Clinical trial NCT01974765
Conditions: Advanced Epithelial Ovarian Recurrent Epithelial Ovarian Fallopian Tube Primary Peritoneal Carcinoma
Keywords: Enzalutamide Androgen Receptor Positive (AR+) 13-119
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2013-11-05; Completion date: 2022-02-28
Enrollment: 59 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase II study. The purpose of this study is to find out what effects, good and/or bad enzalutamide has on the patient and the cancer. All patients who enter the study will be closely monitored for side-effects. If multiple patients develop significant side effects from enzalutamide, the study may be stopped early.

Enzalutamide is an androgen-receptor inhibitor, which means that it blocks the activity of the hormone testosterone. In ovarian, fallopian tube, and primary peritoneal cancers that express the androgen receptor, blocking the androgen-receptor may possibly slow or stop tumor growth. Enzalutamide has been studied in women with breast cancer, but this is the first study using enzalutamide for the treatment of patients with ovarian, primary peritoneal, or fallopian tube cancer.

Detailed description:

Arms: arm 1: After signing a screening consent, patients archival tissue will be evaluated for degree of AR positivity by AR staining. Patients with no archival tissue available will undergo a biopsy (using the modality deemed most appropriate by the patient's physician) for collection of tumor tissue for AR positivity by IHC. Only AR+ patients, defined as ≥5 % positivity by IHC, will be included. All IHC testing will be performed in the MSKCC Clinical CLIA approved laboratory.

All enrolled patients will be treated with enzalutamide 160 mg by mouth QD until progression of disease (POD), unacceptable toxicity or withdrawal from study. All treatments will be administered in the outpatient setting.
Interventions: intervention 1: Enzalutamide
Intervention descriptions: intervention 1: All enrolled patients will be treated with enzalutamide 160mg by mouth QD. Study drugs will be self-administered by patients. A cycle is 28 days.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
A Phase II Trial of Enzalutamide in Patients with Androgen Receptor Positive(AR+) Ovarian, Primary Peritoneal or Fallopian 
Tube Cancer and One, Two or Three Prior Therapies. 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
Principal Investigator/Department: 
Rachel N. Grisham, MD 
Medicine 
Co-Principal  Investigator(s)/Department: 
Jason A. Konner, MD 
Medicine 
Investigator(s)/Department: 
Carol A. Aghajanian,  MD 
Seth Cohen, MD 
Claire Friedman, MD 
Martee L. Hensley, MD, MSc 
Chrisann Kyi, MD 
Vicky Makker, MD 
Roisin E. O'Cearbhaill, MD 
Paul Sabbatini, MD 
Alison Schram, MD 
William P. Tew, MD 
Dmitriy Zamarin, MD, PhD 
Elizabeth Butler, PA-C 
Jessica Gahres, PA-C 
Katy Nickolaus, PA-C 
Chelsea Semrau, PA-C 
Viola Chitiyo, RN 
Vania Hom, RN 
Krysten Soldan, RN 
Sara Weissblum, RN 
Mila Gorsky, MD 
Louise Ligresti, MD 
Janet Cogswell, RN 
Stuart Lichtman, MD 
Sarah Schweber, MD 
Steven Sugarman, MD 
Wanqing  Iris Zhi, MD, PhD 
Jacqueline Bromberg, MD, PhD 
Loren Michel, MD 
Serena Wong, MD 
Michelle Abboud, NP 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Medicine 
Medicine 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
y/Biostatistics 
y/Biostatistics 
Memorial Sloan Kettering Cancer 
Center IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-
2020 
Nicole Heinz, RN 
Nursing 
Raylene Langish, RN 
Nursing 
Arlyn Apollo, MD 
Medicine 
Pamela R. Drullinsky, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Kenneth K. Ng, MD 
Medicine 
Tiffany A. Troso-Sandoval, MD 
Medicine 
Chau T. Dang, MD 
Medicine 
Rachel Sanford, MD 
Medicine 
Maureen Kennedy, RN 
Nursing 
Alexis Leitenberger, NP 
Nursing 
Sherie Mar-Chaim, RN 
Nursing 
Gloria Wasilewski, RN 
Nursing 
Alexia Iasonos, PhD 
Epidemiolog 
Qin Zhou, MA 
Epidemiolog 
Robert Soslow, MD 
Pathology 
Dilip D. Giri, MD 
Pathology 
Jeffrey Girshman, MD 
Radiology 
R di l
Consenting  Professional(s)/Department: 
Carol A. Aghajanian,  MD 
Medicine 
Seth Cohen, MD 
Medicine 
Claire Friedman, MD 
Medicine 
Rachel N. Grisham, MD 
Medicine 
Martee L. Hensley, MD, MSc 
Medicine 
Jason A. Konner, MD 
Medicine 
Chrisann Kyi, MD 
Medicine 
Vicky Makker, MD 
Medicine 
Roisin E. O'Cearbhaill, MD 
Medicine 
Paul Sabbatini, MD 
Medicine 
Alison Schram, MD 
Medicine 
William P. Tew, MD 
Medicine 
Dmitriy Zamarin, MD, PhD 
Medicine 
Mila Gorsky, MD 
Medicine 
Louise Ligresti, MD 
Medicine 
Stuart M. Lichtman, MD 
Medicine 
Sarah J. Schweber, MD 
Medicine 
Steven M. Sugarman, MD 
Medicine 
Wanqing Iris Zhi, MD, PhD 
Medicine 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
 
 
 
Jacqueline Bromberg, MD, PhD 
Medicine 
Loren Michel, MD 
Medicine 
Serena Wong, MD 
Medicine 
Arlyn Apollo, MD 
Pamela R. Drullinsky, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Kenneth K Ng, MD 
Medicine 
Tiffany A. Troso-Sandoval, MD 
Medicine 
Medicine 
Chau T. Dang, MD 
Rachel Sanford, MD 
Medicine 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK  Sites 
Basking Ridge, NJ 
Commack, NY 
Monmouth, NJ 
Nassau, NY 
Westchester, NY 
Manhattan, NY 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 4 of 38 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................................................................................ 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 5 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................... 12 
4.1 
Design ............................................................................................................................... 12 
4.2 
Intervention ................................................................................................................................ 12 
5.0 
THERAPEUTIC/DIAGNOSTIC  AGENTS .............................................................. 14 
6.0 
CRITERIAFOR SUBJECT ELIGIBILITY ............................................................................. 15 
6.1 
Subject Inclusion Criteria .................................................................................................... 15 
6.2 
Subject Exclusion Criteria ................................................................................................... 16 
7.0 
RECRUITMENT PLAN ........................................................................................................................ 18 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 18 
9.0 
TREATMENT/INTERVENTION  PLAN ............................................................................... 19 
10.0    EVALUATION DURING TREATMENT/INTERVENTION .................................................. 21 
11.0 
TOXICITIES/SIDE EFFECTS ................................................................................................... 24 
12.0    CRITERIAFOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 25 
13.0 
CRITERIAFOR REMOVAL FROM STUDY ...................................................................... 30 
14.0 
BIOSTATISTICS ................................................................................................................ 31 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
34 
15.1 Research Participant Registration ...................................................................................... 34 
15.2 Randomization ........................................................................................................................ 34 
16.0   DATA MANAGEMENT ISSUES ........................................................................................ 35 
16.1 Quality Assurance ............................................................................................................... 35 
16.2 Data and Safety Monitoring ..................................................................................................... 35 
17.0   PROTECTION OF HUMAN SUBJECTS............................................................................ 36 
17.1 Privacy ................................................................................................................................. 36 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 36 
18.0   INFORMED CONSENT PROCEDURES ................................................................................ 37 
19.0 
REFERENCES ................................................................................................................... 38 
20.0 
APPENDICES ..................................................................................................................... 40 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 5 of 38 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a phase II, single-institution, open-label trial of enzalutamide 160 mg PO QD  in 
patients with androgen receptor (AR)+ ovarian, fallopian tube or primary peritoneal cancer 
with measurable disease and one, two or three prior cytotoxic treatments. All enrolled 
patients will be treated with enzalutamide 160 mg PO QD until progression of disease 
(POD), unacceptable toxicity or withdrawal from study. All treatments will be administered 
in the outpatient setting. 
 
 
 
 
 
 
 
Enzalutamide 160 mg PO QD until 
POD or unacceptable toxicity 
 
 
 
 
*A maximum of 19 enrolled patients will have 3 prior therapies 
** In cases where multiple blocks are available staining will be performed on unstained 
slides from 3 separate blocks. If ≥ 5% AR tumor staining is seen on ≥ 1 slide the tumor will 
be considered to be AR+. 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIM 
AR< 5% = ineligible for study 
• 
Advanced or recurrent ovarian, 
primary peritoneal or fallopian 
tube cancer. 
• 
1-3 prior cytotoxic treatments*. 
• 
Measurable  disease 
Screening of archival tumor tissue 
in MSKCC CLIA approved lab for 
AR+ by IHC. If no archival tissue is 
available patient must be willing to 
undergo a tumor biopsy.** 
AR≥ 5%=eligible for study entry 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 6 of 38 
 
 
 
Primary Objective: 
 
• 
To estimate the proportion of women with AR(+) ovarian, primary peritoneal, or fallopian 
tube cancer who survive progression free for at least 6 months and the proportion of 
patients who have objective tumor response (complete or partial response) by RECIST 1.1 
criteria when treated with  enzalutamide 160 mg PO QD. 
 
Secondary Objective: 
 
• 
To determine the frequency and severity of adverse events as assessed by NCI CTCAE 
version 4.0 in women with AR (+) ovarian, primary peritoneal, or fallopian tube cancer 
treated with enzalutamide 160 mg PO daily. 
Exploratory Objective: 
 
• 
To perform optional tumor biopsies following treatment with enzalutamide, in order to 
determine the effect of treatment with enzalutamide on androgen receptor expression 
• 
To observe the effect of enzalutamide on serum testosterone and estradiol levels in 
women with AR+ ovarian, primary peritoneal, or fallopian tube cancer. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Androgen Receptor and Ovarian Cancer 
 
Ovarian cancer is the second most common gynecologic malignancy and the leading 
cause of death among women with gynecologic malignancies. There are an estimated 
21,990  new cases and 15,460 cancer-related deaths from ovarian cancer in the United 
States annually [1]. Approximately 75% of women with epithelial ovarian cancer present 
with advanced (stage III or IV) disease. Standard treatment for women presenting with 
advanced ovarian cancer includes cytoreductive surgery followed by combination 
chemotherapy with platinum and taxane agents [2]. The majority of these women will recur 
and be treated with multiple lines of single-agent cytotoxic chemotherapy. Progression- 
free survival following first, second and third remission are 10.2, 6.4 and 5.6 months 
respectively[3]. Long-term survival among women diagnosed with advanced-stage ovarian 
cancer remains < 30%. Additional options for recurrent and persistent disease are clearly 
needed [4, 5]. 
 
Androgen receptors (ARs) are found in 67-90% of cases of epithelial ovarian cancer, and 
are more prevalent than estrogen (32-55% of cases) or progesterone receptors (46-52% 
of cases) in this disease [6-10]. Historically, studies targeting androgen inhibition in 
ovarian cancer using GnRH agonists or AR antagonists have shown a response rate of 0- 
22% and stable disease in 8-70% of women [11-20]. Our group at MSKCC published a 
negative phase II study of goserelin and bicalutamide consolidation therapy in patients 
with 2 or more prior therapies in 2007; androgen inhibition in ovarian cancer has largely 
been ignored since that time [21]. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 7 of 38 
 
 
 
 
However, all clinical studies of androgen inhibition in ovarian cancer to date have been 
performed in an unselected population of patients with multiple lines of prior treatment. 
Recent preclinical data shows that primary cultures of AR+ ovarian cancer cells show an 
increase in cell division when exposed to androgen, and that this activity is reversed when 
androgen in inhibited[22]. In addition, androgen receptor positivity has been shown to 
decrease following chemotherapy, indicating that patients with multiple lines of prior 
treatment may be less likely to be AR+ and therefore less likely to respond to 
antiandrogen  therapy. 
3.2 
Enzalutamide 
 
Enzalutamide is a novel small molecule androgen-receptor antagonist selected for its 
activity against cells overexpressing the androgen receptor [23]. Enzalutamide has a novel 
mechanism of action that is unlike that of bicalutamide and has been shown in preclinical 
studies to provide a more complete suppression of the antiandrogen receptor pathway  
than bicalutamide. Enzalutamide slows growth and induces cell death in AR expressing 
cells via three complementary actions. Enzalutamide blocks testosterone binding to the 
androgen receptor, impedes nuclear translocation of the androgen receptor, and inhibits 
binding of DNA. Preclinical data have demonstrated that enzalutamide is superior to 
bicalutamide in each of these three actions. 
 
In a mouse xenograft model of prostate cancer using an androgen receptor 
overexpressing cell line, Enzalutamide treatment resulted in a dose-dependent reduction 
in tumor volume (p<0.05 and p<0.01 for mid-and high-dose groups vs. vehicle, 
respectively).  Enzalutamide treatment resulted in unmeasurable tumors in 1/7 animals in 
the low-dose group and 3/7 animals in the high-dose group. As expected, bicalutamide 
had little effect on tumor growth. 
Enzalutamide binds with high affinity to the human androgen receptor (Ki= 13 nM). Other 
targets for which measurable enzalutamide binding was detected included the human 
progesterone receptor with a 50% inhibitory concentration (IC50) of 10-25 µM and the rat 
gamma amino butyric acid-gated chloride channel (IC50= 2.6 µM; Ki=2.1 µM [1.0 µg/mL]). 
No significant binding was detected with the remaining 70 receptors. 
 
3.3 
Previous Human Experience with Enzalutamide 
 
The safety and tolerability of enzalutamide have been evaluated in numerous clinical 
studies in both healthy adult male volunteers and in male patients with prostate cancer. 
The duration of exposure ranges from a single dose to more than 4 years. The estimated 
safety, PK, and tolerability are based primarily upon the data collected from the completed 
Phase 1-2 study (S-3100-1-01). 
 
Study S-3100-1-01 was an open label, dose-escalation study of enzalutamide in 140 
patients with advanced prostate cancer. Patients were treated with enzalutamide at doses 
of 30 to 600mg/day until disease progression or intolerable side effects developed. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 8 of 38 
 
 
 
 
In this study, enzalutamide was absorbed rapidly after oral administration, with the median 
time to Cmax after a single dose occurring at 1 hour (range 0.42 to 4 hours postdose). No 
major deviations from dose proportionality were observed over the dose range of 30 to 
600mg. Due to the long t1/2 (~5.8 days), it took approximately 1 month to reach steady 
state. W ith daily oral administration, enzalutamide accumulated approximately 8.33-fold 
relative to a single dose. The peak-to-trough ratio was approximately 1.25, indicating that 
the average difference between the peak and trough concentrations was ≤ 25%. As a 
result of the low daily fluctuations, plasma profiles at steady-state resembled a constant 
infusion. The trough values in individual patients remained constant beyond Day 28 of 
chronic therapy, suggesting time-linear PKs once steady state was achieved. 
Grade 3/4 adverse events reported by at least 3% of patients were fatigue (14%), anemia 
(4%), and back pain (3%). Fatigue was the most frequently reported adverse event, with 
dose-dependent increases of Grade 3 fatigue (0% at 150mg/day, 9% at 240 mg/day, 15% 
at 360mg/day and 20% at 480 mg/day). At doses of 240 mg and above, an increasing 
proportion of patients needed dose reductions for fatigue (1 of 29 patients [3%] who 
received 240mg/day, 3 of 28 patients [11%] who received 360mg/day and 5 of 22 patients 
[23%] who received 480mg/day, compared with 0 of 59 patients who 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 prostate-specific antigen (PSA) rise. 
The dose of 240mg/day was defined as the maximum tolerated dose. 
 
At the highest dose of 600mg/day, 2 of 3 patients had dose-limiting toxicities (DLT) 
(seizure, rash, respectively), both of which led to treatment discontinuation. Other causes 
of treatment discontinuation included rash (n=1 at 480 mg/day), and a myocardial 
infarction after 15 weeks of 360mg/day in a patient with a history of diabetes, 
hypertension, and hypercholesterolemia. One witnessed seizure at 360 mg/day and a 
possible seizure at 480 mg/day were also reported. No deaths and no other drug-related 
serious adverse events were reported. 
 
 
3.3 
Enzalutamide and Prostate Cancer 
 
The AFFIRM trial, a randomized, double-blind, placebo-controlled, phase III  trial,  
evaluated whether enzalutamide could prolong overall survival in men with castration 
resistant prostate cancer who progressed following docetaxel-based chemotherapy. 
Patients who had previously received ≤ 2 regimens of docetaxel-based chemotherapy 
were randomized 2:1 to enzalutamide 160mg PO QD or placebo. Treatment with 
corticosteroids was allowed but not required. Between September 2009 and November 
2010 1,199 patients were randomized. Based on a planned interim analysis at 520 death 
events, the Independent Data Monitoring  Committee recommended the study be unblinded 
and placebo patients offered MDV3100 due to a significant OS benefit (p<0.0001;          
HR 0.631) . The estimated mean OS was 18.4 months for MDV3100 treated patients 
compared to 13.6 months for placebo treated men, a median OS difference of 4.8 
months[24]. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 9 of 38 
 
 
 
The most common (≥5%) grade 1-4 adverse reactions included asthenia or fatigue, back 
pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, 
upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory 
infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, 
anxiety, and hypertension.  Grade 3-4 adverse reactions were reported in 47% of patients 
treated with enzalutamide and in 53% of those on placebo. 
 
Enzalutamide was subsequently FDA approved on August 31, 2012 for treatment of 
patients with metastatic castration-resistant prostate cancer who have previously received 
docetaxel. 
3.4 
Androgen Inhibition and Breast Cancer 
 
The AR is expressed in 60-80% of breast cancers and has been implicated in breast 
cancer biology [25]. High androgen levels are associated with an increased risk of 
developing breast cancer in postmenopausal women and androgens have been shown to 
initiate tumor formation via the AR in animal models [26, 27]. 
A study evaluating the effects of leuprorelin acetate in women with breast cancer 
demonstrated responses (complete or partial) predominantly in premenopausal women 
[28]. In this study, hormone receptor status was unknown on any of the postmenopausal 
patients. The majority of premenopausal patients had ER + disease. Hot-flashes and 
weight gain were the only reported toxicities. 
 
In another study, goserelin was administered to 118 pre-/peri-menopausal women of 
varying ER status. W ith the exception of hot-flashes, the therapy was well tolerated. The 
overall response rate was 45% and median time to progression was 59 weeks [29]. 
 
Abiraterone acetate is a steroidal inhibitor of CYP17 that blocks two important enzymatic 
activities in the synthesis of testosterone. A phase I study of abiraterone acetate in 
estrogen receptor (ER) positive or AR positive advanced breast cancer patients has been 
completed. A total of 25 patients were treated in 6 patient cohorts at doses between 
250mg and 2000mg PO daily. At the 1000mg and 2000mg dose levels good suppression 
of estradiol, testosterone, DHEA and DHEAS were seen. Two patients (both ER+/AR+) 
were previously treated with multiple lines of hormonal therapy but continued on treatment 
with abiraterone acetate for > 11 months. One of these patients achieved a radiographic 
partial response. It was concluded that abiraterone acetate is well tolerated in advanced 
breast cancer patients with preliminary evidence of anti-tumor activity at the 1000mg dose 
level [30]. 
3.5 
Rationale for Current Study 
 
In summary, recent data shows that AR+ primary cultures of ovarian cancer cells 
proliferate in the presence of androgen and this proliferation is reversed by androgen 
inhibition. AR expression may be decreased following exposure to multiple lines of 
cytotoxic chemotherapy. Abiraterone acetate has shown promising results in patients with 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 10 of 38 
 
 
 
AR+ breast cancer; however due to suppression of adrenally produced androgen it can 
produce severe side effects related to hypokalemia, hypertension and edema. In 
the ovarian cancer population, where malignant ascites is common, toxicities 
related to increased edema from abiraterone and prednisone would be significant. 
 
Prior targeted therapies for treatment of ovarian cancer have shown response rates of 0%- 
21% and PFS at 6 months of 6.5%-40.3% in patients with recurrent or advanced 
ovarian cancer and a history of 1-2 prior cytotoxic therapies (Table 1). 
Table 1. 
Study 
Agent 
Target 
N 
Response 
Rate 
PFS at 6 
Months 
170-C 
Gefitinib 
EGFR 
27 
3.7% 
14.8% 
170-D 
Bevacizumab 
VEGFA 
62 
21% 
40.3% 
170-E 
Imatinib 
Bcr-abl/c-kit/PDGFR 
56 
1.8% 
16.1% 
170-F 
Sorafenib 
VEGFR/PDGRR/RAF 
59 
3.4% 
23.7% 
170-G 
Lapatinib 
EGRR/HER2neu 
26 
0.0% 
7.7% 
170-H 
Vorinostat 
HDAC 
27 
3.7% 
7.4% 
170-J 
Enzastaurin 
PKC-beta 
27 
7.4% 
11.1% 
170-K 
Mifepristone 
PR 
22 
4.5% 
13.6% 
170-M 
Dasatinib 
Scr/bcl-abl/c-kit 
34 
0% 
20.6% 
170-N 
A6 
uPAR 
31 
0% 
20.6% 
170-P 
AMG-102 
HGF(c-met) 
Suspended after first stage 
 
 
Earlier studies examining alternative methods of androgen inhibition in ovarian, primary 
peritoneal, and fallopian tube cancer have all been performed in an unselected population 
of women, typically with multiple prior lines of therapy. Drawing on recent advances, the 
present study will be performed in a selected population of women with AR+ advanced 
ovarian, primary peritoneal, or fallopian tube cancer (≥5% by IHC) with measurable 
disease. Enrolled patients will have had only one, two or three prior cytotoxic therapies. 
All enrolled patients will be treated with enzalutamide 160 mg PO QD until progression of 
disease (POD), unacceptable toxicity or withdrawal from study. Based on the prior 
response rates that have been seen with targeted therapy of recurrent or advanced 
ovarian cancer (Table 1), and the relatively benign side effect profile of enzalutamide, we 
will consider this treatment worthy of further study if there is an observed response rate 
of 12.5% or an observed 6 month PFS interval is seen in 22.5% of patients. Given that 
enzalutamide 160 mg PO has not previously been administered to women with ovarian 
cancer this study will utilize a safety lead-in. If ≥ 5 out of the first 15 patients develop a 
DLTduring the first 28 days of treatment then the study will be put on hold. If this does not 
occur then enrollment will continue. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 11 of 38 
 
 
 
 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single-institution, single-arm, open-label, phase II study of enzalutamide 160mg 
by mouth once daily in patients with AR+ recurrent or advanced ovarian,              
primary peritoneal or fallopian tube cancer. After signing a screening consent, patients 
archival tissue will be evaluated for degree of AR positivity by AR staining. Patients 
with no archival tissue available will undergo a biopsy (using the modality deemed most 
appropriate by the patient’s physician) for collection of tumor tissue for AR positivity by 
IHC. Only AR+ patients, defined as ≥5% positivity by IHC, will be included. All IHC 
testing will be performed in the MSKCC Clinical  CLIA approved laboratory. 
All eligible patients will have measurable disease by RECIST 1.1 criteria and will have 
received one, two or three prior cytotoxic treatments for their disease. A maximum of 19 
enrolled patients will have 3 prior therapies. Patients will be treated until POD, intolerable 
toxicity or withdrawal of consent. 
The primary endpoint of this trial is to determine the proportion of women with AR(+) 
ovarian, primary peritoneal, or fallopian tube cancer who survive progression free for at 
least 6 months and the proportion of patients who have objective tumor response 
(complete or partial response) by RECIST 1.1 criteria when treated with enzalutamide 
160mg PO QD. 
 
The frequency and severity of adverse events as assessed by NCI CTCAE version 4.0 will 
be described. Optional tumor biopsies will be performed at end of treatment, in order to 
explore the effect of enzalutamide on tumor AR expression. 
 
4.3 
Intervention 
 
Prior to initiation of treatment patients will sign a screening informed consent form for AR 
IHC testing. If archival tissue is not available then the patient must consent to a biopsy. In 
cases where multiple blocks are available staining will be performed on unstained slides 
from 3 separate blocks. If ≥ 5% AR tumor staining is seen on ≥ 1 slide the tumor will be 
considered to be AR+. Only those patients found to have ≥5% AR by IHC will be eligible 
for treatment. 
 
All enrolled patients will be treated with enzalutamide 160mg PO QD. Study drugs will be 
self-administered by patients. A cycle is 28 days. Patients will be required to maintain a pill 
diary to record each dose of drug taken (see Appendix A). All toxicities will be graded 
using CTCAE version 4.0. Toxicities will be evaluated during physician assessments 
performed every 2 weeks during the first cycle and every 4 weeks during subsequent 
cycles of treatment with enzalutamide. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 12 of 38 
 
 
 
Patients will continue to receive study treatment until POD (as defined by RECIST 1.1), 
unacceptable toxicity or withdrawal of consent. 
Dose modifications will be allowed as described in Section 9. 
 
Enrollment will proceed following a safety lead-in of 15 patients. If ≥ 5 patients develop 
any of the following events classified as dose-limiting toxicity (DLT) during the first 28 
days of treatment the study will be halted and the PI will examine the toxicity profile and 
determine whether lower doses will be added. DLT is defined as: 
• 
Any event consistent with a seizure of any grade 
• 
Grade ≥ 3 diarrhea, nausea, or vomiting that does not improve to Grade 1 within 
14 days of initiating standard of care therapy 
• 
Grade ≥ 3 decreased platelet count with associated bleeding 
• 
Grade ≥ 3 absolute neutrophil count (ANC) that persists for 7 or more days or that 
is associated with fevers (febrile neutropenia) 
• 
Any other ≥ Grade 3 non-hematologic toxicity determined to be related to study 
drug 
If < 5 patients develop one of the above events during the first 28 days of treatment then 
enrollment will proceed following a two-stage design. A total of 28 patients (including the 
first 15) will be enrolled during the first stage. If 3 or more patients have clinical response 
or 5 or more patients have no progression/death at 6 months, then the study will open to 
the second stage of accrual. No more than 9 out of the 28 patients (1/3) enrolled during 
stage I will have 3 prior therapies. In stage II, an additional 30 patients will be enrolled. At 
the end of stage II, if at least 7 of 59 (28+30=58) patients have clinical response or at least 
13 of 59 patients survive progression free for 6 months, this will be considered as a 
positive trial. 
Patients will be evaluated for radiographic response every 2 cycles (8 weeks) and at the 
end of study. Response is defined as the best over-all response achieved by RECIST 1.1 
criteria while on study treatment. 
 
At end of treatment an optional tumor biopsy will be performed in patients who consent to 
this procedure. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Enzalutamide 
 
Enzalutamide is a white to off white solid. It is insoluble in water. It is supplied as soft 
gelatin filled capsules that are filled to contain 40 mg of active pharmaceutical ingredient. 
 
Each patient will self-administer 160mg (4 capsules) PO daily and should be instructed to 
take the 4 enzalutamide capsules with a glass of water at approximately the same time 
each day. Each dose should be recorded in the patient’s pill diary. Enzalutamide can be 
taken with or without food. Patients should not make up missed or vomited doses; patients 


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IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
Page 13 of 38 
 
 
 
should resume dosing at their scheduled time the next day unless otherwise instructed. 
Patients should not take enzalutamide if more than 12 hours have lapsed since the missed 
dose. 
 
5.2 
Storage and Labeling 
 
Enzalutamide should be stored in a secure location with limited access at 77ºF (25ºC), 
with excursions permitted to 59ºF to 86ºF (15ºC to 30ºC). Bottles will be labeled with the 
study protocol number, lot number, contents, directions for use, storage directions, clinical 
trial statement, and Sponsor (Medivation,  Inc.). Patients will be instructed to store study 
drug at room temperature and out of reach of children. 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
 
6.2 
Subject Inclusion Criteria 
 
• 
Advanced or recurrent epithelial ovarian, fallopian tube or primary peritoneal 
carcinoma. Histologic documentation of the original primary tumor is required via 
the pathology report 
• 
AR expression ≥5% by IHC. In cases where multiple blocks are available staining 
will be performed on unstained slides from 3 separate blocks. If ≥ 5% AR tumor 
staining is seen on ≥ 1 slide the tumor will be considered to be AR+. 
• 
Patients with the following histologic cell types are eligible: serous 
adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, 
undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial 
adenocarcinoma, transitional cell carcinoma, malignant Brenner’s tumor, or 
adenocarcinoma not otherwise specified 
• 
Measurable disease as defined by RECIST 1.1. Measurable disease is defined as 
at least one lesion that can be accurately measured in at least one dimension. 
Each lesion must be ≥10mm when measured by CT, MRI or caliper measurement 
by clinical exam; or ≥ 20mm when measured by chest x-ray. Lymph nodes must 
be ≥ 15mm in short axis when measured by CT or MRI 
• 
Patients must have had one prior platinum-based chemotherapeutic regimen for 
management of primary disease 
• 
Patients may have received, but are not required to have received, one or two 
additional cytotoxic regimens for management of recurrent or persistent disease 
• 
Patients who have received only one prior cytotoxic regimen (platinum-based 
regimen for management of primary disease), must have a platinum-free interval 
of less than 12 months, or have progressed during platinum-based therapy, or 
have persistent disease after a platinum-based therapy 
• 
Patients are allowed to receive, but are not required to receive, non-cytotoxic 
therapy (such as bevacizumab) as part of their primary treatment regimen. 
Patients are allowed to receive, but are not required to receive, non-cytotoxic 
therapy for management of recurrent or persistent disease 


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• 
Must be ≥ 18 years of age 
• 
Karnofsky Performance Status (KPS) of ≥ 70% 
• 
Life expectancy of ≥ 12 weeks 
• 
Women of child-bearing potential must have a negative pregnancy test within 14 
days prior to commencement of study treatment 
• 
Women of child bearing potential must use an effective form of contraception 
during study and for at least 6 months after completion of study treatment 
• 
Recovery from effects of recent surgery, radiotherapy, or chemotherapy 
o At least 4 weeks out from their last dose of radiation therapy 
o At least 4 weeks post-op from any major surgical procedure 
o At least 3 weeks out from their last dose of chemotherapy and/or 
biologic/targeted  therapy 
• 
No prior hormonal therapy for treatment of cancer within the past 21 days 
• 
Absence of any psychological, familial, sociological or geographic condition that 
would potentially hamper compliance with the study protocol 
• 
Prior use of or participation in a clinical trial evaluating and agent that either blocks 
androgen synthesis (e.g. abiraterone acetate, TAK-700, TAK-683, TAK-448) or 
targets the AR (e.g., bicalutamide, BMS-641988) (patients who are known to have 
only received placebo in these studies are eligible) 
• 
Laboratory Test Findings performed within 14 days prior to initiation of study drug 
showing: 
o Bone marrow function: 
▪ 
Absolute neutrophil count (ANC) ≥ 1,000/mcL 
▪ 
Platelets ≥ 100,000/mcL 
▪ 
Hemoglobin ≥ 8 g/dL 
o Renal function: 
▪ 
Creatinine ≤ 1.5 x ULN 
o Hepatic function: 
▪ 
Bilirubin ≤ 1.5 x ULN 
▪ 
AST and ALT ≤ 2.5 x ULN 
• 
Resolution of all acute toxic effects of prior therapy to NCI CTCAE (Version 4.0) 
Grade ≤ 1, with the exception of  unresolved Grade 2 neuropathy and Grade 2 
alopecia, which are allowed 
• 
Patients must be able to swallow tablets whole, without crushing 
 
6.3 
Subject Exclusion Criteria 
 
• 
A history of another invasive malignancy (other than non-melanoma skin cancer or 
curatively treated in situ carcinoma) with evidence of disease within the past 3 
years 
• 
Use of a medication known to lower the seizure threshold within 28 days of first 
dose of study drug (see Appendix B for a representative list of medications known 
to lower the seizure threshold) 
• 
Known brain metastasis 


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• 
History of seizure 
• 
Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95mmHg) 
despite medical treatment. Patients with a history of hypertension are allowed 
provided blood pressure is controlled by anti-hypertensive treatment. 
• 
Clinically significant heart disease as evidenced by myocardial infarction or arterial 
thrombotic event within the past 6 months, severe or unstable angina, or New York 
Heart Association (NYHA) Class II-IV  heart disease or cardiac ejection fraction 
measurement of < 50% at baseline 
• 
Refractory nausea and vomiting, requirement for parenteral hydration and/or 
nutrition, drainage gastrostomy tube, malabsorption, external biliary shunt, or 
significant small bowel resection that would preclude adequate study drug 
absorption 
• 
Anticipated or ongoing administration of anti-cancer therapies other than those 
administered in this study 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited from the patients seen by the Gynecologic Medical Oncology 
(GMO) Service, Department of Medicine, at Memorial Sloan-Kettering Cancer Center 
(MSKCC). The investigator will screen patients with ovarian, primary peritoneal and 
fallopian tube cancer to see if they are eligible for this trial. 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review 
portions of their medical records at MSKCC in order to further assess eligibility. They will 
use the information provided by the patient and/or medical record to confirm that the 
patient is eligible and to contact the patient regarding study enrollment. 
 
8.1 
PRETREATMENT EVALUATION 
 
Screening: 
• 
Signature of screening informed consent 
• 
Tumor biopsy or paracentesis, if no archival tissue is available 
• 
Verification of ≥5% AR+ by IHC in tumor tissue 
 
To be completed within 30 days prior to start of study drug: 
 
• 
Signature of treatment informed consent following inclusion and exclusion review 
and determination of patient eligibility for the study 
• 
Physical exam and vital signs (height, weight, pulse, temperature, blood pressure) 
• 
Karnofsky Performance Status (KPS) 
• 
12-lead ECG 
• 
Baseline radiographic tumor assessment (CT or MRI of abdomen and pelvis; CT of 
chest) with documentation of sites of disease per RECIST (version 1.1) 


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Administrative Update 3 : 17-Mar-2020 
Page 16 of 38 
 
 
 
 
To be completed within 14 days prior to start of study drug: 
 
• 
Pregnancy test in women of child bearing potential 
• 
Blood sampling for: 
o CBC with differential 
o Comprehensive Metabolic Panel (Na, K, Cl, CO2, BUN, CREAT, Ca, 
Glucose, Bilirubin, total protein, albumin, alkaline phosphatase, AST, ALT) 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
Enrolled patients will initiate treatment with enzalutamide 160mg by mouth daily beginning 
Day 1 of Cycle 1. A Cycle is 28 days. Four 40 mg enzalutamide capsules should be 
swallowed whole with a glass of water.  Enzalutamide should be taken at the same time 
each day. Missed doses will not be made-up.  All doses, and missed doses will be 
recorded in the patient’s pill diary. Patients will remain on treatment with enzalutamide 
160mg PO QD (with dosage adjustments as described below) until POD, unacceptable 
toxicity or withdrawal of consent. 
While on study, patients will return for assessments with a treating physician every 2 
weeks during the first cycle, and then every 4 weeks. Vital signs, toxicity assessment and 
blood work will be performed at each start of cycle visit. The pill diary will be collected 
and a new drug supply and pill diary will be provided. A +/- 4 day window is allowed for 
each start of cycle assessment. 
 
During screening, every 2 cycles (8 weeks) while on treatment, and at end of study, 
patients will have a CT or MRI of abdomen and pelvis performed. Best overall response 
should be confirmed with repeat imaging performed at ≥ 4 weeks. Chest imaging with CT 
should be performed at baseline. If initial chest imaging is abnormal or continued chest 
imaging is required to monitor tumor response, then it should be repeated every 2 cycles 
(8 weeks) while on treatment and at end of study. There is a +/- 7 day window for 
completion of interval tumor assessments by imaging. 
 
Blood work will be drawn to measure levels of estradiol and testosterone on Day 1 of 
Cycle 1, Day 1 of Cycle 2, and at end of treatment. 
 
An optional research non-billable tumor biopsy will be performed at end of treatment in 
consenting patients with accessible disease. A tube of whole blood will be drawn on Day 1 
of Cycle 1 and on Day 1 of Cycle 2 for gene expression studies and cell free DNA analysis. 
9.2 
Overview of Dose Adjustments  of Enzalutamide for Toxicity 
 
Report of seizure will result in immediate cessation of enzalutamide. A patient who experiences a 
DLT (other than seizure) during the safety lead-in phase may be allowed to continue study 
treatment following adequate recovery and appropriate dose modification. Any dose modification 
of enzalutamide requires consultation with the study sponsor. 


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Administrative Update 3 : 17-Mar-2020 
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• 
If Grade 1 or 2 toxicities occur, give supportive care per institutional guidelines. No 
enzalutamide dose reduction should occur. 
• 
If ≥ Grade 3 toxicities occur that are considered potentially related to enzalutamide, 
including headache, nausea, vomiting or diarrhea, hold enzalutamide until the toxicity 
resolves to ≤ Grade 1, unless baseline is grade 2, then until returns to baseline. 
• 
If enzalutamide is held for ≤28 days it may be restarted at the same or a reduced dose at 
the discretion of the study sponsor (or designee). 
• 
If enzalutamide is held for >28 days the patient should be removed from study treatment 
 
 
9.3 
Drug Interactions 
Any medication (see Appendix B for representative medications) that may predispose the patient 
to seizure disorder should be stopped at least 4 weeks prior to starting treatment with 
enzalutamide. 
 
The following medications or therapies are prohibited during the receipt of study drug: 
• 
Medications, including herbal therapies, with an antitumor effect 
• 
Any investigational agent 
• 
AR antagonists 
• 
5-α reductase inhibitors 
• 
Androgens 
• 
And medication (see Appendix B fro representative medications) that may 
predispose the patient to seizure 
 
9.4 
Precautions Regarding Concomitant Medications 
Please refer to the following link for an up to date list of CYP and P-glycoprotein inhibitors, 
inducers, and substrates. 
 
http://www.fda.gov/Drugs   /DevelopmentApprovalProcess/DevelopmentResources/DrugInteraction  
sLabeling/ucm093664.htm#potency 
 
9.5 
Effects of Enzalutamide on Cytochrome P450 Enzymes and P-Glycoprotein 
 
In vitro studies showed that enzalutamide is an inhibitor of CYP2C8 and CYP2C19 with lesser 
inhibitory effects on CYP2B6 and CYP2C9. Substrates of CYP2B6, CYP2C8, CYP2C9, and 
CYP2C19 that have a narrow therapeutic index (e.g., paclitaxel, phenytoin, warfarin) should be 
used with caution. 
 
In vitro studies showed that enzalutamide may be an inducer of CYP3A4. Co-administration of 
enzalutamide with CYP3A4/5 substrates may reduce oral bioavailability  and/or accelerate 
elimination of the CYP3A4/5 substrate. 
 
In vitro studies showed that enzalutamide is an inhibitor of the efflux transporter P-glycoprotein 
(P-gp). Co-administration of enzalutamide with P-gp substrates may increase the plasma 
concentrations of the P-gp substrate. Use caution when co-administering P-gp substrates (e.g., 
digoxin, fexofenadine, paclitaxel) during enzalutamide treatment. 


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9.6 
Drugs That May Increase Enzalutamide Plasma Concentrations 
 
In vitro studies showed that enzalutamide is metabolized by CYP2C8 and CYP3A4/5. Use caution 
when co-administering a strong CYP2C8 inhibitor (e.g., gemfibrozil) or strong CYP3A4/5 inhibitors 
(e.g., clarithromycin, itraconazole, ketoconazole, grapefruit juice) during enzalutamide treatment. 
 
9.7 
Drugs That May Decrease Enzalutamide Plasma Concentrations 
 
Use caution when co-administering a CYP2C8 inducer (e.g., rifampin) or strong CYP3A4/5 
inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) during enzalutamide 
treatment. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
 
 
Day 1; 
Cycle 1 
Day 15; 
Cycle 1 
Day 1; Cycle 3, 
5, 7… (odd 
cycles)
7
 
Day 1; Cycle 
2,4,8…(even 
cycles)
7
 
End of 
Study 
Treatment 
Informed Consent 
X 
History & Physical 
Exam6 
X 
X 
X7 
X7 
X7 
X 
Toxicity 
Assessment 
X 
X 
X 
X 
X 
X 
Vital Signs 
X1 
X1 
X1 
X1 
X1 
X1 
KPS 
X 
X 
X 
X 
X 
X 
ECG 
X2 
CT of  Chest 
X3 
X3 
X3 
Radiographic 
Tumor 
Assessment  of 
Abd/Pelvis 
X4 
X4 
X4 
CBC with 
Differential 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
(for patients of 
child bearing 
potential) 
X 
Comprehensive 
Metabolic Panel 
X 
X 
X 
X 
X 
X 
Liver function 
Tests 
X 
X 
X 
X 
X 
Blood for 
Hormones 
X 
X9 
X 
Whole blood 
research test 
X8 
X8 
Tumor Biopsy 
X5 
X5 
Dispense 
Enzalutamide 
X7 
X7 
X7 
Screening 


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1: Vital signs: blood pressure, heart rate, temperature and weight. Height need only 
be taken on Cycle 1, Day 1. 
2: Hypokalemia should be corrected prior to ECG collection 
 
3: Chest imaging with CT should be performed at baseline. If initial chest imaging is 
abnormal or continued chest imaging is required to monitor tumor response, then it 
should be repeated every 2 cycles (8 weeks) while on treatment and at end of study. 
There is a 
+/- 7 day window for completion of interval tumor assessments by imaging. 
 
4: Radiographic tumor assessment of abdomen and pelvis may be performed using CT 
or MRI. There is a +/- 7 day window for completion of interval tumor assessments by 
imaging. 
 
5: Patients without adequate archival tissue available will have a biopsy performed. 
Patients who consent for an end of treatment biopsy will have an optional tumor biopsy 
performed at end of treatment. 
6: Includes recording of concurrent medications and focused physical exam. There is a +/- 
4 day window allowable for each start of Cycle assessment. 
 
7: Pill diary and remaining pills should be collected and new pill diary and 1 month supply of 
study drug should be given to patient. 
 
8: One 10 cc tube of whole blood for gene expression analyses will be collected on Day 1 of 
Cycle 1 and Day 1 of Cycle 2 
9: Blood for hormone levels (testosterone and estradiol) will be collected at start of 
treatment, Cycle 2, Day 1 and at end of treatment. 
 
10.1 Research Tests 
 
10.1.a Research Bloods 
 
Serum testosterone level and estradiol level will be drawn on Cycle 1, Day 1 of treatment; 
Cycle 2, Day 1 of treatment, and at end of treatment. These will be collected as research 
non-billable blood draws. These tests will be performed and reported by the MSKCC central 
core laboratory. This testing is being performed to observe the effect of enzalutamide on 
testosterone and estradiol levels in women with ovarian, primary peritoneal, or fallopian tube 
cancer. 
10.1.b Tumor Biopsy 
 
Tumor biopsies will be performed at two time points during this study; a biopsy will be will be 
performed at screening if no archival tissue is available and an optional biopsy will be 
performed at end of treatment. 


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If the patient has archival tissue available that is appropriate for AR IHC staining (block or 
unstained slides), then archival tissue may be used. In cases where multiple blocks are 
available staining will be performed on unstained slides from 3 separate blocks. If ≥ 5% AR 
tumor staining is seen on ≥ 1 slide the tumor will be considered to be AR+. 
 
An optional tumor biopsy will be performed at end of treatment in those patients who have 
POD, consent to biopsy, and have accessible disease. 
Biopsy samples should be fixed in 10% formalin and paraffin embedded. In cases where 
a reasonable size biopsy is obtained (i.e., excisional biopsy, 18 gauge needle), such 
that the pathologist feels there is adequate sample for preparation of both a frozen and 
fixed specimen,  a fresh frozen biopsy should also be collected. At a minimum, enough 
tissue should be collected (by FNA or Core) for generation of a FFPE block for H&E and IHC 
analysis. At a maximum 2 cores should be collected. 
 
Lesions with the greatest change in dimensional size based on interval evaluation are the 
recommended lesions to be excised. W henever possible, biopsies at POD should be 
performed within 3 days of study drug discontinuation. 
 
Biopsies obtained at the time of progressive disease will be used to investigate potential 
mechanisms of acquired resistance. Biopsy samples will be analyzed for level of AR 
positivity by IHC in order to determine if the androgen receptor is downregulated during 
treatment with enzalutamide. 
 
10.2 
Correlative Studies 
 
The degree of nuclear AR expression levels will be determined using standard 
immunohistochemistry methodology on all tissue and reported as percent tumor cells with 
nuclear AR staining. One-three 5 micrometer superplus frost slides will be used for IHC 
testing. This testing will be performed at the Memorial Sloan-Kettering Cancer Center CLIA 
approved Clinical Laboratory using the Dako androgen receptor antibody. Upon receipt of the 
slide in the clinical laboratory, results will be reported within 48 hours. The relationship 
between tumor response and degree of AR expression, and/or AR signaling, will be 
examined. Additional assays for AR signaling, (e.g., gene expression array analyses, 
mutation analyses, or other immunohistochemistry evaluations) may be performed on 
remaining tissue to evaluate for molecular phenotypes and patterns associated with activated 
AR signaling. 
 
Germline DNA will be used both for cell free DNA analysis and as a matched normal for 
MiSeq analysis. MiSeq will be used to evaluate for alterations within the androgen, estrogen, 
and progesterone receptors. Germline DNA from peripheral blood will be used to filter out 
germline variants. The germline DNA sequencing data will be used as a filter to define 
somatic alterations and will not be reported. A 10cc tube of whole blood will be collected on 
Cycle 1, Day 1 and on Cycle 2, Day 1 for use in gene expression analyses. This testing will 
be performed at Memorial Sloan-Kettering Cancer Center. 


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Page 21 of 38 
 
 
 
Archived patient blood and/or tissue may be sent to Medivation Inc. and/or Astellas for 
additional analyses. 
 
Any additional future studies performed using the clinical information, blood, or tissue 
collected from this study will only be performed after completion of appropriate institutional 
approval. 
11.0 TOXICITIES/SIDE EFFECTS 
 
11.1 
Most Frequent Adverse Events 
 
The safety and tolerability of enzalutamide have been evaluated in 13 studies. It is 
estimated that a total of 124 healthy volunteers, 16 subjects with hepatic impairment, and 
approximately 1800 patients with prostate cancer have been exposed to enzalutamide in 
completed, open-label, and ongoing blinded studies. No study has been terminated early for 
safety reasons. 
 
Enzalutamide (160 mg daily) was generally well-tolerated in the placebo-controlled CRPC2 
study of 1199 patients with progressive castration-resistant prostate cancer previously 
treated with docetaxel-based chemotherapy. The adverse events occurring in at least 5% of 
the enzalutamide group and at an incidence at least 2% greater than in the placebo group 
included fatigue (33.6% vs. 29.1%), diarrhea (21.4% vs. 17.5%), hot flush (20.3% vs. 
10.3%), musculoskeletal pain (13.6% vs. 10.0%), headache (11.6% v 5.5%), insomnia 
(8.6% vs. 6.0%), anxiety (6.4% vs. 4.0%), hypertension (6.1% vs. 2.8%), and 
nasopharyngitis (5.1% vs. 3.0%). 
 
Other adverse events reported less commonly than 5% but that may be associated with 
enzalutamide treatment after careful assessment of the adverse events include: falls (4.0% 
vs.1.3%), dry skin (3.6% vs. 1.3%), and pruritus (3.5% vs. 1.3%). A possible cognitive effect 
of enzalutamide was observed with a greater proportion of patients in the enzalutamide- 
treated group (4.1% vs. 1.8%) reporting the following adverse events: memory impairment, 
cognitive disorder, amnesia, disturbance of attention, and dementia. In addition, events 
related to hallucination (visual hallucination, tactile hallucination, 
hallucination) were reported more frequently in the enzalutamide-treated group (1.6% vs. 
0.3%). 
 
During pre-market evaluation, seizure was identified as a risk associated with enzalutamide 
treatment. In the controlled clinical study, 5 patients (0.6%) experienced a seizure out of 800 
patients treated with a daily dose of 160 mg enzalutamide, whereas no seizures occurred in 
patients treated with placebo. One additional serious adverse event reported by the 
Investigator as syncope was identified by the Sponsor as having several features suggesting 
seizure as the most likely diagnosis. Confounding factors may have contributed to the 
occurrence of seizures in several of these cases. Dose appears to be an important predictor 
of seizure, with a greater risk of seizure at daily doses higher than 160 mg. In a dose 
escalation study involving 140 patients, no patients experienced seizures at or below daily 
doses of 240 mg, whereas 3 seizures were reported, 1 each at 360, 480, 
and 600 mg/day. 


Memorial Sloan Kettering Cancer Center 
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Administrative Update 3 : 17-Mar-2020 
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Caution should be used in administering enzalutamide to patients with a history of seizures 
or other predisposing factors including, but not limited to, underlying brain injury, stroke, 
primary brain tumors or brain metastases, or alcoholism. In addition, the risk of seizure may 
be increased in patients receiving concomitant medications that may lower the seizure 
threshold. Enzalutamide should be permanently discontinued in patients who have a seizure 
while on treatment. 
 
11.2 
Safety Measurements 
 
Safety and tolerability will be determined by frequent assessment of adverse events, 
physical examinations, vital signs, and safety laboratory assessments as defined in 
section 10.1. A safety follow-up visit will be conducted approximately 30 days after the last 
dose of enzalutamide. 
 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.2 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment on study. 
 
Evaluable for objective response.  Only those patients 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 response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients 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.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
 
12.2 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by 
chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 


Memorial Sloan Kettering Cancer Center 
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Administrative Update 3 : 17-Mar-2020 
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Note:  Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless progression is documented or a biopsy is obtained to 
confirm persistence at least 90 days following completion of radiation therapy. 
 
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-meas urable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Target les ions.  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.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters. If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target les ions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each 
should be noted throughout follow-up. 


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12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans), but NOT 
lung. 
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe  
specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, 
the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with breath- 
hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET- 
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  PET- 
CT scans are not always done with oral and IV contrast. In addition, the PET portion of the 
CT introduces additional data which may bias an investigator if it is not routinely or serially 
performed.  For these reasons, we will not allow PET-CT use for RECIST 1.1 response 
criteria. 
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. 


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If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
12.4 
Response Criteria 
 
12.41 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) 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 (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note:  the appearance of one or 
more new lesions is also considered progressions). 
 
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. 
 
12.42 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). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status. 


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It must be representative of overall disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
 
12.43 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
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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For Patients 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 as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
13.1 
CRITERIAFOR REMOVAL FROM STUDY 
 
Study treatment will be discontinued for the following reasons: 
 
• 
Progression of disease 
• 
Persistent or unacceptable toxicity despite appropriate dose reductions 
• 
Withdrawal of consent 
• 
If in the opinion of the investigator continuation on study poses 
unreasonable risks to the patient. This might include patients who fail to 
return for adequate follow-up, hampering the ability to monitor toxicities 
Any patient discontinuing study drug should be seen at 30 days post discontinuation for 
the evaluations outlined in the study schedule.  The patient’s tumor status should be 
assessed clinically and, if appropriate, disease progression should be confirmed by 
radiological  assessment. 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note:   Patients 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. 


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𝑁𝑠 
 
 
After discontinuation of the study medication at any point in the study, all ongoing AEs or 
SAEs must be followed until resolution unless, in the investigator’s opinion the condition is 
unlikely to resolve due to the patients underlying disease, or the patient is lost to follow up. All 
new AEs and SAEs occurring during the 30 calendar days after the last dose of study 
medication must be reported and followed to resolution as above.  Patients should be 
contacted at least 30 days after discontinuing study medication to collect and /or complete AE 
information.  Any untoward event occurring subsequent to the 30-day follow-up AE reporting 
period that the investigator assesses as possibly related to the study medication should also 
be reported as an AE. 
 
Any patient, who has not yet shown objective disease progression, should continue to be 
followed as per RECIST 1.1. 
 
14.1 
BIOSTATISTICS 
 
This is a single institution, single-arm unblinded Phase II trial of enzalutamide 160 PO QD in 
patients with AR (+) ovarian, primary peritoneal, or fallopian tube cancer with measurable 
disease following 1-3 prior cytotoxic therapies. The primary endpoint includes both the 
progression free survival (PFS) at 6 months, which detects stabilization of disease, and the 
best overall response(complete or partial response by RECIST 1.1). If 
either endpoint indicates efficacy, the treatment will be considered clinically interesting and 
worthy of further investigation. 
14.2 Safety Lead-in 
 
In order to reduce patient risk, we will examine in detail the first cycle DLT and other safety 
data for the first 15 patients before enrolling the rest of the study’s patients. A patient is 
considered toxicity-free for the purpose of the trial if he/she completes the first cycle of 
therapy (28 days) without experiencing a DLT as defined as: 
 
• 
And event consistent with a seizure of any grade 
• 
Grade ≥ 3 diarrhea, nausea, or vomiting that does not improve to Grade 1 within 
14 days of initiating standard of care therapy 
• 
Grade ≥ 3 platelet count with associated bleeding 
• 
Grade ≥ 3 absolute neutrophil count (ANC) that persists for 7 or more days or that is 
associated with fevers (febrile neutropenia) 
• 
Any other ≥ Grade 3 non-hematologic toxicity determined to be related to study 
drug 
 
If a patient experiences a DLT during cycle 1, but is able to continue on protocol following 
dose holding/dose reduction, they will still be considered a DLT. 
 
Based on Gönen [31], we utilize a Bayesian interpretation for θ (the probability of DLT at a 
planned does; ~Beta(α,β). The number of observed DLTs (Xs) in the safety lead-in 
cohort of Ns  patients is assumed to follow a binomial distribution (P(Xs| θ)∝ 𝜃𝑠  (1 − 𝜃) 
). Therefore, the posterior distribution of P(θ|Xs) is Beta(α+ Xs, β+Ns-Xs). A uniform prior as 


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Beta(α=1, β =1) is used to reflect the uncertainty value for θ as suggested by Gönen [31]. 
 
Let Ns =15, the probability that θ exceeds various targets (i.e. 0.2, 0.3, 0.4) given the 
observed DLT patients’ number (P(θ|Xs)) can be calculated. They are listed in the 
following table: 
 
 
DLT # in the  15 safety lead-in patients 
P(θ>0.2) 
P(θ>0.3) 
P(θ>0.4) 
0 
0.028 
0.003 
0.000 
1 
0.141 
0.026 
0.003 
2 
0.352 
0.099 
0.018 
3 
0.598 
0.246 
0.065 
4 
0.798 
0.450 
0.167 
5 
0.918 
0.660 
0.329 
6 
0.973 
0.825 
0.527 
7 
0.993 
0.926 
0.716 
8 
0.999 
0.974 
0.858 
9 
1.000 
0.993 
0.942 
10 
1.000 
0.998 
0.981 
11 
1.000 
1.000 
0.995 
12 
1.000 
1.000 
0.999 
>=13 
1.000 
1.000 
1.000 
 
 
Based on the table above, if we observe 0/15 patients with DLTs in the safety lead-in cohort, 
there is 0.003 chance that θ exceeds 0.3; whereas, if 5/15 patients with DLTs are observed, 
the chance that θ exceeds 0.3 increases to 0.660. Given these probabilities at the end of 
safety lead-in, we can make informed decisions regarding the appropriateness of the choice 
of the following trial (i.e. if >=5 DLTs observed in the safety lead-in cohort, the trial will be 
halted immediately and the PI will examine the toxicity profile and determine whether lower 
doses will be added). 
 
14.2. Sample size calculation for the two-stage phase II trial 
 
Prior targeted therapies for treatment of ovarian, primary peritoneal, and fallopian tube 
cancer have shown response rates of 0%-21% and PFS at 6 months of 6.5%-40.3% in 
patients with recurrent or advanced ovarian, primary peritoneal, or fallopian tube cancer  
and a history of 1-2 prior cytotoxic therapies.W e hypothesize that treatment with 
enzalutamide will result in an increase in tumor response rate from 5% to 20% or an 
increase in 6-month PFS rate from 15% to 30% (Ho: πrr<=0.05 and πpf s<=0.15 vs. H1: 
πrr>0.05 or πpf s>0.15). To test the null hypotheses in a two-stage design, a method provided 
by Sill and Yothers [32] is used. In particular, in stage I, 28 eligible patients will be 
evaluated, if 3 or more patients have clinical response or 5 or more patients have no 
progression/death at 6 months, then the study will open to the second stage accrual. In 


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stage II, an additional 31 patients will be enrolled. At the end of stage II, if at least 7 of 59 
(28+31=59) patients have clinical response or at least 13 of 59 patients survive progression 
free for 6 months, this will be considered as a positive trial. 
 
Assuming the two primary endpoints are independent, the power in each scenario and the 
type 1 error are listed as in the following table: 
 
PFS rate at 6mo 
 
 
Response 
 
 
 
Assuming the two primary endpoints are highly correlated (as the joint probability of πrr and 
πpfs  is 0.90Xmin(πrr, πpfs) [32]), the power in each scenario and the type 1 error are as the 
following: 
PFS rate at 6mo 
 
 
Response 
 
 
 
When the null hypotheses are true for both the response and the PFS, the chance of 
stopping the trial after stage I enrollment is 49% under independence and 55% under 
dependence. 
 
The clinical response and the  PFS  from the starting of the treatment will be documented for 
each patient (including the patients in the safety lead-in). All the patients enrolled in this 
phase will be included in the main analysis of response and PFS. Patients who are lost to 
follow-up within 6 months are considered as failures for the PFS binary outcome of PFS 
within 6 months: yes/no. The response rate will be calculated. The patients accrued during 
the safety lead-in period will be included in the first stage of two-stage phase II portion. With 
the accrual rate of 3-6 patients per months, accrual of the 28  stage I patients should be 
complete within 9 months. After confirming promising results from stage I, the accrual 
of an additional  30 stage II patients should be complete within 10 months. The expected 
total trial duration is 30 months. 
 
14.3. Other objectives 
Safety and tolerability will be summarized using descriptive statistics. Adverse events will be 
assessed by NCI CTCAE version 4.0 criteria. The serious adverse events will be described 
separately. 
 
The PFS duration will be summarized using the Kaplan-Meier method and the median 
PFS time will be estimated. 
πpfs= 0.3 
πpfs= 0.15 
πrr= 0.20 
0.99 
0.94 
πrr= 0.05 
0.90 
0.10 
πpfs= 0.3 
πpfs= 0.15 
πrr= 0.20 
0.97 
0.92 
πrr= 0.05 
0.90 
0.09 


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The treatment outcomes such as response rate and PFS will be associated with the AR 
expression (actual expression level, on a scale from 0-100%) by using W ilcoxon two 
sample test for relating to response and Cox PH model for relating to PFS. 
 
The effect of enzalutamide (continuous) on levels of serum estradiol and testosterone and 
the effect on tumor AR expression by IHC will be described in graphical form and with 
descriptive statistics. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.3 
Randomization 
 
This is a non-randomized study. 
 
 
16.1 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA)  will be assigned  to the study.  The  responsibilities  of 
the RSA include data collection, abstraction and entry, data reporting, and  problem 
resolution  and prioritization. 
 
The  data  collected  for  this  study  will  be  entered  into  a  secure  database.   Source 
documentation  will be available  to support the computerized patient record. 
 
The estimated rate of accrual will be 5-6 patients per month. All patients will remain on 
treatment until POD, intolerable toxicity, self-discontinuation of study treatment, or removal 
from study for any other reason. 


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16.2 
Quality Assurance 
 
Weekly registration reports will be generated  to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies.  Accrual  rates  and  extent  and  accuracy  of evaluations  and  follow- 
up will be monitored periodically  throughout  the  study  period and potential  problems will 
be brought to the attention  of the study team for discussion and action 
Random-sample  data quality and protocol compliance audits  will be conducted by the 
study team, at a minimum of two times per year, more frequently  if indicated. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring  (DSM) Plans at Memorial  Sloan-Kettering  Cancer 
Center were approved  by the National  Cancer Institute  in September 2001. The plans 
address the new policies  set forth by the NCI in the document entitled  ―Policy of the 
National  Cancer Institute  for Data and Safety Monitoring  of Clinical Trials‖  which can 
be found  at: http://cancertrials.nci.nih.gov/researchers/dsm/index.html.  The DSM 
Plans at MSKCC were established and are monitored  by the Office of Clinical 
Research. The MSKCC Data and Safety Monitoring  Plans can be found on the 
MSKCC  Intranet   at: http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different  mechanisms by which clinical trials are monitored for data, 
safety and quality.  There are institutional  processes in place for quality  assurance (e.g., 
protocol monitoring,  compliance and data verification  audits, therapeutic  response, and 
staff education on clinical research QA) and departmental  procedures  for quality control, 
plus there are two institutional  committees that are responsible for monitoring  the 
activities  of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center‘s Research Council and 
Institutional  Review Board. 
During the protocol development  and review  process, each protocol will be assessed for 
its level of risk and degree of monitoring  required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial  sponsored, NCI cooperative  group, etc.) will be 
addressed  and  the  monitoring   procedures  will  be  established   at  the  time  of  protocol 
activation. 
 
 
 
 
 
 
 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 


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17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is required for 
30-days after the participant’s last investigational treatment or intervention. Any events that occur 
after the 30-day period and that are at least possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. The 
IRB requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the 
SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. 
All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. 
All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 


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• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the report 
will be forwarded to the FDA by the SAE staff through the IND Office 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
 
 
Before any protocol-specific procedures can be carried out, the consenting 


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professional will fully explain the aspects of patient privacy concerning research 
specific information.  In addition to signing the IRB Informed Consent, all patients must 
agree to the Research Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
1. 
Siegel, R., et al., Cancer statistics, 2011: the impact of eliminating socioeconomic and racial 
disparities on premature cancer deaths. CA Cancer J Clin, 2011. 61(4): p. 212-36. 
2. 
Jones, S., et al., Low-grade serous carcinomas of the ovary contain very few point mutations. 
J Pathol, 2012. 226(3): p. 413-20. 
3. 
Hanker, L.C., et al., The impact of second to sixth line therapy on survival of relapsed ovarian 
cancer after primary taxane/platinum-based therapy. Ann Oncol, 2012. 23(10): p. 2605-12. 
4. 
Farley, J., Brady, W., Birrer, M., LAnkes, H., Coleman, R., Morgan, M., Mannuel, R., 
Yamada, D., Mutch, D., Gershenson, D., Gynecologic Oncology Group A Phase II Trial of 
AZD6244 in Women with Recurrent Low-Grade Serous Carcinoma of the Ovary or 
Peritoneum. . 17th International Meeting  of the European Society of Gynaecological 
Oncology September, 2011. 
5. 
Colanta, A., et al., BRAF Mutation Analysis of Fine-Needle Aspiration Biopsies of Papillary 
Thyroid Carcinoma: Impact on Diagnosis and Prognosis. Acta Cytol, 2011. 55(6): p. 563-9. 
6. 
Kuhnel, R., et al., Androgen receptor predominance in human ovarian carcinoma. J Steroid 
Biochem, 1987. 26(3): p. 393-7. 
7. 
Chadha, S., et al., An immunohistochemical evaluation of androgen and progesterone 
receptors in ovarian tumors. Hum Pathol, 1993. 24(1): p. 90-5. 
8. 
Kuhnel, R., et al., Multiple parameter analyses of human ovarian cancer: morphology, 
immunohistochemistry, steroid hormone receptors and aromatase. Anticancer Res, 1988. 
8(2): p. 281-6. 
9. 
Wang, P.H. and C. Chang, Androgens and ovarian cancers. Eur J Gynaecol Oncol, 2004. 
25(2): p. 157-63. 
10. 
Keutgen, X.M., et al., A Panel of Four miRNAs Accurately Differentiates Malignant from 
Benign Indeterminate Thyroid Lesions on Fine Needle Aspiration. Clin Cancer Res, 2012. 
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IRB Number: 13-119 A(16) 
Approval date: 02-Jul-2018 
Administrative Update 3 : 17-Mar-2020 
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20.0 
APPENDICES 
 
List appendices here. Appendices will be stored in a separate file and will be submitted in 
electronic and/or paper format. If electronic format, please submit on file per appendix. 
 
Appendix A: Pill Diary 
Appendix B: List of Medications that May Lower Seizure Threshold 
Appendix C: Fact Card for patient reference