
REGULATORY CONSIDERATIONS .......................................................................................................... 43 
13.1 Protocol Review and Amendments ................................................................................................................ 43 
13.2 Informed Consent .......................................................................................................................................... 43 
13.3 Ethics and Research Practices ...................................................................................................................... 43 
13.4 Study Documentation .................................................................................................................................... 44 
13.5 Records Retention ......................................................................................................................................... 44 
13.6 Multi-Center Guidelines ................................................................................................................................ 44 
14. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 46 
14.1 Primary Analysis ........................................................................................................................................... 46 
14.2 Analysis of Secondary Endpoints .................................................................................................................. 47 
15. 
PUBLICATION PLAN .................................................................................................................................... 48 
16. 
REFERENCES ................................................................................................................................................. 49 
17. 
APPENDICES .................................................................................................................................................. 53 
17.1 Appendix A: Performance Status Criteria ..................................................................................................... 53 
17.2 Appendix B: Required Forms at Registration ............................................................................................... 53 
17.3 Appendix C: Participant’s Pill Diary ............................................................................................................ 53 


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17.4 Appendix D: Representative Medications that May Predispose to Seizure ................................................... 53 
17.5 Appendix E: Data and Safety Monitoring Plan ............................................................................................. 53 
1.0 
INTRODUCTION ............................................................................................................................................ 61 
1.1 
Purpose ......................................................................................................................................................... 61 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ...................................................................... 61 
2.0 
GENERAL ROLES AND RESPONSIBILITIES ......................................................................................... 62 
2.1 
DF/HCC Sponsor ......................................................................................................................................... 62 
2.2 
Coordinating Center ..................................................................................................................................... 63 
2.3 
DF/HCC Office of Data Quality (ODQ) ...................................................................................................... 63 
2.4 
Participating Institution ............................................................................................................................... 63 
3.0 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ....................................................... 64 
3.1 
Protocol Distribution .................................................................................................................................... 64 
3.2 
Protocol Revisions and Closures .................................................................................................................. 64 
3.3 
Informed Consent Requirements ................................................................................................................. 65 
3.4 
IRB Documentation ..................................................................................................................................... 65 
3.5 
IRB Re-Approval .......................................................................................................................................... 65 
3.6 
Participant Confidentiality and Authorization Statement ........................................................................... 66 
3.7 
DF/HCC Multi-Center Registration ............................................................................................................ 66 
3.7.1 Participant Registration and Randomization .............................................................................................. 66 
3.7.2 Initiation of Therapy .................................................................................................................................... 67 
3.7.3 Eligibility Exceptions ................................................................................................................................... 67 
3.7.4 Verification of Registration, Dose Levels, and Arm Designation ............................................................... 68 
3.8 
DF/HCC Protocol Case Number ................................................................................................................. 68 
3.9 
Protocol Deviations, Exceptions and Violations ......................................................................................... 68 
3.9.1 Definitions .................................................................................................................................................... 68 
3.9.2 Reporting Procedures ................................................................................................................................... 68 
3.10 Safety Assessments and Toxicity Monitoring .............................................................................................. 69 
3.10.1 
Guidelines for Reporting Serious Adverse Events ............................................................................. 69 
3.10.2 
Guidelines for Processing IND Safety Reports .................................................................................. 70 
3.11 Data Management ........................................................................................................................................ 70 
3.11.1 
Data Forms Review ............................................................................................................................. 70 
4.0 
REQUSITIONING INVESTIGATIONAL DRUG ....................................................................................... 70 
5.0 
MONITORING: QUALITY CONTROL ...................................................................................................... 71 
5.1 
Ongoing Monitoring of Protocol Compliance ............................................................................................. 71 
5.2 
Evaluation of Participating Institution Performance ................................................................................. 72 


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5.2.1 Monitoring Reports ...................................................................................................................................... 72 
6.0 
AUDITING: QUALITY ASSURANCE ......................................................................................................... 72 
6.1 
DF/HCC Sponsored Trials ........................................................................................................................... 72 
6.2 
Participating Institution ............................................................................................................................... 72 
6.3 
DF/HCC Sponsor and Coordinating Center ............................................................................................... 73 
6.4 
Sub-Standard Performance .......................................................................................................................... 73 
6.4.1 Corrective Actions ........................................................................................................................................ 73 


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1 
1. OBJECTIVES 
 
The primary objective of this trial is to analyze possible AR related mechanisms of resistance 
to enzalutamide. Samples of CRPC will be obtained at baseline and at progression on 
treatment with enzalutamide. Tumor analysis will include AR sequencing (mutations, splice-
variants), AR regulated gene expression, tumor androgen levels, profiling of enzymes 
involved in androgen synthesis/metabolism, and whole-exome and transcriptome sequencing. 
Secondary objectives include assessment of clinical response and correlation of clinical 
response to alterations in the AR signaling axis. Exploratory analyses will be to analyze 
circulating tumor cells (CTCs) for AR nuclear localization, AR splice variant expression and 
AR sequence. Additionally, we will analyze circulating tumor DNA.  
 
1.1 
Study Design 
 
This is a phase II, prospective, multicenter, single-arm study accessing mechanisms of 
resistance to enzalutamide in participants with metastatic CRPC.  
 
1.2 
Primary Objectives 
 
- To analyze possible AR related mechanisms of resistance to enzalutamide in serial 
CRPC biopsies including AR sequencing (mutations, splice variants), AR regulated 
gene expression, tumor androgen levels, profiling of enzymes involved in androgen 
synthesis/metabolism, and whole-exome and transcriptome sequencing. 
 
1.3 
Secondary Objectives  
 
- Assess changes in serum androgen concentrations (including testosterone, 
dihydrotestosterone (DHT), and androgen precursors) between baseline and 
subsequent assessment visits. 
 
- To assess prostate specific antigen (PSA) response to enzalutamide. 
 
-  To assess PSA response duration to enzalutamide.  
 
- To assess response of measurable disease to enzalutamide. 
 
- To assess duration of response of measurable disease to enzalutamide.  
 
- To assess safety and tolerability of enzalutamide.  
 
- To correlate alterations in AR mutation, AR splice variants, TMPRSS2/ERG, AR 
regulated gene expression, tumor androgens, serum androgens, whole-exome and 
transcriptome sequencing with PSA and radiographic response to enzalutamide.  
 


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- To investigate subsequent lines of therapy, including line of agent, name of agent, 
and PSA kinetics following study drug discontinuation and correlate with response 
to study drug. 
1.4 
Exploratory Objectives  
 
- To measure circulating tumor cells (CTCs) as a marker of response to enzalutamide.  
- To analyze CTCs for mechanisms of AR resistance including AR nuclear 
localization, AR splice variant expression and AR sequence. 
- To analyze circulating tumor DNA for mechanisms of AR resistance and correlate to 
response to enzalutamide. 
- To explore the association between quantitative 99mTc-MDP uptake in skeletal 
metastases, measured as activity concentration on quantitative SPECT/CT, with 
anatomical bone findings on CT, laboratory tumor markers (e.g. PSA, circulating 
tumor DNA) and overall response in an imaging substudy of patients enrolled at the 
Dana-Farber Cancer Institute only. 


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2. BACKGROUND 
 
2.1 
Study Agent(s) 
 
2.1.1 Enzalutamide  
 
Enzalutamide, formerly known as MDV3100, is a rationally-designed second 
generation AR inhibitor which functions by blocking several steps in the AR 
signaling cascade. Enzalutamide competitively binds the AR with great potency. 
Additionally, enzalutamide inhibits nuclear translocation of activated AR and 
inhibits the association of activated AR with DNA.[1] 
 
Rational for Using Enzalutamide in Prostate Cancer  
First generation antiandrogens, including bicalutamide, nilutamide, and flutamide, 
are reversible inhibitors of the AR and have a several-fold lower affinity to the 
AR compared with androgens. These agents have been used in the management of 
advanced prostate cancer for decades. Addition of an antiandrogen at the time of 
CRPC has been shown to lower PSA by 50% or more in approximately one-
quarter of patients.[2-4] There is no data supporting the superiority of one 
antiandrogen over another, however nilutamide has been shown to induce PSA 
declines in men who have developed resistance to AR inhibition with flutamide or 
bicalutamide.[5]  
 
It was first noted in the early 1990s that disease progression, despite the 
combination of an LHRH (luteinizing hormone-releasing hormone) agonist and 
an antiandrogen, could be stopped and reversed simply through discontinuation of 
the antiandrogen. Stopping the antiandrogen in men with a rising PSA, termed 
antiandrogen withdrawal, can result in PSA declines in between 10-20% of 
men.[6] Further work demonstrated that in the setting of AR overexpression or 
mutation, conventional antiandrogens have the potential to exhibit paradoxical 
partial agonist activity, promoting prostate cancer progression.[7] Thus, more 
potent antagonists lacking agonist activity are necessary.  
 
 
 
 
 
 
Preclinical Data with Enzalutamide  
Using the nonsteroidal agonist RU59603 as the parent scaffold compound, 
Sawyers and colleagues identified two oral diarylthiohydantoins, RD162 and 
enzalutamide, from a screen of nonsteroidal antiandrogens that retain 
antiandrogen activity in the setting of increased AR expression.[1] Both 
compounds have enhanced affinity for the AR (5-8 fold) compared to the 
antiandrogen bicalutamide. Enzalutamide competitively binds the AR with an 
IC50 of 36 nM compared to 160 nM for bicalutamide. Additionally, enzalutamide 
inhibits nuclear translocation of activated AR, inhibits DNA binding to androgen 
response elements, and inhibits recruitment of coactivators, even in the setting of 
AR overexpression and in prostate cancer cells resistant to antiandrogens. By 


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contrast with bicalutamide, enzalutamide is a pure antagonist with no detectable 
agonist effects in LNCaP/AR prostate cells, which overexpress AR. The drug also 
induces regression of established LNCaP/AR xenograft tumors growing in 
castrated male mice, a model in which bicalutamide treatment only slows tumor 
growth.  
 
Clinical Data with Enzalutamide  
A phase I/II first in man study was initiated in July 2007 at three sites to assess 
safety, pharmacokinetics, tolerability, and antitumor activity.[8] Patients with 
progressive, metastatic CRPC were eligible. The initial dose of enzalutamide was 
30 mg daily, with subsequent dose-escalations in cohorts of 3-6 patients to a 
maximum dose of 600 mg daily. When significant >50% declines in PSA levels 
were observed in the first six patients, enrollment was expanded by an additional 
24 patients (12 pre-chemotherapy, 12 post-chemotherapy) at every dose level 
starting at 60 mg daily. By 12/2008, 140 patients had been enrolled. 
 
After administration of one dose, the drug was rapidly absorbed, and median time 
to Cmax was one hour (range 0.42 minutes – 4 hours). The t1/2 was about 1 week 
(range 3 – 10 days) and was not affected by dose. Full pharmacokinetic profiles 
were linear and consistent over the dose range study. Plasma concentrations 
reached steady state after one month of treatment. Once achievement of steady 
state, the Cmin in individual patients remained constant for several months, 
suggesting time-linear pharmacokinetics. Due to slow clearance from plasma, the 
daily fluctuation in steady-state enzalutamide concentrations were low. The mean 
Cmax/Cmin was 1.2 (range 1.14-1.3) indicating that the average difference between 
the peak and trough concentrations was ≤ 30%. AR binding was assessed in 22 
patients at doses from 60-480 mg daily with FHDT-PET. All patients showed 
clear reduction of FDHT uptake (range 20-100%).  
 
Fatigue was the most frequently reported AE, with dose-dependent increases of 
grade 3 fatigue (0% at 150 mg/day, 9% at 240 mg/day, 15% at 360 mg/day, and 
20% at 480 mg/day). The dose of 240 mg/day was defined as the maximum 
tolerated dose. At doses of 240 mg and above, an increasing proportion of patients 
needed dose reductions for fatigue. Dose reductions were needed in 1 of 29 
patients (3%) that received 240 mg/day, 3 of 28 patients (11%) that received 360 
mg/day, and 5 of 22 patients (23%) that received 480 mg/day, and 0 of 58 patients 
that received 30, 60, or 150 mg/day. After dose reductions, the symptoms 
resolved. Only 1 patient discontinued treatment due to fatigue with an onset 
coinciding with PSA rise. Overall, the most common mild (grade 2) AEs were 
fatigue (n = 38, 27.1%), nausea (n = 12, 8.6%), dyspnea (n = 11, 7.9%), anorexia 
(n = 8, 5.7%), and back pain (n = 8, 5.7%). Fatigue, nausea, and 
anorexia were the only mild AEs with an increasing incidence as the dose of 
enzalutamide was increased. None of the grade 2 events required dose 
modification or the discontinuation of treatment, apart from 1 patient treated at 
480 mg/day who had nausea at baseline and stopped therapy after 7 weeks. 
 


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Two witnessed seizures occurred in patients receiving doses of 600 and 360 
mg/day, and 1 possible seizure occurred at 480 mg/day. Whether enzalutamide 
was responsible for these seizures is unclear, since both patients who had 
witnessed seizures were concurrently taking drugs that could contribute to a 
lowered seizure threshold (olanzapine and prochlorperazine for the patient 
receiving 600 mg/day; methylphenidate for the patient receiving 360 mg/day). 
Both patients also had complicated medical problems that could have contributed 
to their seizures, including hypocalcaemia requiring intravenous calcium, anemia 
requiring red-cell transfusions, and skull metastases requiring skull radiation. 
Other causes of treatment discontinuation included rash in 1 patient that received 
480 mg/day after 10 days and in 1 patient that received 600 mg/day after 3 days, 
and a myocardial infarction after 15 weeks of therapy in a patient with a history of 
diabetes, hypertension, and hypercholesterolemia that received 360 mg/day. All 
patients recovered without sequelae. No deaths and no other drug-related SAEs 
were reported. 
 
In regards to efficacy, antitumor effects were noted at all doses including >50% 
declines in PSA in 78 (56%) patients, response in soft tissue in 13 (22%) of 59 
patients, stabilized bone disease in 61 (56%) of 109 patients, and conversion from 
unfavorable to favorable CTC counts in 25 (49%) of 51 patients. Disease 
regression was dose dependent between daily doses of 30 mg and 150 mg, 
however no additional benefit was noted above this threshold. 
 
Based on these results, two placebo-controlled, randomized phase 3 studies 
(AFFIRM and PREVAIL) were initiated to evaluate the efficacy and safety of 
enzalutamide in patient with advanced prostate cancer. The AFFIRM study 
evaluated the safety and efficacy of enzalutamide in 1,199 patients with CRPC 
after chemotherapy with docetaxel.[9] Patients were randomized in a 2:1 ratio to 
receive oral enzalutamide at a dose of 160 mg per day or placebo. The primary 
endpoint was OS. The study was stopped after a planned interim analysis at the 
time of 520 deaths. The median OS was 18.4 months in the enzalutamide group 
versus 13.6 months in the placebo group (HR 0.63, 95% CI 0.53-0.75, p<0.001). 
The superiority of enzalutamide over placebo was shown with respect to all 
secondary endpoints: ≥50% PSA reduction (54% vs. 2%, p<0.001), soft-tissue 
response rate (29% vs. 4%, p<0.001), the quality-of-life response rate (43% vs. 
18%, p<0.001), time to PSA progression (8.3 vs. 3.0 months, p<0.001), time to 
first SRE (16.7 vs. 13.3 months, p<0.001).  
 
The rates of AEs (Adverse events) between the enzalutamide and placebo group 
were similar. The enzalutamide group had a lower incidence of AEs of grade 3 or 
above (45.3% vs. 53.1%). The median time to first AE was 12.6 months in the 
enzalutamide group compared to 4.2 months in the placebo group. There was a 
higher incidence of all grades of fatigue, diarrhea, hot flashes, musculoskeletal 
pain, and headache in the enzalutamide group compared to placebo. Cardiac 
disorders were noted in 6% of patients receiving enzalutamide and in 8% of 
patients receiving placebo. Hypertension was observed in 6.6% of patients in the 


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enzalutamide group compared to 3.3% in the placebo group. LFT abnormalities 
were reported as AEs in 1% and 2% of the enzalutamide and placebo group, 
respectively. Five of the 800 patients in the enzalutamide group (0.6%) were 
reported to have seizures and no seizures were reported in the placebo group. One 
case of status epilepticus required medical intervention while the other four 
seizures were self-limited. There were potentially predisposing factors in several 
patients, including two patients who had brain metastases, one patient who had 
inadvertently been administered lidocaine intravenously, and one patient with 
brain atrophy in the context of heavy alcohol use and initiation of haloperidol. 
Based on the results of this trial, the FDA approved enzalutamide on 8/31/2012 
for the treatment of patients with metastatic CRPC who have previously received 
docetaxel. 
 
The PREVAIL trial is a double-blinded, randomized, placebo-controlled trial is 
investigating the effectiveness of enzalutamide in patients with metastatic CRPC 
who have not yet received chemotherapy. The primary endpoints are OS (Overall 
survival) and PFS (Progression Free Survival). The trial has reached its target 
accrual of 1,680 patients.  
 
2.2 
Study Disease 
 
Prostate cancer is the most common cancer in men in the United States, with a life time 
risk of 16%, and the second leading cause of death in this population.[10] In 2012, it is 
estimated that 241,740 men will be diagnosed with prostate cancer and 28,170 will die 
of the disease.[10]  
 
ADT (Androgen Deprivation Therapy) is the mainstay of systemic therapy for patients 
with prostate cancer. In patients with advanced disease, despite initial response rates of 
80-90%, nearly all men develop progressive disease within 18-24 months of therapy.[11] 
Men with CRPC have a poor prognosis with median survival of 16-18 months and 
fewer than 20% of patients surviving beyond three years.[12]  
 
2.3 
Rationale 
 
Recent advances in genomics provide unprecedented opportunities for translational 
objectives that inform both treatment response and disease biology. Molecular 
mechanisms of resistance to targeted anti-cancer agents reported in the past few years 
include secondary mutations in target genes, gene amplification and/or overexpression, 
generation of alternatively spliced transcripts, production of new fusion genes, 
mutations in downstream targets and genetic activation of alternate pathways.  
 
The purpose of this study is to elucidate AR related mechanisms of resistance to 
enzalutamide via assessment of serial CRPC metastasis biopsies. Tumor analysis will 
include AR sequencing (mutations, splice-variants), AR regulated gene expression, 
tumor androgen levels, and profiling of enzymes involved in androgen 
synthesis/metabolism. Additionally, via whole-exome and transcriptome sequencing we 


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have the opportunity to perform more holistic studies of drug resistance. Additionally, 
CTCs were measured in Phase I/II trial of enzalutamide and cell numbers were 
demonstrated to correlate with clinical response. We propose to measure CTCs to assess 
response to enzalutamide, in addition to analyzing CTCs for mechanisms of androgen 
resistance.  
 
 
2.4 
Correlative Studies Background 
 
The AR gene is located on chromosome Xq11-12 and is a member of the steroid 
hormone receptor family.[13] The AR is present in benign prostate epithelial cells as 
well as in all stages and grades of primary and metastatic prostate cancer. The AR is a 
110 kDa ligand-activated transcription factor consisting of 917 amino acids that 
contain three important domains: 1) a carboxy-terminal LBD which binds androgens, 
2) a DBD, and 3) a regulatory NTD. Within the NTD lies the AF-1 and AF-5 domains 
which contain binding sites for transcriptional coregulators and are essential for AR 
activity. Under normal conditions, inactive AR is found in the cytoplasm of prostate 
cells and is stabilized by various HSPs, which expose the LBD and allow ligand 
binding. Once bound to ligand, a conformational change occurs in the AR, causing 
dissociation of the HSPs, AR dimerization, and AR migration to the nucleus. Once 
inside the nucleus, the AR DBD binds to specific AREs on the promoter or enhancer 
regions of androgen-regulated genes. Transcription is enhanced by the binding of 
coregulators to AF-1.  
 
Recently, it has become clear that resistance to ADT is mediated by upregulation of 
AR signaling, despite castrate levels of serum testosterone. Proposed mechanisms of 
resistance to castration include: 1) increased AR expression leading to AR activation in 
the presence of low levels of ligand, 2) AR gene mutations leading to promiscuous 
activation of AR signaling by various ligands, 3) AR splice variants leading to 
constitutive activation of AR signaling, and 4) increased intra-tumor expression of 
enzymes involve in steroidogenesis.[14-16] 
 
The AR is expressed at high levels in most cases of CRPC, with the AR gene being 
amplified in about one third of cases.[17, 18] Mutations in the AR that cause promiscuous 
activation by ligand have been detected in at least 15-40% of patients after 
development of resistance.[19] Stranbrough and colleagues profiled the expression 
signatures of primary and metastatic prostate tumors, including both castration-
sensitive and castration-resistant tumors, and found significant increased intratumoral 
expression of AR and genes converting adrenal androgens to testosterone and DHT in 
castrate-resistant tumors.[20] Similarly, Montgomery et al showed that metastatic 
prostate cancers from anorchid men express transcripts encoding steroidogenic 
enzymes and maintain intratumoral androgens at concentrations capable of activating 
AR target genes and maintaining tumor cell survival.  
 
Altered AR mRNA splicing and synthesis of truncated AR variant proteins lacking the 
AR LBD is another mechanism that has been postulated to drive overall resistance to 


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ADT. Although many forms of these splice-variants are maladaptive and lead to a 
nonfunctioning AR protein, AR variants lacking the LBD but retaining the DBD and 
NTD are frequently expressed in CRPC metastases and high levels in prostate cancer 
tissue predict disease progression and shorter survival.[21-24] AR splice-variant mutants 
can thereby be rendered insensitive to circulating or local hormone levels. Recently, it 
was shown the AR gene rearrangements expressing both full-length and AR variants 
are androgen independent and enzalutamide resistant.[25]  
 
3. PARTICIPANT SELECTION 
 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following sections. If there is a question about the inclusion or exclusion criteria, the 
investigator should consult with the PI, 
 and the DFCI study team 
before enrolling the subject in the study.  
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
3.1.1 Be a male ≥ 18 years of age. 
 
3.1.2 Participants must have histologically or cytologically confirmed adenocarcinoma of 
the prostate without ≥50% neuroendocrine differentiation or small cell histology.   
 
3.1.3 Participants must have progressive disease as defined by either:  
 Castrate resistant disease as defined by PCWG.[26] Participants must have a 
rise in PSA on two successive determinations at least one week apart and PSA 
levels ≥ 2 ng/ml (only the screening PSA needs to be ≥ 2 ng/ml) and 
testosterone levels < 50 ng/dL, OR 
 Soft tissue progression defined by RECIST 1.1, OR 
 Bone disease progression defined by PCWG2 with two or more new lesions 
on bone scan. 
3.1.4 Participants must have a testosterone levels < 50 ng/dL.  
3.1.5 CRPC with metastatic disease with at least one site of metastatic disease must be 
amenable to needle biopsy. Soft tissue biopsy sites include: lymph node or visceral 
metastases. Bone sites include lumbar vertebrae, pelvic bones and long bones. 
Excluded sites are thoracic, cervical vertebrae, skull and rib lesions. Biopsy site will 
be selected with guidance of interventional radiologist determining best site to 
optimize balance of obtaining useful tissue for analysis and minimizing risk. 
3.1.6 Participants without orchiectomy must be maintained on LHRH agonist/antagonist 
therapy. 


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3.1.7 Participants may have had any number of previous hormonal therapies 
(antiandrogens, estrogens, finasteride, dutasteride, ketoconazole, abiraterone) 
provided these were discontinued ≥ 4 weeks before enrollment. Participants on 
prednisone 10 mg daily or another equivalent steroid dose are eligible. Participants 
on inhaled steroids are eligible.  
3.1.8 Participants may have had up to two previous cytotoxic therapeutic regimens 
provided these were discontinued ≥ 4 weeks before enrollment.  The use of 
antineoplastic agents for non-cancer therapy (i.e. colitis, rheumatoid arthritis) may 
be allowed provided the patient has been on a stable dose without toxicities greater 
than grade 1.   
3.1.9 At least a 4 week interval from previous prostate cancer treatment other than LHRH 
agonist/antagonist therapy, bisphosphonates, or denosumab to enrollment. 
3.1.10 Participants receiving bisphosphonates therapy or denosumab can be maintained on 
this therapy. If participants have not started bisphosphonates or denosumab, it is 
recommended that they start treatment after the first biopsy. 
 
3.1.11 ECOG performance status < 2 (Karnofsky >60%, see Appendix A).  
 
3.1.12 Participants must have normal organ and marrow function as defined below: 
 WBC ≥ 3,000/mcL 
 ANC ≥ 1,500/mcL 
 Platelets ≥ 100,000/mcL 
 Hemoglobin ≥ 9 g/dL  
 Serum albumin ≥ 3.0 g/dL 
 AST, ALT, and total bilirubin ≤ 1.5 x Institutional ULN  
 Creatinine ≤ 1.5 Institutional ULN or a calculated creatinine clearance ≥ 50 
mL/min using the Cockcroft Gault equation 
 PTT ≤ 60, INR ≤ 1.5 Institutional ULN unless on warfarin therapy 
(investigator would need to determine if safe for participant to stop warfarin 
prior to biopsy) 
3.1.13 Have signed an informed consent document indicating that the subjects understands 
the purpose of and procedures required for the study and are willing to participate in 
the study. 
3.1.14 Be willing/able to adhere to the prohibitions and restrictions specified in this 
protocol. 
3.1.15 Written Authorization for Use and Release of Health and Research Study 
Information (US sites only) has been obtained. 
3.1.16 Able to swallow the study drug whole as a tablet. 


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3.1.17 Participants who have partners of childbearing potential must be willing to use a 
method of birth control with adequate barrier protection as determined to be 
acceptable by the principal investigator during the treatment period and for 1 week 
after last dose of enzalutamide. 
 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study. 
3.2.1 Uncontrolled illness including, but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
or psychiatric illness/social situations that would limit compliance with study 
requirements within 6 months of enrollment.  
3.2.2 Clinically significant heart disease as evidenced by: 
 Myocardial infarction within 6 months of enrollment. 
 Uncontrolled angina within 6 months of enrollment. 
 Congestive heart failure NYHA Class III or IV, or a history of congestive 
heart failure NYHA Class III or IV in the past, unless a screening ECHO or 
MUGA within 3 months results in a left ventricular ejection fraction ≥ 45%.  
 Clinically significant ventricular arrhythmias. 
 History of Mobitz II second degree or third degree heart block without a 
permanent pacemaker in place. 
 Bradycardia as indicated by a heart rate < 50 beats per minute at screening 
visit.  
 Hypotension as indicated by SBP ≤ 85 on 2 consecutive measurements. 
 Uncontrolled hypertension as indicated by SBP > 170 mmHg or DBP > 105 
mmHg on 2 consecutive measurements at screening visit.   
3.2.3 Thromboembolism within 6 months of enrollment.  
3.2.4 History of gastrointestinal disorders (medical disorders or extensive surgery) which 
may interfere with the absorption of the study drug.  
3.2.5 History of seizure or any condition that may predispose to seizure (e.g., prior 
cortical stroke or significant brain trauma, history of loss of consciousness or 


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transient ischemic attack within 12 months of study entry) or concurrent medication 
that may predispose to seizure (see Appendix D).  Diabetics on a stable dose of 
insulin or antihyperglycemic regimen are allowed if they have had no prior seizures 
and no history of loss of consciousness due to hypoglycemia.   
3.2.6 Individuals with a history of a different malignancy and are on treatment for the 
malignancy or the malignancy is documented on screening or other imaging are 
ineligible. Individuals with a history of other malignancies are eligible if they are 
deemed by the investigator to be at low risk for recurrence of that malignancy. 
3.2.7 Known brain metastasis. Participants with brain metastasis can only be included if 
they were treated > 4 week prior to enrollment with radiation and the effects of 
treatment have resolved. Subjects with treated brain metastases must have a post-
treatment brain MRI showing no further progression of prior lesions and no new 
metastatic lesions. Subjects will be ineligible if they have any ongoing symptoms 
from brain metastases or if there continues to be radiographic evidence of cerebral 
edema. 
3.2.8 Have known allergies, hypersensitivity, or intolerance to enzalutamide or their 
excipients.  
3.2.9 Surgery or local prostatic intervention within 30 days of the first dose. In addition, 
any clinically relevant issues from the surgery must have resolved prior to 
enrollment. 
3.2.10 Major surgery or radiation therapy within 4 weeks of enrollment. 
3.2.11 Radium-223, strontium-89, or samarium-153 therapy within 4 weeks of enrollment.  
3.2.12 Radiotherapy, chemotherapy or immunotherapy within 4 weeks, or single fraction 
of palliative radiotherapy within 14 days of administration of enrollment. 
3.2.13 Prior treatment with enzalutamide.  
3.2.14 Current enrollment in an investigational drug or device study or participation in 
such a study within 30 days of enrollment. 
3.2.15 Concomitant use of medications that may alter pharmacokinetics of enzalutamide. 
See section 5.3.  
3.2.16 Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not 
resolved to a NCI CTCAE (version 4) grade of ≤ 1. Chemotherapy induced 
alopecia and grade 2 peripheral neuropathy are allowed.  
 
3.2.17 Condition or situation which, in the investigator’s opinion, may put the participant 
at significant risk, may confound the study results, or may interfere significantly 
with participant’s participation in the study. 


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3.2.18 Individuals not willing to comply with the procedural requirements of this protocol. 
 
3.2.19 HIV-positive individuals on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with enzalutamide. 
Appropriate studies will be undertaken in participants receiving combination 
antiretroviral therapy when indicated. 
 
3.3 
Inclusion of Minorities and Other Underrepresented Populations 
 
Every effort will be made to include men from minority populations. The enrollment of 
minority men will reflect the proportion of minority participants at the sites 
participating in the trial. 
 
 
4. REGISTRATION PROCEDURES 
   
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System 
(CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. 
Any participant not registered to the protocol before protocol therapy begins will be 
considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will 
complete the protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a 
participant does not receive protocol therapy following registration, the participant’s 
registration on the study must be canceled. Registration cancellations must be made in 
OnCore as soon as possible.  
 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Participating Institutions 
 
Eligible participants will be entered on study centrally at DFCI by the Study 
Coordinator. All sites should call the Study Coordinator at 
 to verify 
treatment availability. The required forms will be provided to all participating 
institutions by the DFCI study coordination.  
 


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Following registration, participants should begin protocol treatment within 5 days. 
Issues that would cause treatment delays should be discussed with the Overall PI.  If a 
participant does not receive protocol therapy following registration, the participant’s 
registration on the study may be canceled.  The Study Coordinator should be notified of 
cancellations as soon as possible. 
 
4.4 
Registration Process for Other Participating Institutions 
 
To register a participant, the documents listed in Appendix B should be completed by 
the research nurse or data manager and faxed to 
 or emailed to the DFCI 
study coordinator (see section 3.7.1 of the DSMP (Appendix E).  
 
The research nurse or data manager at the participating site will then call or e-mail  the 
Study Coordinator to verify eligibility. To complete the registration process, the 
Coordinator will follow DF/HCC Standard Operating Procedure for Human Subject 
Research Titled Subject Protocol Registration (SOP #: REGIST-101) and register the 
participant on the protocol.  The coordinator will fax or e-mail the participant study 
number, and if applicable the dose treatment level, to the participating site. 
 
 
 
 
 


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5. TREATMENT PLAN  
All protocol required therapy will be prescribed by prescription and taken by the participant 
on an outpatient basis. A baseline metastasis biopsy will be done prior to starting protocol 
therapy.  
Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide 
taken orally. All participants without orchiectomy will be maintained on LHRH 
agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies 
on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation 
of study treatment to time of discontinuation from the study (Appendix C). Participants will be 
continued on therapy until evidence of symptomatic or radiographic progression or taken off 
study for another reason.  
A metastasis biopsy will be performed while the participant is still on enzalutamide at the time 
of progression.   For DFCI participants, if the biopsy site (baseline and progression) is a pelvic 
bone both an aspirate and core biopsy will be obtained.  After progression biopsy is 
performed, protocol therapy will be discontinued. Participants who stop protocol therapy 
before receiving four cycles of enzalutamide will not be asked to undergo a second biopsy. 
The tumor biopsy at the end of study is otherwise mandatory and can be done +/- 14 days of 
determination of progression. Situation where the participant stops protocol therapy for 
reasons other than progression after receiving 4 cycles of enzalutamide should be discussed 
with the PI if it is felt that biopsy would not represent progressive disease. For DFCI 
participants, quantitative SPECT/CT imaging substudy will be performed in addition to 
standard bone scanning at baseline and at the time of the first two follow up bone scans. 
 
Expected toxicities and potential risks as well as dose modifications for enzalutamide are 
described in Section 6 (Expected Toxicities and Dosing Delays/Dose Modifications). No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy.  
 
Treatment Description 
Agent 
Pre-medications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Enzalutamide 
Can be taken with or 
without food. The 
capsules should be 
swallowed whole 
with water. Do not 
chew, dissolve, or 
open capsules. 
160 mg 
Oral 
Once daily 
28 days 
(4 weeks) 
 
5.1 
Pre-treatment Criteria 
   
5.1.1 Cycle 1, Day 1: The following parameters must be met: 


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 WBC ≥ 3,000/mcL 
 ANC ≥ 1,500/mcL 
 Hemoglobin ≥ 9 g/dL  
 AST/ALT ≤ 1.5 x Institutional ULN 
 Total bilirubin ≤ 1.5 x Institutional ULN 
 
If these parameters are not met, the participant can be evaluated on a weekly 
basis.  
 
Agent Administration  
 
5.2.1 Enzalutamide 
 Administration: 160 mg (oral) once daily. Treatment will be continued until 
evidence of symptomatic or radiographic progression or the participant is taken 
off the study for another reason.  
 
 Dosing: 160 mg (oral) taken once daily as four 40 mg capsules. Possible dose 
modifications are outlined in Section 6.  
 
 Vital Signs: Vital signs including blood pressure, pulse, weight and temperature 
should be taken on day 1 of each cycle, and at the time of any symptom 
evaluation.  
 
 Compliance: Enzalutamide can be taken with or without food. Enzalutamide may 
be taken at any time during the day, but should be taken at the same time each 
day. A missed dose should be taken as soon it is remembered. If twelve or more 
hours have lapsed since a missed dose, participants should not take the missed 
dose; rather the participant should resume dosing at the next scheduled dose. 
Participants should not double up or take more than one dose of enzalutamide per 
day. Vomited doses should not be made up. If doing compliance is not 100% in 
the absence of toxicity, the participant should be re-instructed regarding the 
proper dosing procedures and continue in the protocol. Participants will be asked 
to record actual dosing in a drug diary (Appendix C).  
5.3 
General Concomitant Medications and Supportive Care Guidelines  
 
Supportive Care Radiation 
Palliative radiation to any bone lesion is allowed if the patient has otherwise stable 
disease.  Local palliative radiation to the area of the prostate or pelvis may also be 
allowed if the patient has otherwise stable disease. 
 
Drugs that Inhibit or Induce CYP2C8 
In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of 
enzalutamide was administered alone or after multiple oral doses of gemfibrozil (strong 


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CYP2C8 inhibitor). Gemfibrozil increased the composite AUC of enzalutamide plus N-
desmethyl enzalutamide by 2.2-fold with minimum effect on Cmax. Therefore, co-
administration of enzalutamide with strong CYP2C8 inhibitors should be avoided as 
they would require a dose reduction of enzalutamide, which will not be permitted at 
study drug initiation.  If co-administration of enzalutamide with a strong CYP2C8 
inhibitor cannot be avoided, the dose of enzalutamide should be reduced to 80 mg once 
daily.  
 
The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not 
been evaluated in vivo. Co-administration of enzalutamide with strong or moderate 
CYP2C8 inducers (i.e. rifampin) may alter the plasma exposure of enzalutamide and 
should be avoided.  
 
 
 
 
Drugs that Inhibit or Induce CYP3A4 
In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of 
enzalutamide was administered alone or after multiple oral doses of itraconazole (strong 
CYP3A4 inhibitor). Itraconazole increased the AUC0-∞ of enzalutamide plus N-
desmethyl enzalutamide by 1.3-fold with no effect on Cmax. 
 
The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not 
been evaluated in vivo. Co-administration of enzalutamide with strong CYP2C8 
inducers (i.e. carbamazepine, phenobarbital, phenytoin, rifabutin, rifamin, rifapentine) 
may decrease the plasma exposure of enzalutamide and should be avoided. Moderate 
CYP3A4 inducers (i.e. bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. 
John’s Wort may also reduce the plasma exposure of enzalutamide and should be 
avoided.  
 
 
 
 
Effects of Enzalutamide on Drug Metabolizing Enzymes 
In an in vivo phenotypic cocktail drug-drug interaction trial in patients with CRPC, a 
single oral dose of the CYP probe cocktail (for CYP2C8, CYP2C9, CYP2C19, 
CYP3A4) was administered before and concomitantly with enzalutamide (following at 
least 55 days of dosing at 160 mg daily). Results showed that in vivo, at steady state, 
enzalutamide reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin 
(CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Thus, enzalutamide is a 
strong CYP3A4 inducers and a moderate CYP2C9 and CYP2C19 inducer. Concomitant 
use of enzalutamide with narrow therapeutic index drugs that are metabolized by 
CYP3A4 (i.e. alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (i.e. phenytoin, warfarin) and 
CYP2C19 (i.e. S-mephenytoin) should be avoided, as enzalutamide may decrease their 
exposure. If co-administration with warfarin cannot be avoided, additional INR 
monitoring is warranted. In this study, enzalutamide did not cause clinically meaningful 
changes in exposure to the CYP2C8 substrate (pioglitazone). 
 
In vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic 
acid metabolite caused direct inhibition of multiple CYP enzymes including CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5; however, subsequent clinical 


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data showed that enzalutamide is an inducer of CYP2C9, CYP2C19, and CYP3A4 and 
had no clinically meaningful effect on CYP2C8. In vitro, enzalutamide caused time-
dependent inhibition of CYP1A2. 
 
In vitro studies showed that enzalutamide caused induction of CYP3A4 and that 
enzalutamide is not expected to induce CYP1A2 at therapeutically relevant 
concentrations. In vitro, enzalutamide, N-desmethyl enzalutamide, and the major 
inactive carboxylic acid metabolite are not substrates for human P-glycoprotein. In 
vitro, enzalutamide and N-desmethyl enzalutamide are inhibitors of human P-
glycoprotein, while the major inactive carboxylic acid metabolite is not. 
 
Class  
Example Drugs 
Recommendation 
Strong CYP2C8 
Inhibitors  
Gemfibrozil 
If co-administration with 
gemfibrozil cannot be avoid, 
reduce enzalutamide dose 
Strong CYP2C8 
Inducers  
Rifampin  
Concomitant use ineligible 
Strong CYP3A4 
Inhibitors  
Itraconazole 
No initial dose adjustment  
Strong/Moderate 
CYP3A4 
Inducers  
Carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifamin, 
rifapentine, osentan, efavirenz, 
etravirine, modafinil, nafcillin, 
and St. John’s Wort 
Concomitant use ineligible 
CYP3A4 
Substrate  
Alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, 
sirolimus and tacrolimus 
Avoid concomitant use of 
substrates with a narrow 
therapeutic index  
CYP2C9 
Substrate  
Phenytoin, warfarin 
Avoid concomitant use of 
substrates with a narrow 
therapeutic index 
CYP2C19 
Substrate  
S-mephenytoin 
Avoid concomitant use of 
substrates with a narrow 
therapeutic index 
CYP2C8 
Substrate 
Pioglitazone 
No dose adjustment  
 
If at any time an investigator suspects a drug-drug interaction due to enzalutamide, the 
PI, 
 should be contacted at 
 or paged at 
 Additional information is provided in the enzalutamide 
Investigator’s Brochure.  
 
 
 
 


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5.4 
Duration of Therapy  
 
Duration of therapy will depend on individual response, evidence of disease 
progression, and tolerance. In the absence of treatment delays due to AEs, treatment 
may continue until one of the following criteria: 
 
 Symptomatic or radiographic disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable AE(s) 
 Treatment emergent seizure  
 Participant decided to withdraw from the study 
 General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the opinion of the treated investigator.  
 
Protocol therapy may be held for up to six weeks in the event of an AE and the 
participant may be restarted on therapy when the toxicity has resolved to ≤ grade 1, In 
the event of therapy being held for more than six weeks, it is recommended that the 
participant come off protocol however the treating physician may obtain permission to 
continue on the protocol with permission of the PI, 
 if the 
treating physician feels it is in the participant’s best interest.  
 
5.5 
Duration of Follow-Up 
 
Participants will be followed for up to 5 years post-study discontinuation or until death, 
whichever comes first. Participant follow up visits will be at the research clinic for the 
first 2 years of follow-up.  Following the first 2 years, participant follow-up can be done 
via medical record review and/or by phone.  Participants will be followed for 
subsequent lines of therapy, including line of agent, name of agent, and PSA kinetics 
following study drug discontinuation and correlate with response to study drug.  This 
information will be updated every 6 months.  The research team will collect this 
information during patient clinic visits, by phone, or via medical record review. 
 
5.6 Criteria for Removal from Study 
 
Participants will be removed from study when any of the criteria listed in Section 5.4 
applies. The reason for study removal and the date the participant was removed must 
be documented in the study-specific CRF. Alternative care options will be discussed 
with the participant.  
 
Participants will be removed from treatment at the time of unacceptable AEs but will 
remain on study (i.e. enrolled on the protocol) until resolution of any AEs.  
 
In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the PI, 
 at 
 or page 
  


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6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
The starting dose of enzalutamide will be 160 mg daily. In the presence of any enzalutamide 
related toxicities > grade 2 (NCI CTCAE version 4), during treatment with enzalutamide at 
the starting dose level, the dose of enzalutamide will be decreased to 120 mg daily in the 
subsequent dose level. Two levels of dose de-escalation are planned for the study. If > grade 
2 toxicity occurs at dose level -2, participants will be removed from the protocol.  
 
Dose Level 
Enzalutamide 
Starting dose level 
160  mg orally once daily  
-1 
120 mg orally once daily  
-2 
80 mg orally once daily  
 
Toxicity assessments will be done using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) (version 4) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All AEs experienced by participants will be collected from the time of the first dose of study 
treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
 
6.1 
Anticipated Toxicities 
  
A list of the AEs and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be 
made or whether the event requires expedited reporting in addition to routine reporting. 
  
6.1.1 AEs for Enzalutamide  
 
In the randomized clinical trial in patients with metastatic CRPC who had 
previously received docetaxel, patients received enzalutamide 160 mg orally 
once daily (N = 800) or placebo (N = 399). The median duration of treatment 
was 8.3 months with enzalutamide and 3.0 months with placebo. All patients 
continued ADT. Patients were allowed, but not required, to take glucocorticoids. 
During the trial, 48% of patients on the enzalutamide arm and 46% of patients on 
the placebo arm received glucocorticoids. All AEs and laboratory abnormalities 
were graded using NCI CTCAE version 4. 
 


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The most common adverse drug reactions (≥ 5%) reported in patients receiving 
enzalutamide in the randomized clinical trial were asthenia/fatigue, back pain, 
diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, 
Institutional ULN respiratory infection, muscular weakness, dizziness, insomnia, 
lower respiratory infection, spinal cord compression and cauda equina syndrome, 
hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse 
reactions were reported among 47% of enzalutamide -treated patients and 53% of 
placebo-treated patients. Discontinuations due to AEs were reported for 16% of 
enzalutamide-treated patients and 18% of placebo-treated patients. The most 
common adverse reaction leading to treatment discontinuation was seizure, 
which occurred in 0.9% of the enzalutamide-treated patients compared to none 
(0%) of the placebo-treated patients.  
 
Seizures 
In the randomized clinical trial, 7 of 800 (0.9%) patients treated with 
enzalutamide 160 mg once daily experienced a seizure. No seizures occurred in 
patients treated with placebo. Seizures occurred from 31 to 603 days after 
initiation of enzalutamide. Patients experiencing seizure were permanently 
discontinued from therapy and all seizures resolved. There is no clinical trial 
experience regarding re-administering enzalutamide to patients who experienced 
seizures. See Appendix D for representative medications that may predispose to 
seizure.  
 
Laboratory Abnormalities 
In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of 
patients on enzalutamide (1% Grade 3-4) and in 6% of patients on placebo (no 
Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both 
arms; 0.5% of patients on enzalutamide and 1% on placebo experienced Grade 3-
4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on 
enzalutamide (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-
4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on enzalutamide 
and 2% of patients on placebo. 
 
Infections 
In the randomized clinical trial, 1.0% of patients treated with enzalutamide 
compared to 0.3% of patients on placebo died from infections or sepsis. 
Infection-related SAEss were reported in approximately 6% of the patients on 
both treatment arms. 
 
Falls and Fall-related Injuries 
In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% 
of patients treated with enzalutamide compared to 1.3% of patients on placebo. 
Falls were not associated with loss of consciousness or seizure. Fall-related 
injuries were more severe in patients treated with enzalutamide and included 
non-pathologic fractures, joint injuries, and hematomas. 


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Hallucinations 
In the randomized clinical trial, 1.6% of patients treated with enzalutamide were 
reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on 
placebo. Of the patients with hallucinations, the majority were on opioid-
containing medications at the time of the event. Hallucinations were visual, 
tactile, or undefined. 
 
6.2 
Toxicity Management/Dose Modifications/Delays 
 
Enzalutamide is generally well-tolerated based on phase III data. Instructions on 
management of enzalutamide related toxicities > grade 2 (NCI CTCAE version 4) are 
detailed in section 6.0. Evidence of seizure will results in cessation of treatment with 
enzalutamide and withdrawal from the study. Management of other toxicities is detailed 
below. 
 Grade 1-2 Toxicities: Management per investigator. No study treatment dose 
reduction indicated.  
 Grade 3 of Higher Toxicities: Hold enzalutamide. Enzalutamide can be held for a 
maximum of 6 weeks. Hold will not affect assessment schedule. When toxicity 
resolves to ≤ grade 1, resume at first dose modification level (120 mg daily). 
Prophylactic medications should be considered. If toxicity recurs, hold study 
medication and adjust or add medications to mitigate the toxicity. When 
recurrent toxicity has resolved to ≤ grade 1, resume enzalutamide at 80 mg daily. 
If grade 3 toxicity recurs, the participant will be discontinued from the study. 
 
Dose may NOT be re-escalated after it has been reduced. 
 
 
 


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7. DRUG FORMULATION AND ADMINISTRATION  
 
7.1 
Enzalutamide  
 
Refer to the package insert for enzalutamide information. 
 
7.1.1 Description 
Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-
cyano-3-(trifluoromethyl)phenyl]-5,5dimethyl-4-oxo-2-
sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. 
The molecular weight is 464.44 and molecular formula is C21H16F4N4O2S. 
 
7.1.2 Mechanism of Action 
Enzalutamide is an androgen receptor inhibitor that acts on different steps in the 
androgen receptor signaling pathway. Enzalutamide has been shown to 
competitively inhibit androgen binding to androgen receptors and inhibit androgen 
receptor nuclear translocation and interaction with DNA. A major metabolite, N-
desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. 
Enzalutamide decreased proliferation and induced cell death of prostate cancer cells 
in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model. 
 
7.1.3 Pharmacokinetics 
The pharmacokinetics of enzalutamide and its major active metabolite (N-
desmethyl enzalutamide) were evaluated in patients with metastatic CRPCand 
healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately 
described by a linear two-compartment model with first-order absorption. 
 
Absorption 
Following oral administration (enzalutamide 160 mg daily) in patients with 
metastatic CRPC, the median time to reach Cmax is 1 hour (range 0.5 to 3 hours). At 
steady state, the plasma mean Cmax values for enzalutamide and N-desmethyl 
enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, 
and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 
μg/mL (30% CV), respectively. 
With the daily dosing regimen, enzalutamide steady state is achieved by Day 28, 
and enzalutamide accumulates approximately 8.3-fold relative to a single dose. 
Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-
trough ratio of 1.25). At steady state, enzalutamide showed approximately dose 
proportional pharmacokinetics over the daily dose range of 30 to 360 mg. 
A single 160 mg oral dose of enzalutamide was administered to healthy volunteers 
with a high-fat meal or in the fasted condition. A high-fat meal did not alter the 
AUC to enzalutamide or N-desmethyl enzalutamide.  


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Distribution and Protein Binding 
The mean apparent volume of distribution of enzalutamide in patients after a single 
oral dose is 110 L (29% CV). Enzalutamide is 97% to 98% bound to plasma 
proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma 
proteins. 
 
Metabolism 
Following single oral administration of 14C-enzalutamide 160 mg, plasma samples 
were analyzed for enzalutamide and its metabolites up to 77 days post dose. 
Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid 
metabolite accounted for 88% of the 14C-radioactivity in plasma, representing 30%, 
49%, and 10%, respectively, of the total 14C-AUC0-∞. 
In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of 
enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible 
for the formation of the active metabolite (N-desmethyl enzalutamide). 
 
Elimination 
Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral 
administration of 14C-enzalutamide 160 mg, 85% of the radioactivity is recovered 
by 77 days post dose: 71% is recovered in urine (including only trace amounts of 
enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% 
of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide). 
 
The mean apparent clearance of enzalutamide in patients after a single oral dose is 
0.56 L/h (range 0.33 to 1.02 L/h). 
 
The mean terminal t1/2 for enzalutamide in patients after a single oral dose is 5.8 
days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide 
in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is 
approximately 7.8 to 8.6 days. 
 
7.1.4 Form 
Enzalutamide is a white crystalline non-hygroscopic solid. It is practically 
insoluble in water. Enzalutamide is provided as liquid-filled soft gelatin 
capsules for oral administration. Each capsule contains 40 mg of enzalutamide 
as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are 
caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated 
hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, 
titanium dioxide, and black iron oxide. 
 
7.1.5 Storage and Stability 
Pharmacy Storage Requirements 
The study treatment will be stored in a secure area and administered only to 
participants entered into the clinical study in accordance with the conditions 
specified in this protocol. Bottles of study treatment should be stored at a room 


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temperature between 20º-25º C in a dry place and kept with container tightly 
closed.  
 
Storage Requirements for the Participant 
Bottles of study treatment should be stored at room temperature with the cap 
kept on tightly and should not be refrigerated. Participants should be advised to 
keep all medications out of the reach and out of sight of children. 
 
Enzalutamide should not be handled by pregnant women. 
 
7.1.6 Compatibility 
Treatment with enzalutamide will be administered via oral capsules. 
Enzalutamide is the only treatment agent which will be administered on the 
protocol.  
7.1.7 Handling 
There are no specific instructions for handling enzalutamide. Study treatment 
must only be dispensed by a Pharmacist or medically qualified staff. Study 
treatment is to be dispensed only to participants enrolled in this study. Once the 
study treatment is prepared for a participant, it can only be administered to that 
participant.  
 
7.1.8 Availability 
Enzalutamide capsules will be provided to each site. Participants will be provided 
with a 30-day supply to allow for visits to occur every 28 days with a ± 3 day 
window. Information presented on the labels for investigative product will 
comply with applicable local regulations. Site pharmacist will dispense the study 
treatment to each participant in accordance with this protocol under the guidelines 
of the site’s dispensation standard operating procedure. The agentwill be provided 
from commercial supply and will be provided free-of-charge.  
 
7.1.9 Ordering 
Enzalutamide is to be ordered from Astellas Pharmaecuticals or their designee.  A 
drug order form as well as instructions on how to order study drug will distributed 
to study sites prior to site activation.  
 
7.1.10 Accountability 
Accountability for study treatment is the responsibility of the investigator.  
 
The study site must maintain accurate records demonstrating dates and amount of 
study treatment (enzalutamide) received, to whom dispensed (participant by 
participant accounting), and accounts of any study treatment accidentally or 
deliberately destroyed. At the end of the study, reconciliation must be made 
between the amount of study treatment supplied, dispensed, and subsequently 
destroyed. 


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At the time of delivery of study treatment to the site, the investigator, designee, or 
Pharmacist (where appropriate) will confirm that the supplies for the study have 
been received. This following information will be confirmed: lot numbers, 
quantities shipped/delivered, and date of receipt. 
 
7.1.11 Destruction and Return 
Drug should be destroyed at the site, after the sponsor– investigator approves the 
drug destruction policy at the site. Destruction will be documented in the Drug 
Accountability Record Form.  
 
8. CORRELATIVE/SPECIAL STUDIES 
 
Correlative studies will include analysis of prostate tumor from serial biopsies for AR 
modifications including AR sequence-mutations/splice variants, AR regulated gene 
expression, tumor androgen levels, profiling of enzymes involved in androgen synthesis 
and metabolism, and whole- exome and transcriptome sequencing. In addition, as an 
exploratory analysis we will analyze CTCs for mechanisms of AR resistance to include AR 
nuclear localization, AR sequencing, AR splice variant analysis and whole-exome and 
transcriptome sequencing. Lastly, we will analyze circulating tumor DNA for mechanisms 
of AR resistance to include AR sequencing and whole- exome and transcriptome 
sequencing.  In addition, serum androgens will be measured. The correlative studies are 
required. A Laboratory Manual with instructions on sample collection and processing will 
be provided to study sites.  
 
CTC research samples will be sent to the 
 at the University of Wisconsin for 
analysis purposes.  
8.1 
Statistical Data Analysis 
 
Determination of biological and molecular endpoints to analyze possible AR related 
mechanisms of resistance to enzalutamide in serial tumor biopsies will occur as 
follows: 
 
 AR sequencing  
o Mutations – continuous variable from microarray data 
o TMPRSS2:ERG translocation status – categorical variable from PT 
PCR (yes vs. no) 
o AR splice variants – categorical variable from RT PCR (native vs. 
alternative) 
 AR regulated gene expression – continuous variable from microarray data  
 Tumor androgen levels – continuous variable from mass spectroscopy data  
 Profiling of enzymes involved in androgen synthesis/metabolism – continuous 
variable from microarray data 


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 Whole-exome and transcriptome sequencing – continuous variable from 
sequencing analysis  
 
Continuous data will be evaluated by calculating mean percent change in level. 
Categorical data will be evaluated by yes/no change in status. Ordinal/count number 
data will be evaluated by mean percent change in total count.  


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9.  STUDY CALENDAR 
 
 
Pre- Studya 
Day 1 of Each Cycleb      
(+/- 3 days) 
Every 12 weeks 
(+/- 1 week) 
End of Treatment 
Visitq 
Follow Up Visitsr 
(Every 6 months 
+/- 1 month) 
Informed Consent 
X 
 
 
 
 
History and Physicalc 
X 
X 
 
X 
 
ECOG Performance 
Status 
X 
X 
 
X 
 
Vital Signsd 
X 
X 
 
X 
 
Hematologye 
X 
X 
 
X 
 
Serum Chemistryf 
X 
X 
 
X 
 
Liver Function Testg 
X 
X 
 
X 
 
Coagulation Factorsh 
X 
 
 
 
 
EKG 
X 
 
 
 
 
Serum Testosterone 
X 
 
 
 
 
Research Labsi 
X 
X 
X 
X 
 
PSAj 
X 
X 
 
X 
X 
CT/MRIk 
X 
 
X 
 
 
Bone Scanl 
X 
 
X 
 
 
Distributionm 
 
X 
 
 
 
Compliance Assessment 
 
X 
 
 
 


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Prior and Concomitant 
Medications 
X 
X 
 
 
 
Adverse Eventsn 
X 
X 
 
X 
 
Tumor Biopsyo 
X 
 
 
Xp 
 
a: Baseline evaluations are to be conducted within 30 days prior to registration. Scans must be done within 60 days prior to 
registration. All baseline screening should be done prior to registration.  
b: A cycle will be defined as 28 days.  
c: Physical examination should include general description of participant, head, eyes, ears, nose, and throat, chest, abdominal, 
extremities, neurologic, skin, and lymph node examination. Any other evaluation is up to the discretion of the practitioner. It will 
not be considered a violation if the exam is not described as outlined here.  
d: Vital signs included upright blood pressure, heart rate, respiratory rate, body temperature and weight.  
e: Hematology testing to include WBC, ANC, hemoglobin, and platelet count.  
f: Serum chemistry to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, albumin, magnesium.  
g: LFTs to include AST, ALT, alkaline phosphatase, total bilirubin and direct bilirubin.  
h: Coagulation factors to include PT, PTT, and INR.  
i: Research labs to include a blood sample for germline DNA/RNA analysis, serum hormones (to include DHEA, DHEA-S, 
androstenedione, testosterone, DHT), a blood sample for circulating tumor DNA analysis, a blood sample for CTC analysis. Blood 
for germline DNA/RNA will be collected at pre-study visit. Hormone levels will be collected at pre-study visit, every 12 weeks on 
study, at off-study. CTCs will be collected at pre-study visit, Day 1 of each cycle, and off study. Pre-study and off study CTC 
samples will be shipped overnight. CTCs collected on Day 1 of each cycle will be processed (buffy coat) and stored for delivery. 
Circulating tumor DNA will be collected at pre-study visit, every 12 weeks on study, at off-study.  
j: If a digital rectal examination is performed, PSA must be sampled prior to the examination.  For patients enrolling for PSA 
progression, this is defined as a rise in PSA on two successive determinations at least one week apart and PSA levels ≥ 2 ng/ml 
(only the screening PSA needs to be ≥ 2 ng/ml).  
k: If baseline CT chest does not demonstrate prostate cancer, do not need to be repeated on study unless the investigator suspects 
new findings based on clinical signs/symptoms.  
l: For DFCI participants only, one bed position of quantitative SPECT/CT will be performed as an imaging substudy concurrently 
with the standard of care bone scans at baseline and at the time of the first two follow up standard of care bone scans. The field of 
view will be determined by the nuclear medicine physician depending on the location of the lesions on the planar images. 
m: Study agent is enzalutamide. Subjects with be continued on LHRH agonist/antagonist as prescribed. Subjects will begin taking 
study agent on Day 1/Cycle 1.  
n: AEs should be collected from the date informed consent is signed until 30 days after discontinuation from the study.  
o: Tumor biopsy must be performed prior to starting study medication. Participants will need to be screening and registered before 
having a biopsy. Friday should be avoided due to difficult of processing bone biopsies on the weekend.  For DFCI participants, if 
the biopsy site (baseline and progression) is a pelvic bone both an aspirate and core biopsy will be obtained.   
p: Participants who stop the protocol therapy before receiving four cycles of enzalutamide will not be asked to undergo the second 
biopsy. The tumor biopsy at the end of the study can be done +/- 14 days of the determination of progression. Enzalutamide will be 
discontinued following completion of the second biopsy. Situations where the participant stops protocol therapy for reasons other 
than progression after receiving four cycles of enzalutamide should be discussed with the PI if it felt that the biopsy would not 
represent progressive disease. 
q: The End of Treatment Visit will be the visit at which it is determined that the patient will no longer be taking treatment given 
disease progression, toxicity, or other reason. 
r: Follow up Visits: Participants will be followed for up to 5 years post-study discontinuation or until death, whichever comes first. 
Participant follow up visits will be at the research clinic for the first 2 years of follow-up.  Following the first 2 years, participant 
follow-up can be done via medical record review and/or by phone.  Participants will be followed for subsequent lines of therapy, 
including line of agent, name of agent, and PSA kinetics following study drug discontinuation and correlate with response to study 
drug.  This information will be updated every 6 months.  The research team will collect this information during patient clinic visits, 
by phone, or via medical record review. 
 
 


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10. MEASUREMENT OF EFFECT  
 
Although response is not the primary endpoint of this trial, participants with measurable 
disease will be assessed by RECIST (1.1) for soft tissue progression, PCWG-2 (2008) for 
bone disease progression, bone scan and PSA criteria. For the purposes of this study, 
participants will be evaluated every four weeks by PSA and every 12 weeks by CT and bone 
scan. Participants should not be taken off treatment until documented symptomatic 
progression or progression by imaging.  
 
The following will be used to determine progression in this study: 
 
 PSA Progression: For those who experience a decline on PSA from baseline, PSA 
progression will be defined as an increase in PSA that is ≥ 25% and ≥ 2 ng/mL above 
nadir which is confirmed by a second value three or more weeks later. For 
participants who do not experience a decline from baseline, PSA progression will be 
defined as PSA ≥ 25% and ≥ 2 ng/mL after 12 weeks. 
 
 Radiographic Disease Progression: For bone disease, radiographic progression will 
be defined as the appearance of ≥ 2 new lesions on bone scan. For soft tissue/lymph 
node disease, radiographic progression will be defined using RECIST 1.1 criteria.  
PCWG-2 (2008) will be used to define bone disease progression.  
 
 If any of the following criteria that are also described in Section 5.4 are met: 
 Symptomatic or radiographic disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable AE(s) 
 Treatment emergent seizure  
 Participant decided to withdraw from the study 
 General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the opinion of the treated investigator.  
10.1 
Antitumor Effect– Solid Tumors 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the RECIST 1.1.  
10.1.1 Definitions 
Evaluable for Target Disease Response. Only those participants who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for 
target disease response. These participants will have their response classified 
according to the definitions stated below. Note: Participants who exhibit 
objective disease progression or die prior to the end of cycle 1 will also be 
considered evaluable. 


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Evaluable for Non-Target Disease Response. Participants who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for non-target disease 
response. These participants will have their response classified according to the 
definitions stated below. (Note: Participants who exhibit objective disease 
progression or die prior to the end of cycle 1 will also be considered evaluable.) 
10.1.2 Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one (1) lesion 
that can be accurately measured in at least one dimension with longest diameter  
> 20 millimeters (mm) using conventional techniques (CT, MRI, x-ray) or  >10 
mm with spiral CT scan. Measurable lesions must be at least 2 times the slice 
thickness in mm. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). Ultrasound cannot be used to measure lesions. 
A lesion in a previously irradiated area is not eligible for measurable disease 
unless there is objective evidence of progression of the lesion prior to study 
enrollment. Lesions in previously irradiated areas must be clearly identified as 
such.  
 
Malignant lymph nodes. To be considered pathologically enlarged and 
measurable, a lymph node must be > 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm) or pathological lymph nodes with > 10 to < 
15mm short axis, are considered non-measurable disease. Leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, abdominal masses identified by physical exam that 
are not measurable by reproducible imaging techniques, and cystic lesions are all 
considered non-measurable. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Lesions must be 
accurately measured in 1 dimension with a minimum size of 10 mm by CT or 
MRI (slice thickness no greater than 5 mm), 20 mm by chest x-ray. Nodes must 
have a short axis > 15 mm. The short axis should be included in the sum of the 
lesions in the calculation of response. Nodes that shrink to < 10 mm are 
considered normal. Target lesions should be selected on the basis of their size, be 
representative of all the involved organs, and should be lesions that can be 
followed with reproducible repeated measurements.  


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Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered target lesions if the soft tissue component meets 
the definition of measurability as defined above. Cystic lesions thought to 
represent cystic metastases can be considered as target lesions. However, if non-
cystic lesions are present, these are preferred for selection as target lesions. 
Lesions in previously irradiated areas or areas subject to other loco-regional 
therapy are usually not considered measurable unless there has been 
demonstrated progression of that lesion.  
Non-target lesions. All other lesions, including small lesions < 10 mm or 
pathological lymph nodes measuring > 10 mm to < 15 mm in short axis, as well 
as truly non-measurable lesions, which include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses identified by physical exam that 
are not measurable by reproducible imaging techniques.  
10.1.3 Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation, using a ruler, 
calipers, or digital measurement tool. 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 anti-tumor effect of a 
treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and > 10 mm in 
diameter as assessed using calipers. For the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung; however, CT 
is preferable. 
Conventional CT and MRI. These techniques should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the 
chest, abdomen, and pelvis. Head and neck tumors and those of extremities 
usually require specific protocols. 


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Tumor markers. Tumor markers alone cannot be used to assess response. The 
following parameters will be recorded on a monthly basis: 
 PSA decline will be measuring according to revised PCWG-2 (2008) 
criteria.[26] 
 PSA changes will be recorded on all participants. 
 TTPP will be based on revised PCWG-2 (2008) criteria.  
 The maximal decline in PSA for each participant will be recorded for 
each participant. 
 The date of the maximal PSA decline (nadir date) will be recorded for 
each participant, as will the duration from the start of therapy to the 
nadir PSA.   
10.1.4 Response Criteria  
10.1.4.1 Evaluation of Target Lesions 
  
Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph node must have reduction in short axis to < 10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum diameters. 
 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
with at least a 5 mm absolute increase in the sum of all lesions. The 
appearance of one or more new lesions* denotes disease progression.  
 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must 
be given. 
Note: If tumor response data is missing for target lesions, the overall 
assessment must be UN unless there is new disease that would result in an 
overall assessment of PD. However, if there is missing or unevaluable data 
for non-target lesions, but data is available for all target lesions, the overall 
response for that time point will be assigned based on the sum LD of all 
target lesions. Additionally, the assessment of CR cannot be made if there 
is missing or unevaluable data for non-target lesions. In this case, the 
overall assessment would be PR. 


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*Definition of New Lesion: The finding of a new lesion should be 
unequivocal (i.e. not due to difference in scanning technique, imaging 
modality, or findings thought to represent something other than tumor (ex: 
new bone lesions may be healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical location 
that was not scanned at baseline is considered new and will indicate PD. If 
a new lesion is equivocal (because of small size, etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is 
confirmed, progression should be declared using the date of the initial scan 
on which the lesion was discovered.  
10.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis).  
Note: If tumor markers are initially above the Institutional ULN normal 
limit, they must normalize for a subject to be considered in complete 
clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesions 
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. 
When the participant also has measurable disease, to achieve 
‘unequivocal progression’ on the basis of the non-target disease, 
there must be an overall level of substantial worsening in non-
target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. A modest ‘increase’ in the size 
of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be 
extremely rare. When the participant has only non- measurable 
disease, worsening in non-target disease cannot be easily 
quantified. A useful test that can be applied when assessing non-
targets for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in 
tumor burden representing an additional 73% increase in ‘volume’ 


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(which is equivalent to a 20% increase diameter in measurable 
lesions), an increase in pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from ‘localized’ to ‘widespread’. 
 
Unknown (UN): Assessment of non-target lesions cannot be made due 
to insufficient or unevaluable data. In this case, a concise explanation 
must be given. 
 
*Definition of New Lesion: The finding of a new lesion should be 
unequivocal (i.e. not due to difference in scanning technique, imaging 
modality, or findings thought to represent something other than tumor 
(ex: new bone lesions may be healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size, etc.), 
follow-up evaluation will clarify if it truly represents new disease and if 
PD is confirmed, progression should be declared using the date of the 
initial scan on which the lesion was discovered.  
10.1.4.3  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 participant's best response assignment will 
depend on the achievement of both measurement and confirmation 
criteria. 
For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for 
when Confirmation is 
Required: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not 
evaluated 
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:   Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration". Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
For Participants with Non-Measurable Disease (i.e., Non-Target 
Disease) 
Non-Target Lesions 
New 
Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD* 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*Non-CR/non-PD is preferred over stable disease for non-target disease since SD is 
increasingly used an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised.  
10.1.5 Duration of Response 
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 recurrence or progressive disease (PD) is 
objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started, or death due to any cause. 
Participants without events reported are censored at the last disease 
evaluation. 
Duration of overall complete response: The duration of overall CR is 
measured from the time measurement criteria are first met for CR until the 
first date that recurrent or progressive disease is objectively documented, or 
death due to any cause. Participants without events reported are censored at 
the last disease evaluation. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 
10.1.6 Time to Progression  


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Time to Progression: Time to Progression (TTP) is defined as the time from 
registration to progression, or censored at the date of last disease evaluation for 
those without progression reported. 
10.1.7 Response Review 
Central review of the radiology assessments is planned using tumor metrics 
core at the DFCI. 
10.2 Other Response Parameters 
Descriptive statistics (including mean, standard deviation (SD), minimum, 
maximum, median, interquartile range) will be provided on levels of serum 
hormones and changes from baseline.  
10.2.1 SPECT/CT 
In an imaging substudy, patients enrolled at DFCI only will undergo quantitative 
SPECT/CT as part of the standard of care bone scans at baseline, and at the time of the 
first two follow up bone scans. The field of view will be determined by the nuclear 
medicine physician depending on the location of the lesions on the planar images. The 
imaging parameters for SPECT/CT will follow DFCI institutional policies for 
SPECT/CT bone scanning. xSPECT Quant software will be used to determine activity 
concentration on quantitative SPECT/CT in target bone lesions before and after 
therapy. Descriptive statistics (including mean, standard deviation (SD), minimum, 
maximum, median, interquartile range) will be provided on activity concentration of 
99mTc-MDP on quantitative SPECT/CT. The data collected from the imaging substudy 
is exploratory and not used as part of decision making for the response assessment.  
 


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11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 
Definitions 
11.1.1 Adverse Event (AE) 
 
An AE is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or 
any procedure specified in the protocol, even if the event is not considered to be 
related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests.  
11.1.2 Serious adverse event (SAE) 
 
A SAE is any adverse event, occurring at any dose and regardless of causality 
that:  
 Results in death 
 Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
 Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
 Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
 Is a congenital anomaly or birth defect; or 
 Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be SAEs are hospitalizations for: 


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 routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
 emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
 respite care 
 
11.1.3 Expectedness 
 
AEs can be 'Expected' or 'Unexpected.'  
 
Expected AE 
 
Expected AEs are those that have been previously identified as resulting 
from administration of the agent. For the purposes of this study, an AE is 
considered expected when it appears in the current AE list, the 
Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected AEs associated with the 
study agent(s). 
 
Unexpected AE 
 
 
For the purposes of this study, an AE is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the 
current AE list, the Investigator’s Brochure, the package insert or when it 
is not included in the informed consent document as a potential risk.   
11.1.4 Attribution 
 
Attribution is the relationship between an AE or SAE and the study treatment. 
Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment.  
 Unlikely - The AE is doubtfully related to the study treatment. 
 Unrelated - The AE is clearly NOT related to the study treatment. 
11.2 
Procedures for AE and SAE Recording and Reporting 
 


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Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will 
be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 
11.3 
Reporting Requirements 
 
The DF/HCC will serve as the coordinating center for this multi-site trial. Each 
participating investigator is required to abide by the reporting requirements set by the 
DF/HCC. The study must be conducted in compliance with FDA regulations, local 
safety reporting requirements, and reporting requirements of the principal investigator. 
Each investigative site will be responsible to report SAEs that occur at that institution 
to their respective IRB. It is the responsibility of each participating investigator to 
report SAEs to the study sponsor and/or others as described below.  
11.4 
Reporting to the Study Sponsor 
11.4.1 SAE Reporting 
 
All SAEs that occur after the initial dose of study treatment, during treatment, or 
within 30 days of the last dose of treatment must be reported to the DF/HCC 
Overall PI on the local institutional SAE form. This includes events meeting the 
criteria outlined in Section 11.1.2, as well as the following: 
 
 Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with the 
intervention. 
 
 All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 
 All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 


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Note: If the participant is in long term follow up, report the death at the time 
of continuing review.  
 
Participating investigators must report each SAE to the DF/HCC Overall PI and 
Astellas Pharmaco-Vigilance Department within 24 hours of learning of the 
occurrence. In the event that the participating investigator does not become aware 
of the SAE immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it 
and document the time of his or her first awareness of the AE. Report SAEs by 
telephone, email or facsimile to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Astellas Pharma Global Department – United States  
 
 
 
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the SAE. Follow-up information should describe 
whether the event has resolved or continues, if and how the event was treated, and 
whether the participant will continue or discontinue study participation. 
11.4.2 Non-SAE Reporting  
 
Non-SAEs will be reported to the DF/HCC Overall PI on the toxicity CRFs.   
 
11.5 
Reporting to the IRBs 
 
Investigative sites within DF/HCC will report all SAEs directly to the DFCI OHRS. 
 
Other investigative sites should report SAEs to their respective IRB according to the 
local IRB’s policies and procedures in reporting AEs. A copy of the submitted 
institutional SAE form should be forwarded to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The DF/HCC PI will submit SAE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting AEs.  


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11.6 
Reporting to the FDA 
 
This study is IND Exempt.   
 
11.7 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
11.8 
Monitoring of Adverse Events and Period of Observation 
 
All AEs, both serious and non-serious, and deaths that are encountered from initiation 
of study intervention, throughout the study, and within 30 days of the last study 
intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall PI and their respective IRB of any unanticipated death or 
AE occurring after a participant has discontinued or terminated study participation that 
may reasonably be related to the study.   
12. DATA AND SAFETY MONITORING 
12.1 
Data Reporting 
12.1.1 Method  
The ODQ will collect, manage, and perform quality checks on the data  for this 
study.  
12.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or 
electronic) to the ODQ is as follows: 
 


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Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with ODQ. 
On Study Form 
Within 14 days of registration. 
Baseline Assessment Form 
Within 14 days of registration. 
Treatment Form 
Within 10 days of the last day of the cycle. 
AE Report Form 
Within 10 days of the last day of the cycle. If 
AEs are ongoing at the end of the last cycle, 
continue to submit AE reports until resolution 
or 30 days post-treatment. 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation. 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or 
being taken off study for any reason. 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call. 
 
12.2 
Safety Meetings 
 
The DF/HCC DSMC will review and monitor toxicity and accrual data from this trial. 
The committee is composed of clinical specialists with experience in oncology and who 
have no direct relationship with the study. Information that raises any questions about 
participant safety will be addressed with the Principal Investigator and study team. 
 
 The DSMC will review each protocol up to four times a year or more often if required 
to review toxicity and accrual data.  Information to be provided to the committee may 
include:  up-to-date participant accrual; current dose level information; all grade 2 or 
higher unexpected AEs that have been reported; summary of all deaths occurring within 
30 days for Phase I or II protocols; for gene transfer protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request.  
12.3 
Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall PI (or Protocol Chair) or DF/HCC. The purpose of 
these audits or inspections is to examine study-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, 
and accurately reported in accordance with the protocol, institutional policy, GCP, 
and any applicable regulatory requirements.  
 


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All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion.  
 
See section 5.0 of the Data Safety Monitoring Plan (Appendix E) for additional details 
on monitoring of external sites for this study. 
 
13. REGULATORY CONSIDERATIONS 
13.1 
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall PI (or Protocol Chair) will disseminate 
protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
13.2 
Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. 
The participant must be given a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or 
research file.  
13.3 
Ethics and Research Practices 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
 
US CFR governing clinical study conduct and ethical principles that have their 
origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
  


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o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
  
o Title 21 Part 56 – Institutional Review Boards 
  
o Title 21 Part 312 – Investigational New Drug Application 
  
 
State laws 
 
DF/HCC research policies and procedures        
  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy.  
13.4 
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
13.5 
Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
13.6 
Multi-Center Guidelines 
This protocol will adhere to the policies and requirements of the DF/HCC. The specific 
responsibilities of the DF/HCC Overall PI (or Protocol Chair), Coordinating Center, 
and Participating Institutions are presented in the Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan (see Appendix E). 


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 The DF/HCC Overall PI/Coordinating Center is responsible for distributing all 
IND Action Letters or Safety Reports to all participating institutions for 
submission to their individual IRBs for action as required. 
 Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and AE reporting at each site.  
 Except in very unusual circumstances, each participating institution will order the 
agent(s) directly from the supplier. A participating site may order the agent(s) 
only after the initial IRB approval for the site has been forwarded to the 
Coordinating Center.  


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14. STATISTICAL CONSIDERATIONS  
14.1 
Primary Analysis  
 
The primary objective of this trial is to analyze possible AR related mechanisms of 
resistance to enzalutamide in serial CRPC biopsies including AR sequencing 
(mutations, splice variants), AR regulated gene expression, tumor androgen levels, 
profiling of enzymes involved in androgen synthesis/metabolism, and whole-exome 
and transcriptome sequencing. These data are of various forms resulting in different 
measures for a given participant: (a) continuous data will be evaluated by calculating 
mean percent change in level, (b) ordinal data will be evaluated by the mean percent 
change in count, and (c) categorical binary data will be evaluated by No/Yes change in 
status.  
 
For the primary analysis, only participants who received at least 2 cycles of 
enzalutamide and experienced progression will be eligible. We plan to enroll a total of 
66 participants to obtain 40 evaluable participants. A 60% overall yield is based on the 
assumptions that 95% of participants are eligible, 90% of these participants have paired 
biopsies and 70% of participants have evaluable tumors for each sample.  
 
The target sample size is based on power to evaluate a mean percent change in level. 
The hypothesis is that AR reactivation can lead to resistance to enzalutamide. We will 
evaluate the mean percent change in a set of resistance parameters using the paired t-
test. All continuous variables will be evaluated as a set. A mean percent change of 30% 
would be considered biologically significant. The effect size is defined as the mean 
percent change divided by the standard deviation (SD) of percent change, which is 
unknown in this population. The table below provides the mean percent change that can 
be detected with 80% or 90% power under various scenarios of SD given a one-sided 
0.025 alpha and 40 evaluable participants. For example, there is 80% power to detect 
mean percent change of 22.7% given a SD of 50% corresponding to an effect 
size=0.454 SD. The mean percent change presented ranges from 13.6%-31.5%. 
Therefore, this study is designed with satisfactory power to show a biologically 
significant mean percent change in a set of resistance parameters.  
 
Paired Tumor Samples (n=40) 
  
Paired t-test, 1-sided alpha=0.025 
Power=80%, Effect Size=0.454 SD 
Standard Deviation 
30% 
40% 
50% 
60% 
Mean Percent Change 
13.6% 
18.2% 
22.7% 
27.3% 
Power=90%, Effect Size=0.526 SD 
Standard Deviation 
30% 
40% 
50% 
60% 
Mean Percent Change 
15.8% 
21.0% 
26.3% 
31.5% 
 
 


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Number of Subjects/Study Duration: 
We plan to enroll a total of 66 participants to obtain 40 evaluable participants. 
Assuming an accrual rate of 6 participants per month, enrollment will take 11 months. 
Participants will be treated with enzalutamide 160 mg orally per day. We will assess 
PSA at baseline and day 1 of each 28-day cycle until radiographic progression defined 
by PCWG2. Participants will continue on therapy until radiographic or symptomatic 
progression or taken off study for another reason. 
14.2 
Analysis of Secondary Endpoints 
 
Safety and tolerability of enzalutamide will be evaluated. All participants who receive 
at least 1 dose of study drug will be included in these analyses. A summary of all Grade 
1-4 treatment-related toxicities will be provided by toxicity type and maximum grade. 
The maximum grade consolidates the reports of a given type of toxicity for a participant 
over time by taking the maximum grade across time (i.e. a participant appears only once 
for a given type of toxicity). Participants with reports of multiple toxicities of different 
types are reported multiple times under the relevant toxicity categories. ‘Treatment-
related’ toxicities are defined by an attribution as possible, probable or definite.  With 
66 participants, the maximum width of a 90% CI for a given toxicity rate is 22%. The 
probability of observing at least one rare severe toxicity (true rate=5%) is 95%. The 
number of cycles completed with and without dose modifications and treatment delays. 
 
PSA response to enzalutamide will be summarized as frequency and percent. 
Participants who are unevaluable for response will be included in the denominator as 
nonresponders when calculating the response rate. Duration of PSA response for the 
regimen of enzalutamide will be defined relative to the first achievement of PSA 
response and will be estimated using the method of Kaplan and Meier. PSA response 
will be measured according to PCWG2 (2008) criteria.  
 
Participants with measurable disease will be evaluated for response using RECIST 1.1 
criteria. Duration of response of bone lesions or measurable disease will be described 
using Kaplan-Meier estimates. 
 
The set of AR resistance measures will be summarized using descriptive statistics 
(mean, median, standard deviation (SD), interquartile range (IQR)). Correlation among 
measures will be assessed graphically with scatter plots and using Pearson correlation 
coefficients (or Spearman if appropriate).  
 
The two-group t-test will be used to examine the difference in level and/or change pre- 
to post-treatment in levels by PSA and RECIST (measurable disease participants) 
response outcome. Assuming 40 evaluable participants, if PSA response rate is 25% (10 
responders and 30 non-responders), there is 80% power to detect an effect of 1.05 SD at 
a two-sided significance level of 0.05. Continuous levels may be dichotomized at the 
median for further evaluation. Association between response and categorical variables 
will be evaluated using Fisher’s exact test. Analyses of these correlative endpoints will 
be exploratory and adjustments will not be made for multiple comparisons. 


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48 
 
 
 
15. PUBLICATION PLAN 
 
The data will be collected by 
 and analyzed by 
 and the statistical team 
at DFCI. It is anticipated that the results will be made public within 12 months of the end 
of data collection. A report is planned to be published in a peer-reviewed journal, however 
initial release may be an abstract that meets the requirements of the International 
Committee of Medical Journal Editors. 


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16. REFERENCES  
 
1. 
Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-
generation antiandrogen for treatment of advanced prostate cancer. Science. 
2009;324(5928):787-90. 
2. 
Joyce R, Fenton MA, Rode P, Constantine M, Gaynes L, Kolvenbag G, et al. High dose 
bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J 
Urol. 1998;159(1):149-53. 
3. 
Kucuk O, Fisher E, Moinpour CM, Coleman D, Hussain MH, Sartor AO, et al. Phase II 
trial of bicalutamide in patients with advanced prostate cancer in whom conventional 
hormonal therapy failed: a Southwest Oncology Group study (SWOG 9235). Urology. 
2001;58(1):53-8. 
4. 
Scher HI, Liebertz C, Kelly WK, Mazumdar M, Brett C, Schwartz L, et al. Bicalutamide 
for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol. 
1997;15(8):2928-38. 
5. 
Kassouf W, Tanguay S, Aprikian AG. Nilutamide as second line hormone therapy for 
prostate cancer after androgen ablation fails. J Urol. 2003;169(5):1742-4. 
6. 
Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al. Antiandrogen 
withdrawal alone or in combination with ketoconazole in androgen-independent prostate 
cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22(6):1025-33. 
7. 
Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular 
determinants of resistance to antiandrogen therapy. Nat Med. 2004;10(1):33-9. 


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50 
 
 
8. 
Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour 
activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 
2010;375(9724):1437-46. 
9. 
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival 
with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 
2012;367(13):1187-97. 
10. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 
2012;62(1):10-29. 
11. 
Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibitors for prostate cancer therapy. J Steroid 
Biochem Mol Biol. 2011;125(1-2):23-31. 
12. 
Nakamura Y, Suzuki T, Fukuda T, Ito A, Endo M, Moriya T, et al. Steroid sulfatase and 
estrogen sulfotransferase in human prostate cancer. Prostate. 2006;66(9):1005-12. 
13. 
Friedlander TW, Ryan CJ. Targeting the androgen receptor. Urol Clin North Am. 
2012;39(4):453-64. 
14. 
Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in prostate cancer: a hard 
habit to break? Cancer Cell. 2009;16(6):458-62. 
15. 
Reid AH, Attard G, Barrie E, de Bono JS. CYP17 inhibition as a hormonal strategy for 
prostate cancer. Nat Clin Pract Urol. 2008;5(11):610-20. 
16. 
Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al. Antiandrogen 
withdrawal alone or in combination with ketoconazole in androgen-independent prostate 
cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22(6):1025-33. 


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51 
 
 
17. 
Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T. 
Amplification and overexpression of androgen receptor gene in hormone-refractory 
prostate cancer. Cancer Res. 2001;61(9):3550-5. 
18. 
Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, et al. In vivo 
amplification of the androgen receptor gene and progression of human prostate cancer. 
Nat Genet. 1995;9(4):401-6. 
19. 
Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, et al. Mutation 
of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl 
J Med. 1995;332(21):1393-8. 
20. 
Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, et al. Increased 
expression of genes converting adrenal androgens to testosterone in androgen-independent 
prostate cancer. Cancer Res. 2006;66(5):2815-25. 
21. 
Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, et al. A novel androgen receptor splice 
variant is up-regulated during prostate cancer progression and promotes androgen 
depletion-resistant growth. Cancer Res. 2009;69(6):2305-13. 
22. 
Hornberg E, Ylitalo EB, Crnalic S, Antti H, Stattin P, Widmark A, et al. Expression of 
androgen receptor splice variants in prostate cancer bone metastases is associated with 
castration-resistance and short survival. PLoS One. 2011;6(4):e19059. 
23. 
Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. Ligand-independent 
androgen receptor variants derived from splicing of cryptic exons signify hormone-
refractory prostate cancer. Cancer Res. 2009;69(1):16-22. 


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52 
 
 
24. 
Li Y, Alsagabi M, Fan D, Bova GS, Tewfik AH, Dehm SM. Intragenic rearrangement and 
altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer 
progression. Cancer Res. 2011;71(6):2108-17. 
25. 
Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. Androgen receptor 
splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell 
lines. Cancer Res. 2013;73(2):483-9. 
26. 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and 
end points of clinical trials for patients with progressive prostate cancer and castrate levels 
of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J 
Clin Oncol. 2008;26(7):1148-59. 
27. 
Stein MN, Goodin S, Dipaola RS. Abiraterone in prostate cancer: a new angle to an old 
problem. Clin Cancer Res. 2012;18(7):1848-54. 
28. 
Mostaghel EA, Nelson PS. Intracrine androgen metabolism in prostate cancer progression: 
mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin 
Endocrinol Metab. 2008;22(2):243-58. 
29. 
Ryan CJ, Shah S, Efstathiou E, Smith MR, Taplin ME, Bubley GJ, et al. Phase II study of 
abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer 
displaying bone flare discordant with serologic response. Clin Cancer Res. 
2011;17(14):4854-61. 
 
 
 
 


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17. APPENDICES 
17.1 
Appendix A: Performance Status Criteria 
17.2 
Appendix B: Required Forms at Registration 
17.3 
Appendix C: Participant’s Pill Diary 
17.4 
Appendix D: Representative Medications that May Predispose to Seizure 
17.5 
Appendix E: Data and Safety Monitoring Plan 
 
 
 
 


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


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Appendix B: Required Forms at Registration 
 
The DFCI coordinator will Fax to DFCI ODQ: 
 
 Current IRB approved consent form signed by participant and Investigator (MD 
only) 
 HIPAA authorization form (if separate from the informed consent document) 
  Signed and dated DFCI eligibility checklist (signed by MD or RN) 
 The following source documentation is typically required:  
 Please note: Additional documentation may be required by the lead institution. 
o Labs for PSA values used to determine eligibility (Lab values used to 
determine eligibility, including screening PSA) 
o Documentation of prior treatments/procedures performed to treat 
prostate cancer (e.g. Chemotherapy, Cryotherapy, Hormone Therapy, 
o Radiation therapy with start and stop dates and dosing information if 
applicable) 
o Reports documenting disease status 
 Chest CT 
 CT or MRI Abdomen and Pelvis 
 Bone Scan  
o Pathology Report  
o Concomitant medication list 
o Progress note or equivalent documentation of consenting visit 
o Progress note documenting medical history and oncologic history 
o Screening Labs 
 Complete Blood Count with differential  
 Electrolytes  
 Liver Function Tests   
 Total Testosterone 
 PSA 
 Coagulation Factors  
o Screening visit note, with BP, vital signs, ECOG Performance status 
o Screening ECG 


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Appendix C: Participant’s Pill Diary 
 
Today’s Date:  ____________________ Participant Study ID:  ____________________ 
Participant Name: _____________________ Cycle Number:  ____________________ 
 
INSTRUCTIONS TO THE PARTICIPANT: 
1. Complete one form for each cycle (28 days). 
2.   You will take ____ capsules each day by mouth. 
3. Record the date, the number of capsules you took, and when you took them. 
4. If you have any comments or notice any side effects, please record them in the comments column.  
5. Please bring your pill bottle and this form to your physician when you go to your next appointment. 
Date  
Day 
Number of 
Capsules  
Time 
Comments  
Date 
Day 
Number of 
Capsules 
Time 
Comments  
 
1 
 
 
 
 
15 
 
 
 
 
2 
 
 
 
 
16 
 
 
 
 
3 
 
 
 
 
17 
 
 
 
 
4 
 
 
 
 
18 
 
 
 
 
5 
 
 
 
 
19 
 
 
 
 
6 
 
 
 
 
20 
 
 
 
 
7 
 
 
 
 
21 
 
 
 
 
8 
 
 
 
 
22 
 
 
 
 
9 
 
 
 
 
23 
 
 
 
 
10 
 
 
 
 
24 
 
 
 
 
11 
 
 
 
 
25 
 
 
 
 
12 
 
 
 
 
26 
 
 
 
 
13 
 
 
 
 
27 
 
 
 
 
14 
 
 
 
 
28 
 
 
 
 
Participant’s Signature: ____________________________________________ Date: ___________________________ 
 
Physician’s office will complete this section: 
Date participant started protocol treatment: 
________________________________________________________________ 
Date participant was removed from study: 
_________________________________________________________________ 
Participant’s planned daily dose: 
________________________________________________________________________ 
Total number of pills taken this month: ________________________________________________________________ 
Physician/Nurse/Data Manager’s Signature: ________________________ Date: _______________________________ 
 
 


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Appendix D: Representative Medications that May Predispose to Seizure 
 
Classification 
Generic Name  
Trade Name  
Antiasthmatic drugs 
Aminophylline 
Neophyllin, Albina, 
Kyophyllin, etc 
Theophylline 
Theodur, Uniphyl, etc. 
Atypical antipsychotics 
Clozapine 
Clozaril, etc. 
Olanzapine 
Zyprexa, etc. 
Risperidone 
Risperdal, etc. 
Quetiapine 
Seroquel, etc. 
Perospirone 
Lullan, etc. 
Aripiprazole 
Abilify, etc. 
Blonanserin 
Lonasen, etc. 
Insulin  
Insulin aspart 
Novorapid, etc. 
Insulin lispro 
Humalog, etc. 
Insulin glulisine 
Apidra, etc. 
Human insulin 
Humulin, Novolin, etc. 
Insulin glargine 
Lantus, etc. 
Insulin detemir 
Levemir, etc. 
Lithium  
Lithium carbonate 
Limas, etc. 
Pethidines  
Pethidine hydrochloride 
Pethidine hydrochloride, 
Opystan, Pethilorfan, etc. 
Phenothiazine antipsychotics 
Chlorpromazine 
Wintermin, Contomin, 
Vegetamin, etc. 
Trifluoperazine 
Trifluoperazine powder, etc. 
Levomepromazine 
Hirnamin, Levotomin, etc. 
Fluphenazine 
Flumezin, Fludecasin, etc. 
Prochlorperazine 
Novamin, Compazine, etc. 
Propericiazine 
Apamin, Neuleptil, etc. 
Perphenazine 
PZC, Trilafon, etc. 
Certain antidepressants  
Bupropion 
Wellbutrin, Xyban, etc. 
Amitriptyline 
Tryptanol, etc. 
Imipramine 
Imidol, Tofranil, etc. 
Maprotiline 
Ludiomil, etc. 
Mirtazapine 
Reflex, Remeron, etc. 
Amoxapine 
Amoxan, etc. 
Dosulepin hydrochloride 
Prothiaden, etc. 
Nortriptyline hydrochloride 
Noritren, etc. 
Lofepramine hydrochloride 
Amplit, etc. 
Mianserin hydrochloride 
Tetramide, etc. 
Setiptiline maleate 
Tecipul, etc. 
Trimipramine maleate 
Surmontil, etc. 
Clomipramine hydrochloride 
Anafranil, etc. 
  


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APPENDIX E 
Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1.0 
INTRODUCTION 
61 
1.1 
Purpose ......................................................................................................................................................... 61 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ...................................................................... 61 
2.0 
GENERAL ROLES AND RESPONSIBILITIES 
62 
2.1 
DF/HCC Sponsor ......................................................................................................................................... 62 
2.2 
Coordinating Center ..................................................................................................................................... 63 
2.3 
DF/HCC Office of Data Quality (ODQ) ...................................................................................................... 63 
2.4 
Participating Institution ............................................................................................................................... 63 
3.0 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
64 
3.1 
Protocol Distribution .................................................................................................................................... 64 
3.2 
Protocol Revisions and Closures .................................................................................................................. 64 
3.3 
Informed Consent Requirements ................................................................................................................. 65 
3.4 
IRB Documentation ..................................................................................................................................... 65 
3.5 
IRB Re-Approval .......................................................................................................................................... 65 
3.6 
Participant Confidentiality and Authorization Statement ........................................................................... 66 
3.6.1 
DF/HCC Multi-Center Protocol Confidentiality 
66 
3.7 
DF/HCC Multi-Center Registration ............................................................................................................ 66 
3.7.1 Participant Registration and Randomization .............................................................................................. 66 
3.7.2 Initiation of Therapy .................................................................................................................................... 67 
3.7.3 Eligibility Exceptions ................................................................................................................................... 67 
3.7.4 Verification of Registration, Dose Levels, and Arm Designation ............................................................... 68 
3.8 
DF/HCC Protocol Case Number ................................................................................................................. 68 
3.9 
Protocol Deviations, Exceptions and Violations ......................................................................................... 68 
3.9.1 Definitions .................................................................................................................................................... 68 
3.9.2 Reporting Procedures ................................................................................................................................... 68 
3.10 Safety Assessments and Toxicity Monitoring .............................................................................................. 69 
3.10.1 
Guidelines for Reporting Serious Adverse Events ............................................................................. 69 
3.10.2 
Guidelines for Processing IND Safety Reports .................................................................................. 70 
3.11 Data Management ........................................................................................................................................ 70 
3.11.1 
Data Forms Review ............................................................................................................................. 70 
4.0 
REQUSITIONING INVESTIGATIONAL DRUG 
70 
5.0 
MONITORING: QUALITY CONTROL 
71 
5.1 
Ongoing Monitoring of Protocol Compliance ............................................................................................. 71 
5.2 
Evaluation of Participating Institution Performance ................................................................................. 72 


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5.2.1 Monitoring Reports ...................................................................................................................................... 72 
6.0 
AUDITING: QUALITY ASSURANCE 
72 
6.1 
DF/HCC Sponsored Trials ........................................................................................................................... 72 
6.2 
Participating Institution ............................................................................................................................... 72 
6.3 
DF/HCC Sponsor and Coordinating Center ............................................................................................... 73 
6.4 
Sub-Standard Performance .......................................................................................................................... 73 
6.4.1 Corrective Actions ........................................................................................................................................ 73 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC 
that will be participating in the research protocol. 
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures  
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth 
Israel Deaconess Medical Center (BIDMC), Children’s Hospital Boston (CHB), Brigham 
and Women’s Hospital (BWH)) responsible for the coordination, development, 
submission, and approval of a protocol as well as its subsequent amendments per the 
DFCI IRB and applicable regulatory guidelines (Food and Drug Administration (FDA, ).  
The Lead Institution is typically the home of the DF/HCC Sponsor. The Lead Institution 
also typically serves as the Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable 
protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies (i.e. FDA). The DF/HCC Sponsor has ultimate authority over the protocol and is 
responsible for the conduct of the study at DF/HCC and all Participating Institutions. In 
most cases the DF/HCC Sponsor is the same person as the DF/HCC Principal Investigator; 
however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a 
DF/HCC Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor 
as having the ultimate authority and responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity (i.e. Lead Institution) that provides administrative 


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support to the DF/HCC Sponsor in order that he/she may fulfill the responsibilities 
outlined in the protocol document and DSMP, and as specified in applicable regulatory 
guidelines. In general, the Lead Institution is the Coordinating Center for the DF/HCC 
Multi-Center Protocol. Should the DF/HCC Sponsor decide to use a CRO, the CRO will 
be deemed the Coordinating Center.   
 
DF/HCC Office of Data Quality: A unit within DF/HCC developed to computerize and 
manage data, and to provide a Quality Control and Quality Assurance function for 
DF/HCC trials.   
 
 
2.0 GENERAL ROLES AND RESPONSIBILITIES 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general 
responsibilities:  
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, 
 will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
 Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.  
 Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
 Submit the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
 Assure all Participating Institutions are using the correct version of the protocol. 
 Ensure that each participating investigator and study team receives adequate protocol 
training and/or a Site Initiation Visit prior to enrolling participants and throughout 
trial’s conduct as needed. 
 Ensure the protocol will be provided to each participating site in a language 
understandable to all site personnel when English is not the primary language.  
 Monitor progress and overall conduct of the study at all Participating Institutions.  
 Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(FDA) reporting requirements are met.  
 Review data and maintain timely submission of data for study analysis.  
 Act as the single liaison with FDA (investigator-held IND trials) as applicable. 
 Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
 Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
 Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site.  
 


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2.2 Coordinating Center  
 
The Coordinating Center will assume the following general responsibilities: 
 Assist in protocol development  
 Maintain copies of Federal Wide Assurance and Institutional Review Board (IRB) 
approvals from all Participating Institutions. 
 Maintain FDA correspondence, as applicable. 
 Maintain updated roster of participants.  
 Verify eligibility. 
 Verify response. 
 Oversee the data collection process from Participating Institutions. 
 Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to DF/HCC Sponsor for timely review.   
 Distribute adverse events reported to the DF/HCC Sponsor that fall under the 
DFCI IRB Adverse Event Reporting Policy to all participating investigators. 
 Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with. 
 
 
 Monitor Participating Institutions either by on-site or virtual monitoring.  
 Maintain Regulatory documents of all Participating Institutions.  
 Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc).  
 Maintain documentation of all communications. 
 Ensure that each Participating Institution has the appropriate assurance on file with 
the Office of Human Research Protection (OHRP).     
 
2.3 DF/HCC Office of Data Quality (ODQ) 
 
In addition to the Coordinating Center, the DF/HCC ODQ provides the following support 
services to assist the DF/HCC Sponsor: 
 Develop protocol specific case report forms (CRF/eCRFS). 
 QA/QC data of protocol specific CRFs.  
 Provide a central participant registration, which includes review of consent and 
eligibility. 
 Provide auditing services (funding and ODQ approval required). 
 
2.4 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable Federal 
Regulations and DF/HCC requirements, the protocol and HIPAA requirements. All 
Participating Institutions will provide a list of personnel assigned to the role for oversight 
of data management at their site to the Coordinating Center.  
 
The general responsibilities for each Participating Institution are as follows: 
 Commit to the accrual of participants to the protocol. 


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 Submit protocol and/or amendments to their local IRB. 
 Maintain a regulatory binder in accordance with DF/HCC requirements. 
 Provide the Coordinating Center with regulatory documents as requested. 
 Participate in protocol training prior to enrolling participants and throughout the 
trial as needed (i.e. teleconferences). 
 Update Coordinating Center with research staff changes on a timely basis. 
 Register participants through the Coordinating Center.  
 Submit source documents, research records, and CRFs per protocol specific 
submission guidelines to the Coordinating Center. 
 Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements.  
 Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
 Secure and store investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements. 
 Have office space, office equipment, and internet access that meet HIPAA 
standards. 
 
 
3.0 DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
 Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification. 
 
 Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 


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 Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the 
Coordinating Center, will update the Participating Institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. Participating institutions must follow the DF/HCC requirement 
that only attending physicians obtain informed consent and re-consent to interventional 
trials (i.e. drug and/or device trials).   
 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
 Approval letter of the Participating Institution's IRB  
 Copy of the Informed Consent Form approved by the Participating Institution’s 
IRB  
 Participating IRB’s approval for all amendments 
 
It is the Participating Institution's responsibility to notify its IRB of protocol amendments.  
Participating Institutions will have 90 days from receipt to provide the Coordinating 
Center their IRB approval for amendments to a protocol.    
 
3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 


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The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval 
date.   
 
 
3.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPAA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the 
course of a study, the study participant must sign an Authorization.  This Authorization 
may or may not be separate from the informed consent document.  The Coordinating 
Center, with the approval from the DFCI IRB, will provide a consent template, which 
covered entities (Participating Institutions) must use.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials.  However, because of the nature of these trials, certain protected health 
information must be collected per NCI requirements. These are the primary reasons why 
DF/HCC has chosen to use Authorizations, signed by the participant in the trial, rather 
than limited data sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center must 
have the participant’s full name & social security number “blacked out” and the assigned 
DF/HCC ODQ case number (as described below) and DF/HCC protocol number written 
in (with the exception of the signed informed consent document). Participant initials may 
only be included or retained for cross verification of identification 
 
3.7 DF/HCC Multi-Center Registration  
 
3.7.1 Participant Registration and Randomization  
To register a participant, the following documents should be completed by the 
Participating Institution and faxed to the Coordinating Center at Dana-Farber 
Cancer Institute at 
 or e-mailed to the DFCI Clinical Research 
Coordinator and Research Nurse team.  
 
 Current IRB approved informed consent document signed by participant and 


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investigator 
 HIPAA authorization form (if separate from the informed consent document) 
 Signed and dated DFCI eligibility checklist  
 The following source documentation is typically required. Please note additional 
documentation may be required by the lead institution: 
– Labs for PSA values used to determine eligibility (lab values used to 
determine eligibility, including screening PSA) 
– Documentation of prior treatments/procedures performed to treat 
prostate cancer (e.g. Chemotherapy, Cryotherapy, Hormone Therapy, 
Radiation therapy with start and stop dates and dosing information if 
applicable) 
– Reports documenting disease status: Chest CT, CT or MRI Abdomen 
and Pelvis. Bone Scan  
– Pathology Report  
– Concomitant medication list 
– Progress note or equivalent documentation of consenting visit 
– Progress note documenting medical history and oncologic history 
– All screening labs 
– Screening visit note, with BP, vital signs, ECOG Performance status 
– Screening ECG 
 
The Coordinating Center will review the submitted documents in order to verify 
eligibility and consent. To complete the registration process, the Coordinating Center 
will: 
 Register the participant on the study with the DF/HCC Clinical Trial Management 
System (CTMS). 
 Upon receiving confirmation of registration the Coordinating Center will inform 
the Participating Institution and provide the study specific participant case number, 
and if applicable the dose treatment level.  
 
Treatment may not begin without confirmation from the Coordinating Center 
that the participant has been registered.  
 
Randomization can only occur during normal business hours, Monday through Friday 
from 8:00 AM to 5:00 PM Eastern Time. 
 
3.7.2 Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives a faxed or e-
mailed copy of the participant’s registration confirmation memo from the Coordinating 
Center. Therapy must be initiated per protocol guidelines.  The DF/HCC Sponsor and 
DFCI IRB must be notified of any exceptions to this policy. 
 
3.7.3 Eligibility Exceptions 
 


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No exceptions to the eligibility requirements for a protocol without DFCI IRB approval 
will be permitted. All Participating Institutions are required to fully comply with this 
requirement. The process for requesting an eligibility exception is defined below. 
 
3.7.4 Verification of Registration, Dose Levels, and Arm Designation 
 
A registration confirmation memo for participants registered to DF/HCC Multi-Center 
Protocol will be faxed or emailed to the registering institution within one business day of 
the registration.  Treatment may not be initiated until the site receives a faxed or e-mailed 
copy of the registration confirmation memo. 
 
3.8 DF/HCC Protocol Case Number 
 
At the time of registration, the following identifiers are required for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 
number. 
Participating 
Institutions 
should 
submit 
all 
de-identified 
subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.   
 
3.9 Protocol Deviations, Exceptions and Violations 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
  
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe derivations from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional 
policy for reporting to their local IRB. 
 
3.9.1 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
  
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation.   
 
3.9.2  Reporting Procedures 
 


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DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all 
protocol violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original 
submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 
3.10 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.10.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 11.  
 
 
 
 
Participating Institutions must report the AEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB SAE Reporting Requirements.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 


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investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Investigators will review any distributed AE reports, send a copy to their 
IRB according to their local IRB’s policies and procedures, and file a copy with their 
regulatory documents. 
 
3.10.2 Guidelines for Processing IND Safety Reports  
 
FDA regulations require sponsors of clinical studies to notify the FDA and all 
participating investigators of any adverse experience associated with the use of the 
investigational agent that is both serious and unexpected. The DF/HCC Sponsor will 
review all IND Safety Reports and ensure that all IND Safety Reports are distributed to 
the Participating Institutions.  The Participating Investigators are to review, send a copy to 
their IRB according to their local IRB’s policies and procedures, and file a copy with their 
regulatory documents. 
  
 
 
3.11 Data Management 
The DF/HCC ODQ develops a set of either paper or electronic case report forms 
(CRF/eCRFs), for use with the protocol.  These forms are designed to collect data for each 
study. The DF/HCC ODQ provides a web based training for eCRF users. See section 12 of 
protocol. 
   
3.11.1 Data Forms Review 
 
When data forms arrive at the DF/HCC ODQ, they are reviewed for completeness, 
protocol treatment compliance, adverse events (toxicities) and response. Data submissions 
are monitored for timeliness and completeness of submission. Participating Institutions are 
notified of their data submission delinquencies in accordance with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution 
will receive a written or electronic query from the DF/HCC ODQ Data Analyst or study 
monitor.  Responses to all queries should be completed and submitted within 14 calendar 
days.  Responses may be returned on the written query or on an amended paper case report 
form, or in the case of electronic queries, within the electronic data capture (eDC) system. 
In the case of a written query for data submitted on a paper case report form, the query 
must be attached to the specific data being re-submitted in response.   
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  These 
reports are compiled by the DF/HCC ODQ and distributed a minimum of four times a 
year.  
 
 
4.0 REQUSITIONING INVESTIGATIONAL DRUG  
 
 


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The ordering of investigational agent is specified in the protocol section 7.19.  
 
Participating Institutions should order their own agent regardless of the supplier (i.e. 
pharmaceutical company.)   
 
 
 
5.0 MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the ODQ provides quality 
control oversight for the protocol. 
 
5.1 Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions will be required to submit participant source documents to 
the Coordinating Center for monitoring upon request. Participating Institution may also be 
subject to on-site monitoring conducted by the Coordinating Center.  
 
Source documents confirming eligibility are to be sent to DFCI by the participating 
institutions and reviewed by DFCI study staff including a clinician prior to external site 
participant registration.  
 
 The DF/HCC Lead Institution will implement monitoring activities ongoing to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and subject safety. Additional monitoring practices may include but are not 
limited to; source verification, review and analysis of the following: eligibility 
requirements of all participants , informed consent procedures, adverse events and all 
associated documentation, study drug administration / treatment, regulatory records and 
site trial master files, protocol deviations, pharmacy records, response assessments, and 
data management.  
 
 Site visits will generally occur once a year for sites that are actively enrolling participants 
and have participants in treatment. Virtual monitoring (source documents are sent to DFCI 
for review) may be performed in lieu of a site visit if the study staff and PI determine that 
virtual monitoring is appropriate for the site. The decision to perform virtual monitoring in 
lieu of a site visit will be based upon the site’s enrollment, study compliance history, 
history collaborating with DFCI on other multi-center studies, and number of participants 
in active treatment. 
 
 We hope to monitor approximately 50% of participants enrolled from external sites. The 
target number of participants monitored may change depending upon monitor findings.  
 
 Monitoring will occur before the clinical phase of the protocol begins and will continue 
during protocol performance through study completion.  
 


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 All data submitted to the DF/HCC ODQ will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements. The Lead Institution or designee 
and if applicable ODQ Data Analysts assigned to the Protocol will perform the ongoing 
protocol data compliance monitoring with the support of the Participating Institution’s 
Coordinators, the Principal Investigators, and the Protocol Chair. 
  
Teleconferences between DFCI and the participating sites will be conducted on 
approximately a monthly basis. Meeting minutes for teleconferences will be issued to all 
participating sites. Site initiation visits will be conducted via teleconference. Ongoing 
training will also be conducted via teleconference as needed. The Coordinating Center, 
Dana Farber Cancer Institute will be available to all participating sites for resolving 
questions, concerns and facilitating compliance. 
 
5.2 Evaluation of Participating Institution Performance 
 
 
5.2.1 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and virtual monitoring 
of Participating Institutions to ensure protocol compliance and ability to fulfill 
responsibilities of participating in the study. The DF/HCC Sponsor may increase the 
monitoring activities at Participating Institutions that are unable to comply with the 
protocol, DF/HCC Sponsor requirements or federal and local regulations. Participating 
Institutions may also be subject to an audit as determined by the DF/HCC Sponsor. 
 
6.0 AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents.  Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
6.1 DF/HCC Sponsored Trials 
An audit may be performed by the ODQ at the request of the DF/HCC Sponsor if serious 
instances of non-compliance are found during routine monitoring. 
 
6.2 Participating Institution 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve 
this protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after 
the audit date.  
 


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6.3 DF/HCC Sponsor and Coordinating Center  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up.  For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.4 Sub-Standard Performance 
 
The DF/HCC Sponsor, DFCI IRB, is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
6.4.1 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely accurate data, adherence to protocol requirements, and compliance with state and 
federal regulations, will be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation.