Clinical trial NCT02407054
Conditions: Prostate Cancer Metastatic
Sponsor: Eli Lilly and Company
Start date: 2015-04-29; Completion date: 2020-04-16
Enrollment: 142 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the safety and effectiveness of the study drug known as LY3023414 in combination with enzalutamide in men with prostate cancer.

Detailed description:

Arms: arm 1: Participants received 200 milligrams (mg) LY3023414 orally twice daily (BID) during the initial week to assess pharmacokinetics (PK). Thereafter, participants received 200 mg of LY3023414 BID in combination with 160 mg of enzalutamide QD beginning Cycle 1 Day 1. A treatment cycle was defined as 28 days. arm 2: Participants received 200 mg LY3023414 orally BID in combination with 160 mg enzalutamide orally once daily (QD). arm 3: Participants received placebo in combination with 160 mg enzalutamide QD.
Interventions: intervention 1: LY3023414 intervention 2: Enzalutamide intervention 3: Placebo
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol GU 115/I6A-MC-CBBD 
 
A Double-Blinded, Placebo-Controlled, Randomized Phase II Study of Enzalutamide With or 
Without the PI3 Kinase/mTOR Inhibitor LY3023414 in Men with Metastatic Castration 
Resistant Prostate Cancer 
 
NCT02407054 
 
Approval Date: 25-Feb-2017 


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S/S P O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3:   2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 1 of 9 5
G U 1 1 5 /I 6 A-M C -C B B D
A D o u ble -Bli n de d, Pl ace b o -C o ntr olle d, R a n d o mize d P h ase II St u d y of 
E nz al ut a mi de Wit h or Wit h o ut t he PI 3 Ki n ase/ m T O R I n hi bit or L Y 3 0 2 3 4 1 4 
i n Me n wit h Met ast atic C astr ati o n Resist a nt Pr ost ate C a ncer
S A R A H C A N N O N D E V E L O P M E N T 
I N N O V A TI O N S, L L C  S TU D Y N U M B E R :
G U 1 1 5
S P O N S O R S T U D Y N U M B E R :
I 6 A-M C -C B B D
S T U D Y D R U G( S):
L Y 3 0 2 3 4 1 4
S P O N S O R:
Eli Lill y a n d C o m pa n y
I n dia na p olis, I n dia na, U S A  4 6 2 8 5
C O N T R A C T R E S E A R C H O R G A NI Z A TI O N:
Sara h Ca n n o n De vel o p me nt I n n o vati o ns, L L C
3 3 2 2 West E n d A ve n ue , S uite 9 0 0
Nas h ville, T N  3 7 2 0 3
1- 8 7 7- M Y - 1-S C RI
as ksara h @sara hca n n o n.c o m
S T U D Y C H AI R:
Da na Far ber Ca ncer I nstit ute
La n k Ce nter f or Ge nit o uri nar y O nc ol o g y
4 5 0 Br o o kli ne A ve
B ost o n, M A 0 2 2 1 5
S P O N S O R C O N T A C T :
Eli Lill y a n d C o m pa n y
K ol bl gasse 8 - 1 0
A- 1 0 3 0 Vie n na, A ustria
D A T E FI N A L:
1 0 Dece m ber 2 0 1 4
A M E N D M E N T N U M B E R:
1
A M E N D M E N T D A T E:
2 7 Fe br uar y 2 0 1 5
A M E N D M E N T N U M B E R
2
A M E N D M E N T D A T E
3 0 J ul y 2 0 1 5
A M E N D M E N T N U M B E R
3
A M E N D M E N T D A T E
2 5 Ja n uar y 2 0 1 7
A p pr o v al D at e: 2 5- F e b- 2 0 1 7 G M T
P P D
P P D
P P D
P P D


CONFIDENTIAL
STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
GU 115/ I6A-MC-CBBD
AMENDMENT 3: 25 January 2017
v 4.0
Page 2 of 95
Clinical Study Statement of Compliance
A Double-Blinded, Placebo-Controlled, Randomized Phase II Study of 
Enzalutamide With or Without the PI3 Kinase/mTOR Inhibitor LY3023414 
in Men with Metastatic Castration Resistant Prostate Cancer
This clinical study shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but not 
be limited to:

International Conference on Harmonisation (ICH) Guidelines on Good Clinical 
Practice (GCP)

Ethical principles that have their origins in the Declaration of Helsinki 

Food and Drug Administration (FDA) Code of Federal Regulation (CFR):
o
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects
o
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators
o
Title 21CFR Part 56, Institutional Review Boards
o
Title 21CFR Part 312, Investigational New Drug Application
o
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
As the Study Chair and/or Principal Investigator, I understand that my signature on the 
protocol constitutes my agreement and understanding of my responsibilities to conduct the 
clinical study in accordance to the protocol and applicable regulations.  Furthermore, it 
constitutes my understanding and agreement that any changes initiated by myself, without 
prior agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such.
As the Contract Research Organization (CRO) Representative, I understand that my signature 
constitutes agreement and understanding of acceptance of the defined and contracted sponsor 
responsibilities as defined by the protocol, applicable Clinical Trial Agreements (CTA), and/or 
business contracts.  Additionally, my signature constitutes my understanding and agreement 
that any changes to the protocol, CTA, or contracts shall be implemented with the Sponsor’s 
review and approval prior to implementation.
As the Sponsor Representative, I understand that my signature constitutes agreement and 
understanding of acceptance of the defined and contracted Sponsor responsibilities to the CRO 
and the Principal Investigator as defined by the protocol, applicable Clinical Trial Agreements 
(CTA), and/or business contracts, but does not in any capacity relieve me of my responsibilities 
as the Sponsor.  Additionally, my signature constitutes my understanding and agreement that 
any changes to the protocol, CTA, or contracts shall be implemented timely with my review 
and approval prior to implementation.


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 3 of 9 5
P P D
P P D
P P D
P P D
P P D
P P D


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 4 of 9 5
P P D
P P D
P P D
P P D
P P D


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 5 of 9 5
P P D
P P D
P P D
P P D
P P D


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 6 of 9 5
P P D
P P D
P P D
P P D
P P D


CONFIDENTIAL
STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
GU 115/ I6A-MC-CBBD
AMENDMENT 3: 25 January 2017
v 4.0
Page 7 of 95
Clinical Study Principal Investigator Signature Form
A Double-Blinded, Placebo-Controlled, Randomized Phase II Study of 
Enzalutamide With or Without the PI3 Kinase/mTOR Inhibitor LY3023414 
in Men with Metastatic Castration Resistant Prostate Cancer
SARAH CANNON DEVELOPMENT
INNOVATIONS STUDY NUMBER:
GU 115
SPONSOR STUDY NUMBER:
I6A-MC-CBBD
DATE FINAL:
10 December 2014
AMENDMENT NUMBER:
1
AMENDMENT DATE: 27 February 2015
AMENDMENT NUMBER:
2
AMENDMENT DATE:
30 July 2015
AMENDMENT NUMBER:
3
AMENDMENT DATE:
25 January 2017
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol.
__________________________
__________________________         ______________
Principal Investigator Name
Principal Investigator Signature
Date


CONFIDENTIAL
STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
GU 115/ I6A-MC-CBBD
AMENDMENT 3: 25 January 2017
v 4.0
Page 8 of 95
GU 115 Clinical Study Summary of Changes
AMENDMENT NUMBER:
3
AMENDMENT DATE:
25 January 2017
Global Change
SCRI Development Innovations was changed to Sarah Cannon Development Innovations 
throughout the protocol.  The address for Sarah Cannon Development Innovations was updated.
Study Duration:  The total duration of the study is approximately 40 25 months which includes 
31 16 months of enrollment and 9 months of expected treatment duration.
Study Centers:  This study will be conducted at approximately 48 18 sites
Section 2.1 Primary Objective
The primary objective of this study is:
To compare progression-free survival (PFS) – PSA, radiographic, or Prostate Cancer Clinical 
Trials Working Group (PCWG2) symptomatic progression - in men with mCRPC who are 
receiving enzalutamide plus LY3023414 versus enzalutamide plus placebo using Prostate Cancer 
Clinical Trials Working Group (PCWG2) criteria.
Section 3.1 Inclusion Criteria and Synopsis
3.
Prostate cancer progression documented by PSA and/or radiographic progression 
according to PCWG2 criteria (Appendix F). PSA levels must have a starting value of at 
least 2.0 ng/mL that have increased on 3 occasions obtained a minimum of 1 week apart.
4.
Prior abiraterone treatment completed at least 2 weeks prior to Cycle 1 Day 1.   Patient 
must have failed prior abiraterone treatment to be eligible.
8.
Adequate hematologic function defined as:
•
Absolute neutrophil count (ANC) ≥1500/μL
•
Platelets ≥100,000/µL (transfusions to obtain this level are not allowed)
•
Hemoglobin ≥8 g/dL
Section 3.2 Exclusion Criteria and Synopsis
6. History of (a) seizure or any condition that may predispose to seizure (prior cortical 
stroke or significant brain trauma) within 12 months prior to Day 1 of Cycle 1; (b) loss of 
consciousness or transient ischemic attack within 12 months prior to Day 1 of Cycle 1.
12.Have a history of New York Heart Association (NYHA) Class ≥3 congestive heart 
failure (CHF), QTc interval > 450 480 ms on screening electrocardiogram (ECG) per 
Friderica’s formula at several consecutive days of assessment, unstable angina, or 
myocardial infarction (MI) in 6 months prior to study drug administration.


CONFIDENTIAL
STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
GU 115/ I6A-MC-CBBD
AMENDMENT 3: 25 January 2017
v 4.0
Page 9 of 95
GU 115 Clinical Study Summary of Changes
AMENDMENT NUMBER:
3
AMENDMENT DATE:
25 January 2017
Section 5.1.1 LY3023414 or Placebo
Patients should take the morning and evening doses of LY3023414 approximately 12 hours apart 
(preferably within a 10- to 14-hour range).  Patients should not consume food for approximately 
1 hour before taking the dose of LY3023414 or matching placebo and should remain in a fasting 
state for 1 hour post-dose.  LY3023414 or matching placebo should be taken with a glass of 
water at approximately the same time each day.  LY3023414 or matching placebo can be taken 
with or without food.  Patients should swallow the capsules as a whole and should not chew or 
crush them.  
Section 5.1.2 Enzalutamide
Enzalutamide will be self-administered by the patient.  Enzalutamide will be taken together with 
one of the two daily doses of LY3023414 or matching placebo.  Therefore, patients should not 
consume food for approximately 1 hour before taking the dose of enzalutamide and should 
remain in a fasting state for 1 hour post-dose. Enzalutamide can be taken with or without food  
Enzalutamide capsules should be swallowed whole.  Patients should not chew, dissolve, or crush 
them.  
Section 5.7 Pharmacogenetic (PGx) Assessment
The PGx sample is part of the biomarker sample.  Therefore, there is no separate kit for PGx 
samples.  Samples will only be used for investigations related to disease and drug or class of 
drugs under study in the context of this clinical program.
Section 10.2 Sample Size Consideration and Synopsis
PASS14 PASS13 Version (copyright 2015 2014) was used to calculate sample size.
Two interim analyses were planned at approximately 39% information rate and 82% 
information rate.  Approximately 0% of total type I error and 20% of total type II error were 
spent at the first interim.  The first interim analysis is planned to be conducted when a total of 
36 PFS events are observed.  Approximately 20% of total type I error and 0% of total type II 
error were spent at the second interim.  The second interim analysis is planned to be 
conducted when a total of 75 PFS events are observed.
The interim analysis is planned at approximately 75% information rate, with approximately 40% 
of total type I error and 0% of total type II error spent at the interim.  The interim analysis will be 
conducted when a total of 70 PFS events are observed.
Section 10.6.1 Final Analysis
The final analysis of the study will be triggered when 92 96 patients have had an event (disease 
progression or all cause death).


CONFIDENTIAL
STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
GU 115/ I6A-MC-CBBD
AMENDMENT 3: 25 January 2017
v 4.0
Page 10 of 95
GU 115 Clinical Study Summary of Changes
AMENDMENT NUMBER:
3
AMENDMENT DATE:
25 January 2017
Section 10.6.2 Planned Interim Analysis
The first interim analysis will be conducted when a total of 36 PFS events are observed for 
futility assessment. The one sided p-value of 0.774 will be used as the boundary to assess the 
efficacy of enzalutamide plus LY3023414 versus enzalutamide plus placebo for the first 
interim analysis. If the P-value is more than 0.774, the study will be terminated for futility. 
The second interim analysis will be conducted when a total of 75 PFS events are observed. 
One-sided p-value of 0.042 will be used as the boundary to assess the efficacy of enzalutamide 
plus LY3023414 versus enzalutamide plus placebo for the second interim analysis. 
One-sided p-value of 0.2 will be used as the boundary to assess the efficacy of enzalutamide 
plus LY3023414 versus enzalutamide plus placebo in the final analysis.
Interim analysis will be conducted when a total of 70 PFS events are observed.  One-sided p-
value of 0.077 will be used as the boundary to access the efficacy of enzalutamide plus 
LY3023414 versus enzalutamide plus placebo during the interim analysis.  One-sided p-value of 
0.195 will be used as the boundary to access the efficacy of enzalutamide plus LY3023414 
versus enzalutamide plus placebo in the final analysis.
Schedule of Assessments
Footnote f - PT/INR will only need to be repeated if abnormal at baseline or if clinically 
indicated.  Patients requiring the initiation of an anti-coagulation therapy during study treatment 
should have their coagulation test performed on a weekly basis.
Footnote s - The PGx sample should be collected C1D1. If the sample is not able to be collected 
C1D1, it can be collected anytime during C1 or C2. The PGx sample is part of the biomarker 
sample and does not require a separate kit.


CONFIDENTIAL
STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
GU 115/ I6A-MC-CBBD
AMENDMENT 3: 25 January 2017
v 4.0
Page 11 of 95
GU 115/I6A-MC-CBBD PROTOCOL SYNOPSIS
Title of Study:
A Double-Blinded, Placebo-Controlled, Randomized Phase II Study of Enzalutamide With 
or Without the PI3 Kinase/mTOR Inhibitor LY3023414 in Men with Metastatic Castration 
Resistant Prostate Cancer
Sarah Cannon 
Development
Innovations Study 
Number:
GU 115 
Sponsor Study 
Number:
I6A-MC-CBBD
Sponsor:
Eli Lilly and Company, Indianapolis, IN
Study Duration:
The total duration of the study is approximately 40 months 
which includes 31 months of enrollment and 9 months of 
expected treatment duration.
Phase of Study:  II
Study Centers:
This study will be conducted at approximately 48 sites
Number of 
Patients:
Approximately 144 medically or surgically castrated male patients with metastatic, 
castration resistant prostate cancer (mCRPC) who have shown disease progression on 
abiraterone will be enrolled. Part A will include approximately 6-12 patients to assess 
pharmacokinetics (PKs)/safety.  Part B will include 132 patients to assess progression-free 
survival (PFS).
Objectives:
Primary Objective
The primary objective of this study is:

To compare progression-free survival (PFS) – PSA, radiographic, or Prostate 
Cancer Clinical Trials Working Group (PCWG2) symptomatic progression - in men 
with mCRPC who are receiving enzalutamide plus LY3023414 versus 
enzalutamide plus placebo using PCWG2 criteria.
Secondary Objectives
The secondary objectives of this study are:

To compare the clinical response rates (RRs) in men with mCRPC who are 
receiving enzalutamide plus LY3023414 versus enzalutamide plus placebo and who 
have measurable disease at baseline using Response Evaluation Criteria in Solid 
Tumors (RECIST) v 1.1 (Eisenhauer et al. 2009).

To compare time to clinical (symptomatic or radiographic) and/or PSA progression 
(TTP) in men with mCRPC who are receiving enzalutamide plus LY3023414 
versus enzalutamide plus placebo using PCWG2 criteria.

To compare the maximum decline in PSA that occurs following treatment in men 
with mCRPC who are receiving enzalutamide plus LY3023414 versus 
enzalutamide plus placebo.

To demonstrate the safety and tolerability of 200 mg twice daily (BID) oral 
LY3023414 given in combination with 160 mg once daily (QD) oral dose of 
enzalutamide.

To evaluate potential pharmacokinetic (PK) drug interactions (i.e. impact of 
enzalutamide on LY3023414 exposure) and to further characterize LY3023414 PK 
properties.

To characterize the safety profile of enzalutamide plus LY3023414 as compared to 
enzalutamide plus placebo in this patient population.


CONFIDENTIAL
STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
GU 115/ I6A-MC-CBBD
AMENDMENT 3: 25 January 2017
v 4.0
Page 12 of 95
GU 115/I6A-MC-CBBD PROTOCOL SYNOPSIS
Objectives:
Exploratory Objective
The exploratory objective of this study is:

To collect blood and archival tissue for exploratory studies to identify potential 
biomarkers predictive of clinical efficacy of study treatment and disease 
progression in this patient population.
Study Design:
This is a double-blinded, placebo-controlled, randomized Phase II study of the combination 
of enzalutamide plus LY3023414 versus enzalutamide plus placebo in medically or 
surgically castrated men with mCRPC who have shown disease progression on abiraterone.  
Cycles will be 28 days in length.  Patients will be treated until disease progression 
(radiographic or PCWG2 symptomatic progression), or until they develop an unacceptable 
adverse event (AE) requiring discontinuation of the drug, or patient/physician choice.  
Patients with PSA progression are allowed and encouraged to continue treatment until 
clinical (symptomatic or radiographic) progression.
Lead-In (Part A)
A lead-in (Part A) of approximately 6-12 patients will be conducted prior to the randomized 
Phase II portion of the study to assess safety, tolerability, and available PK data for potential 
PK interaction.  Prior to starting this combination therapy on Cycle 1 Day 1, patients in Part 
A will be given single agent LY3023414 200 mg every 12 hours (BID) during the initial 
week (called Week -1) to assess LY3023414 PKs at a steady state (Section 5.6) on Day -1 
(last day of that Week -1).
Double-blinded, Placebo-Controlled Randomized Study (Part B)
After dose is established in Part A, a total of 132 patients will be randomized in a 1:1 ratio to 
enzalutamide 160 mg orally QD in combination with LY3023414 200 mg or matching 
placebo orally BID (Part B).  Randomization will be stratified based on two factors: 1) the 
presence or absence of visceral disease (i.e. non-lymph node soft tissue disease), and 2) if 
patients previously received chemotherapy in the hormone-sensitive setting when 
commencing androgen deprivation therapy (ADT).  
Study Drugs, 
Doses, and Modes 
of Administration:
Enzalutamide 160 mg will be administered orally QD.
LY3023414 200 mg or matching placebo will be administered orally BID.
Inclusion Criteria:
1.
Histologically or cytologically confirmed adenocarcinoma of the prostate.
2.
Metastatic disease documented by positive bone scan or metastatic lesions on CT, MRI.  
If lymph node metastasis is the only evidence of metastasis, it must be ≥ 2 cm in 
diameter.
3.
Prostate cancer progression documented by PSA and/or radiographic progression 
according to PCWG2 (Appendix F).  PSA levels must have a starting value of at least 
2.0 ng/mL that have increased on 3 occasions obtained a minimum of 1 week apart.
4.
Prior abiraterone treatment completed at least 2 weeks prior to Cycle 1 Day 1.  Patient 
must have failed prior abiraterone treatment to be eligible.
5.
If patient has previously been treated with RA-223 dichloride, treatment must be 
completed at least 4 weeks prior to Cycle 1 Day 1 (minimum 4 week wash out period).


CONFIDENTIAL
STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
GU 115/ I6A-MC-CBBD
AMENDMENT 3: 25 January 2017
v 4.0
Page 13 of 95
GU 115/I6A-MC-CBBD PROTOCOL SYNOPSIS
Inclusion Criteria, 
continued:
6.
If a patient was treated with abiraterone, but their last treatment prior to enrolment was 
an anti-androgen other than abiraterone, PSA or symptomatic progression will need to 
be documented.  The minimum washout period for these agents is as follows:

6 weeksfor long acting agents (nilutamide, bicalutamide) 

4 weeks for short acting agents (flutamide).  
Patients whose PSA did not decline for 3 or more months in response to an anti-androgen 
given as a second line or later intervention will require only a 2-week washout prior to Cycle 
1 Day 1.
7.
Surgically or medically castrated, with testosterone levels of < 50 ng/dL.  If the patient 
is being treated with LHRH agonists (patients who have not undergone orchiectomy), 
this therapy must be continued throughout the study.
8.
Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.
9.
Ability to swallow the study drugs whole.
10. Adequate hematologic function defined as:

Absolute neutrophil count (ANC) ≥1500/μL

Platelets ≥100,000/µL (transfusions to obtain this level are not allowed)

Hemoglobin ≥8 g/dL
11. Adequate liver function defined as:

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the 
upper limit of normal (ULN).  If the liver has tumor involvement, AST and ALT 
equaling ≤5 times ULN are acceptable.

Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin elevation due 
to Gilbert’s disease or a similar syndrome involving slow conjugation of bilirubin).
12. Adequate renal function defined as serum creatinine < 1.5 x ULN OR creatinine 
clearance  > 45 mL/min Cockcroft-Gault formula for patients with serum creatinine 
> 1.5x ULN.
13. Adequate coagulation parameters, defined as International Normalization Ratio (INR) 
≤2.  Patients with history of blood clots may receive anticoagulation with low 
molecular weight heparin, central line prophylaxis-dose warfarin, or anti-factor Xa 
agents.
14. Patients 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 and sponsor during the study and for 3 months after last study 
drug administration.
15. Male, Age ≥18 years.
16. Willingness and ability to comply with study and follow-up procedures.
17. Ability to understand the nature of this study and give written informed consent.
18. Availability of tumor tissue (formalin-fixed paraffin-embedded [FFPE] blocks) or 
unstained slides from any time since diagnosis of prostate cancer disease (i.e., archival 
tumor samples).  If no tumor samples are available the patient might still be eligible 
following discussion between the investigator and the Medical Monitor.


CONFIDENTIAL
STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
GU 115/ I6A-MC-CBBD
AMENDMENT 3: 25 January 2017
v 4.0
Page 14 of 95
Exclusion Criteria:
1.
Patients that have received the following prior treatments for CRPC
Prior cytotoxic chemotherapy. Note: Patients may have received docetaxel in 
the hormone-sensitive setting.
a.
PI3K/AKT /mTOR agent (including TORC1 and TORC2 inhibitors)
b.
Immune checkpoint inhibitors (e.g. inhibitors of CTLA4, PD1, PD1)
c.
Prior investigational new generation potent anti-androgen therapy (such as 
ARN 509).
d.
Prior treatment with enzalutamide.
2.
Pathological finding consistent with small cell carcinoma of the prostate.
3.
Concurrent use of other investigational agent(s).
4.
Prior systemic treatment with an azole drug (fluconazole, itraconazole) within 4 weeks 
of Cycle 1 Day 1.
5.
Known brain metastasis.
6.
History of (a) seizure or any condition that may predispose to seizure (prior cortical 
stroke or significant brain trauma) within 12 months prior to Day 1 of Cycle 1; (b) loss 
of consciousness or transient ischemic attack within 12 months prior to Day 1 of Cycle 
1.
7.
Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg or diastolic 
BP ≥95 mmHg).  Patients with a history of hypertension are allowed, provided blood 
pressure is controlled by anti-hypertensive treatment.
8.
Have serious pre-existing medical conditions (at the discretion of the investigator).
9.
Have known acute or chronic leukemia or current hematologic malignancies that, in the 
judgment of the investigator and sponsor, may affect the interpretation of results.
10. Have insulin-dependent diabetes mellitus. Patients with a type 2 diabetes mellitus are 
eligible if adequate control of blood glucose level is obtained by oral anti-diabetics as 
documented by HbA1c <7%.
11. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of oral therapy 
(e.g. ulcerative disease, uncontrolled nausea, vomiting, Grade ≥2 diarrhea, and 
malabsorption syndrome).
12. Have a history of New York Heart Association (NYHA) Class ≥3 congestive heart 
failure (CHF), QTc interval > 480 ms on screening electrocardiogram (ECG) per 
Friderica’s formula, unstable angina, or myocardial infarction (MI) in 6 months prior to 
study drug administration.
13.
Clinically significant electrolyte imbalance ≥ Grade 2.
14. Currently receiving treatment with therapeutic doses of warfarin sodium.  Low 
molecular weight heparin and oral Xa inhibitors are allowed.
15. Have initiated treatment with bisphosphonates or approved RANK ligand (RANK-L) 
targeted agents (e.g. denosumab) ≤28 days prior to Day 1 of Cycle 1.
16. Concurrent serious infections requiring parenteral antibiotic therapy.
17. Have a second primary malignancy that in the judgment of the investigator and Medical 
Monitor may affect the interpretation of results.
18. Have an active, known fungal, bacterial, and/or known viral infection including:

human immunodeficiency virus (HIV) (screening not required)

hepatitis A (screening not required)

hepatitis B or C (screening not required).
19. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol.


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STUDY DRUG:  LY3023414
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GU 115/I6A-MC-CBBD PROTOCOL SYNOPSIS
Correlative 
Testing:
Blood and archival tumor samples will be collected to evaluate biomarker including but not 
limited to PI3K pathway components.  Tumor and blood samples may be analyzed to 
explore potential biomarkers (e.g. gene signature[s]) predictive for response to study 
treatment. Mutational status, copy number variations, and/or protein products of cancer-
related genes (including, but not limited to, PIK3CA, PTEN, or RAS and AR-V7) may be 
analyzed at a laboratory designated by the sponsor.
Statistical 
Methodology:
Determination of sample size:
Sample size considerations for the randomized portion of the study (Part B) are based on the 
primary endpoint of PFS and one interim analysis of efficacy.  The median PFS in the 
control arm of enzalutamide is estimated to be 4 months (Schrader et al. 2014) and a 
clinically meaningful hazard ratio (HR) is taken to be 0.7, equating to a median PFS in the 
enzalutamide plus LY3023414 arm of 5.7 months.  Based on a 16-month accrual period (3 
months ramp up plus 13 months full recruitment), a minimum of 9 months follow-up after 
the last patient has been randomized, and a lost to follow-up/non-compliance rate of no more 
than 10%, a total of 132 patients will be randomized in a 1:1 ratio between the two treatment 
arms. With a total of 92 events, the study will have at least 80% power to test the primary 
hypothesis using a one-sided, log rank test at the 0.20 significance level.
Two interim analyses were planned at approximately 39% information rate and 82% 
information rate. Approximately 0% of total type I error and 20% of total type II error were 
spent at the first interim.  The first interim analysis is planned to be conducted when a total 
of 36 PFS events are observed.  Approximately 20% of total type I error and 0% of total type 
II error were spent at the second interim. The second interim analysis is planned to be 
conducted when a total of 75 PFS events are observed.


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 1 6 of 9 5
G U 1 1 5/I 6 A -M C -C B B D C O N T A C T I N F O R M A TI O N
S ar a h C a n n o n De vel o p me nt I n n o v ati o ns C o nt act 
I nf or m ati o n:
Sara h Ca n n o n De vel o p me nt I n n o vati o ns
1 1 0 0 C harl otte A ve. , S uite 8 0 0
Nas h ville, T N  3 7 2 0 3
1- 8 7 7- M Y - 1-S C RI
as ksara h @sara hca n n o n.c o m
St u d y C h air:
Da na Far ber Ca ncer I nstit ute
La n k Ce nter f or Ge nit o uri nar y O nc ol o g y
4 5 0 Br o o kli ne A ve
B ost o n, M A 0 2 2 1 5
Me dic al M o nit or:
Sara h Ca n n o n De vel o p me nt I n n o vati o ns
1 1 0 0 C harl otte A ve. , S uite 8 0 0
Nas h ville, T N 3 7 2 0 3
 
S p o ns or C o nt act I nf or m ati o n:
Eli Lill y a n d C o m pa n y
K ol bl gasse 8 - 1 0
A- 1 0 3 0 Vie n na, A ustria
S afet y De pt. F a x #:
1 - 8 6 6 -6 4 4 -1 6 9 7
Re g ul at or y P h o ne # / F a x #:
Re g ul at or y E m ail:
1 -8 7 7 -M Y -1 -S C RI / 1 -6 1 5 -5 2 4 -4 5 1 8
S C RI Re g ulat or y @ S C RI -I n n o vati o ns.c o m
S ar a h C a n n o n De vel o p me nt I n n o v ati o ns
E nr oll me nt P h o ne #:
1 -8 6 6 -3 4 6 -1 0 6 2
P P D
P P D
P P D
P P D
P P D
P P D


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STUDY DRUG:  LY3023414
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LIST OF ABBREVIATIONS
ADT
Androgen deprivation therapy
AE
Adverse event
ALP
Alkaline phosphatase
ALT (SGPT)
Alanine aminotransferase
ANC
Absolute neutrophil count
AR
Adverse reaction
AST (SGOT)
Aspartate aminotransferase
BID
Twice daily
CBC
Complete blood count
CFR
Code of Federal Regulations
CI
Confidence interval
CMP
Comprehensive metabolic profile
CR
Complete remission
CRPC
Castration Resistant Prostate Cancer
CT
Computerized tomography
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
INR
International Normalized Ratio
IP
Investigational product
IRB
Institutional Review Board
LHRH
Luteinizing hormone-releasing hormone
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OR
Objective response
ORR
Overall response rate
OS
Overall survival
PCWG2
Prostate Cancer Clinical Trials Working Group
PD
Progressive disease
PDx
Pharmacodynamic
PGx
Pharmacogenomics
PHI
Protected health information
PI3K
Phosphatidylinositol-3-kinase
PFS
Progression-free survival


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STUDY DRUG:  LY3023414
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LIST OF ABBREVIATIONS (continued)
PK
Pharmacokinetic
PR
Partial response
PSA
Prostate specific antigen
PTEN
Phosphatase and tensin homolog (gene)
QA
Quality assurance
QD
Once daily
RANK-L
Receptor activator of nuclear factor kappa-B ligand
RECIST
Response Evaluation Criteria in Solid Tumors
RR
Response rate
SAE
Serious adverse event
SAR
Suspected adverse reaction
SD
Stable disease
SUSAR
Suspected Unexpected Serious Adverse Reaction
TTP
Time to progression
UAE
Unexpected adverse event
ULN
Upper limit of normal


CONFIDENTIAL
STUDY DRUG:  LY3023414
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TABLE OF CONTENTS
1.
INTRODUCTION .............................................................................................23
1.1
Background........................................................................................................23
1.2
Treatment for Prostate Cancer ............................................................................23
1.3
LY3023414........................................................................................................24
1.3.1
Safety Pharmacology..........................................................................................25
1.3.2
Nonclinical Pharmacokinetics/Pharmacodynamics .............................................25
1.3.3
Clinical Experience with LY3023414.................................................................26
1.4
Rationale for the Study.......................................................................................27
2.
STUDY OBJECTIVES......................................................................................28
2.1
Primary Objective ..............................................................................................28
2.2
Secondary Objectives .........................................................................................28
2.3
Exploratory Objective ........................................................................................29
3.
STUDY PATIENT POPULATION AND DISCONTINUATION......................29
3.1
Inclusion Criteria................................................................................................29
3.2
Exclusion Criteria ..............................................................................................31
3.3
Discontinuation from Study Treatment ...............................................................32
4.
STUDY REGISTRATION.................................................................................33
5.
STUDY DESIGN...............................................................................................33
5.1
Treatment Plan...................................................................................................38
5.1.1
LY3023414 or Placebo.......................................................................................38
5.1.2
Enzalutamide .....................................................................................................38
5.2
Treatment Duration ............................................................................................39
5.3
Treatment Assignment Unblinding Procedures...................................................39
5.4
Concomitant Medications...................................................................................39
5.4.1
Permitted Concomitant Medications...................................................................39
5.4.2
Prohibited Concomitant Medications ..................................................................40
5.4.3
Concomitant Medications to be avoided .............................................................40
5.5
Correlative Studies .............................................................................................41
5.5.1
Samples for Pharmacogenetics and/or Tailoring Biomarkers ..............................41
5.6
Pharmacokinetic Assessments ............................................................................42
5.7
Pharmacogenomic (PGx) Assessement...............................................................45
6.
DOSE MODIFICATIONS .................................................................................46
7.
STUDY ASSESSMENTS AND EVALUATIONS.............................................47


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7.1
Overview ...........................................................................................................47
7.2
Baseline Study Assessments...............................................................................47
7.3
Study Treatment Assessments ............................................................................48
7.3.1
Single Agent LY3023414 Day -7 (Part A only, Week -1)...................................48
7.3.2
Cycle 1 – Day 1..................................................................................................49
7.3.3
Cycle 1 – Day 15 (Part A patients only) .............................................................49
7.3.4
Cycle 2 and all Subsequent Cycles, Day 1 (±72 hours) .......................................50
7.4
Response Assessment – Prior to Cycle 3 and After Every 2 Cycles ....................50
7.5
PSA Progression ................................................................................................51
7.6
End of Treatment Visit .......................................................................................51
7.7
Follow-up...........................................................................................................52
7.7.1
Follow-up for Patients Who Discontinue Prior to Disease Progression ...............52
8.
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION.............................................................................52
8.1
LY3023414 or Placebo.......................................................................................52
8.1.1
Labeling, Packaging, and Supply........................................................................52
8.1.2
Precautions and Risks Associated with LY3023414 ...........................................53
8.2
Enzalutamide .....................................................................................................53
8.2.1
Labeling, Packaging, and Supply........................................................................53
8.2.2
Precautions and Risks Associated with Enzalutamide.........................................53
8.3
Accountability for All Study drugs .....................................................................53
9.
RESPONSE EVALUATIONS AND MEASUREMENTS..................................54
10.
STATISTICAL CONSIDERATIONS................................................................54
10.1
Statistical Design................................................................................................54
10.2
Sample Size Considerations ...............................................................................54
10.3
Analysis Population ...........................................................................................55
10.4
Data Analysis.....................................................................................................55
10.4.1
Demographics and Baseline Characteristics........................................................55
10.4.2
Efficacy Analysis ...............................................................................................55
10.4.3
Safety Analysis ..................................................................................................57
10.4.4
Pharmacokinetics/Pharmacodynamics ................................................................58
10.5
Handling of Missing Data ..................................................................................58
10.6
Analysis Time Point...........................................................................................59
10.6.1
Final Analysis ....................................................................................................59
10.6.2
Planned Interim Analysis ...................................................................................59
10.6.3
Safety Review ....................................................................................................59
10.6.4
Unblinding Patients............................................................................................60


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11.
SAFETY REPORTING AND ANALYSES .......................................................60
11.1
Adverse Events ..................................................................................................60
11.2
Serious Adverse Events......................................................................................62
11.2.1
Adverse Event and Serious Adverse Event Reporting.........................................63
11.3
Complaint Handling ...........................................................................................64
12.
QUALITY ASSURANCE AND QUALITY CONTROL ...................................64
12.1
Monitoring .........................................................................................................64
12.2
Audits and Inspections .......................................................................................64
13.
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS............64
13.1
Institutional Review Board Approval .................................................................65
13.2
Regulatory Approval..........................................................................................65
13.3
Informed Consent...............................................................................................65
13.3.1
Confidentiality ...................................................................................................66
13.4
Financial Information.........................................................................................67
14.
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY........67
14.1
Amendments to the Protocol ..............................................................................67
14.2
Documentation Required to Initiate the Study ....................................................68
14.3
Study Documentation and Storage......................................................................68
14.4
Data Collection ..................................................................................................70
14.5
Disclosure and Publication Policy ......................................................................70
15.
REFERENCES ..................................................................................................72
16.
APPENDICES ...................................................................................................75
LIST OF TABLES
Table 1
Pharmacokinetic Sample Collection Times – Part A Patients only.........44
Table 2
Pharmacokinetic Sample Collection Times – Part B Patients only .........45
Table 3
Dose Level Modifications .....................................................................47
LIST OF FIGURES
Figure 1
Study Schema........................................................................................37


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LIST OF APPENDICES
Appendix A:
ECOG Performance Status Criteria...................................................75
Appendix B:
New York Heart Association (NYHA) Classification of Cardiac 
Disease .................................................................................................76
Appendix C:
Guidelines for Fertile Male Patients...................................................77
Appendix D:
Schedule of Assessments and Study Plan ...........................................78
Appendix E:
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1...........................................................................................81
Appendix F:
PCWG2 Criteria..................................................................................85
Appendix G:
Drugs That Prolong QT Interval and/or Induce Torsades de 
Pointes..................................................................................................88
Appendix H:
List of QT Prolonging Drugs to be Used with Caution......................90
Appendix I:
Common CYP1A2 Inducers, CYP2C9 and CYP2C19 Inducers 
and Substrates, Substrates for CYP3A4, CYP2C8 Inducers, 
CYP3A Inducers and Inhibitors, and P-gp/CYP3A Dual 
Inhibitors .............................................................................................92
Appendix J:
Schematic to Represent the PK Sampling..........................................95


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1.
INTRODUCTION
1.1
Background
Prostate cancer is the most commonly diagnosed cancer in men with an estimated 233,000 new 
cases in the United States in 2014 and is the second-leading cause of cancer death in men with an 
estimated 29,480 deaths in 2014 (American Cancer Society 2014).  The majority of patients are 
diagnosed with and treated for localized disease.  However, a percentage of patients do present 
with metastatic disease at diagnosis, and others develop metastatic disease after completing 
definitive treatment.  Androgen deprivation therapy (ADT) is the cornerstone of treatment for 
metastatic prostate cancer; the goal of this line of therapy is primarily palliative and for 
prolongation of survival, but not as a cure.  Initial androgen deprivation is typically achieved 
with bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone 
(LHRH) therapy.  
In 2014, it was shown that use of docetaxel at the time of ADT for metastatic hormone-sensitive 
prostate cancer prolonged overall survival (OS) by 13 months (Sweeney et al. 2014).  Patients 
treated with androgen deprivation (medical or surgical castration) who develop disease 
progression in the presence of adequately depressed serum testosterone are considered to have 
castration-resistant prostate cancer (CRPC).  Approved therapeutic options for the management 
of patients with CRPC include cytotoxic therapies (mitoxantrone, docetaxel and cabazitaxel), 
immunotherapy (sipuleucel T), an alpha particle emitting radioactive therapeutic agent (radium 
RA 223 dichloride), and second generation hormonal therapies (abiraterone and enzalutamide).  
The goal of treatment with these agents is to prolong survival, improve quality of life, and/or 
slow progression of the disease (Bennett et al. 2014).
1.2
Treatment for Prostate Cancer
Enzalutamide (Xtandi®, Astellas Pharma US, Inc.) is a second-generation androgen antagonist 
that targets multiple steps in the androgen signaling pathway with no reported agonistic effects 
(Sementas et al. 2013, El-Amm et al. 2013).  The drug was originally approved by the Food and 
Drug Administration (FDA) in August 2012 for the treatment of patients with mCRPC who have 
previously received docetaxel (Ning et al. 2013).  This approval was based on the results of a 
double-blind, placebo-controlled, randomized phase III trial that compared enzalutamide 160 mg 
orally daily with placebo (Scher et al. 2012).  The study was stopped prematurely at the time of 
an interim analysis based on the significant improvement in OS that was observed with 
enzalutamide compared to placebo (18.4 vs. 13.6 months; hazard ratio (HR) 0.63; p <0.001).  
The secondary endpoints of prostate-specific antigen (PSA) response rate (RR) (54% vs. 2%) 
and soft-tissue RR (29% vs. 4%) also favored the enzalutamide arm.  
In September 2014, the FDA subsequently approved enzalutamide for patients with mCRPC 
regardless of prior docetaxel exposure based on data from the PREVAIL trial.  These data 
demonstrated the efficacy of enzalutamide in prolonging OS in men with chemotherapy-naïve 
mCRPC who have failed to respond following ADT and have few or no symptoms (Beer et al. 
2014). Men receiving enzalutamide experienced a statistically significant OS benefit compared 
to those receiving placebo (HR 0.71; 95% confidence interval (CI): 0.60-0.84, p<0. 001).  


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Radiographic progression-free survival (PFS) was also prolonged and there was a 17 month 
delay in the time to initiation of chemotherapy in men receiving enzalutamide.  The RR in men 
with soft tissue metastatic disease was 59% in men receiving enzalutamide compared to 5% of 
patients receiving placebo; the median time to PSA progression was prolonged from 2.8 to 11.2 
months with treatment.  In addition, the percentage of men with PSA decline from baseline of 
>90% was 47% in the abiraterone-naïve population.  Data has shown that a larger decline in PSA 
is associated with improvements in survival (Kelley et al. 1993).
There have not been large randomized trials to evaluate the efficacy of newer generation 
androgen antagonists after previous exposure to another newer generation androgen antagonist.  
Multiple smaller trials have evaluated the activity of enzalutamide in patients that have 
previously received abiraterone and vice versa.  These data suggest the response rates and time to 
progression are vastly diminished when receiving enzalutamide after abiraterone exposure 
(Noonan et al. 2013, Loriot et al. 2013, Smith et al. 2014, Schrader et al. 2014, Badrising et al. 
2014, Cheng et al. 2014).  This is not surprising seeing as both agents target the androgen 
receptor.  Specifically, Schrader, et al, studied enzalutamide in 35 patients with castrate-resistant 
prostate cancer previously treated with docetaxel and abiraterone and found a median time to 
progression on enzalutamide of 4.0 months which will serve as the benchmark for this trial 
(Schrader et al. 2014).
1.3
LY3023414
The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of 
rapamycin (mTOR) pathway is one of the most frequently dysregulated pathways in cancer, and 
loss of phosphatase and tensin homolog (gene) (PTEN) leading to constitutive activation of the 
PI3K pathway, is common in advanced prostate cancer (Tang et al. 2014, Edlind et al. 2014, 
Hong et al. 2014, Bitting et al. 2013).  Furthermore, preclinical studies demonstrate an 
association between the PI3K-AKT-mTOR and androgen receptor signaling axes that is 
potentiated as prostate cancer cells develop resistance to ADT and vice versa (Bitting et al. 2013, 
Carver et al. 2011).  Similar crosstalk has been demonstrated between the estrogen receptor 
signaling pathway and the PI3K/AKT/mTOR pathway in breast cancer.  Everolimus, an oral 
mTOR inhibitor, was recently approved in combination with exemestane for the treatment of 
women with advanced hormone receptor-positive, human epidermal growth factor receptor 2 
(HER2)-negative breast cancer after failure of treatment with letrozole or anastozole after 
demonstrating prolonged PFS in this setting (Baselga J. et al. 2012).
LY3023414 is an orally available, small molecule dual kinase inhibitor of class I PI3K isoforms 
and mTOR with good solubility across a wide pH range. In vitro kinase studies have shown that 
LY3023414 binds to the adenosine triphosphate (ATP) active site of PI3K to competitively 
inhibit phosphorylation of phosphatidylinositol-4, 5-bisphosphate (PIP2) at low nanomolar 
concentrations. In nonclinical studies, LY3023414 has demonstrated potent in vivo target 
inhibition that was linked to potent antitumor efficacy.  The nonclinical toxicology profile of 
LY3023414 has enabled a safe clinical starting dose, and a benefit-risk profile acceptable for 
cancer treatment with the toxicities observed in animal species that are manageable, monitorable, 
and likely reversible.  Clinical experience with LY3023414 is discussed in Section 1.3.3. 


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Safety Pharmacology 
1.3.1
1.3.1.1
Nonclinical Toxicology
LY3023414 was evaluated in nonclinical toxicology studies up to 1 month in duration using 
daily oral dosing in rats and dogs to characterize the toxicity.  Based on results from nonclinical 
studies in the rat and the dog, toxicities patients may experience include (but are not limited to) 
gastrointestinal toxicity, bone marrow and lymphoid organ toxicity (decreases in lymphocytes), 
and sores/scabbing of the skin.  Pharmacologic effects of PI3K/mTOR inhibition related to 
glucose metabolism have also been observed, including hyperinsulinemia, hyperglycemia, and 
QT interval prolongation in nonclinical studies.  In a rat embryo -fetal developmental pilot study 
of LY3023414, embryo-fetal lethality was seen along with an increase in fetal and litter 
incidence of external, visceral, and skeletal malformations.
For additional details on nonclinical toxicology data, see Section 5.2.1 of the Investigator’s 
Brochure (IB).
1.3.1.2
Nonclinical Efficacy Pharmacology Summary
LY3023414 is a potent selective inhibitor of the class I PI3K isoforms mTOR and DNA-PK, 
with selectivity in kinase enzyme assays as an ATP competitive inhibitor of PI3K (inhibition 
binding constant [Ki] of 8.5nM). LY3023414 demonstrated inhibitory activity against 
PI3K/mTOR pathway targets in vitro and in vivo as measured by phosphoprotein levels from 
cultured cells and tumor xenografts. LY3023414 showed antiproliferative and cell-cycle 
arresting effects in cultured cancer cells, and anti-angiogenesis activity via inhibition of in vitro 
vascular cord formation.  LY3023414 has excellent solubility and oral bioavailability across a 
wide pH range, allowing for simple suspension formulations to be used for or al administration in 
nude mice.  In xenograft tumor models, LY3023414 demonstrated dose-and time-dependent 
target inhibition, as well as antitumor efficacy in a wide range of tumor models (including renal 
cancer and non-small cell lung carcinoma [NSCLC]). The mouse pharmacokinetic 
(PK)/pharmacodynamics (PDx) model indicates a direct inhibition of downstream target 
phosphoproteins (such as, phospho Akt [pAkt], phospho 70S6K [p70S6K]). LY3023414 has 
potential for combination with standard of care agents to produce synergistic effects in cell 
culture and in vivo xenograft models.
Nonclinical Pharmacokinetics/Pharmacodynamics
1.3.2
Bioavailability of LY3023414 was 66% in dogs, and the clearance was less than hepatic blood 
flow.  No accumulation of LY3023414 was noted following repeated dosing to rats and dogs.  
Also, no consistent gender differences in toxicokinetic parameters were observed in rats or dogs 
throughout the 1-month study.  In vivo metabolism data showed that LY3023414 is metabolized 
predominantly via oxidation in rats and via oxidation and glucuronidation in dogs.  In both 
species, LY3023414 was the largest circulating entity in plasma.  Overall, clearance of 
LY3023414 in rats was primarily via metabolism while clearance in dogs involved metabolism 
as well as elimination via feces and urine.  Fecal excretion was the major route of elimination for 
LY3023414-related radioactivity in both species.


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 2 6 of 9 5
Cli nic al E x perie nce wit h L Y 3 0 2 3 4 1 4
1. 3. 3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 2 7 of 9 5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 4
R ati o n ale f or t he St u d y
T he PI 3 K a n d A R si g nali n g pat h wa ys re g ulate eac h ot her t hr o u g h c o m ple x reci pr ocal fee d bac k 
mec ha nis ms; u pre g ulat i on of t he A R pat h wa y  see ms t o c o u nter t he effect of small -m o lec ule 
i n hi bit ors of t he PI 3 K/ A kt pat h wa y w he n a d mi nistere d as si n gle a ge nts (We n et al. 2 0 0 0 , Li n et 
al. 2 0 0 1, Car ver et al. 2 0 1 1 ). Li ke t he A R si g nali n g pat h wa y in pr ostate ca ncer, t here is e vi de nce 
i n breast ca ncer t hat t he estr o ge n rece pt or sig nali n g pat h wa y int eracts wit h t he PI 3 K pat h wa y in 
a si milar fas hi o n.  I n a p hase 3 st u d y  of w o me n wit h breast ca ncer w h o ha d pr o gresse d o n a n 
ar o matase i n hi bit or, a d di n g t he m T O R i n hi bit or e ver oli m us t o e xe mesta ne pr o d uce d a 6 -m o nt h 
i ncrease i n pr o gressi on- free s ur vi val (Basel ga J. et al . 2 0 1 2).  T his trial pr o vide d rati o n al e f or t he 
st u d y of c o m bi ne d tar geti n g of t he A R a n d PI 3 K pat h wa ys wit h e nzal uta mi de a n d t he PI 3 K 
i n hi bit or B E Z 2 3 5 i n P T E N-deficie nt pr ostate cell li nes; t his c o m bi nat i on treat me nt res ult e d i n a 
mar ke d i ncrease i n a p o pt osis, w hile o nl y m o dest c yt ostatic act i vity was see n wi t h eac h 
i n di vi d ual a ge nt (Car ver et al. 2 0 1 1 ).  T he A kt i n hi bit or A Z D 5 3 6 3 i n c om bi nati o n wit h 
e nzal uta mi de s h o we d si milar s y ner gist ic acti vity i n a n ot her precli nical st u d y (T h o m as et al. 
2 0 1 3) , pr o vi di n g f urt her s u p p ort f or cli nical e val uati o n of a c o m bi nati on tar geti n g t he 
PI 3 K/ A kt/ m T O R pat h wa y a n d t he a n dr o ge n- rece pt or a xis i n patie nts wit h pr ostate ca ncer.  As 
e nzal uta mi de is a p pr o ve d f or patie nts wit h m C R P C i n t his setti n g a n d t he PI 3 K pat h wa y is 
fre q ue ntl y d ysre g ulate d i n patie nts wit h pr ostate ca ncer, a d di n g L Y 3 0 2 3 4 1 4 t o e nzal uta mi de is 
a n attractive strate g y  for i mpr o vi n g o utc o m es o ver e nzal uta mi de al o ne. 
T his d o u ble -bli n de d, place b o -c o ntr olle d, ra n d o mize d P hase II st u d y will e val uate P F S i n me n 
wi t h mC R P C treate d wit h e nzal uta mi de wit h or wit h o ut t he PI 3 K/ m T O R i n hi bit or L Y 3 0 2 3 4 1 4,
w h o ha ve s h o w n disease pr o gressi o n o n t he a dre nal i n hi bit or, a birater o ne.  Si nce a f or mal P hase 
I b st u d y has n ot bee n c o n d ucte d wit h t he c o m bi nati o n re gi me n of L Y 3 0 2 3 4 1 4 a n d e nzal uta mi de, 
C CI


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there will be a lead-in (Part A) of approximately 6-12 patients to assess safety, tolerability, and 
potential PK interaction.  Prior to starting this combination therapy on Cycle 1 Day 1, patients in 
Part A will be given single agent LY3023414 every 12 hours (BID) during the initial week 
(called Week -1) to assess LY3023414 PKs at a steady state (Section 5.6) on Day -1 (last day of 
that Week -1).  Once Part A is completed and the combination regimen is shown to be tolerated, 
all subsequent patients will be randomized to receive enzalutamide in combination with 
LY3023414 or in combination with a matching placebo (Part B).  
In numerous clinical trials evaluating AR antagonists, some patients never have a PSA decline 
on abiraterone (after enzalutamide) or enzalutamide (after abiraterone), suggesting primary 
resistance to AR-targeted agents (Noonan et al. 2013, Loriot et al. 2013, Smith et al. 2014, 
Schrader et al. 2014, Badrising et al. 2014, Cheng et al. 2014).  The mechanisms of resistance are 
multifactorial and a better understanding is needed.  A recent report of constitutive AR splice 
variants (AR-Vs) may represent a potential resistance mechanism and AR-V7 may be the most 
important one.  Recently, a prospective biomarker study showed that presence of AR-V7 in 
circulating tumor cells (CTC) of CRPC men on abiraterone or enzalutamide resulted in 
decreased progression-free survival (PSA, clinical, and radiographic) as compared to men whose 
CTCs were AR-V7 negative.  Furthermore, some AR-V7 negative patients became positive 
during treatment, suggesting acquired resistance (Antonarakis et al. 2014).  To explore potential 
mechanism of resistance to AR therapy, this study may evaluate the impact of variants of the 
androgen receptor and other biomarkers (including, but not limited to, PIK3CA, PTEN, RAS, or
AR-V7) in blood and tissue.
2.
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of this study is:

To compare progression-free survival (PFS) – PSA, radiographic, or Prostate Cancer 
Clinical Trials Working Group (PCWG2) symptomatic progression - in men with 
mCRPC who are receiving enzalutamide plus LY3023414 versus enzalutamide plus 
placebo using PCWG2 criteria.
2.2
Secondary Objectives
The secondary objectives of this study are:

To compare the clinical response rates (RRs) in men with mCRPC who are receiving 
enzalutamide plus LY3023414 versus enzalutamide plus placebo who have measurable 
disease at baseline using Response Evaluation Criteria in Solid Tumors (RECIST) v 
1.1(Eisenhauer et al. 2009).

To compare time to clinical (symptomatic or radiographic) and/or PSA progression 
(TTP) in men with mCRPC who are receiving enzalutamide plus LY3023414 versus 
enzalutamide plus placebo using PCWG2 criteria.


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STUDY DRUG:  LY3023414
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
To compare the maximum decline in PSA that occurs following treatment in men with 
mCRPC who are receiving enzalutamide plus LY3023414 versus enzalutamide plus 
placebo.

To demonstrate the safety and tolerability of 200 mg twice daily (BID) oral 
LY3023414given in combination with 160 mg once daily (QD) oral dose of 
enzalutamide.

To evaluate potential pharmacokinetic (PK) drug interactions (i.e. impact of enzalutamide 
on LY3023414 exposure) and to further characterize LY3023414 PK properties.

To characterize the safety profile of enzalutamide plus LY3023414 as compared to 
enzalutamide plus placebo in this patient population.
2.3
Exploratory Objective
The exploratory objective of this study is:

To collect blood and archival tissue for exploratory studies to identify potential 
biomarkers predictive of clinical efficacy of study treatment and disease progression in 
this patient population.
3.
STUDY PATIENT POPULATION AND DISCONTINUATION
3.1
Inclusion Criteria
Patients must meet all of the following criteria in order to be included in the research study:
1. Histologically or cytologically confirmed diagno sis of adenocarcinoma of the prostate.
2. Metastatic disease documented by positive bone scan or metastatic lesions on CT, MRI.  
If lymph node metastasis is the only evidence of metastasis, it must be ≥ 2 cm in 
diameter.
3. Prostate cancer progression documented by PSA and/or radiographic progression 
according to PCWG2 criteria (Appendix F).  PSA values must have a starting value of at 
least 2.0 ng/mL that have increased on 3 occasions obtained a minimum of 1 week apart.
4. Prior abiraterone treatment completed at least 2 weeks prior to Cycle 1 Day 1.  Patient 
must have failed prior abiraterone treatment to be eligible.
5. If patient has previously been treated with RA-223 dichloride, treatment must be 
completed at least 4 weeks prior to Cycle 1 Day 1 (minimum 4 week wash out period).
6. If a patient was treated with abiraterone, but their last treatment prior to enrolment was an 
anti-androgen as last treatment prior to enrolment, PSA or symptomatic progression will 
need to be documented.  The minimum washout period for these agents is as follows:

6 weeks for long acting agents (nilutamide, bicalutamide) 

4 weeks for short acting agents (flutamide).  


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Patients whose PSA did not decline for 3 or more months in response to an anti-androgen 
given as a second line or later intervention will require only a 2-week washout prior to 
Cycle 1 Day 1.
7. Surgically or medically castrated, with testosterone levels of < 50 ng/dL.  If the patient is 
being treated with LHRH agonists (patients who have not undergone orchiectomy), this 
therapy must be continued throughout the study.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 
(Appendix A).
9. Able to swallow the study drugs whole.
10. Adequate hematologic function defined as:
-
Absolute neutrophil count (ANC) ≥1500/μL
-
Platelets ≥100,000/µL (transfusions to obtain this level are not allowed)
-
Hemoglobin ≥8 g/dL
11. Adequate liver function defined as:
-
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the 
upper limit of normal (ULN).  If the liver has tumor involvement, AST and ALT 
equaling ≤5 times ULN are acceptable.
-
Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin elevation due 
to Gilbert’s disease or a similar syndrome involving slow conjugation of 
bilirubin)
12. Adequate renal function defined as serum creatinine < 1.5 x ULN OR creatinine 
clearance > 45 mL/min by Cockcroft-Gault formula for patients with serum creatinine 
> 1.5x ULN.
13. Adequate coagulation parameters, defined as International Normalization Ratio (INR) 
≤2.  Patients with history of blood clot may receive anticoagulation with low molecular 
weight heparin, central line prophylaxis-dose warfarin, or anti-factor Xa agents.
14. Patients 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 and sponsor during the study and for 3 months after last study drug 
administration.
15. Male, Age ≥18 years.
16. Willingness and ability to comply with study and follow -up procedures.
17. Ability to understand the nature of this study and give written informed consent.
18. Availability of tumor tissue (formalin-fixed paraffin-embedded [FFPE] blocks) or 
unstained slides from any time since diagnosis of prostate cancer disease (i.e., archival 
tumor samples).  If no tumor samples are available the patient might still be eligible 
following discussion between the investigator and the Medical Monitor.


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3.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1. Patients that have received the following prior treatments for CRPC
a.
Prior cytotoxic chemotherapy  Note: Patients may have received docetaxel in the 
hormone-sensitive setting.
b. PI3K/AKT /mTOR agent (including TORC1 and TORC2 inhibitors) for the 
treatment of CRPC.  
c.
Immune checkpoint inhibitors (e.g. inhibitors of CTLA4, PD1, PDL1)
d. Prior investigational new generation potent anti-androgen therapy (such as ARN 
509).
e.
Prior treatment with enzalutamide.
2. Pathological finding consistent with small cell carcinoma of the prostate.
3. Concurrent use of another investigational agent(s).
4. Prior systemic treatment with an azole drug (fluconazole, itraconazole) within 4 weeks of 
Cycle 1 Day 1.
5. Known brain metastasis.
6. History of (a) seizure or any condition that may predispose to seizure (prior cortical 
stroke or significant brain trauma) within 12 months prior to Day 1 of Cycle 1; (b) loss of 
consciousness or transient ischemic attack within 12 months prior to Day 1 of Cycle 1.
7. Uncontrolled hypertension (systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 
95 mmHg).  Patients with a history of hypertension are allowed, provided blood pressure 
is controlled by anti-hypertensive treatment.
8. Have serious pre-existing medical conditions (at the discretion of the investigator).
9. Have known acute or chronic leukemia or current hematologic malignancies that, in the 
judgment of the investigator and Medical Monitor, may affect the interpretation of 
results.
10. Have insulin-dependent diabetes mellitus. Patients with a type 2 diabetes mellitus are 
eligible if adequate control of blood glucose level is obtained by oral anti-diabetics as 
documented by HbA1c <7%.
11. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of oral therapy 
(e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, and 
malabsorption syndrome).


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12. Have a history of New York Heart Association (NYHA) Class ≥3 congestive heart failure 
(CHF), QTc interval > 480 ms on screening electrocardiogram (ECG) per Friderica’s 
formula, unstable angina, or myocardial infarction (MI) in 6 months prior to study drug 
administration.
13. Clinically significant electrolyte imbalance ≥Grade 2.
14. Currently receiving treatment with therapeutic doses of warfarin sodium.  Low molecular 
weight heparin and oral Xa inhibitors are allowed.
15. Have initiated treatment with bisphosphonates or approved RANK ligand (RANK-L) 
targeted agents (e.g. denosumab) ≤28 days prior to Day 1 of Cycle 1.
16. Concurrent serious infections requiring parenteral antibiotic therapy.
17. Have a second primary malignancy that in the judgment of the investigator and sponsor 
may affect the interpretation of results.
18. Have an active, known fungal, bacterial, and/or known viral infection including:

human immunodeficiency virus (HIV) (screening not required)

hepatitis A (screening not required)

hepatitis B or C (screening not required).
19. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol.
3.3
Discontinuation from Study Treatment
Patients will be discontinued from study treatment for any of the following reasons:

Disease progression (except PSA progression)

Irreversible or intolerable AE thought to be related to study drugs

Conditions requiring therapeutic intervention not permitted by the protocol

Intercurrent illness (this will be at the investigator’s discretion)

Inability of the patient to comply with study requirements or lost to follow-up

Patient requests to discontinue treatment

Patient withdraws consent from the study 

Investigator or Sponsor team, for any ethical, medical, or scientific reason, while 
considering the rights, safety, and well-being of the patient(s), stops the study or stops the 
patient participation in the study.

Any patient requiring an AE-related dose delay of more than 21 days due to a study drug 
related AE must be discontinued from the study, unless discussed with the Medical 
Monitor.
After discontinuation from protocol treatment, patients must be followed for AEs for a minimum 
of 30 days, after their last dose of study drugs.  All new AEs possibly related to the study drugs 


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occurring during this 30 day period must be reported and followed until resolution, unless, in the 
opinion of the investigator, these values are not likely to improve, because of the underlying 
disease.  In this case, the investigators must record his or her reasoning for this decision in the 
patients’ medical records and as a comment in the electronic Case Report Form (eCRF).  
All patients who have Grade 3 or 4 laboratory abnormalities (per National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.03) 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), at 
the time of discontinuation must be followed until the laboratory values have returned to Grade 1 
or 2, unless it is, in the opinion of the investigator, not likely that these values are to improve.  In 
this case, the investigator must record his or her reasoning for making this decision in the 
patients’ medical records and as a comment on the CRF.
4.
STUDY REGISTRATION
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks, and 
discomforts.  Institutional Review Board (IRB) approval of this protocol and consent form is 
required.  Eligible patients who wish to participate in the study will be enrolled into the study.
Registration must occur prior to the initiation of protocol therapy.  Patient registration will be 
performed by Sarah Cannon Development Innovations and will be outlined in the Study 
Reference Manual.  
In Part B, patients who agree to participate in the study and meet eligibility criteria will be 
randomly assigned treatment (1:1) to LY3023414 plus enzalutamide or placebo plus 
enzalutamide stratified by visceral disease status (present or absent) and prior chemotherapy in 
the hormone-sensitive setting when commencing ADT (yes or no).  Randomization will be 
performed using an IWRS (see Study Manual).
5.
STUDY DESIGN
This is a double-blinded, placebo-controlled, randomized Phase II study of the combination of 
enzalutamide plus LY3023414 versus enzalutamide plus placebo in patients with mCRPC who 
have shown disease progression on abiraterone.  
Lead-In (Part A)
Since a formal Phase Ib study has not been conducted with the combination regimen of 
LY3023414 and enzalutamide, there will be a lead-in (Part A) of approximately 6-12 patients to 
assess safety, tolerability, and available PK data for potential PK interaction.
Prior to starting this combination therapy on Cycle 1 Day 1, patients in Part A will be given 
single agent LY3023414 every 12 hours (BID) during the initial week (called Week -1) to assess 
LY3023414 PKs at a steady state (Section 5.6) on Day -1 (last day of that Week -1).  Thereafter, 
patients will receive 200 mg of LY3023414 BID in combination with 160 mg of enzalutamide 
QD beginning Cycle 1 Day 1.  A treatment cycle will be defined as 28 days.  LY3023414 PK 


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will be again evaluated during the combination therapy dosing (in Cycle 1) to explore any 
potential intra-patient PK interactions with enzalutamide.  If no safety signals are reported and 
the PK profile is acceptable then this combination regimen (LY3023414 200 mg BID + 
enzalutamide 160 mg QD) will be the regimen to be studied in the randomized part of the study 
(Part B) which will commence without the single agent dosing Week -1.
After at least 6 patients have been treated for a full cycle in Part A, a Safety Internal Monitoring 
Committee (SIMC) will conduct a review of the safety and available PK data prior to the 
initiation of the randomized part (Part B) of the study.  If 2 (or more) of 3 or 2 (or more) of 6 
patients in Part A experience DLTs as defined in Section 5, 3 to 6 additional patients will be 
treated at the next lower dose of LY3203414 defined in Table 3 (150 mg PO BID) and assessed 
for DLTs prior to initiation of the randomized Part B portion of the study.  If there is a PK 
interaction deemed to be clinically significant by the SIMC, the SIMC may recommend 
enrollment of approximately 6 additional patients to further evaluate the safety of the 
combination, or explore other doses of LY3023414 in combination with enzalutamide.  In the 
case of unacceptable and/or unmanageable toxicity of the combination the SIMC may decide to 
discontinue the study upon completion of Part A or proceed with a lower LY3023414 dose level 
tolerated in combination with enzalutamide.  All outcomes from these safety reviews will be 
communicated in a timely manner to the participating investigators so that they may notify their 
IRBs.  No amendment will be needed to proceed with an adjusted dose level of LY3023414.
The SIMC will, at a minimum, be composed of a Sponsor-Assigned Clinical Research Physician, 
Study Chair, Medical Monitor, Safety Scientist, and Biostatistician.


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A toxicity will be considered dose-limiting if it occurs within the first cycle of treatment (28 
days) to Part A patients and is deemed at least possibly related to study drug.  Dose-limiting 
toxicities will be defined as any one of the following AEs:

Grade 4 thrombocytopenia; Grade 4 neutropenia ≥7 days; Grade ≥3 febrile neutropenia; 
and Grade ≥3 thrombocytopenia with Grade ≥2 hemorrhage;

Grade ≥ 3 non-hematologic toxicity despite maximal medical management with the 
exception of:  

Diarrhea, nausea, or vomiting that resolves to ≤ Grade 2 within 48 hours  

ALT/AST elevation that resolves to ≤ Grade 2 within 7 days 

Grade 3 mucositis that resolves to ≤ Grade 2 within 7 days.  Grade 4 
mucositis of any duration will be considered a DLT.

Grade 3 fasting hyperglycemia that resolves to ≤ Grade 2 within 7 days.  
Grade 4 hyperglycemia of any duration that results in intensive care unit
admission will be considered a DLT.

Grade 3 fatigue that resolves to ≤ Grade 2 within 5 days. 

Grade 3 hypertension controlled with medical therapy.  

Any lab abnormalities that are not clinically significant and resolve in 72 
hours.

Hy’s law: Hepatocellular injury defined as ALT (or AST) > 3X ULN and total bilirubin 
> 2X ULN with no significant cholestasis (ALP< 2X ULN) and no other cause which 
explains the abnormality in liver tests.

Treatment delay of ≥14 days due to unresolved AE

Any other study drug related AE that is clinically significant, does not respond to 
supportive care, or is judged to be an unacceptable and/or unmanageable study drug 
related AE by the investigator in collaboration with the Medical Monitor.
Determination of Dose-Limiting Toxicities
The patient population used for determination of DLTs will consist of patients who have met the 
minimum safety evaluation requirements of the study, and/or who have experienced a DLT.  
Minimum safety requirements will be met if, during Cycle 1 of treatment, the patient receives at 
least 75% of study drug regimen (LY3023414 and enzalutamide) and is observed for at least 28 
days following the first dose of study drugs.
Double-blinded, Placebo-Controlled Randomized Study (Part B)
Once Part A has been evaluated by the SIMC and the dose and schedule of LY3023414 in 
combination with enzalutamide is selected to move forward, the double-blinded, placebo-
controlled randomized portion (Part B) will be initiated.  
Approximately 132 patients will be enrolled in Part B and they will be randomized (1:1) to one 
of two treatment groups:


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
Arm 1 (experimental group) enzalutamide plus LY3023414 

Arm 2 (control group) enzalutamide plus matching placebo
LY3023414 (200 mg BID) or matching placebo will be administered orally BID.  All patients 
will receive enzalutamide 160 mg QD.  
A treatment cycle will be defined as 28 days.  Response to treatment will be evaluated every 2 
cycles using RECIST v 1.1 (Appendix E) and per PCWG2 criteria for patients with bone disease 
(see Appendix E) and monthly by PSA.  Patients will be treated until disease progression 
(radiographic or PCWG2 symptomatic progression), death, toxicity requiring cessation of 
treatment, or withdrawal of consent.  Patients that discontinue on the study will not be replaced.   
Patients with PSA progression are allowed and encouraged to continue treatment until clinical 
(symptomatic or radiographic) progression.
The Study Schema is presented in Figure 1.


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Figure 1
Study Schema
aA minimum of 6 patients, may be enlarged if 
needed
Part A - Lead-in 
n = 6-12a patients
Every Cycle
LY3023414 (200mg BID) +
enzalutamide (160mg QD) + 
for 28 days
After Part A Cycle 1, 
Monitor for safety and 
monitor for PK data (e.g 
by batch of approximately 
6 patients)
Part B - Randomized Study 
Double-blinded, Placebo-Controlled 
n =132 patients
Stratified by 

visceral disease status (present or absent) and

prior chemotherapy in the hormone-sensitive 
setting when commencing ADT (yes or no)
Arm 1
LY3023414 200 mg BID
+
enzalutamide 160 mg QD
Arm 2
Placebo 200 mg BID
+
enzalutamide 160 mg QD
Restaging
Tumor assessments every 2 cycles
PSA measurement monthly
Treat until disease progression  
or occurrence of unacceptable toxicity
Patients with PSA progression are allowed and encouraged to continue 
treatment until symptomatic or radiographic progression.
Single Agent (Week -1) –
Days -7 to -1 
LY3023414 (200mg BID) 
for 7 days (PK performed on 
day -1)


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5.1
Treatment Plan
Patients will self-administer LY3023414 or matching placebo and enzalutamide daily by oral 
administration.  The order in which these drugs and/or placebo are taken is not relevant to this 
study.
On the PK days (see Section 5.6), patients will be asked hold study drugs administration until the 
pre-dose PK sample at the investigating site has been collected.
LY3023414 or Placebo
5.1.1
LY3023414 or matching placebo will be self-administered by the patient BID on continuous 
daily dosing.
Patients should take the morning and evening doses of LY3023414 approximately 12 hours apart 
(preferably within a 10- to 14-hour range).  LY3023414 or matching placebo should be taken 
with a glass of water at approximately the same time each day.  LY3023414 or matching placebo 
can be taken with or without food.  Patients should swallow the capsules as a whole and should 
not chew or crush them.  
If the patient misses a dose of LY3023414 or matching placebo, the patient should take the dose 
as soon as possible, but not less than 6 hours before the next dose is due for twice daily dosing.  
If the next dose is due in less than 6 hours, the patient should skip the missed dose and take the 
next dose as scheduled.
If vomiting occurs after taking LY3023414 or matching placebo, the patient should be instructed 
not to retake the dose.  Patients should take the next scheduled dose of LY3023414 or matching 
placebo.  If vomiting persists the patient should contact the investigator.
LY3023414 or matching placebo compliance will be assessed by pill counts on Day 1 of each 
cycle.  The research staff will count and document the amount of LY3023414 or matching 
placebo taken and returned by the patient.
Enzalutamide
5.1.2
All patients will receive a standard regimen of enzalutamide 160 mg (four 40 mg capsules) QD 
for continuous daily dosing.
Enzalutamide will be self-administered by the patient.  Enzalutamide will be taken together with 
one of the two daily doses of LY3023414 or matching placebo.  Enzalutamide can be taken with 
or without food.  Enzalutamide capsules should be swallowed whole.  Patients should not chew, 
dissolve, or crush them.  
If a dose of enzalutamide is missed, the patient should take it as soon as they remember.  If the 
patient forgets to take his dose before 6:00 pm, then the dose should be withheld that day and the 
enzalutamide should be restarted the following day.  However, patients that expe rience fatigue 
while taking enzalutamide may take it at night after Cycle 1 of treatment.  The Medical Monitor 
should be consulted for PK logistics post Cycle 1 for patients who require dosing at night .  
Enzalutamide achieves steady state by day 28 of treatment.  
At each new cycle, patients will be prescribed sufficient supplies until the next visit.  


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STUDY DRUG:  LY3023414
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Enzalutamide drug compliance will be assessed at the beginning of a new cycle.  
5.2
Treatment Duration
The end of the study is defined as the last visit of the last patient on the study.
Patients will be evaluated for toxicity and symptomatic progression at the start of each cycle.  
PSA will be measured at the beginning of each 28 day cycle.  Prior to Cycle 3 and after every 2 
cycles, restaging will occur with imaging and PSA as defined in Appendix D (Schedule of 
Assessments).  
Patients will be allowed to continue on therapy as long as they do not meet the discontinuation 
criteria listed in Section 3.3, and are considered, by the investigator, to still be receiving clinical 
benefit (patients may continue on therapy after progression criteria have been met only if they 
are considered to be receiving clinical benefit after consulting with the study Medical Monitor
and depending upon availability of study drug).
5.3
Treatment Assignment Unblinding Procedures
It is very important for all study personnel to respect the blinded nature of the study; there is no 
intention to routinely unblind individual patients at any time prior to the conclusion of the study.  
In the event of an emergency unblinding thought to be related to LY3023414 (or matching 
placebo) or a medication error, a request for urgent safety unblinding should be made to the 
Medical Monitor.  Emergency unblinding will be allowed only when approved by the Medical 
Monitor.  The investigator may hold administration of LY3023414 or matching placebo while 
waiting for a decision on unblinding to be made.  All unblinding must be documented by the site.
Examples of emergencies requiring unblinding include: 

A life-threatening, unexpected AE that is thought to be related to LY3023414 and for 
which unblinding would change or influence treatment decisions.

Medication error, such as an accidental overdose, that would warrant unblinding in order 
to more effectively manage toxicity.
For additional information regarding unblinding procedures please refer to the Study Reference 
Manual.
5.4
Concomitant Medications
Patients will be instructed not to take any additional medications except those listed in 
Section 5.4.1 below during the course of the study without prior approval of the investigator and 
Sponsor.  At each visit, the patient will be asked about any new medications he is taking or has 
taken after the start of the study drug.
Permitted Concomitant Medications
5.4.1
Premedication with anti-emetics is allowed according to standard practice guidelines.
Medications may be administered for maintenance of existing conditions prior to study 
enrollment or for a new condition that develops while on study, including but not limited to the 
following:


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
Bisphosphonate use, as recommended according to practice guidelines

Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor use, as 
recommended according to practice guidelines

Anticoagulation with coumadin -derivatives will not be permitted.  However, a maximum 
daily dose of 1 mg will be permitted for port line patency.  Should a thrombotic event 
occur while the patient is receiving treatment the patient may continue, but low molecular 
weight heparin (LMWH) will be the preferred treatment.

Patients who develop hyperglycemia during the study should be treated according to the 
American Diabetes Association guidelines.  It is recommended to start treatment wit h 
metformin.
Other medications considered necessary for the patient’s safety and well-being may be given at 
the discretion of the investigator with the exception of those listed in Section 5.4.2.
Prohibited Concomitant Medications
5.4.2
The following treatments are prohibited while in this study:

No other investigational therapy should be given to patients.  No anticancer agents other 
than the study medications should be given to patients.  If such agents are required for a 
patient, then the patient must first be withdrawn from the study.
Concomitant Medications to be avoided
5.4.3
The following treatments should be avoided while in this study:
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer (see 
Appendix I).  
o
Avoid strong of CYP2C8 inhibitors, as they can increase the plasma exposure to 
enzalutamide (Appendix I). If co-administration is necessary, consider reducing 
the dose of enzalutamide.
o
Avoid strong or moderate CYP3A4 or CYP2C8 inducers as they can alter the 
plasma exposure of enzalutamide (Appendix I).
o
Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic 
index, as enzalutamide may decrease the plasma exposures of these drugs. If 
enzalutamide is co-administered with warfarin (CYP2C9 substrate), conduct 
additional INR monitoring.
LY3023414 is a weak inhibitor of CYP3A4 and from in vitro data the major cytochrome P450 
involved in the clearance of LY3023414 was identified as CYP3A (~80%):
o
Avoid strong inhibitors of CYP3A4 and strong and moderate inducers of 
CYP3A4 (other than enzalutamide)
o
Drugs causing QTc interval prolongations should be avoided (Appendix H)
Approximately 20% of LY3023414 is metabolized by CYP1A2.  Therefore, 


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o
Particular attention should be paid in recording CYP1A2 inducers/inhibitor in the 
concomitant medication (Appendix I).
o
Smoking should be avoided and for all patients smoking habit should be recorded.
Patients receiving these agents should be treated with other equivalent medications if possible:
o
Patients should avoid grapefruit, Seville oranges, or Star fruit.
o
Herbal preparations/medications should be avoided throughout the study.  These 
herbal medications include, but are not limited to: St. John’s wort, kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng.  Patients should stop using these herbal medications 7 days 
prior to first dose of study drug.
5.5
Correlative Studies
Biological samples (i.e., blood and fresh or archival tissue samples, primary or metastatic 
lesions) will be requested and may be analyzed to identify potential biomarkers predictive of 
clinical efficacy of the study drugs and disease progression in this patient population.  The time 
points for the collection of samples for correlative testing are specified in Appendix D.
Tumor biopsy specimens from the primary site or from metastatic lesions from all patients with 
available archived tissue will be collected.  Tumor and blood specimens may be tested for 
biomarkers including, but not limited to, mutation and expression of PIK3CA, PTEN, or RAS and 
others.  Samples may be assessed by targeted exome sequencing or other techniques as 
scientifically appropriate.  The status of these biomarkers will be analyzed in an attempt to 
correlate to the clinical patient outcome (e.g. RR and PFS).  Blood samples drawn from the 
patients at baseline, Day 1 of Cycle 1, and every 2 cycles thereafter, and at end of treatment visit
may be assessed to explore potential gene signature(s) for clinical benefit to study treatment, 
such as PIK3CA, PTEN, or RAS and AR-V7.
Information regarding shipment, handling, and length of retention time, etc. of tissue and blood 
will be provided in the Laboratory Manual.
Samples for Pharmacogenetics and/or Tailoring Biomarkers
5.5.1
Collection of samples for biomarker research is also part of this study.  Blood and Tissue 
samples will be collected.
Samples for biomarker research to be collected from all patients in this study are the follow ing:
•
blood
•
tumor tissue (if available; archival or fresh, primary or metastatic lesions)
Samples may be tested to identify biomarkers predictive of clinical efficacy and disease 
progression in this patient population.
Samples will be stored and analysis may be performed on biomarker variants thought to play a 
role in PI3K pathways, including, but not limited to, PIK3CA, PTEN, or RAS and AR-V7, to 
evaluate their association with observed clinical outcomes to study treatment. 


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 4 2 of 9 5
I n t he e ve nt of a n u ne x pected A E or t he o bser vat i on of u n us ual res p o nse, t he p har mac o ge netic 
bi o mar ker sa m ples ma y  be ge n ot ype d a n d a nal ysis ma y  be perf or me d t o e valuate a ge net ic 
ass ociat i on wit h res p o nse t o L Y 3 0 2 3 4 1 4 a n d e nzal uta mi de .  T hese i n vesti gati ons ma y be li mite d 
t o a f oc use d ca n di date ge ne st u d y or, if a p pr o priate, ge n o me wi de a nal ysis ma y be perf or me d t o 
i de ntif y re gi ons of t he ge n o me ass ociate d wit h t he varia bilit y o bser ve d i n dr u g res p o nse.  T he 
p har mac o ge net ic bi o mar ker sa m ples will o nl y  be use d f or i n vest i gati ons relat e d t o disease a n d 
dr u g or class o f dr u gs u n der st u d y  in t he c o nte xt of t his cli nical pr o gra m.  T he y  will not be use d 
f or br oa d e x plor at or y u ns pecifie d disease or p o p ulati o n ge netic a nal ysis.  T he sa m ples will be 
c o de d wit h t he patie nt n u m ber a n d st ore d f or u p t o a ma xi m u m 1 5 years after t he last patie nt visit 
f or t he st u d y at a facility selecte d b y t he s p o ns or.  T he sa m ples a n d a n y data ge nerate d fr o m 
t he m ca n o nl y be li n ke d bac k t o t he patie nt b y in vestig at or site pers o n nel.  T he d urati o n all o ws 
t he s p o ns o r t o res p o n d t o re g ulat or y re q uests relate d t o t he L Y 3 0 2 3 4 1 4.
S a m ples will be destr o ye d acc or di n g t o a pr ocess c o nsiste nt wit h l ocal re g ulat i on.
5. 6
P h ar m ac o ki netic Assess me nts
L Y 3 0 2 3 4 1 4 mea n half- life (t 1/ 2) is a p pr o xi matel y 2 h o urs ra n gi n g fr o m 1 t o 5 h o urs he nce a 1 2 
h o ur peri o d p ost d ose is s uita ble t o i n vest i gate L Y 3 0 2 3 4 1 4 e x p os ure. M ore i nf or mat i on a b o ut 
L Y 3 0 2 3 4 1 4 P K is a vaila ble i n S ect i on 1. 3. 3 a n d i n t he L Y 3 0 2 3 4 1 4 I B. 
 
 
 
 
 
 
 
As state d i n S ect i on 1. 3. 3 , L Y 3 0 2 3 4 1 4 is a wea k i n hi bit or of C Y P 3 A 4. I n a d diti on, t he i n -vit r o 
data i n dicate t hat L Y 3 0 2 3 4 1 4 is N O T a n i n d ucer or a n i n hi bit or of C Y P 2 C 8, t he maj or meta b o lic 
e nz y me f or e nzal uta mi de. C o nse q ue nt l y, f or mal, wit hi n patient s, c o mparis o n of e nzal uta mi de 
A U C after a d mi nistrati o n of e nzal ut a mi de al o ne a n d i n c o m bi nat i on wit h L Y 3 0 2 3 4 1 4 will N O T 
be d o ne i n t his C B B D st u d y  beca use it is n ot a ntici pate d t hat L Y 3 0 2 3 4 1 4 will si g nifica ntl y 
i ncrease (i. e. > 1. 5 f o l d c ha n ge) e nzal uta mi de e x p os ure. 
L Y 3 0 2 3 4 1 4 is p ossi bl y  a C Y P 3 A 4 s u bstrate, a n d as enzaluta mi de is a str o n g C Y P 3 A 4 i n d ucer, 
enzaluta mi de ma y i m pact L Y 3 0 2 3 4 1 4 A U C. 
F or all t he reas o n s o utli ne d a b o ve, L Y 3 0 2 3 4 1 4 e x p os ure will be i n vest i gate d i n all Part A 
patie nts (i.e. i n at least 6 a n d u p t o 1 2 patie nts) at stea d y state after si n gle -a ge nt L Y 3 0 2 3 4 1 4 
m o n ot hera p y for 7 da y s a n d after c o mbi nat i on t hera p y wit h e nzal uta mi de f or at least 1 5 da ys
(see Ta ble 1 a n d A p pe n di x J). T he enzal uta mi de mea n half -life (t 1/ 2) is a p pr o xi matel y 1 4 0 
h o urs a n d t heref ore stea d y  state f oll owi n g dail y a d mi nistrati o n ca n be c o nsi dere d t o be al m ost 
reac he d (at least 8 0 %) after 1 5 da ys. T hese data will e na ble, f or mal, wit hi n pat ient s, 
c o mparis o n of L Y 3 0 2 3 4 1 4 A U C after a d mi nistrati o n of L Y 3 0 2 3 4 1 4 al o ne a n d i n c o m bi nati o n 
wi t h enzal uta mi de.  
C CI


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STUDY DRUG:  LY3023414
SARAH CANNON DEVELOPMENT INNOVATIONS/SPONSOR STUDY NUMBER(S): 
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Based on the limited intra-patient variability in LY3023414 exposure (~25%) in study CBBA, 
the sample size of 6 to 12 patients is adequate to investigate the impact of enzalutamide on 
LY3023414 exposure.  Enzalutamide is anticipated to decrease LY3023414 exposure.  A 
decrease of 30 % of LY3023414 exposure in the presence of enzalutamide should be detected 
with a sample of 6 to 12 patients.  The 90% confidence interval around a mean value of 1.5 for 
the ratio LY3023414 AUC alone: LY3023414 AUC in the presence of enzalutamide should be 
1.2 to 1.8 for a sample size of 10 patients.
Furthermore, the plan includes investigation of enzalutamide PK to determine enzalutamide 
AUC at steady state (on day 15) when administered in combination with LY3023414 in all Part 
A patients (i.e. in at least 6 and up to 12 patients). Enzalutamide exposure will be compared to 
historical data following enzalutamide single agent therapy.  Additionally, the PK parameters of 
the active N-desmethyl enzalutamide metabolite may be determined. 
LY3023414 concentration will be characterized in whole blood (per the schedule presented in
Table 1). Venous blood will be drawn at each time point using a micro sampling technique 
(dried blood spot [DBS] sampling) for quantifying LY3023414 concentration. A hematocrit 
value (which can be obtained from a complete blood count [CBC]) is required within +/- 2 days 
of sampling for PK.  In Part A, classical plasma samples will also be drawn to compare
LY3023414 concentrations.  Detailed instructions and supplies for the collection, handling, and
shipping of blood and plasma samples will be provided by either the sponsor or Sarah Cannon 
Development Innovations.  LY3023414 will be assayed using a validated DBS or plasma liquid 
chromatography (LC)-mass spectrometry (MS)/MS method.
Pharmacokinetic studies will be done during Part A to determine plasma levels of enzalutamide 
following concurrent administration of enzalutamide with LY3023414.  Additionally, 
concentrations of the active N-desmethyl enzalutamide metabolite may be quantified.  The 
schedule for collection of whole blood specimens is presented in Table 1.  Detailed instructions 
and supplies for the collection, handling, and shipping of plasma samples will be provided by 
either the Sponsor or Sarah Cannon Development Innovations.  Enzalutamide will be assayed 
using a validated LC-MS/MS method.


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Table 1
Pharmacokinetic Sample Collection Times – Part A Patients only
Study Visit
Collection Time (± 15 minutes)
LY3023414 PK-
DBS/Plasma
Sample
Enzalutami
de PK 
Plasma 
Sample
Week -1, Day -1a
Pre-dose
1.5, 3, and 6 hours post LY3023414 dose

Cycle 1, Day 1 a
Pre-dose of LY3023414 and enzalutamide 

Cycle 1, Day X (Day 
15 –Day 28)b, c, d
Pre-dose of LY3023414 and enzalutamide
1.5, 3, and 6 hours post LY3023414 dose 


Cycle 1, Day X + 1b, c, 
d
Pre-dose of LY3023414 and enzalutamide


Cycle 2, Day 1 b, c
Pre-dose of LY3023414 and enzalutamide
1.5 hours post LY3023414 and 
enzalutamide dose 


Cycle 3, Day 1 b, c
Pre-dose of LY3023414 and enzalutamide
1.5 hours post LY3023414 and 
enzalutamide dose


a: On Day -1, last day of Week -1, the morning LY3023414 dose is given and PK samples taken to estimate the 
exposure of LY3023414 as monotherapy.  On Day 1, a pre-dose sample is taken prior to initiation of the 
combination treatment LY3023414 + enzalutamide (this sample is about 12 hours post the Day-1 evening 
LY3023414 dose)
b: It is planned that the morning dose of LY3023414/placebo will be taken together/concomitantly with the daily 
dose of enzalutamide.
c: On PK days, pre-dose measurements and dose administration will be done in a fasted state.  Patients should 
remain fasted for 1 hour post- dose.
d: Day X of Cycle 1 is any day between Day 15 and Day 28.
In addition, limited blood sample collection is planned in Part B of the study to assess 
LY3023414 steady state concentrations in a larger patient population as presented in Table 2.


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Table 2
Pharmacokinetic Sample Collection Times – Part B Patients only
Study Visit
Collection Time (± 15 minutes)
LY3023414 PK-
DBS Sample
Cycle 2, Day 1
Pre-dose of LY3023414/placebo and enzalutamide 
1.5 hours post LY3023414/placebo dose a, b

Cycle 3, Day 1
Pre-dose of LY3023414/placebo and enzalutamide 
1.5 hours post LY3023414/placebo dose a, b

a: It is planned that the morning dose of LY3023414/placebo will be taken together/ concomitantly with the daily 
dose of enzalutamide.
b: On PK days, pre-dose measurements and dose administration will be done in a fasted state.  Patients should 
remain fasted for 1 hour post- dose.
On the days when PK samples are collected, patients will not take their LY3023414/ placebo and 
enzalutamide dose until after the pre-dose specimen is obtained.
On the PK days the date and time and amount of the LY3023414/placebo doses associated with 
the LY3023414 PK samples must be recorded in the eCRF. 
For Part A, on the PK days of combination therapy, the date and time and amount of the 
enzalutamide doses associated with the enzalutamide PK samples must be recorded in the eCRF.
The date and time of samples collection will be recorded in the requisition form.
Samples for Drug Concentration Measurements Pharmacokinetics
A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and Study team.
Bioanalytical samples collected to measure LY3023414 and enzalutamide concentrations will be 
retained for a maximum of 1 year following last patient visit for the study.
5.7
Pharmacogenomic (PGx) Assessement
There is growing evidence that genetic variation may impact a patient’s response to therapy. 
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.
In the event of an unexpected AE, the samples may be genotyped and analysis may be performed 
to evaluate a genetic association with response to LY3023414. These investigations may be 
limited to targeted exome sequencing approach of known targets involved in drug metabolism or, 
if appropriate, genome-wide association studies may be performed to identify regions of the 
genome associated with the variability observed in drug response.
The PGx sample is part of the biomarker sample.  Therefore, there is no separate kit for PGx 
samples.  Samples will only be used for investigations related to disease and drug or class of 
drugs under study in the context of this clinical program. They will not be used for broad 


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exploratory unspecified disease or population genetic analysis. Samples will be identified by the 
patient number (coded) and stored for up to 15 years after the last patient visit for the study at a 
facility selected by the sponsor. The sample and any data generated from it can only be linked 
back to the patient by investigator site personnel.
6.
DOSE MODIFICATIONS
If an AE occurs, the AE will be graded utilizing the NCI CTCAE v 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
and appropriate supportive care treatment will be administered as needed to decrease the signs 
and symptoms thereof.  Dose adjustments will be based on the organ system exhibiting the 
greatest degree of toxicity.
Doses of LY3023414 will be modified based on hematologic and non-hematologic toxicity.  If 
dose reductions are necessary, they will be permanent for the remainder of the treatment.  No
dose reductions due to study drug related toxicities of LY3023414 or enzalutamide are permitted 
in Part A during Cycle 1.  
During Part B and after Cycle 1 in Part A, dose reductions for enzalutamide and LY3023414 
may be adjusted according to Table 3.  If the responsible study drug can be identified, it may be 
adjusted according to the dose modification table and the patient may continue with the other 
study drug, as appropriate.  If the patient is receiving the lowest allowable dose and experiences 
an AE requiring a dose reduction, the offending study drug should be discontinued.  If the 
offending study drug is discontinued, the patient may continue single-agent treatment.  
If any AE occurs, it should resolve to a level that, in the opinion of the investigator, is reasonable 
to allow for continuation of treatment taking into consideration the recommendations below.
If a patient experiences a Grade 3 drug-related AE or an intolerable Grade 2 AE: 
•
LY3023414 dosing should be withheld until symptoms improve to ≤ Grade 1 or baseline 
then may be resumed at a reduced dose according to Table 3.  In part B only, re-
escalation of LY3023414 may be considered if clinically warranted, following discussion 
and approval by the medical monitor.  
•
Enzalutamide dosing must be withheld for one week or until symptoms improve to 
< Grade 2 then may be resumed per the package insert at the same or reduced dose 
according to Table 3.  
Permanently discontinue study drugs for Grade 4 adverse events.  Re-challenge of patients with 
dose-reduced study drug(s) following recovery from Grade 4 AEs may be considered on a case-
by-case basis in consultation with the medical monitor.  
Grade 3 or 4 laboratory changes that are not clinically significant and which can be corrected 
within 48 hours may not require dose modification.
If the AE is clearly attributable to one drug, then dose reduction of only that drug is necessary.
For toxicities possibly caused by both drugs, the dose levels of both should be reduced.


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Any patient requiring an AE-related dose delay of more than 21 days from the intended day of 
the next scheduled dose due to a study drug related AE must be discontinued from the study, 
unless discussed with the Medical Monitor.
Dose delays within a cycle do not alter the start of the next scheduled cycle.  Assessments for 
any missed visit will be done when the patient returns to the clinic.  These would need to be 
entered into the EDC as unscheduled.
A maximum of two dose reductions per drug are allowed in this study.  If more than two dose 
reductions of study drug(s) are necessary for a patient, the responsible agent will be 
discontinued.
Table 3
Dose Level Modifications
Dose Level
LY3023414 or Placebo
Enzalutamide
Starting Dose 
200 mg PO BID
160 mg PO QD
Dose Level -1
150 mg PO BID
120 mg PO QD
Dose Level -2
100 mg PO BID
80 mg PO QD
7.
STUDY ASSESSMENTS AND EVALUATIONS
7.1
Overview
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedule of Assessments for this study is shown in Appendix D.  The baseline physical 
examination, medical history, ECOG performance status, CBC, Comprehensive Metabolic 
Profile (CMP), urinalysis, prothrombin time (PT)/INR, and blood for biomarker analysis should 
be done ≤7 days prior to initiation of treatment.  However, if these initial examinations are 
obtained within 72 hours of Cycle 1 Day 1, they do not have to be repeated on Day 1.  Scans, 
ECG, testosterone levels, and PSA must be performed ≤4 weeks prior to initiation of treatment.
7.2
Baseline Study Assessments
The following information will be collected and procedures will be per formed for each patient at 
screening:

Written informed consent prior to any other study-related procedures (≤28 days prior to 
initiation of treatment)

Medical history

Physical examination, measurements of height (first visit), weight

Vital signs (resting heart rate, blood pressure [BP], and oral temperature)

ECOG performance status (Appendix A)

Electrocardiogram (ECG) performed locally (repeat if clinically indicated)

Concomitant medication review


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
CBC with 3-part differential and platelets

Fasting CMP to include: glucose, blood urea nitrogen (BUN), creatinine, sodium, 
potassium, chloride, calcium, carbon dioxide (CO 2), alkaline phosphatase (ALP), AST, 
ALT, total bilirubin, total protein albumin, phosphorus, and lactate dehydrogenase 
(LDH).

PT/INR (repeat if clinically indicated)

Blood for biomarker analysis 

Blood for testosterone level

HbA1c blood sample 

Urine dipstick

PSA blood sample

CT scan of chest

CT scan of the abdomen and pelvis  

Bone scan- technetium only

Archived or fresh tumor tissue (see Section 5.5)
7.3
Study Treatment Assessments
Single Agent LY3023414 Day -7 (Part A only, Week -1)
7.3.1

Physical examination including measurement of weight

Vital signs (unless collected within the previous 72 hours)

ECOG PS (unless collected within the previous 72 hours [see Appendix A])

AE assessment

Concomitant medication review 

CBC, including 3-part differential and platelets (unless collected within the previous 72 
hours) 

Fasting CMP plus LDH (unless collected within the previous 72 hours) 

PT/INR (repeat only if abnormal at baseline or if clinically indicated)

Urine dipstick (unless collected within the previous 72 hours)

PK blood samples ( Day -1, pre-dose,1.5 , 3, and 6 hours post LY3023414 dose ± 15 
minutes [see Table 1])  

PSA blood sample (unless collected within the previous 72 hours)

Dispense LY3023414 and patient diary 


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Cycle 1 – Day 1
7.3.2

Physical examination including measurement of weight (Part B patients only)

Vital signs (unless collected within the previous 72 hours)

ECOG PS (unless collected within the previous 72 hours [see Appendix A])

ECG- predose

AE assessment

Concomitant medication review 

CBC, including 3-part differential and platelets (unless collected within the previous 72 
hours) 

Fasting CMP plus LDH (unless collected within the previous 72 hours) 

PT/INR (repeat only if abnormal at baseline or if clinically indicated)

PK blood sample – Part A patients only (pre-dose of LY3023414 and enzalutamide ± 15 
minutes [see Table 1])  

PGx blood sample (If the sample is not collected C1D1, it can be collected anytime 
during C1 or C2)

Biomarker blood sample (pre-dose)

PSA blood sample (unless collected within the previous 72 hours)

Urine dipstick (unless collected within the previous 72 hours)

Dispense LY3023414 or matching placebo and patient diary (Part A patients will not 
receive a placebo)

Dispense enzalutamide
Cycle 1 – Day 15 (Part A patients only)
7.3.3

Vital signs 

ECOG PS (see Appendix A) 

AE assessment 

Concomitant medication review

Study drug compliance assessment 

CBC, including 3-part differential and platelets

Fasting CMP plus LDH

PK blood sample (any day [day X] between Day 15 and Day 28, pre-dose of LY3023414 
and enzalutamide, 1.5 , 3, and 6 hours post LY3023414 dose ± 15 minutes [see Table 1]).  


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A hematocrit value (which can be obtained from a CBC) is required within +/- 2 days of 
sampling for PK.

PK blood sample (on day X+1 between Day 16 and Day 29, pre-dose of LY3023414 and 
enzalutamide ± 15 minutes [see Table 1]). A hematocrit value (which can be obtained 
from a CBC) is required within +/- 2 days of sampling for PK.

Urine dipstick
Cycle 2 and all Subsequent Cycles, Day 1 (±72 hours) 
7.3.4

Physical examination including measurement of weight

Vital signs 

ECOG PS (see Appendix A) 

ECG predose (Cycles 2, 3, and 4 only)

AE assessment 

Concomitant medication review  

Study drug compliance assessment

CBC, including 3-part differential and platelets  

Fasting CMP plus LDH 

PT/INR (repeat only if abnormal at baseline or if clinically indicated)

PK blood sample, (see Table 1 and Table 2)

Blood collected for biomarker analysis (pre-dose of Day 1 Cycle 3 and Day 1 of every 2 
cycles thereafter) 

HbA1c blood sample (starting with Cycle 3 Day 1 and every 2 cycles thereafter)

Urine dipstick

PSA blood sample

Dispense LY3023414 or matching placebo (Part A patients will not receive a placebo) 
and patient diary

Dispense enzalutamide
7.4
Response Assessment – Prior to Cycle 3 and After Every 2 Cycles 
Patients will be radiographically evaluated for response to treatment prior to Cycle 3 and after 
every 2 cycles of treatment (i.e. Cycle 5, Cycle 7, etc.).  The following assessments will be 
performed in addition to determination of PSA levels (which are taken on Day 1 of each cycle):


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
CT scans of chest (repeat only if abnormal at baseline)

CT of the abdomen and pelvis 

Bone scan- technetium only
Lymph nodes and bone lesions should be evaluated using PCWG2 criteria (Appendix F) not 
RECIST v 1.1.  Patients with progressive disease or unacceptable toxicity should be discontinued 
from the study; patients with stable disease or response to therapy w ill continue treatment.
7.5
PSA Progression
PSA progression is defined as ≥25% increase and ≥2 ng/mL increase above the nadir or baseline 
value for patients who had a PSA decrease on treatment which is confirmed by a second value 3 
or more weeks later.  
For patients without a decrease on treatment, PSA progression is defined as ≥25% increase and 
an absolute increase of ≥2 ng/mL after 12 weeks.  
PSA progressions must be confirmed at the next study visit 4 weeks later.  PSA will be collected 
at screening and on Day 1 of each treatment cycle.  
Patients with PSA progression are allowed and encouraged to continue treatment until 
symptomatic or radiographic progression.
7.6
End of Treatment Visit 
The follow-up evaluations required after treatment ends due to completion of the planned study 
treatment period, disease progression, or once the patient is discontinued due to unacceptable 
toxicity or decision to discontinue treatment by the patient or the study physician are specified in 
Appendix D.
After withdrawal from or completion of protocol treatment, patients must be followed for AEs 
for at least 30 (+3) calendar days after the last dose of study drug.  The following assessments 
will be performed.

Physical examination including measurement of weight

Vital signs

ECOG PS (see Appendix A)

ECG

AE assessment

Concomitant medication review  

Study drug compliance assessment

CBC, including 3-part differential and platelets  

Fasting CMP plus LDH

Blood sample for biomarker analysis

HbA1c blood sample

Urine dipstick


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
PSA (does not have to be repeated if done within 4 weeks of End of Study 
Treatment visit)

CT scan chest (repeat only if abnormal at baseline; does not have to be repeated if 
done within 8 weeks of End of Study Treatment visit )

CT of the  abdomen and pelvis (does not have to be repeated if done within 8 
weeks of End of Study Treatment visit)

Bone scan- technetium only (does not have to be repeated if done within 8 weeks 
of End of Study Treatment visit). 
7.7
Follow-up
Follow-up for Patients Who Discontinue Prior to Disease Progression
7.7.1
Patients who discontinue study treatment prior to the occurrence of disease progression will be 
followed every 2 months (±2 weeks) from the date of last dose of study drug until disease 
progression or for up to 3 years whichever comes first.  Assessments at these visits will be 
performed as described in Appendix D.
8.
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION
8.1
LY3023414 or Placebo
Investigational Product
Dosage Form and Strength
Manufacturer
LY3023414 or Placebo
25mg, 100mg, and 200mg capsules
Eli Lilly and Company
Labeling, Packaging, and Supply
8.1.1
LY3023414 and the matching placebo will be supplied as capsules by Eli Lilly and Company.
At each visit, patients will be dispensed sufficient supplies until the next visit.  Study drug 
compliance will be assessed at each patient visit.  The research staff will count and document the 
amount of LY3023414 and the matching placebo taken and returned by the patient.
The immediate packaging will contain a statement that administration is limited to 
investigational use only.
LY3023414 and matching placebo must be kept in a secure place under appropriate storage 
conditions.  Storage conditions for LY3023414 are included on the investigational product label.
The Sponsor or its representatives must be granted access on reasonable request to check 
LY3023414 and matching placebo storage, dispensing procedures, and accountability records.


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If another formulation of LY3023414 and the accompanying matching placebo becomes 
available at a later point in time (e.g. tablets), that might be used instead of capsules for this 
study.
Precautions and Risks Associated with LY3023414
8.1.2
Precautions and risks are located in the LY3023414 IB.
8.2
Enzalutamide
Investigational Product
Dosage Form and Strength
Manufacturer
Enzalutamide
40 mg capsules
Astellas Pharma US, Inc.
Enzalutamide will be administered orally as capsules.
Additional information can be found in the Enzalutamide US Package Insert (PI) 
https://www.astellas.us/docs/us/12A005-ENZ-WPI.pdf.
Labeling, Packaging, and Supply
8.2.1
At each visit, patients will be prescribed sufficient enzalutamide until the next visit.  Study drug 
compliance will be assessed at each patient visit.  
Enzalutamide must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for enzalutamide are included in the USPI https://www.astellas.us/docs/us/12A005-
ENZ-WPI.pdf.
Precautions and Risks Associated with Enzalutamide
8.2.2
Please refer to the enzalutamide USPI https://www.astellas.us/docs/us/12A005-ENZ-WPI.pdf for 
detailed information on the risks associated with the use of enzalutamide.
8.3
Accountability for All Study drugs
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
LY3023414 and matching placebo supplies at the site.
All LY3023414 and matching placebo inventories must be made available for inspection by the 
monitor, Sponsor, or representatives of the aforementioned and regulatory agency inspec tors 
upon request.
At the end of the study, all Sarah Cannon Development Innovations Drug Accountability Record 
Form(s) for LY3023414 and matching placebo will be completed by the site and sent to the 
Sarah Cannon Development Innovations Regulatory Department.  Study drug supplies must not 
be destroyed unless prior approval has been granted by the Sponsor or its representative.  Please 
contact Sarah Cannon Development Innovations regarding disposal of any study drug.
No drug accountability will be done for enzalutamide.


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 5 4 of 9 5
9.
R E S P O N S E E V A L U A TI O N S A N D M E A S U R E M E N T S
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y  usi n g t he P C W G 2 criteria 
(A p pe n di x F ).  T hese criteria will be f oll o we d f or deter mi ni n g t he c ha n ge i n P S A le vels.  P S A 
le vels will be meas ure d m o nt hl y t hr o u g h o ut t he st u d y.  E valuat i on of P S A le vels will be t he 
pri mar y  e val uati on f or efficac y o utc o mes i n me n wit h n o meas ura ble disease at baseli ne.
Me n wi t h meas urea ble disease at baseli ne will be e val uate d usi n g t he R E CI S T v 1. 1 (see 
A p pe n di x E ).  T u mors will be assesse d at scree ni n g, after e ver y  2 c ycles, a n d at f oll o w -u p visits.  
Reassess me nt of t u m or will be d o ne b y t he sa me met h o ds use d t o esta blis h baseli ne t u m or 
meas ure me nts.  All res p o n di n g patie nts ( C R a n d P R) m ust ha ve t heir res p o nse c o nfir me d n o less 
t ha n 4 wee ks after t he first d oc u me ntati o n of res p o nse.  F or S D, meas ure me nts m ust meet t he S D 
criteria at least 6 wee ks after st u d y e ntr y.
F or pati e nts e val uate d usi n g b ot h P S A c ha n ges a n d R E CI S T v 1. 1, t he earliest deter mi ne d date 
of pr o gressio n will be use d t o deri ve pr o gressi o n -base d efficac y o ut c o mes .
1 0.
S T A TI S TI C A L C O N SI D E R A TI O N S
1 0. 1
St atistic al Desi g n
T his is a d o u ble -bli n de d, place b o -c o ntr olle d, ra n d o mize d P hase II st u d y of t he c o m bi nati on of 
e nzal uta mi de pl us L Y 3 0 2 3 4 1 4 vers us e nzal uta mi de pl us place b o i n me n wit h m C R P C w h o ha ve 
s h o w n disease pr o gressio n o n a birater o ne. 
T he pri mar y , sec o n dar y a n d e x pl orat or y o bject i ves are f o u n d i n S ectio n 2 .
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


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10.3
Analysis Population
The following analysis populations will be used:

All patients who have signed the informed consent form (i.e. screening failures plus 
patients enrolled) will comprise the All Patients Set ( APS).  The All Patients Set will be 
used to describe the patient disposition.

All enrolled patients randomized to treatment arms will comprise the Full Analysis Set 
(FAS).  Information using this population will be tabulated by treatment arm, as 
randomized (Intent to Treat) according to the IWRS, unless otherwise indicated. This 
population will be used for the primary analyses of the efficacy endpoints.

All randomized patients having no major protocol deviations will comprise the Per 
Protocol Analysis Set (PPAS).  Those protocol deviations that are deemed to have an 
important impact on the analysis of study endpoints and leading to the exclusion of a 
patient will be listed in the Statistical Analysis Plan (SAP) prior to database lock.  This 
analysis set will be used for sensitivity analyses of efficacy endpoints.

All patients who have received at least one dose of study treatment will comprise the 
Safety Analysis Set (SAF).  Patients will be allocated as treated. 
10.4
Data Analysis
Descriptive statistics, including mean, median, standard deviations, minimum and maximum for 
all continuous measures will be tabulated and reported.  Percentages and frequencies for all 
categorical measures will also be presented.  A SAP outlining methods for analysis and data 
display will be developed and approved prior to unblinding.  Any deviation(s) from the approved 
plan or ad-hoc evaluations or analyses will be properly documented in the clinical study report.
Demographics and Baseline Characteristics
10.4.1
Demographic and baseline disease characteristics will be summarized by treatment group.  Data 
to be tabulated will include demographic features such as age, sex and race, as well as 
stratification factors and disease-specific characteristics.
The number and percentages of patients screened, randomized, treated, completed the 
treatment/study and withdrawn from treatment/study for any reasons will be presented overall 
and also by treatment group.
Efficacy Analysis
10.4.2
All efficacy analyses will be performed using the FAS.  Sensitivity analyses may be performed 
using the PPAS.
Measurement of PSA levels, bone scans and CT scans will be performed for all patients at 
screening, after every 2 cycles (PSA will be measured monthly), and at follow-up visits before a 
subsequent anti-cancer therapy or death.  
Tumor reassessment will be done by the same method used to establish baseline tumor 
measurements for each patient.  For a response of stable disease (SD), measurements must meet 
the SD criteria at least 6 weeks after study entry.


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10.4.2.1
Primary Endpoint
Progression–free survival (PFS)
PFS will be the primary endpoint for this study.  PFS is defined as the time from randomization 
until the date of disease progression per PCWG2 or death by any cause regardless of whether the 
patient withdraws from study drug or receives a subsequent anti-cancer therapy (as determined 
by the investigator).  Patients who have not progressed or died at the time of assessment will be 
censored at the time of the last date of assessment (tumor evaluation or PSA level).  Patients who 
are randomized but do not receive treatment and patients who have no evaluable visits will be 
censored on day 0 unless they die within two visits of baseline.  In the event patients demonstrate 
progression based on RECIST v 1.1, PSA levels, and/or bone scans at differing points, the 
earliest date of documented progression will be used to calculate PFS.
PFS will be derived based on relevant scan or lab dates, and not associated visit dates.  In the 
event that RECIST v 1.1 assessments are conducted across multiple days, the date of progression 
will be based on the earliest of the dates of the component that triggered the progression.  When 
censoring, the patient will be censored at the latest of the dates contributing to the particular visit 
assessment.
Treatment group differences will be tested using an unstratified log rank test. The stratified 
analysis using the stratification factors defined as part of the randomization process will be 
performed as sensitivity analysis.
The Kaplan-Meier (Kaplan E and Meier P 1958) product limit method will be used to estimate 
the median PFS and the associated 95% CI for the two treatment arms. Progression-free survival 
will additionally be analyzed using a Cox Proportional Hazards Model, and will be used to 
estimate the HR of PFS in the enzalutamide plus LY3023414 arm relative to the enzalutamide 
plus placebo arm and the associated 95% CI.
10.4.2.2
Secondary Endpoints
Overall Response Rate (ORR)
The ORR based on each patient’s best objective response will be determined for all patients 
evaluable via the RECIST v 1.1 criteria.  The ORR (%) will be calculated as the number of 
patients with best objective response of CR or PR divided by the number of patients with 
measurable disease at baseline.  The best objective response for a given patient will be based on 
objective responses determined from data obtained up to: progression, the last evaluable 
assessment in the absence of progression, or initiation of subsequent anticancer therapy.  Patients 
for whom an objective response cannot be determined or for who the best objective response is 
‘not evaluable’ (NE) will be considered non-responders.  The ORR will be summarized along 
with the 95% Clopper Pearson CI for each treatment arm. 
Treatment group comparisons in ORR will be evaluated using Chi-square test and Cochran-
Mantel Haenszel test adjusted by stratification factors.
Percent change from baseline in PSA levels
The percent change from baseline in PSA levels after 12 weeks on study and the maximum 
percent change from baseline will be summarized using box-whisker plots for each treatment 


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arm.  For patients who discontinue on or before the 12 week assessment or for whom the 12 
week assessment is missing, the last observation prior to the week12 assessment will be utilized.  
Patients with no post-baseline PSA data will be excluded from the summaries.
Time to Disease Progression (TTP)
TTP will be calculated as the time from randomization to objective disease progression.  The 
date of progression will be determined as described above for PFS.  Patients who die for any 
reason prior to disease progression will be censored at the time of death.  Treatment group 
differences will be tested using a stratified log rank test as for PFS.  
TTP will be analyzed in the same manner as those in PFS.
Study Drug Interactions
As specified in Sections 5.6 and 10.4.4, collection of PK samples is planned to be able to 
compare, within patient, the steady state LY3023414 AUC, Cmax, and Ctrough (Cmin) following 
LY3023414 administration as a single agent and in combination with enzalutamide.  These data 
will enable to determine whether enzalutamide impacts LY3023414 exposure.
As specified in Sections 5.6 and 10.4.4, collection of PK samples is planned to determine in a 
limited number of patients (Part A, Lead-In), the steady state exposure of enzalutamide.  These 
results will be compared to historical enzalutamide data.  This population to population 
comparison of enzalutamide exposure is believed to be adequate given that it is not anticipate 
that LY3023414 would impact enzalutamide clearance.
10.4.2.3
Exploratory Endpoints
The number and proportion of patients having an alteration in pre-specified markers at baseline, 
including but not limited to PIK3CA, PTEN, RAS, and AR-V7, may be presented if deemed 
relevant.  The relationship between clinical outcomes and the presence of alterations in each 
marker may also be summarized using methods appropriate for each specific clinical outcome as 
specified in the SAP.
10.4.2.4
Subgroup Analyses
For exploratory purposes, efficacy sub-group analyses may also be performed if applicable, 
using the FAS/PPAS.  The details of these analyses and selection of the prognostic factors and/or 
baseline characteristics will be specified in the SAP.
Safety Analysis
10.4.3
The NCI CTCAE v 4.03 will be used to grade all AEs (severity grade).  A copy of the CTCAE 
scoring system may be downloaded from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
Duration and treatment of toxicities will be recorded.  The safety measures will be assessed on 
an ongoing basis.  The safety variables will be assessed by body system.  Any AEs that are 
considered probably or possibly study drug-related will be monitored until resolution or 
stabilization.
Toxicity profile data will include AEs and laboratory parameters.  Safety data will be tabulated 
for all patients who receive any amount of study medication , overall and by part and treatment 


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group.  Adverse terms recorded on the eCRFs will be standardized using the Medical Dictionary 
for Regulatory Activities (MedDRA).  Treatment -emergent AEs (TEAEs), defined as events that 
start or worsen after the first dose of study treatment, will be summarized and t abulated in 
accordance with system organ class (SOC) and preferred term by overall incidence, severity, and 
relationship to study treatment.  The tabulation of laboratory parameters will indicate the normal 
range of each parameter.  Each value will be classified according to CTCAE v 4.03 where 
applicable.
Other safety endpoints, including laboratory results, vital signs and ECG findings, will be 
summarized for all patients in the Safety Analysis Set, overall and by part and treatment group. 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
and they will be listed and summarized by treatment group.
Pharmacokinetics/Pharmacodynamics
10.4.4
Pharmacokinetic analyses will be conducted on patients who have received at least 1 dose of the 
study drug and have had sufficient post-dose samples collected to allow estimation of PK 
parameters.  Blood and plasma (Part A only) concentrations of LY3023414 and plasma 
concentration for enzalutamide will be used to calculate LY3023414 and enzalutamide PK 
parameters, respectively.  The PK parameters will be calculated by standard noncompartmental 
methods.
The primary parameters for analysis will be maximum concentration (Cmax) and area under the 
concentration-time curve (AUC) of LY3023414 and Enzalutamide following multiple doses.  
Other noncompartmental parameters, such as t1/2, CLss/F, and Vss/F may be reported.  These 
parameters will be listed by individual patient and summarized by descriptive statistics (means, 
medians, ranges, standard deviations and coefficient of variation and, as appropriate.
For Part A the ratio of LY3023414 AUCs when administered concomitantly with enzalutamide 
over single agent will be computed to quantify the possible impact of enzalutamide on 
LY3023414 exposure (LY3023414 AUC ratio = AUC,ss, alone : AUC, ss, presENZ ; with 
the dosing interval for LY3023414 that is 12 h, ss meaning that the PK assessment is done at 
steady state ; alone and presENZ meaning that LY3023414 was administered either alone or with 
enzalutamide).  The result will be summarized by descriptive statistics (mean, median, range, 
standard deviations and coefficient of variation) and the 90% confidence interval for this ratio 
will be computed.
Additional exploratory analyses will be performed if warranted by data and other validated PK 
software programs may be used if appropriate and approved by Global Pharmacokinetic 
management.  It is planned that LY3023414 PK data will be analyzed using the nonlinear mixed 
effect modeling (NLME) techniques.  The version of any software used for the analysis will be 
documented and the program will meet the Lilly requirements of software validation. 
Further details on the PK/PD analysis will be documented in a separate PK/PD analysis plan.
10.5
Handling of Missing Data
Except where noted above, missing data will not be estimated or imputed.


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 5 9 of 9 5
1 0. 6
A n al ysis Ti me P oi nt
Fi n al A n al ysis
1 0. 6. 1
T he fi nal a nal ysis o f t he st u d y will be trig gere d w he n 9 2 patie nts ha ve ha d a n e ve nt ( disease 
pr o gressi o n or all ca use deat h).
Pl a n ne d I nteri m A n al ysis
1 0. 6. 2
 
 
T he res ults fr o m t he i nteri m a nal yses will be e xa mi ne d b y a Lill y  int er nal assess me nt c o m mittee 
t hat will be esta blis he d pri or t o t he i ncl usi o n of t he first patie nt i n t he trial.  T he Lill y i nter nal 
assess me nt  c o m mittee will c o nsist of at least a Lill y me dical direct or, a Lill y cli nical researc h 
p h ysicia n/cli nical researc h scie nt ist, a n d a Lill y st atisticia n a n d will ma ke rec o m me n dati o ns 
a b o ut t he trial.  T he o utc o me of t he i nteri m a nal yses will be d oc u me nte d, a n d a writte n letter will 
be s u b mitte d t o t he I R B(s) a n d t he i n vesti gat ors f or d oc u me ntati o n p ur p oses. E nr oll me nt will 
c o nti n ue w hile t he i nteri m a nal ysis is bei n g perf or me d.
S afet y Re vie w
1 0. 6. 3
After at l east 6 patie nts ha ve bee n treate d f or a f ull c ycle, a SI M C will re vie w t he safet y a n d P K 
data pri or t o t he i nit iati on of t he ra n d o mize d p hase of t he st u d y.  If 2 ( or m ore) of 3 or 2 ( or 
m o re) of 6 patie nts i n Part A e x perie nce D L Ts as defi ne d i n Sect i on 5 , 3 t o 6 a d ditio n al p atie nts 
will be treate d at t he ne xt l o wer d ose of L Y 3 2 0 3 4 1 4 defi ne d i n Ta ble 3 ( 1 5 0 mg P O BI D) a n d 
assesse d f or D L Ts pri or t o i nit iati o n of t he ra n d o mize d Part B p orti o n of t he st u d y.  If t here is 
sig nifica nt P K i nteractio n see n, t he SI M C ma y rec o m me n d e nr olli n g a p pr o xi matel y 6 a d dit i onal 
patie nts t o f urt her e val uate t he safet y of t he c o m bi nati on, or e x pl ore ot her d ose c o m bi nat i ons t o 
ass ure safet y at a ma xi mal e x p os ure of st u d y dr u g.  I n t he case of u nacce pta ble a n d/ or 
u n ma na gea ble t o xicit y of t he c o m bi nati on t he SI M C ma y deci de t o di sc o nti n ue t he st u d y u p o n 
c o mplet i on of Part A or pr ocee d wit h a l o wer L Y 3 0 2 3 4 1 4 d ose le vel t olerate d i n c o m bi nat i on 
wi t h e nzal uta mi de.  A n y o utc o me of t hese safety re vie ws will be c o m m u nicate d i n a ti mel y 
ma n ner t o t he partici pat i n g i n vesti gat ors s o t hat t he y ma y n otif y t heir I R Bs.  N o a me n d me nt will 
be nee de d t o pr ocee d wit h a n a dj uste d d ose le vel of L Y 3 0 2 3 4 1 4.
F or Part B of t he st u d y , safety will c o nt i n ue t o be m onit ore d as defi ne d b y t he me dical 
m o nit ori n g pla n.  T he safet y pr ofile will be re vie we d b y t he Me dical M o nit or a n d S p o ns or 
Desi g nees. 
T he SI M C will, at a mi ni m u m, be c o m p ose d of a S p o ns or -Assi g ne d Cli nical Researc h P h ysicia n, 
St u d y  C hair, Me dical M o nit or, Safety Scie ntist, a n d Bi ostatisticia n.
C CI


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The criteria for assessing safety in these patients are found in Section 5.
Unblinding Patients
10.6.4
There is no intention to routinely unblind individual patients at any time.  Individual requests for 
urgent safety unblinding require the approval of the Medical Monitor.  
There also may be instances where unblinding of a patient(s) may be required for a safety review 
at the request of the Sarah Cannon Development Innovations Medical Monitor or SIMC or for 
Regulatory Authority reporting requirements.
After all patients have completed protocol treatment and the database has been locked, the trial 
will be unblinded for analysis of the safety and efficacy outcomes.
11.
SAFETY REPORTING AND ANALYSES 
Investigators are responsible for monitoring the safety of patients who have entered into this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.  The investigator is responsible for the 
appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option, all 
AEs that are serious or that caused the patient to discontinue before completing the study.  The 
patient should be followed until the event is resolved, the event is no longer considered to be 
drug-related, the event becomes stable or returns to baseline, a new treatment is initiated for the 
patient, or the patient dies or is lost to follow -up.  Frequency of AE and SAE follow-up 
evaluation is left to the discretion of the investigator.
Investigators or their designees must document their review of each laboratory report.
11.1
Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation patient administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from labs, 
ECGs, vital sign measurements, and so on, that occur should also be reported to Lilly or its 
designee as an AE using the same guidelines and schedules as those for AEs.  Lack of drug 
effect is not an AE in clinical studies because the purpose of the clinical study is to establish drug 
effect.
The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the study schedule.  All AEs 
observed will be graded using CTCAE Version 4.03.


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The CTCAE Version 4.03 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  For AEs without 
matching terminology within the CTCAE Version 4.03 criteria, the investigator will be 
responsible for selecting the appropriate SOC and assessing severity grade based on the intensity 
of the event.  Note that both CTCAE term (actual or coded) and severity grade must be selected 
by study site personnel and collected on the CRF.  This collection is in addition to verbatim text 
used to describe the AE.  
Minor updates to the CTCAE Version 4.03 from the National Cancer Institute (NCI) will not 
necessitate a protocol amendment and the use of updated CTCAE Version 4.0 will not be 
considered a protocol violation.  
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within MedDRA.
Cases of pregnancy that occur during paternal exposures to study drug should be reported.  Data 
on fetal outcome and breastfeeding should be collected, if feasible, for regulatory reporting and 
drug safety evaluation.  
For all enrolled patients, study site personnel will record the occurrence and nature of each 
patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  All AEs 
related to protocol procedures are reported to Lilly or designee.
If a patient's dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee the circumstances and data leading to any 
such dosage reduction or discontinuation of treatment.  This information must also be 
documented in the eCRF.
The investigator decides whether he or she interprets the observed safety signals as either related 
to disease, to the study medication, study procedure, or other concomitant treatment or 
pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible.

Does not know:  the investigator cannot determine.

Not related:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures, all “probably related,” “possibly related,” or “does 
not know” AEs and SAEs will be defined as related to study drug.


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11.2
Serious Adverse Events
Previously planned (that is, prior to signing the informed consent form [ICF]) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened during the course 
of the study.
Preplanned hospitalizations or procedures for preexisting conditions that are already recorded in 
the patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study therapy or other protocol-required procedure) should not 
be considered SAEs.
An SAE is any AE during this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition.  
Serious AEs due to disease progression, including death, should not be reported unless the 
investigator deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  Alerts issued via telephone are to be 
immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.
If an investigator becomes aware of SAEs occurring after the patient’s participation in the study 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the sponsor, and the SAEs will be entered in the 
Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the study may be 
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Adverse Event and Serious Adverse Event Reporting
11.2.1
Prior to Administration of Study Drug(s)
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the informed consent document.  For patients who do not 
enroll in the study (that is, receive at least 1 dose of study drug), only AEs and SAEs related to 
protocol procedures are required to be collected.
On Study
All AEs and SAEs, regardless of relatedness to study drug, or protocol procedures, occurring 
while the patient is receiving study drug(s) must be reported to Lilly or its designee.  A patient is 
considered to be receiving study drug from the time he/she receives the first dose of study 
drug(s) to when he/she receives the last dose of study drug(s).
Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drug, or protocol procedures, occurring 
during the Follow-Up Visit must be reported to Lilly or its designee.  The Follow-Up Visit starts 
the day after the last dose of study drug.  At the end of the Follow -Up Visit, the patient will be 
required to have specific safety assessments according to the Study Schedule (Appendix D).  The 
timing of these safety assessments is 30 days ± 3 days after the last dose of study drug.
Following the safety assessments, which mark the end of the Follow -Up Visit, the patient will be 
discontinued from the study, unless there is an ongoing AE or SAE that is possibly related t o 
study drug.  In this instance, the patient should be seen for subsequent follow-up visits until the 
event is resolved, the event is no longer considered to be drug-related, the event becomes stable 
or returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.  
After the Follow-Up Visit, only new AEs or SAEs that are considered possibly related to study 
drug or protocol procedures should be reported to Lilly or their designee.
To report an SAE, the Lilly SAE Report Form should be completed with the necessary 
information.
The SAE report should be sent to Lilly via fax using the following contact information (during 
both business and non-business hours):
Lilly Safety Department
Safety Dept. Fax #:      1- 866-644-1697
Transmission of the SAE report should be confirmed by the site personnel submitting the report.
Follow-up information for SAEs and information on non -serious AEs that become serious should 
also be reported to Lilly as soon as it is available; these reports should be submitted using the 
Lilly SAE Report Form.  The detailed SAE reporting process will be provided to the sites in the 
SAE reporting guidelines contained in the Study Reference Manual.
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB.


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11.3
Complaint Handling
Lilly collects product complaints on study drugs and drug delivery systems used in clinical trials 
in order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Complaints related to unblinded concomitant drugs are reported directly to the manufacturers of 
those drugs/devices in accordance with the package insert.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or delegate will be reported.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
12.
QUALITY ASSURANCE AND QUALITY CONTROL
12.1
Monitoring
Site monitoring shall be conducted to ensure that patient protection, study procedures, 
laboratory, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, GCP/ICH and, when appropriate, regulatory guidelines.
12.2
Audits and Inspections
The investigator will permit study-related quality audits and inspections by the Sponsor or its 
representative(s), government regulatory authorities, and the IRB of all study-related documents 
(e.g., source documents, regulatory documents, data collection instruments, case report forms).  
The investigator will ensure the capability for review of applicable study-related facilities.  The 
investigator will ensure that the auditor or inspector or any other compliance or QA reviewer is 
given access to all study-related documents and study-related facilities.
Participation as an investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the IRB, the Sponsor or its representative(s).
13.
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS
This research study will be conducted according to the standards of Good Clinical Practice 
outlined in the ICH E6 Tripartite Guideline and CFR Title 21 part 312, applicable government 
regulations, institutional research policies and procedures and any othe r local applicable 
regulatory requirement(s).


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13.1
Institutional Review Board Approval
The clinical study protocol, ICF, IB, available safety information, patient documents (e.g., study 
diary), patient recruitment procedures (e.g., advertisements), information about payments (i.e., 
Principal Investigator payments) and compensation available to the patients and documentation 
evidencing the Principal Investigator’s qualifications should be submitted to the IRB for ethical 
review and approval if required by local regulations, prior to the study start.
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to 
ensure appropriate, initial, and on-going, IRB study review.  The Principal Investigator/Sponsor 
(as appropriate) must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  Investigators 
will be advised by the Sponsor or designee whether an amendment is considered substantial or 
non-substantial and whether it requires submission for approval or notification only to an IRB.
Safety updates for LY3023414, will be prepared by the Sponsor or its representative as required, 
for distribution to the investigator(s) and submission to the relevant IRB.
13.2
Regulatory Approval
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities.
13.3
Informed Consent
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.
The informed consent form will be submitted for approval to the IRB that is responsible for 
review and approval of the study.  Each consent form must include all of the relevant elements 
currently required by the relevant regulatory authorities, as well as local county authority or state 
regulations and national requirements.
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an informed consent form.  A notation that written informed 
consent has been obtained will be made in the patient’s medical record.  A copy of the informed 
consent form, to include the patient’s signature, will be provided by the investigator to the 
patient.
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study should be obtained.


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Confidentiality
13.3.1
13.3.1.1
Patient Confidentiality
Confidentiality of patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of following:

What protected health information (PHI) will be collected from patients in this study

Who will have access to that information and why

Who will use or disclose that information

That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws

The information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study

Whether the authorization contains an expiration date

The rights of a research patient to revoke his or her authorization
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period.
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the investigator and institution permit authorized representatives of Sponsor, the regulatory 
authorities and the IRB direct access to review the patient’s original medical records at the site 
for verification of study-related procedures and data. 
Measures to protect confidentiality include: only a unique study number and initials will identify 
patients in the eCRF or other documents submitted to the Sponsor.  This information, together 
with the patient’s date of birth, will be used in the database for patient identification.  Patient 
names or addresses will not be entered in the eCRF database system.  No material bearing a 
patient’s name will be kept on file by Sponsor.  Patients will be informed of their rights within 
the ICF.
13.3.1.2
Investigator and Staff Information
Personal data of the investigators and sub-investigators may be included in the Sponsor or the 
Sarah Cannon Development Innovations database, and shall be treated in compliance with all 
applicable laws and regulations.  When archiving or processing personal data pertaining to the 
investigator or sub investigator, the Sponsor and/or Sarah Cannon Development Innovations 


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shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized party.
13.4
Financial Information
The finances for this clinical study will be subject to a separate written agreement between the 
Sponsor and applicable parties.  Any Investigator financial disclosures as applicable to 21CFR 
Part 54 shall be appropriately provided and retained.
14.
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY
14.1
Amendments to the Protocol
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation.
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor or its representative.  All amendments require review and approval of the 
Sponsor and the Principal Investigator supporting the study.  The written amendment must be 
reviewed and approved by the Sponsor, and submitted to the IRB at the investigator’s facility for 
the board’s approval.
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB of record for the Investigator’s facility.
The amendment will be submitted formally to the relevant regulatory authorities by the Sponsor 
as applicable, and IRB approved obtained specifically when an increase to dosing or patient 
exposure and/or patient number has been proposed; or, when the addition or removal of an 
Investigator is necessitated.
Items requiring a protocol amendment with IRB and if necessary other relevant regulatory 
authorities approval may include but are not limited to, the following:

Change to study design

Risk to patient

Increase to dose or patient exposure to drug

Patient number increase

Addition or removal of tests and / or procedures

Addition/removal of a Study Chair
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained.


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14.2
Documentation Required to Initiate the Study
Before the study may begin in the United States (US) certain documentation required by FDA 
regulations and ICH GCP must be provided by the Investigator.  The required documentation 
should be submitted to:
Sarah Cannon Development Innovations
1100 Charlotte Ave., Suite 800
Nashville, TN  37203
Documents at a minimum required to begin a study in the US include, but are not limited to, the 
following:

A signature-authorized protocol and contract

A copy of the official IRB approval of the study and the IRB members list

Current Curricula Vitae for the principal investigator and any associate investigator(s) 
who will be involved in the study

Indication of appropriate accreditation for any laboratories to be used in the study and a 
copy of the normal ranges for tests to be performed by that laboratory

Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed

A copy of the IRB -approved consent form  containing permission for audit by 
representatives of  Sarah Cannon Development Innovations, the Sponsor, the IRB, and 
the FDA

Financial disclosure forms for all investigators listed on Form FDA 1572 (if applicable, 
i.e., for covered trials)

Site qualification reports, where applicable

Verification of Principal Investigator acceptability from local and/or national debarment 
list(s) 
14.3
Study Documentation and Storage
The Principal Investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties and should ensure that all persons assisting in the conduct of the study 
are informed of their obligations.  All persons authorized to make entries and/or corrections on 
the CRFs are to be included on this document.  All entries in the patient’s CRF are to be 
supported by source documentation where appropriate.
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patient’s CRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence.


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The Principal Investigator and each study staff member is responsible for maintaining a 
comprehensive and centralized filing system (e.g., regulatory binder or investigator study file 
[ISF]) of all study-related (essential) documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced.  The ISF should contain as a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, 
including key documents such as the IB and any amendments, protocol and any amendments, 
signed ICFs, copies of completed CRFs, IRB approval documents, Financial Disclosure forms, 
patient identification lists, enrollment logs, delegation of authority log, staff qualification 
documents, laboratory normal ranges, records relating to the study drug including accountability 
records.  Drug accountability records should, at a minimum, contain information regarding 
receipt, shipment, and disposition.  Each form of drug accountability record, at a minimum, 
should contain Principal Investigator name, date drug shipped/received, date, quantity and 
batch/code, or lot number for identity of each shipment.  In addition, all original source 
documents supporting entries in the CRF must be maintained and be readily available.
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation.
The IRB shall maintain adequate documentation / records of IRB activities as per 21CFR Part 
56.115 for at least 3 years after completion of the research.
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last 
marketing application has been approved by FDA; or, in the event that the marketing application 
has not been approved by FDA, for no less than 2 years after the last shipment / delivery of the 
drug for investigational use is discontinued and FDA has been notified that the investigation has 
been discontinued.
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., eCRFs and medical records), all 
original, signed informed consent forms, and copies of all eCRFs, records, SAE Reporting forms, 
source documents, detailed records of treatment disposition, and related essential regulatory 
documents.  The documents listed above must be retained by the investigator for as long as 
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval).  Sponsor or its 
representatives will notify the investigator(s)/institutions(s) when the study-related records are no 
longer required.
If the investigator relocates, retires, or for any reason withdraws from the study, both the Sponsor 
and its representative should be prospectively notified.  The study records must be transferred to 
an acceptable designee, such as another investigator, another institution, or to the Sponsor.  The 
investigator must obtain the Sponsor’s written permission before disposing of any records, even 


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if retention requirements have been met.  All study files will be maintained by the Sponsor or its 
representative throughout the study.  If study files are maintained by a representative of the 
Sponsor, the study files will be transferred to the Sponsor at the conclusion of the study.
14.4
Data Collection
The study CRF is the primary data collection instrument for the study.  Case report forms will be 
completed using the English language and should be kept current to enable the Sponsor to review 
the patients’ status throughout the course of the study.
In order to maintain confidentiality, only study number, patient number, initials and date of birth 
will identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to Sarah 
Cannon Development Innovations and replaced instead with the patient number and patient’s 
initials.  The investigator will maintain a personal patient identification list (patient numbers with 
corresponding patient identifiers) to enable records to be identified and verified as authentic.  
Patient data/information will be kept confidential, and will be managed according to applicable 
local, state, and federal regulations.
All data requested by the eCRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown.”  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided.
The investigator will electronically sign and date the patient CRF casebook indicating that the 
data in the CRF has been assessed.  Each completed CRF will be signed and dated by the 
Principal Investigator, once all data for that patient is final.
14.5
Disclosure and Publication Policy
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study may be 
published and/or presented as per the Sponsor’s disclosure process.
Inclusion of the investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, int erpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the study.  The investigator acknowledges that the study 
is part of a multi-center study and agrees that any publication by the investigator of the results of 
the study conducted at research site shall not be made before the first multi-center publication.  
In the event there is no multi-center publication within fifteen (15) months after the study has 
been completed or terminated at all study sites, and all data has been received, the investigator 
shall have the right to publish its results from the study, subject to the notice requirements 
described herein and subject to acknowledgement of the Sponsor as appropriate.  Investigator 
shall provide the Sponsor thirty (30) days to review a manuscript or any poster presentation, 
abstract or other written or oral material which describes the results of the study for the purpose 
only of determining if any confidential or patentable information is disclosed thereby.  If the 


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Sponsor requests in writing, the investigator shall withhold any publication or presentation an 
additional sixty (60) days solely to permit the Sponsor to seek patent protection and to remove 
any Sarah Cannon Development Innovations Confidential Information from all publications.


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15.
REFERENCES
American Cancer Society 2014
American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 
2014.
Antonarakis et al. 2014
Antonarakis ES, Lu C, Wang H et al. AR-V7 and resistance to enzalutamide and abiraterone in 
prostate cancer. N Engl J Med. 2014;371:1028-1038.
Badrising et al. 2014
Badrising S, van der Noort V, van Oort IM et al. Clinical activity and tolerability of 
enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who 
progress after docetaxel and abiraterone treatment. Cancer 2014;120: 968-975.
Baselga J. et al. 2012
Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor–
positive advanced breast cancer. N Engl J Med. 2012;366:520-529.
Beer et al. 2014
Beer TM, Armstrong AJ, Rathkopf Y, et al. Enzalutamide in metastatic prostate cancer 
(mCRPC) before Chemotherapy. N Engl J Med. 2014;371:424-33.
Bennett et al. 2014
Bennett and Ingason. Enzalutamide (Xtandi) for Patients with Metastatic, Resistant Prostate 
Cancer. Annals Pharmacotherapy. 2014;48:530-537.
Bitting et al. 2013
Bitting RL, and Armstrong AJ. Targeting the PI3K/Akt/mTOR pathway in castration-resistant 
prostate cancer. Endocr-Relat Cancer. 2013;20:R83-R99.
Carver et al. 2011
Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and 
androgen receptor signaling in PTEN-deficient prostate cancer. Can Cell. 2011;19:575-586.
Cheng et al. 2014
Cheng HH, Nadal R, Gulati R et al. The effect of prior abiraterone (Abi) use on the activity of 
enzalutamide (Enza) in men with mCRPC. ASCO Meeting Abstracts 2014;32: 18.
Edlind et al. 2014
Edlind MP and Hsieh AC. PI3K-AKT-mTOR signaling in prostate cancer progression and 
androgen deprivation therapy resistance. Asian J Androl. 2014;16:378-386.


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Eisenhauer et al. 2009
Eisenhauer E, Therasse P, Bogaerts J et al. New Response Evaluation Criteria in Solid Tumors:
Revised RECIST Guideline (version 1.1). European Journal of Cancer 2009;45:228-247.
El-Amm et al. 2013
El-Amm J, Patel N, Freeman A, et al. Metastatic Castration-Resistant Prostate Cancer: Critical 
Review of Enzalutamide Clinical Medicine Insights: Oncology 2013;7:235-245. 
Hong et al. 2014
Hong SW, Shin JS, Moon JH, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, induces cell 
death through alternate routes in prostate cancer cells depending on the PTEN genotype. 
Apoptosis. 2014;19:895-904.
Kaplan E and Meier P 1958
Kaplan E, Meier P: Nonparametric estimation from incomplete observations . J Am Stat Assoc. 
1958;5:457–481.
Kelley et al. 1993
Kelly WK, Scher HI, Mazumdar M et al. Prostate-specific antigen as a measure of disease 
outcome in metastatic hormone-refractory prostate cancer. J Clin Oncol. 1993;11: 607-615.
Li et al. 2008
Li Y, Wang Z, Kong D, Li R, Sarkar SH & Sarkar FH. Regulation of Akt/FOXO3a/GSK-
3beta/AR signaling network by isoflavone in prostate cancer cells. Journal of Biological 
Chemistry. 2008;283:27707–27716.
Lin et al. 2001
Lin HK, Yeh S, Kang HY & Chang C. Akt suppresses androgen-induced apoptosis by 
phosphorylating and inhibiting androgen receptor. PNAS: 2001;98 7200–7205.
Loriot et al. 2013
Loriot Y, Bianchini D, Ileana E et al. Antitumour activity of abiraterone acetate against 
metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide 
(MDV3100). Ann Oncol. 2013;24:1807-1812.
Ning et al. 2013
Ning YM, Pierce W, Maher VE, et al.  Enzalutamide for Treatment of Patients with Metastatic 
Castration-Resistant Prostate Cancer Who Have Previously Received Docetaxel: U.S. Food and 
Drug Administration Drug Approval Summary. Clin Cancer Res. 2013;19:6067-6073.
Noonan et al. 2013
Noonan KL, North S, Bitting RL et al. Clinical activity of abiraterone acetate in patients with 
metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol. 2013; 
24:1802-1807.


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Scher et al. 2012
Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after 
Chemotherapy. N Engl J Med. 2012;367:1187-1197.
Scher et al. 2008
Scher HI, Halabi S, Tannock I 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;26:1148-1159.
Schrader et al. 2014
Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalutamide in castration-resistant prostate 
cancer patients progressing after docetaxel and abiraterone. Eur Urol. 2014;65:30-36.
Sementas et al. 2013
Sementas J, Dizeyi N, Persson JL. Enzalutamide as a second generation antiandrogen for 
treatment of advanced prostate cancer. Drug Design, Dev and Therapy. 2013;7:875-881.
Smith et al. 2014
Smith MR, Matheny S, Saad F et al. Response to androgen signaling (AS)-directed therapy after 
treatment with abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant 
prostate cancer (mCRPC): Post hoc analysis of study COU-AA-302. ASCO Meeting Abstracts 
2014; 32: 21.
Sweeney et al. 2014
Sweeney C, Yu-Hui C, Carducci MA, et al. Impact on overall survival (OS) with 
chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic 
prostate cancer (mPrCa): An ECOG-led phase III randomized trial. J Clin Oncol. 2014; 32:5s
(suppl; abstr LBA2).
Tang et al. 2014
Tang KD and Ling MT. Targeting Drug-Resistant Prostate Cancer with Dual PI3K/MTOR 
Inhibition. Curr Med Chem. 2014; Apr 13 epub ahead of print.
Thomas et al. 2013
Thomas C, Lamoureux F, Crafter C, Davies BR, Beraldi E, Fazli L, Thaper D, Gleave ME, & 
Zoubeidi A.  Synergistic targeting of PI3K/Akt pathway and androgen receptor axis significantly 
delays castration-resistant prostate cancer progression in vivo.  Molecular Cancer Therapeutics. 
2013;12:2342.
Wen et al. 2000
Wen Y, Hu MC, Makino K, Spohn B, Bartholomeusz G, Yan DH & Hung MC 2000. HER-2/neu 
promotes androgen-independent survival and growth of prostate cancer cells through the Akt 
pathway. Cancer Research. 2000; 60:6841–6845.


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16.
APPENDICES
Appendix A: ECOG Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity.  Fully active, able to carry 
on all pre-disease performance without 
restriction.
100
Normal, no complaints, no evidence of 
disease.
90
Able to carry on normal activity; minor 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but ambulatory 
and able to carry out work of a light or 
sedentary nature (e.g., light housework, 
office work).
80
Normal activity with effort; some signs or 
symptoms of disease.
70
Cares for self, unable to carry on normal 
activity or to do active work.
2
In bed < 50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about more 
than 50% of waking hours.
60
Requires occasional assistance, but is able to 
care for most of his/her needs.
50
Requires considerable assistance and 
frequent medical care.
3
In bed > 50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours.
40
Disabled, requires special care and 
assistance
30
Severely disabled, hospitalization indicated.  
Death no 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


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 7 6 of 9 5
 
 
 
 
 
 
 
 
 
 
 
 
C CI


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Appendix C: Guidelines for Fertile Male Patients
Fertile male patients, defined as all males physiologically capable of conceiving offspring, with 
female partners of childbearing potential must use condoms plus spermicidal agent during the 
study treatment period and for 3months after the last dose of study drug, and should not father a 
child during this period.
Male patients must also refrain from donating sperm during their participation in the study.
Pregnancies
Pregnancy outcomes must be collected for the female partners of any males who took study 
drug(s) in this study.  Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother.


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Appendix D: Schedule of Assessments and Study Plan
Assessments  
Screening
Study Treatment
Off-
Treatment
Follow-Up
Single 
Agent
Week -1 
LY302414 
(Part A 
only)
Cycle 1
Cycle 2 & All 
Subsequent 
Cycles
(±72 hrs)
Response Assessments 
Prior to Cycle 3 & 
every 2nd Cycle 
thereafter (i.e. 5,7, etc.) 
End of Study 
Treatmentq
Off Treatment Prior to 
Progressionr
Baselinea
D -7 
D -1
D1
D15p
D1
TESTS AND OBSERVATIONS
Informed consent
X
Medical history
X
Physical examb 
X
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
ECOG PS 
X 
X
X
X
X
X
X
12-lead ECGd
X
X
Xd
X
Adverse event evaluation
X
X
X
X 
X
Concomitant medication 
review  
X
X
X
X
X
X
Study drug compliance 
assessment
X
X
X
STUDY TREATMENT (Continuous Dosing)
LY3023414 or matching 
placebo BIDj
Xn
Xn,o
X
X
X
Enzalutamide 160 mgj QD
X
X
X
LABORATORY EVALUATIONS
CBC, 3-part differential, and 
platelets
X
X
X
X
X 
X
Fasting CMPe plus LDH
X
X
X
X
X
X
PT/INRf
X
Xf
Xf
Xf
Urine dipstick
X
X
X
X
X
X
Biomarker blood sampleg
Xg
Xg
Xg
X
Testosterone blood sample
X
HbA1c blood sampleh
X
Xh
Xh
PK blood samplei,j
Xi,j
Xi,j
Xi,j
Xi,j
PGx blood sample
Xs


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Appendix D: Schedule of Assessments (continued)
Assessments  
Screening
Study Treatment
Off-Treatment
Follow-Up
Single 
Agent 
Week -1 
LY302414 
(Part A 
only)
Cycle 1
Cycle 2 & All 
Subsequent 
Cycles
(±72 hrs)
Response Assessments 
Prior to Cycle 3 & 
every 2nd Cycle 
thereafter (i.e. 5, 7, 
etc) 
End of Study 
Treatmentq
Off Treatment Prior to 
Progressionr
Baselinea
D -7 
D -1
D1
D15p
D1
LABORATORY EVALUATIONS
Archived or fresh 
tumor tissue (optional)
X
STAGING
PSAl
X
Xl
X
Xl
Xl
Xl
Bone scanm
X
Xk,m
Xk,m
Xk,m
CT scan of chest, 
abdomen and pelvisn
X
Xk,n
Xk,n
Xk,n
a
The physical examination, medical history, concomitant medications recorded ≤7 days prior to study entry, ECOG PS, CBC including differential and platelets, CMP, 
urinalysis, and PT/INR should be done ≤7 days prior to initiation of treatment.  However, if these initial examinations are obtained within 72 hours prior to the initiation
of treatment they do not have to be repeated.  Scans to document evaluable disease (i.e., tumor measurement), 12-lead ECG, testosoterone levels, and PSA should be 
performed ≤4 weeks prior to initiation of treatment.     
b
Physical examination will include measurements of height and weight at the baseline visit.  Physical examinations (PE) done at all other times during the study will 
include only weight.  Only Part B patients will need a physical exam on Cycle 1 Day 1.
c
Vital signs include resting heart rate, blood pressure, oral temperature
d
ECG performed locally at baseline, predose on Cycles 1 -4, and at the End of Treatment visit.  Repeat if clinically indicated.
e
Fasting CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST, ALT, total bilirubin, total protein, 
albumin, phosphorus, and LDH.  
f
PT/INR will only need to be repeated if abnormal at baseline or if clinically indicated.  
g
Biomarker blood samples will be taken at baseline and pre-dose on Day 1 of Cycles 1, and 3 and every 2 cycles thereafter, and at the End of Treatment visit.
h
HbA1c blood sample will be taken at baseline,  Cycle  3 and every 2 cycles thereafter, and at the End of Treatment visit.


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Appendix D: Schedule of Assessments (continued)
i
PK blood samples will have a window of ± 15 minutes.  PK blood samples for patients who are participating in Part A will be Day -1, pre-dose, 1.5, 3, and 6 hours post 
LY3023414 dose; Cycle 1 Day 1 pre-dose of LY3023414 and enzalutamide; Cycle 1 Day X - any day between Day 15 and Day 28, pre-dose of LY3023414 and 
enzalutamide, 1.5, 3, and 6 hours post LY3023414 dose; and Cycle 1 Day X + 1- between Day 16 and Day 29, pre-dose of LY3023414 and enzalutamide (see Table 1).  
PK blood samples for all patients will be taken pre-dose of LY3023414/placebo and enzalutamide and 1.5 hours post LY3023414/placebo dose on Cycle 2 Day 1 and 
Cycle 3 Day 1 (see Table 2).  A hematocrit value (which can be obtained from a CBC) is required within +/- 2 days of collection of sampling for PK  
j
On PK days, pre-dose measurements and dose administration will be done in a fasted state.  Patients should remain fasted for 1 hour post- dose.
k
Patients will be restaged prior to Cycle 3 and after every 2 cycles of treatment thereafter (every 8 weeks).  Patients with progressive disease or unacceptable toxicity 
should be discontinued from treatment; patients with stable disease or response to therapy will continue treatment.
l
PSA blood samples will be taken ≤4 weeks prior to initiation of treatment, on Week -1 Day -7 for Part A patients, Cycle 1 Day 1 (unless collected within the previous 72 
hours) Day 1 of every cycle, and at the End of Study visit if not taken in the previous 4 weeks.  Patients with PSA progression are allowed and encouraged to continue 
treatment until symptomatic or radiographic progression.
m
Bone scans- technetium only - ≤4 weeks prior to initiation of treatment, prior to Cycle 3 and after every 2 cycle s of treatment thereafter, and at the End of Study visit if 
scans were not taken in the previous 8 weeks.  Bone lesions should be evaluated using PCWG2 criteria and not RECIST v 1.1. 
n
CT scans of the chest, abdomen and pelvis ≤4 weeks prior to initiation of treatment.  CT scan of the chest should be repeated only if abnormal at baseline. CT scans of 
the abdomen and pelvis should be taken prior to Cycle 3 and after every 2 cycles of treatment thereafter, and at the End of Study visit (if scans were not taken in the 
previous 8 weeks).  Lymph nodes should be evaluated using PCWG2 criteria and not RECIST v 1.1.
o
Part A patients do not receive a placebo.
p
Only Part A patients come in on Cycle 1 Day 15.
q
After patients complete therapy or are discontinued from treatment they will visit the study center 30 days (+3) after finishing treatment for end of treatment assessments.  
Patients must be followed for AEs for 30 calendar days after the last dose of study drug.
r
Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 2 months (±2 weeks) from the date of last dose of study 
drug until disease progression or for up to 3 years whichever comes first.  
s
The PGx sample should be collected C1D1. If the sample is not able to be collected C1D1, it can be collected anytime during C1 or C2.  The PGx sample is part of the 
Biomarker sample and does not require a separate kit.


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 8 1 of 9 5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
C CI


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 8 2 of 9 5
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 8 3 of 9 5
 
  
 
  
 
 
  
 
 
 
  
   
 
 
 
 
 
 
 
 
  
 
 
 
 
C CI


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 8 4 of 9 5
 
 
 
 
 
C CI


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 8 5 of 9 5
 
 
 
 
 
 
 
 
  
 
 
 
 
 
C CI
C CI


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 8 6 of 9 5
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
C CI


C O N FI D E N TI A L
S T U D Y D R U G :  L Y 3 0 2 3 4 1 4
S A R A H C A N N O N D E V E L O P M E N T IN N O V A TI O N S / SP O N S O R S T U D Y N U M B E R (S ): 
G U 1 1 5/ I 6 A-M C -C B B D
A M E N D M E N T 3: 2 5 Ja n uar y 2 0 1 7
v 4. 0
Pa ge 8 7 of 9 5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


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AMENDMENT 3: 25 January 2017
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Appendix G: Drugs That Prolong QT Interval and/or Induce Torsades de Pointes
All QT-prolonging drugs listed below should be avoided for all patients from screening through 
permanent discontinuation of study treatment.   
Drug
QT risk(*)
Comment
Amiodarone
Known risk for TdP
Females>Males,TdP risk regarded as low
Arsenic trioxide
Known risk for TdP
Astemizole
Known risk for TdP
No Longer available in U.S.
Bepridil
Known risk for TdP
Females>Males
Chloroquine
Known risk for TdP
Chlorpromazine
Known risk for TdP
Cisapride
Known risk for TdP
Restricted availability; Females>Males.
Disopyramide
Known risk for TdP
Females>Males
Dofetilide
Known risk for TdP
Domperidone
Known risk for TdP
Not available in the U.S.
Droperidol
Known risk for TdP
Halofantrine
Known risk for TdP
Females>Males
Haloperidol
Known risk for TdP
When given intravenously or at higher-than-
recommended doses, risk of sudden death, QT 
prolongation and torsades increases.
Ibutilide
Known risk for TdP
Females>Males
Levomethadyl
Known risk for TdP
Mesoridazine
Known risk for TdP
Methadone
Known risk for TdP
Females>Males
Pentamidine
Known risk for TdP
Females>Males
Pimozide
Known risk for TdP
Females>Males
Probucol
Known risk for TdP
No longer available in U.S.
Procainamide
Known risk for TdP
Quetiapine
Possible risk for TdP
This drug is a sensitive 3A4 substrate
Quinidine
Known risk for TdP
Females>Males
Sotalol
Known risk for TdP
Females>Males
Sparfloxacin
Known risk for TdP
Tacrolimus
Possible risk for TdP
This drug is a sensitive 3A4 sibstrate with narrow TI
Terfenadine
Known risk for TdP
No longer available in U.S.
Thioridazine
Known risk for TdP
Vardenafil
Possible risk for TdP
This drug is a sensitive 3A4 substrate
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor of the respective enzyme.


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Appendix H: List of QT Prolonging Drugs to be Used with Caution
Below is a list of drugs with a known risk for Torsades de Pointes (TdP).
Drug
QT risk
Comment
Alfuzosin
possible risk for Torsades de Pointes
Amantadine
possible risk for Torsades de Pointes
Amitriptyline
conditional risk for Torsades de Pointes
Azithromycin
possible risk for Torsades de Pointes
Chloral hydrate
possible risk for Torsades de Pointes
Citalopram
conditional risk for Torsades de Pointes
Clomipramine
conditional risk for Torsades de Pointes
Clozapine
possible risk for Torsades de Pointes
Desipramine
conditional risk for Torsades de Pointes
Diphenhydramine
conditional risk for Torsades de Pointes
Dolasetron
possible risk for Torsades de Pointes
Doxepin
conditional risk for Torsades de Pointes
Dronedarone
possible risk for Torsades de Pointes
Felbamate
possible risk for Torsades de Pointes
Flecainide
possible risk for Torsades de Pointes
Fluoxetine
conditional risk for Torsades de Pointes
Foscarnet
possible risk for Torsades de Pointes
Fosphenytoin
possible risk for Torsades de Pointes
Galantamine
conditional risk for Torsades de Pointes
Gatifloxacin
possible risk for Torsades de Pointes
Gemifloxacin
possible risk for Torsades de Pointes
Granisetron
possible risk for Torsades de Pointes
Imipramine
conditional risk for Torsades de Pointes
Indapamide
possible risk for Torsades de Pointes
Isradipine
possible risk for Torsades de Pointes
Levofloxacin
possible risk for Torsades de Pointes
Lithium
possible risk for Torsades de Pointes
Mexiletine
conditional risk for Torsades de Pointes
Moexipril/HCTZ
possible risk for Torsades de Pointes
Moxifloxacin
possible risk for Torsades de Pointes
Nicardipine
possible risk for Torsades de Pointes
Nortriptyline
conditional risk for Torsades de Pointes
Octreotide
possible risk for Torsades de Pointes
Ofloxacin
possible risk for Torsades de Pointes


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Appendix H:
List of QT Prolonging Drugs to be Used with Caution (continued)
Drug
QT risk
Comment
Ondansetron
possible risk for Torsades de Pointes
Oxytocin
possible risk for Torsades de Pointes
Paliperidone
possible risk for Torsades de Pointes
Paroxetine
conditional risk for Torsades de Pointes
Perflutren lipid 
microspheres
possible risk for Torsades de Pointes
Protriptyline
conditional risk for Torsades de Pointes
Ranolazine
possible risk for Torsades de Pointes
Risperidone
possible risk for Torsades de Pointes
Roxithromycin*
possible risk for Torsades de Pointes
*not available in the United 
States
Sertindole
possible risk for Torsades de Pointes
Sertraline
conditional risk for Torsades de Pointes
Solifenacin
conditional risk for Torsades de Pointes
Tizanidine
possible risk for Torsades de Pointes
Trazodone
conditional risk for Torsades de Pointes
Trimethoprim-Sulfa
conditional risk for Torsades de Pointes
Trimipramine
conditional risk for Torsades de Pointes
Venlafaxine
possible risk for Torsades de Pointes
Ziprasidone
possible risk for Torsades de Pointes
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT


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Appendix I:
Common CYP1A2 Inducers, CYP2C9 and CYP2C19 Inducers and 
Substrates, Substrates for CYP3A4, CYP2C8 Inducers, CYP3A Inducers and Inhibitors, 
and P-gp/CYP3A Dual Inhibitors 
The following list describes medications and foods which are common inhibitors, inducers and substrates 
of CYP2C9 and CYP2C19, substrates of CYP34A, inducers of CYP2C8, inducers and inhibitors of 
CYP3A, and dual inhibitors of PgP and CYP3A.  
This list should not be considered all-inclusive.  
CYP1A2 Inducers
Moderate Inducers
50-80% decrease in AUC:

montelukast 

phenytoin
Weak Inducers
20-50% decrease in AUC:

moricizine

omeprazole 

phenobarbital
CYP2C9 Substrates with Narrow Therapeutic Range
CYP2C9 Inducers

Phenytoin

Warfarin (s)
Moderate:

Carbamazepine

Rifampin
CYP2C19 Substrates with Narrow Therapeutic 
Range
CYP2C19 Inducer

S-mephenytoin
Moderate:

Rifampin
CYP3A4 Substrates with Narrow Therapeutic Range
CYP2C8 Inhibitor

Alfentanil 

Astemizole 

Cisapride 

Cyclosporine 

Dihydroergotamine 

Ergotamine 

Fentanyl 

Pimozide

Quinidine

Sirolimus

Tacrolimus

Terfenadine
Strong:

Gemfibrozil


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Appendix I:
Common CYP1A2 Inducers, CYP2C9 and CYP2C19 Inducers and 
Substrates, Substrates for CYP3A4, CYP2C8 Inducers, CYP3A Inducers and Inhibitors, 
and P-gp/CYP3A Dual Inhibitors (continued)
CYP3A4 Substrates (Oral Administration)
CYP3A/P-gp Dual Inhibitors

Midazolam 

Buspirone 
Strong:

Clarithromycin

Conivaptan

Diltiazem

Dronedarone

Indinavir/ritonavir

Itraconazole

Ketoconazole

Lopinavir/ritonavir

Ritonavir
Moderate:

Diltiazem

Dronedarone

Erythromycin

Verapamil


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Appendix I:
Common CYP1A2 Inducers, CYP2C9 and CYP2C19 Inducers and 
Substrates, Substrates for CYP3A4, CYP2C8 Inducers, CYP3A Inducers and Inhibitors, 
and P-gp/CYP3A Dual Inhibitors (continued)
CYP3A Inducers
CYP3A Inhibitors
Strong:

Avasimibe

Carbamazepine

Phenytoin

Rifampin (rifampicin)

St. John’s wort (hypericum perforatum)
Strong:

Boceprevir

Clarithromycin

Conivaptan

Grapefruit juice

Indinavir

Itraconazole

Ketoconazole

Lopinavir/ritonavir

Mibefradil

Nefazodone

Nelfinavir

Posaconazole 

Ritonavir

Saquinavir

Telaprevir

Telithromycin

Voriconazole
Moderate:

Amprenavir

Aprepitant

Atazanavir

Ciprofloxacin

Cyclosporine

Darunavir/ritonavir

Diltiazem

Erythromycin

Fluconazole

Fosamprenavir

Grapefruit juice (citrus parasidi fruit juice)

Imatinib

Verapamil
Source: FDA’s Drug Development and Drug Interactions: Table of Substrates, Inhibitors and the University of Washington’s 
Drug Interaction Database.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm


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Appendix J:
Schematic to Represent the PK Sampling

SAP_001.pdf: 
Statistical A nal ysis Pla n G U 1 1 5/I 6 A- M C -C B B D  ( V 2) 
 
A D o u ble- Bli n de d, Place b o- C o ntr olle d, Ra n d o mize d P hase II St u d y of E n zal uta mi de Wit h or 
Wit h o ut t he PI 3 Ki nas e/ m T O R I n hi bit or L Y 3 0 2 3 4 1 4 i n Me n wit h Metastatic Castrati o n 
Resista nt Pr ostate Ca ncer  
 
N C T 0 2 4 0 7 0 5 4 
 
A p pr o val Dat e: 1 7 A pr 2 0 1 7 


 
 
 
 
 
 
 
St atistic al A n al ysis Pl a n  
 
 
 
 
 
 
 
A D o u ble -Bli n de d, Pl ace b o -C o ntr olle d, R a n d o mize d P h ase II St u d y of 
E nz al ut a mi de Wit h or Wit h o ut t he PI 3 Ki n ase/ m T O R I n hi bit or  L Y 3 0 2 3 4 1 4  
  
i n Me n wit h Met ast atic C astr ati o n Resist a nt Pr ost ate C a ncer   
 
 
 
 
 
 
 
S p o ns or:  
Eli Lill y a n d C o m p a n y  
I n di a n a p olis, I n di a n a, U S A 4 6 2 8 5 
St u d y Dr u g:  
L Y 3 0 2 3 4 1 4 
 
S C RI Pr ot oc ol N u m b er:  
 
G U 1 1 5  
 
S p o ns or Pr ot oc ol N u m b er:  
 
1 6 A -M C -C B B D  
Pr e p ar e d B y:  
S C RI D e v el o p m e nt I n n o v ati o ns (I n n o v ati o ns)  
 
 
 
 
 
 
 
 
 
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P:  C D S -0 1 0 2  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P  [ A] 
P a g e 1 of 3 5 
C o nfi d e nti al  
 
[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
Hist or y of C h a n g es  
 
T his d oc u m e nt h as u n d er g o n e t h e f oll o wi n g c h a n g es:  
 
 
V ersi o n N u m b er  
V ersi o n D at e  
D escri pti o n of C h a n g es  
1. 0  
J ul y 1 6 2 0 1 5 
Ori gi n al d oc u m e nt  
2. 0  
M ar 8 2 0 1 7  
U p d at e d wit h f utilit y i nt eri m at 3 6 P F S ev e nts  
 
M ar 8 2 0 1 7  
U p d at e d S ecti o n 3. 1 b y a d diti o n al d et ails o n c e ns or d at es  
 
M ar 8 2 0 1 7  
U p d at e d t h e Si g n Off P a g e  
 
A pr 1 7 2 0 1 7  
Misc ell a n e o us u p d at es  


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 3  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
St atistic al A n al ysis Pl a n R e vi e w a n d A p pr o v al  
 
 
0 4/ 2 1/ 2 0 1 7 0 1: 4 9 P M 
E D T  
 
I a m a p pr o vi n g 
t hi s d o c u m e nt. 
D at e  
 
0 4/ 2 3/ 2 0 1 7 0 8: 0 8 P M 
E D T  
I a m a p pr o vi n g 
t hi s d o c u m e nt. 
D at e  
0 4/ 2 4/ 2 0 1 7 0 6: 4 4 A M 
E D T  
 
I a m a p pr o vi n g 
t hi s d o c u m e nt. 
D at e  
I a m a p pr o vi n g 
t hi s d o c u m e nt. 
D at e  
0 4/ 2 4/ 2 0 1 7 0 6: 5 3 A M 
E D T  
P P D


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 4  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
T a bl e of C o nt e nt s  
T a bl e  of  C o nt e nt s  .............................................................................................  4 
Gl o s s ar y ..........................................................................................................  6 
1  
I ntr o d u cti o n ..............................................................................................  8 
O bj e cti v e s  ..........................................................................................  8 
Pri m ar y  O bj e cti v e  ......................................................................................  8 
S e c o n d ar y  O bj e cti v e s  .................................................................................  8 
E x pl or at or y  O bj e cti v e s  ...............................................................................  8 
St u d y  D e si g n  ......................................................................................  9 
Tr e at m e nt  Gr o u p s  .....................................................................................  9 
St ati sti c al  C o n si d er ati o n s  .....................................................................  9 
S a m pl e  Si z e J u stifi c ati o n  ............................................................................  9 
R a n d o mi z ati o n  ........................................................................................  1 0  
Ti mi n g  Of  A n al y si s  ............................................................................  1 0  
R e s p o n si biliti e s  .................................................................................  1 1  
A n al y si s S oft w ar e  .............................................................................  1 1  
2  
D efi niti o n of  A n al y si s  S et s  ........................................................................  1 1  
All  P ati e nt s  .......................................................................................  1 1  
F ull A n al y si s  S et ( F A S )  ......................................................................  1 1  
P er Pr ot o c ol A n al y si s  S et ( P P A S )  ......................................................... 1 2  
S af et y A n al y si s  S et ( S A F )  ..................................................................  1 2  
P h ar m a c o ki n eti c s A n al y si s  S et  ( P K A S )  ................................................. 1 2  
3  
Effi c a c y P ar a m et er s  / E n d p oi nt s  ................................................................  1 2  
Effi c a c y  E n d p oi nt s  .............................................................................  1 2  
Pri m ar y Effi c a c y P ar a m et er  / E n d p oi n t ....................................................... 1 2  
S e c o n d ar y Effi c a c y P ar a m et er s  / E n d p oi nt s  ................................................. 1 3  
D efi niti o n  of  E n d p oi nt s .......................................................................  1 3  
T u m or R e s p o n e s a n d R e s p o n s e  R at e  .......................................................... 1 5  
P S A  R e s p o n s e  .........................................................................................  1 6  
Ti m e t o  Pr o gr e s si o n ( T T P )  ........................................................................  1 6  
O v er all  S ur vi v al  ( O S )  ...............................................................................  1 7  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 5  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
P er c e nt C h a n g e fr o m B a s eli n e i n  P S A L e v el s  ............................................... 1 7  
P h ar m a c o ki n eti c s P ar a m et er s  ....................................................................  1 7  
G e n er al R ul e s i n D eri vi n g Ti m e T o  E v e nt V ari a bl e s  ................................ 1 9  
St art  D at e  ..............................................................................................  1 9  
E v e nt  D at e s  ............................................................................................  1 9  
C ut - off  D at e  ............................................................................................  1 9  
H a n dli n g of Mi s si n g  Effi c a c y  D at a  ........................................................ 2 0  
4  
S af et y P ar a m et er s  / E n d p oi nt s  ..................................................................  2 0  
A d v er s e  E v e nt s  .................................................................................  2 0  
L a b or at or y  P ar a m et er s  ......................................................................  2 0  
Ot h er V ari a bl e s  .................................................................................  2 0  
H a n dli n g of Mi s si n g  S af et y  D at a  .......................................................... 2 1  
5  
St ati sti c al  M et h o d s  ..................................................................................  2 2  
D efi niti o n of D at e s  / D a y s  ..................................................................  2 2  
D eri vi n g  St u d y  D a y  ..................................................................................  2 2  
G e n er al  C o n si d er ati o n  .......................................................................  2 2  
St u d y  P o p ul ati o n ...............................................................................  2 2  
Effi c a c y  A n al y si s  ...............................................................................  2 4  
S af et y  A n al y si s  .................................................................................  2 6  
Pri or/ C o n c urr e nt M e di c ati o n s a n d  C o n c o mit a nt  M e di c ati o n s  .................... 2 9  
P h ar m a c o ki n eti c A n al y si s r e s p o n si bilit y of Lill y  P K P D  gr o u p  .................... 2 9  
P h ar m a c o d y n a mi c A n al y s e s  ............................................................... 2 9  
Q u alit y of  Lif e A n al y s e s  ......................................................................  2 9  
P h ar m a c o e c o n o mi c s  A n al y s e s  ............................................................. 2 9  
6  
R ef er e n c e s  .............................................................................................  2 9  
7  
A p p e n di c e s  .............................................................................................  3 0  
A p p e n di x 1 : S c h e d ul e  of  A s s e s s m e nt s  ................................................. 3 0  
A p p e n di x 2 : T a bl e s, Fi g ur e s a n d  Li sti n g s  S h ell s  .................................... 3 4  
A p p e n di x 3 : I n - T e xt T a bl e s a n d  Fi g ur e s  S p e cifi c ati o n s  ........................... 3 4  
A p p e n di x 4 : D eri v e d V ari a bl e s a n d  D at a s et s S p e cifi c ati o n s  .................... 3 5  


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 6  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
Gl o s s ar y 
 
A D T  
A n dr o ge n de pri vati o n t hera p y  
A E  
A d verse e ve nt  
A L P  
Al kali ne p h os p hatase  
A L T ( S G P T)  
Ala ni ne a mi n otra nsferase  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A R  
A d verse reacti o n  
A S T ( S G O T)  
As partate a mi n otra nsferase  
BI D  
T wice dail y  
C B C  
C o m plete bl o o d c o u nt  
C F R  
C o de of Fe deral Re g ulati o ns  
CI  
C o nfi de nce i nter val  
C M P  
C o m pre he nsi ve meta b olic pr ofile  
C R  
C o m plete re missi o n  
C R P C  
Castrati o n Resista nt Pr ostate Ca ncer  
C T  
C o m p uterize d t o m o gra p h y  
D L T  
D ose -li miti n g t o xicit y 
D M C  
Data M o nit ori n g C o m mittee  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F  
electr o nic Case Re p ort F or m  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I N R 
I nter nati o nal N or malize d Rati o 
I P 
I n vesti gati o nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
L H R H  
L utei nizi n g h or m o ne -releasi n g h or m o ne 
N CI C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse  
E ve nts  
O R  
O bjecti ve res p o nse  
O R R  
O verall res p o nse rate  
O S  
O verall s ur vi val  
P C W G 2  
Pr ostate Ca ncer Cli nical Trials W or ki n g Gr o u p  
P D  
Pr o gressi ve disease  
P D x  
P har mac o d y na mic  
P HI  
Pr otecte d healt h i nf or mati o n  
PI 3 K  
P h os p hati d yli n osit ol -3 -ki nase  
P F S  
Pr o gressi o n -free s ur vi val 


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 7  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
 
 
P K  
P har mac o ki netic  
P R  
Partial res p o nse  
P S A  
Pr ostate s pecific a nti ge n  
P T E N  
P h os p hatase a n d te nsi n h o m ol o g ( ge ne)  
Q A  
Q ualit y ass ura nce  
Q D  
O nce dail y  
R A N K -L  
Rece pt or acti vat or of n uclear fact or ka p pa -B li ga n d  
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R R  
Res p o nse rate  
S A E  
Seri o us a d verse e ve nt  
S A R  
S us pecte d a d verse reacti o n  
S C RI  
Sara h Ca n n o n Researc h I nstit ute  
S D  
Sta ble disease  
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
T T P  
Ti me t o pr o gressi o n  
U A E  
U ne x pecte d a d verse e ve nt  
U L N  
U p per li mit of n or mal  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 8  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
1  
I n t r o d u cti o n  
 
T hi s d o c u m e nt d e s cri b e s t h e St ati sti c al A n al y si s Pl a n f or st u d y 1 6 A - M C - C B B D, A 
D o u bl e - Bli n d e d, Pl a c e b o - C o ntr oll e d, R a n d o mi z e d P h a s e II St u d y of E n z al ut a mi d e 
Wit h or Wit h o ut t h e PI 3 Ki n a s e/ m T O R I n hi bit or L Y 3 0 2 3 4 1 4 i n M e n wit h M et a st ati c 
C a str at i o n R e si st a nt Pr o st at e C a n c er, s p o n s or e d b y Eli Lill y & C o m p a n y. 
 
 
O bj e c ti v e s  
 
P ri m a r y O bj e c ti v e  
 
•  
T h e pri m ar y o bj e cti v e of t hi s st u d y i s t o c o m p ar e pr o gr e s si o n - fr e e s ur vi v al 
( P F S ) - P S A, r a di o gr a p hi c, or Pr o st at e C a n c er Cli ni c al Tri al s W or ki n g  Gr o u p 
( P C W G 2 ) s y m pt o m ati c pr o gr e s si o n - i n m e n wit h m C R P C w h o ar e r e c ei vi n g 
e n z al ut a mi d e pl u s L Y 3 0 2 3 4 1 4 v er s u s e n z al ut a mi d e pl u s pl a c e b o u si n g 
Pr o st at e C a n c er Cli ni c al Tri al s W or ki n g Gr o u p ( P C W G 2 )  crit eri a.  
 
 
S e c o n d a r y O bj e c ti v e s  
 
T h e s e c o n d ar y o bj e cti v e s of t hi s st u d y ar e:  
•  
T o c o m p ar e t h e cli ni c al r e s p o n s e r at e s ( R R s) i n m e n wit h m C R P C w h o ar e 
r e c ei vi n g e n z al ut a mi d e pl u s L Y 3 0 2 3 4 1 4 v er s u s e n z al ut a mi d e pl u s pl a c e b o  a n d 
w h o h a v e m e a s ur a bl e di s e a s e at b a s eli n e u si n g R e s p o n s e E v al u ati o n Crit eri a 
i n S oli d T u m or s ( R E CI S T ) v 1. 1 ( Ei se n h a u er et al.  2 0 0 9 ).  
•  
T o c o m p ar e ti m e t o cli ni c al ( s y m pt o m ati c or r a di o gr a p hi c) a n d / or P S A 
pr o gr e s si o n ( T T P ) i n m e n wit h m C R P C w h o ar e r e c ei vi n g e n z al ut a mi d e  pl u s 
L Y 3 0 2 3 4 1 4 v er s u s e n z al ut a mi d e pl u s pl a c e b o u si n g P C W G 2  crit eri a.  
•  
T o c o m p ar e t h e m a xi m u m d e cli n e i n P S A t h at o c c ur s f oll o wi n g tr e at m e nt  i n 
m e n wit h m C R P C w h o ar e r e c ei vi n g e n z al ut a mi d e pl u s L Y 3 0 2 3 4 1 4 v er s u s 
e n z al ut a mi d e pl u s pl a c e b o.  
•  
T o d e m o n str at e t h e s af et y a n d t ol er a bilit y of 2 0 0 m g t wi c e d ail y ( BI D )  or al 
L Y 3 0 2 3 4 1 4 gi v e n i n c o m bi n ati o n wit h 1 6 0 m g o n c e d ail y ( Q D ) or al d o s e of 
e n z al ut a mi d e.  
•  
T o e v al u at e p ot e nti al p h ar m a c o ki n eti c ( P K ) dr u g i nt er a cti o n s (i. e. i m p a ct of 
e n z al ut a mi d e o n L Y 3 0 2 3 4 1 4 e x p o s ur e) a n d t o f urt h er c h ar a ct eri z e  L Y 3 0 2 3 4 1 4 
P K  pr o p erti e s.  
•  
T o c h ar a ct eri z e t h e s af et y pr ofil e of e n z al u t a mi d e pl u s L Y 3 0 2 3 4 1 4 a s 
c o m p ar e d t o e n z al ut a mi d e pl u s pl a c e b o i n t hi s p ati e nt  p o p ul ati o n.  
 
E x pl o r at o r y O bj e c ti v e s  
 
T h e e x pl or at or y o bj e cti v e of t hi s st u d y i s:
•  
T o c oll e ct bl o o d a n d ar c hi v al ti s s u e f or e x pl or at or y st u di e s t o i d e ntif y 
bi o m ar k er s pr e di cti v e of cli ni c al effi c a c y a n d di s e a s e pr o gr e s si o n i n  t hi s 
p ati e nt  p o p ul ati o n.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 9  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
S t u d y D e si g n  
 
 
T hi s i s a d o u bl e - bli n d e d, pl a c e b o - c o ntr oll e d, r a n d o mi z e d P h a s e II st u d y of t h e 
c o m bi n ati o n of e n z al ut a mi d e pl u s L Y 3 0 2 3 4 1 4 v er s u s e n z al ut a mi d e pl u s pl a c e b o i n 
m e di c all y or s ur gi c all y c a str at e d m e n wit h m C R P C w h o h a v e s h o w n di s e a s e 
pr o gr e s si o n o n a bir at er o n e.  
C y cl e s will b e 2 8 d a y s i n l e n gt h. P ati e nt s will b e tr e at e d u ntil di s e a s e pr o gr e s si o n 
(r a di o gr a p hi c or P C W G 2 s y m pt o m ati c pr o gr e s si o n ), or u ntil t h e y d e v el o p a n 
u n a c c e pt a bl e a d v er s e e v e nt ( A E ) r e q uiri n g di s c o nti n u ati o n of t h e dr u g, or 
p ati e nt / p h y si ci a n c h oi c e. P ati e nt s wit h P S A pr o gr e s si o n ar e all o w e d a n d e n c o ur a g e d 
t o c o nti n u e tr e at m e nt u ntil cli ni c al ( s y m pt o m ati c or r a di o gr a p hi c) pr o gr e s si o n.  
 
L e a d - I n ( P a r t A )  
A l e a d - i n ( P art A ) of a p pr o xi m at el y 6- 1 2 p ati e nt s will b e c o n d u ct e d pri or t o t h e 
r a n d o mi z e d P h a s e II p orti o n of t h e st u d y t o a s s e s s s af et y, t ol er a bilit y, a n d p ot e nti al 
P K i nt er a cti o n. Pri or t o st arti n g t hi s c o m bi n ati o n t h er a p y o n C y cl e 1 D a y 1, p ati e nt s 
i n P art A will b e gi v e n si n gl e a g e nt L Y 3 0 2 3 4 1 4 2 0 0 m g e v er y 1 2 h o ur s ( BI D ) d uri n g 
t h e i niti al w e e k ( c all e d W e e k • 1 ) t o a s s e s s L Y 3 0 2 3 4 1 4 P K s at a st e a d y s t at e o n D a y - 
1 (l a st d a y of t h at W e e k  -1 ).  
 
D o u bl e - bli n d e d, Pl a c e b o - C o n t r oll e d R a n d o mi z e d S t u d y ( P a r t B )  
Aft er s af et y a n d t ol er a bilit y of t h e d o s e i s e st a bli s h e d i n P art A, a t ot al of 
a p pr o xi m at el y 1 3 2 p ati e nt s will b e r a n d o mi z e d i n a 1 : 1 r ati o t o e n z al ut a mi d e 1 6 0 m g 
or all y Q D i n c o m bi n ati o n wit h L Y 3 0 2 3 4 1 4 2 0 0 m g or m at c hi n g pl a c e b o or all y BI D 
( P art B ). R a n d o mi z ati o n will b e str atifi e d b a s e d o n t w o f a ct or s: 1 ) t h e pr e s e n c e or 
a b s e n c e of vi s c er al di s e a s e (i. e. n o n - l y m p h n o d e s oft ti s s u e di s e a s e), a n d 2 ) if 
p ati e nt s pr e vi o u sl y r e c ei v e d c h e m ot h er a p y i n t h e h or m o n e - s e n siti v e s etti n g w h e n 
c o m m e n ci n g a n dr o g e n d e pri v ati o n t h er a p y ( A D T ). I nt eri m effi c a c y a n al y s e s will b e 
p erf or m e d at t h e p oi nt s i n di c at e d i n S e cti o n 1. 3  
 
T r e a t m e n t G r o u p s  
 
P ati e nt s will b e r a n d o mi z e d i n a 1 : 1 r ati o t o e n z al ut a mi d e 1 6 0 m g or all y Q D i n 
c o m bi n ati o n wit h L Y 3 0 2 3 4 1 4 2 0 0 m g or m at c hi n g pl a c e b o or all y BI D i n P art B. T h e 
t w o tr e at m e nt gr o u p s di s pl a y e d i n d at a s u m m ari e s a s ‘ L Y 3 0 2 3 4 1 4’ a n d ‘ Pl a c e b o’ 
gi v e n t h at all p ati e nt s will r e c ei v e e n z al ut a mi d e.  
 
 
S t a ti s ti c al C o n si d e r a ti o n s  
 
 
 
 
 
 
 
 
 
 
 
 
C CI


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 0  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
 
 
 
 
 
 
 
R a n d o mi z a ti o n  
 
P ati e nt s will b e r a n d o ml y a s si g n e d tr e at m e nt ( 1 : 1 ) t o L Y 3 0 2 3 4 1 4 pl u s e n z al ut a mi d e 
or pl a c e b o pl u s e n z al ut a mi d e str atifi e d b y vi s c er al di s e a s e st at u s ( pr e s e nt or a b s e nt ) 
a n d pri or c h e m ot h er a p y i n t h e h or m o n e - s e n siti v e s etti n g w h e n c o m m e n ci n g A D T 
( y e s or n o). R a n d o mi z ati o n w ill b e p erf or m e d u si n g a n I W R S. 
 
 
Ti mi n g Of A n al y si s  
 
 
A S af et y I nt er n al M o nit ori n g C o m mitt e e ( SI M C ) will c o n d u ct a r e vi e w of t h e s af et y 
a n d P K d at a of t h e l e a d - i n p h a s e ( p art A ) p ati e nt pri or t o t h e i niti ati o n of t h e 
r a n d o mi z e d p h a s e p art B of t h e st u d y. T h e SI M C will r e vi e w t h e r e s ult s of t h e s af et y 
d at a at ti m e p oi nt s s p e cifi e d i n t h e s af et y m a n a g e m e nt pl a n f or t h e st u d y. T h e d at a 
c ut - off d at e f or t a bl e, li sti n g a n d gr a p h pr o d u cti o n will b e b a s e d o n t h e l a st l e a d - i n 
p ati e nt’ s c o m pl eti o n of hi s / h er fir st c y cl e of tr e at m e nt.  
 
 
 
 
 
 
 
 will b e u s e d a s t h e b o u n d ar y t o a s s e s s t h e effi c a c y of 
e n z al ut a mi d e pl u s L Y 3 0 2 3 4 1 4 v er s u s e n z al ut a mi d e pl u s pl a c e b o i n t h e fi n al a n al y si s.  
 
T h e r e s ult s fr o m t h e i nt eri m a n al y s e s will b e e x a mi n e d b y a Lill y i nt er n al a s s e s s m e nt 
c o m mitt e e (I A C ) t h at will b e e st a bli s h e d pri or t o t h e i n cl u si o n of t h e fir st p ati e nt i n 
t h e tri al. T h e I A C will c o n si st at l e a st of a Lill y M e di c al Dir e ct or, a Lill y C R P or cli ni c al 
r e s e ar c h s ci e nti st n ot a s s o ci at e d wit h t h e st u d y, P K s ci e nti st a n d a Lill y st ati sti ci a n 
n ot a s s o ci at e d wit h t h e st u d y. I A C will e x a mi n e t h e i nt eri m r e s ult s a n d m a k e 
r e c o m m e n d ati o n s a b o ut t h e tri al. T h e i nt eri m a n al y s e s will b e u s e d t o e n s ur e t h e 
d o s e r e gi m e n i s t ol er a bl e i n t hi s st u d y a n d t h e a s s e s s m e nt c o m mitt e e will d et er mi n e 
if a n y c h a n g e s ar e n e e d e d. T h e y m a y al s o s er v e t o g et a n e arl y r e a d o n f utilit y 
(i nt eri m a n al y si s 1 ) or effi c a c y (i nt eri m a n al y si s 2 ) t hr o u g h s urr o g at e s ( e. g. 
c o nti n u o u s t u m or m e a s ur e m e nt s ) or cli ni c al effi c a c y e n d p oi nt s f or f ut ur e pl a n ni n g.  
M or e d et ail s will b e pr o vi d e d i n t h e I A C C h art er.  
C CI
C CI
C CI


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 1  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
I n a d diti o n t o t h e effi c a c y a n al y si s, t h e i nt eri m a n al y s e s will al s o i n cl u d e di s p o siti o n, 
d e m o gr a p hi c s, b a s eli n e c h ar a ct eri sti c s, s af et y s u m m ar y, a n d st u d y dr u g 
a d mi ni str ati o n. A p pli c a bl e T F L s t o b e g e n er at e d f or t h e i nt eri m a nl a y si s will b e 
m ar k e d wit h a n ‘ *I A’ i n t h e t a bl e of c o nt e nt s.  
 
T h e fi n al a n al y si s will t a k e pl a c e w h e n t h er e ar e 9 2 P F S e v e nt s.  
 
 
 
R e s p o n si bili ti e s  
 
T h e fi n al st ati sti c al a n al y si s f or t h e st u d y will b e p erf or m e d b y S C RI D e v el o p m e nt 
I n n o v ati o n s. P h ar m a c o ki n eti c p ar a m et er e sti m ati o n a n d m o d elli n g will b e p erf or m e d 
b y Lill y i nt er n al p h ar m a c o ki n eti c gr o u p. T h e i nt eri m a n al y s e s will b e p er f or m e d b y 
st ati sti ci a n s a n d st ati sti c al pr o gr a m m er s w h o ar e i n d e p e n d e nt of st u d y c o n d u ct. T h e 
P K p ar a m et er s g e n er ati o n, s u m m ar y of P K a n al y si s ar e t h e r e s p o n si biliti e s of Eli 
Lill y’ s p h ar m a c o ki n eti c gr o u p.  
 
 
A n al y si s S of t w a r e  
 
A n al y s e s will b e p erf or m e d u si n g S A S ® v er si o n 9. 4 or hi g h er. T h e a n al y si s of t h e 
c o n c e ntr ati o n d at a a n d P K p ar a m et er s g e n er ati o n i s t h e r e s p o n si bilit y of Eli Lill y P K 
gr o u p a s p er t h e w or k pl a n. T h e P K p ar a m et er s will b e e sti m at e d u si n g Wi n N o nli n ® 
wit hi n P h o e ni x 6. 3 ( or hi g h er) ( P h ar s i g ht. a C ert ar a T M C o m p a n y ) a n d a n y s oft w ar e, 
a p pr o v e d a n d v ali d at e d b y Eli Lill y gl o b al P K P D or g a ni s ati o n, t o a n al y s e t h e P K d at a 
u si n g n o n - li n e ar mi x e d eff e ct m o d elli n g t e c h ni c s. A s e p ar at e P K a n al y si s pl a n i s 
d e v el o p e d b y Eli Lill y f or t h e P K a n al y si s.  
 
 
2  
D efi ni ti o n of A n al y si s  S e t s  
 
T h e f oll o wi n g a n al y si s s et s will b e u s e d i n t hi s st u d y.  
 
 
All P a ti e n t s  
 
All p ati e nt s w h o h a v e si g n e d t h e i nf or m e d c o n s e nt f or m (i. e. s cr e e ni n g f ail ur e s pl u s 
p ati e nt s e nr oll e d ) will c o m pri s e t h e All P ati e nt s S et ( A P S ). T h e A P S  will b e u s e d t o 
d e s cri b e t h e p ati e nt di s p o siti o n a n d all - c a u s e d e at h s i n b ot h P art A a n d P art B  
 
 
F ull A n al y si s S e t ( F A S )  
 
 
All e nr oll e d p ati e nt s r a n d o mi z e d t o a tr e at m e nt ar m i n P art B will c o m pri s e t h e F ull 
A n al y si s S et ( F A S ) r e g ar dl e s s of r e c ei pt of tr e a m e nt. I nf or m ati o n u si n g t hi s 
p o p ul ati o n will b e t a b ul at e d b y tr e at m e nt ar m, a s r a n d o mi z e d (I nt e nt t o Tr e at ) 
a c c or di n g t o t h e I W R S, u nl e s s ot h er wi s e i n di c at e d. T hi s p o p ul ati o n will b e u s e d f or 
t h e pri m ar y a n al y s e s of t h e effi c a c y e n d p oi nt s.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 2  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
P e r P r o t o c ol A n al y si s S e t ( P P A S )  
 
 
 
T h e P er Pr ot o c ol p o p ul ati o n i s a s u b s et of t h e F A S p o p ul ati o n a n d c o n si st s of t h e 
r a n d o mi z e d a n d tr e at e d p ati e nt s w h o d o n ot h a v e a m aj or pr ot o c ol vi ol ati o n ( e. g. 
cli ni c all y i m p ort a nt a n d p ot e nti all y i m p a ct effi c a c y e v al u ati o n s) a s li st e d b el o w :  
•  
P ati e nt h a s n ot m et t h e i n cl u si o n / e x cl u si o n  crit eri a  
•  
P ati e nt h a s r e c ei v e d c ert ai n n o n - p er mitt e d t h er a pi e s d uri n g  st u d y  
•  
P ati e nt w a s n ot all o c at e d t o t h e tr e at m e nt gr o u p d et er mi n e d b y  t h e 
r a n d o mi z ati o n, or r e c ei v e d i n c orr e ct st u d y  dr u g  
 
Pri or t o d at a b a s e l o c k, t h er e will b e a ( bli n d e d ) r e vi e w of all r e p ort e d pr ot o c ol 
vi ol ati o n s t o d et er mi n e t h e i n cl u si o n / e x cl u si o n of p ati e nt s i n e a c h a n al y si s s et.  
 
 
S af e t y A n al y si s S e t ( S A F )  
 
 
All p ati e nt s w h o h a v e r e c ei v e d at l e a st o n e (f ull or p arti al )  d o s e of st u d y tr e at m e nt 
will c o m pri s e t h e S af et y A n al y si s S et ( S A F ). I n t h e e v e nt of mi sr a n d o mi z ati o n, 
p ati e nt s will b e a s si g n e d t o tr e at m e nt gr o u p s b a s e d o n w h at w a s a ct u all y r e c ei v e d 
f or all s af et y e v al u ati o n s. 
P art A p ati e nt s w h o h a v e r e c ei v e d at l e a s e  o n e d o s e of st u d y tr e at m e nt ar e 
c o n si d er e d t h e S af et y A n al y si s S et ( S A F ).  
 
 
P h a r m a c o ki n e ti c s A n al y si s S e t ( P K A S )  
 
 
P h ar m a c o ki n eti c s a n al y si s will b e a d dr e s s e d i n a s e p ar at e S A P.  
 
 
3  
Effi c a c y P a r a m e t e r s /  E n d p oi n t s  
 
 
 
Effi c a c y E n d p oi n t s  
 
P ri m a r y Effi c a c y P a r a m e t e r / E n d p oi n t  
 
T h e pri m ar y effi c a c y e n d p oi nt i s pr o gr e s si o n - fr e e s ur vi v al ( P F S ), w hi c h i s d efi n e d a s 
t h e ti m e fr o m r a n d o mi z ati o n u ntil t h e d at e of di s e a s e pr o gr e s si o n ( P D ) a c c or di n g t o 
Pr o st at e C a n c er Cli ni c al Tri al s W or ki n g Gr o u p ( P C W G 2 ) crit eri a or d e at h.  
 
T o e v al u at e t h e r o b u st n e s s of P F S, t h e pr o gr e s si o n b y c at e g ori e s a c c or di n g t o 
P C W G 2, P F S d efi n e d b y r a di ol o gi c al pr o gr e s si o n (r P F S ), P F S d efi n e d b y r a di ol o gi c al 
pr o gr e s si o n a n d s y m pt o m ati c di s e a s e pr o gr e s si o n, a n d P F S d efi n e d b y P S A 
pr o gr e s si o n will b e a n al y z e d f or s e n siti vit y of t h e pri m ar y a n al y si s. T h e fir st t w o  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 3  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
e n d p oi nt s a b o v e ar e dir e ct m e a s ur e m e nt of cli ni c al b e n efit i n t u m or a s s e s s m e nt 
r at h er t h a n P S A pr o gr e s si o n.  
 
S e c o n d a r y Effi c a c y P a r a m e t e r s / E n d p oi n t s  
 
•  
O v er all R e s p o n s e R at e s ( O R R s) u si n g R e s p o n s e E v al u ati o n Crit eri a i n S oli d 
T u m or s ( R E CI S T ) v  1. 1  
•  
Ti m e t o di s e a s e pr o gr e s si o n ( T T P ) p er P C W G 2 crit eri a i s d efi n e d a s ti m e fr o m 
r a n d o mi z ati o n u ntil t h e d at e of di s e a s e pr o gr e s si o n ( P D ) a c c or di n g t o  P C W G 2 
crit eri a  
•  
R a di ol o gi c al Pr o gr e s si o n - fr e e s ur vi v al (r P F S ), w hi c h i s d efi n e d a s t h e ti m e 
fr o m r a n d o mi z ati o n u ntil t h e d at e of r a di ol o gi c al di s e a s e pr o gr e s si o n ( P D ) or 
d e at h  
•  
P er c e nt a g e c h a n g e i n P S A fr o m b a s eli n e t o 1 2 w e e k s, a n d t h e m a xi m u m 
d e cli n e i n P S A t h at o c c ur s f oll o wi n g tr e at m e nt a c c or di n g t o P C W G 2  crit eri a  
•  
Ti m e t o s y m pt o m ati c di s e a s e pr o gr e s si o n d efi n e d b y P C W G 2  
•  
T h e e v e nt t y p e s u n d er s y m pt o m ati c  pr o gr e s si o n  
•  
S af et y e n d p oi nt s i n cl u d e s A d v er s e E v e nt s, L a b or at or y E v al u ati o n s,  Vit al 
Si g n s, E C G, P h y si c al e x a mi n ati o n f i n di n g s, a n d E C O G  
•  
Dr u g e x p o s ur e.  
•  
P h ar m a c o ki n eti c ( P K ) p ar a m et er s of L Y 3 0 2 3 4 1 4 al o n e a n d wit h  e n z al ut a mi d e  
 
E x pl o r a t o r y E n d p oi n t s  
•  
Bi o m ar k er s c oll e ct e d fr o m bl o o d a n d ar c hi v al ti s s u e will b e u s e d i n a d - h o c 
a n al y si s t o i d e ntif y p ot e nti al pr e di cti v e f a ct or s i n cli ni c al effi c a c y a n d di s e a s e 
pr o gr e s si o n i n t hi s p ati e nt  p o p ul ati o n.  
 
D efi ni ti o n of E n d p oi n t s  
 
 
P r o g r e s si o n F r e e S u r vi v al b a s e d o n P C
W G 2 c rit e ri a  
 
 
P C
W G 2 Di s e a s e P r o g r e s si o n D at e:  
 
T h e P C W G 2 pr o gr e s si o n d at e f or t h e pri m ar y e n d p oi nt will b e t h e e arli e st d at e 
a m o n g a n y of t h e t hr e e e v e nt d at e s d e s cri b e d b y t h e Pr o st at e C a n c er Cli ni c al Tri al s 
W or ki n g Gr o u p ( P C W G 2 ) crit eri a :  
1 )  D at e of R a di o gr a p hi c  Pr o gr e s si o n  
 
A p p e ar a n c e of 2 or m or e n e w l e si o n s o n b o n e s c a n, a n d, f or t h e fir st r e a s s e s s m e nt 
o nl y, a c o nfir m at or y s c a n p erf or m e d 6 or m or e w e e k s l at er t h at s h o w s a mi ni m u m  of 
2 or m or e a d diti o n al n e w l e si o n s.  T h e d at e of pr o gr e s si o n i s t h e d at e of t h e fir st 
s c a n t h at s h o w s t h e  c h a n g e.  
Or  
 
S oft  ti s s u e di s e a s e t ar g et l e si o n pr o gr e s si o n b y m o difi e d R E CI S T v. 1. 1 t o r e p ort 
c h a n g e s i n l y m p h n o d e s t h at w er e ≥ 2 0 m m i n di a m et er at b a s eli n e wit h a d diti o n al  


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 4  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
r e q uir e m e nt t h at pr o gr e s si o n at fir st a s s e s s m e nt b e c o nfir m e d b y a s e c o n d s c a n 6 or 
m or e w e e k s l at er. T h e d at e of pr o gr e s si o n i s t h e d at e of t h e fir st s c a n t h at s h o w s t h e 
c h a n g e. N ot e t h at f or s o m e tr e at m e nt s, a l e si o n m a y i n cr e a s e i n si z e b ef or e it 
d e cr e a s e s.  
 
T h e e arli er d at e of a b o v e t w o pr o gr e s si o n d at e i s t h e d at e of r a di ol o gi c al pr o gr e s si o n.  
 
2 )  D at e of P S A  Pr o gr e s si o n  
 
F or p ati e nt wit h a d e cr e a s e o n tr e at m e nt, P S A pr o gr e s si o n i s d efi n e d a s ≥2 5 % 
i n cr e a s e a n d ≥2 n g / m L i n cr e a s e a b o v e t h e n a dir. 
F or p ati e nt s wit h o ut a d e cr e a s e o n tr e at m e nt, P S A pr o gr e s si o n i s d efi n e d a s ≥2 5 % 
a n d a ≥2 n g / m L fr o m b a s eli n e aft er 1 2 w e e k s.  
P S A pr o gr e s si o n s m u st b e c o nfir m e d at t h e n e xt st u d y vi sit 3 or m or e w e e k s l at er. 
P S A will b e c oll e ct e d at s cr e e ni n g a n d o n D a y 1 of e a c h tr e at m e nt  c y cl e.  
P S A pr o gr e s si o n al o n e will n ot  b e c o n si d er e d di a g n o sti c of di s e a s e pr o gr e s si o n, 
t h er ef or e it will n ot b e u s e d a s a r e a s o n t o di s c o nti n u e st u d y  tr e at m e nt. 
 
3 )  D at e of S y m pt o m ati c  Pr o gr e s si o n  
 
S y m pt o m ati c pr o gr e s si o n i s d efi n e d a s e vi d e n c e of u n e q ui v o c al s y m pt o m ati c or 
cli ni c al pr o gr e s si o n d efi n e d b y at l e a st 1 of t h e f oll o wi n g :  
•  
A m ar k e d e s c al ati o n i n c a n c er - r el at e d p ai n t h at i s a s s e s s e d b y t h e 
I n v e sti g at or t o i n di c at e t h e n e e d f or ot h er s y st e mi c t h er a p y or p alli ati v e 
r a di ot h er a p y. I g n or e e arl y c h a n g e s ( ≤ 1 2 w e e k s) i n p ai n or h e alt h - r el at e d 
q u alit y of lif e i n a b s e n c e of c o m p elli n g e vi d e n c e of di s e a s e pr o gr e s si o n. 
C o nfir m pr o gr e s si o n of p ai n or h e alt h - r el at e d q u alit y of lif e ≥ 3 w e e k s  l at er, 
•  
A n i m m e di at e n e e d f or i niti ati o n of n e w a nti c a n c er tr e at m e nt, s ur gi c al  or 
r a di ol o gi c al i nt er v e nti o n f or c o m pli c ati o n s d u e t o t u m or  pr o gr e s si o n,  
•  
A m ar k e d d et eri or ati o n i n E C O G p erf or m a n c e st at u s t o Gr a d e 3 or hi g h er,  or  
 
•  
It i s f elt t o b e i n t h e b e st i nt er e st of t h e p ati e nt t o c o m e off st u d y d u e t o 
cli ni c al  pr o gr e s si o n  
P r o g r e s si o n F r e e S u r vi v al b a s e d o n P C
W G 2  
 
Pr o gr e s si o n - fr e e s ur vi v al ( P F S ) i s d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n u ntil t h e 
d at e of di s e a s e pr o gr e s si o n ( P D ) a c c or di n g t o Pr o st at e C a n c er Cli ni c al Tri al s W or ki n g 
Gr o u p ( P C W G 2 ) crit eri a or d e at h. P F S will b e c e n s or e d i n t h e f oll o wi n g s e n ari o s:  
•  
If p ati e nt h a s n eit h er P D n or d e at h, t h e P F S will b e c e n s or e d at l a st 
r a di ol o gi c al t u m or a s s e s s m e nt d at e or P S A l a b a s s e s s m e nt  d at e.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 5  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
•  
If p ati e nt h a d P D or D e at h o c c urr e d m or e t h a n 8 4 d a y s ( 3 t u m or a s s e s s m e nt 
i nt er v al s ) aft er pr e vi o u s t u m or r a di ol o gi c al a s s e s s m e nt or P S A l a b 
a s s e s s m e nt. T h e P F S will b e c e n s or e d at l a st r a di ol o gi c al t u m or a s s e s s m e nt 
d at e or P S A l a b a s s e s s m e nt d at e.  
•  
If p ati e nt d o e s n ot h a v e p o st b a s eli n e t u m or a s s e s s m e nt, P S A a s s e s s m e nt, 
n or d e at h wit hi n 8 4 d a y s aft er r a n d o mi z ati o n, t h e P F S will b e c e n s or e d at  D a y 
1.  
•  
If p ati e nt d o e s n ot h a v e v ali d b a s eli n e t u m or a s s e s s m e nt or P S A a s s e s s m e nt, 
t h e P F S will b e c e n s or e d at D a y 1.  
P r o g r e s si o n F r e e S u r vi v al S e n siti vit y A n al y si s F o r P ri m a r y E n d p oi n t s  
 
 
Si mili arl y, t h e P F S ti m e t o e v e nt e n d p oi nt s will b e d efi n e d a n d e v al u at e d f or t h e 
f oll o wi n g c at e g ori e s a s s e n siti vit y a n al y si s: 
 
•  
R a di ol o gi c al Pr o gr e s si o n - fr e e s ur vi v al (r P F S ), w hi c h i s d efi n e d a s t h e ti m e 
fr o m r a n d o mi z ati o n u ntil t h e d at e of r a di ol o gi c al di s e a s e pr o gr e s si o n ( P D ) or 
d e at h. P ati e nt s w h o d o n ot h a v e a n e v e nt or h a v e st art e d o n a n y s u b s e q u e nt 
a nti - c a n c er t h er a p y wit h o ut a n y d o c u m e nt ati o n of pr o gr e s si o n will b e 
c e n s o r e d o n t h e d at e of pr e vi o u s r a di ol o gi c al t u m or a s s e s s m e nt  d at e.  
•  
Pr o gr e s si o n Fr e e S ur vi v al d efi n e d b y b ot h r a di ol o gi c al pr o gr e s si o n  a n d 
s y m pt o m ati c di s e a s e pr o gr e s si o n d efi n e d b y  P C W G 2.  
•  
Pr o gr e s si o n Fr e e S ur vi v al d efi n e d b y R E CI S T, p ati e nt wit h o ut d o c u m e nt e d  
pr o gr e s si o n will b e c e n s or e d o n l a st t u m or a s s e s s m e nt d at e wit h S D, P R  or 
C R.  
 
A b o v e ti m e t o e v e nt v ari a bl e i s g e n er all y d efi n e d a s t h e ti m e fr o m d at e of 
r a n d o mi z ati o n t o t h e fir st e v e nt of i nt er e st. P ati e nt s w h o h a v e st art e d o n a n y 
s u b s e q u e nt a nti - c a n c er  t h er a p y wit h o ut a n y d o c u m e nt ati o n of pr o gr e s si o n will b e 
c e n s or e d o n t h e d at e of pr e vi o u s r a di ol o gi c al a s s e s s m e nt d at e.  
 
T u m o r R e s p o n e s a n d R e s p o n s e R at e 
Ti m e p oi n t O v e r all T u m o r R e s p o n s e  
Ti m e p oi nt o v er all t u m or r e s p o n s e will b e e v al u at e d, u si n g t h e R E CI S T 1. 1 crit eri a, 
e v er y 2 w e e k s u ntil di s e a s e pr o gr e s si o n ( a s d et er mi n e d b y t h e i n v e sti g at or). T h e 
c at e g ori e s ar e a s f oll o w s :  
•  
C o m pl et e r e s p o n s e  ( C R )  
•  
P arti al r e s p o n s e  ( P R )  
•  
St a bl e di s e a s e  ( S D )  
•  
Pr o gr e s si v e di s e a s e  ( P D )  
•  
N ot E v al u a bl e  ( N E )  
 
T h e ti m e p oi nt o v er all r e s p o n s e at e a c h a s s e s s m e nt a n d t h e b e st o v er all r e s p o n s e 
m a y b e d et er mi n e d b y I n v e sti g at or a n d will b e d eri v e d pr o gr a m m ati c all y.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 6  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
Di s cr e p a n ci e s will b e q u eri e d, b ut I n v e sti g at or a s s e s s m e nt will b e u s e d f or a n al yti c al 
p ur p o s e s.  
 
O v e r all R e s p o n s e R a t e  
 
O v er all R e s p o n s e R at e ( O R R ) i s t h e pr o p orti o n of p ati e nt s w h o s e b e st o v er all 
r e s p o n s e i s C o m pl et e R e s p o n s e ( C R ) or P arti al R e s p o n s e ( P R ). O nl y p ati e nt s wit h 
m e a s ur a bl e di s e a s e at b a s eli n e will b e i n cl u d e d i n t h e a n al y si s of O R R.  
 
B e s t O v e r all R e s p o n s e i s deri v e d b a s e d o n t h e ti m e p oi nt r e s p o n s e 
i nf or m ati o n o n t h e C R F a c c or di n g t o R E CI S T crit eri a : 
•  
If a p ati e nt h a s at l e a st t w o C R a n d t h e fir st a n d t h e l a st C R d at e s  ar e 
m or e t h a n 2 8 d a y s a p art, t h e n t h e b e st o v er all r e s p o n s e i s d efi n e d a s 
C R.  
•  
If a p ati e nt h a s P R a n d a n ot h er C R / P R wit h m or e t h a n 2 8 d a y s  a p art, 
t h e n t h e b e st o v er all r e s p o n s e f or t hi s p ati e nt i s P R.  
•  
F or t h o s e p ati e nt s w h o d o n ot h a v e c o nfir m e d C R or P R, if t h e 
p ati e nt’ s l a st t u m or a s s e s s m e nt r e c or d of C R / P R / S D i s at l e a st 4 2 
d a y s aft er d at e of r a n d o mi z ati o n, t h e n b e st o v er all r e s p o n s e i s  d efi n e d 
a s  S D.  
•  
F or t h o s e p ati e nt s w h o d o n ot h a v e S D d efi n e d a s a b o v e, b ut  t h e y 
h a v e P D, t h eir b e st o v er all r e s p o n s e i s  P D.  
•  
Ot h er wi s e, b e st o v er all r e s p o n s e i s d efi n e d a s  N E.  
T h e d eri v ati o n a b o v e will b e i m pl e m e nt e d u si n g S A S t o e v al u at e t h e a c c ur a c y 
of t h e b e st o v er all r e s p o n s e i n t h e C R F.  
 
B a s e d o n p ati e nt s’ b e st o v er all r e s p o n s e d uri n g t h e st u d y, t h e f oll o wi n g r at e s ar e 
c al c ul at e d :  
•  
Di s e a s e C o ntr ol R at e ( D C R ) = Pr o p orti o n of p ati e nt s wit h a b e st  o v er all 
r e s p o n s e of C R, P R, or S D.  
•  
E arl y Pr o gr e s si o n R at e ( E P R ) = Pr o p orti o n of p ati e nt s wit h pr o gr e s si v e 
di s e a s e wit hi n 1 2 w e e k s of  r a n d o mi z ati o n  
 
 
P S A R e s p o n s e  
 
P S A r e s p o n s e i s d efi n e d a s m or e t h a n 5 0 % a n d 9 0 % r e d u cti o n fr o m b a s eli n e t o 
l o w e st p o st b a s eli n e v al u e aft er 7 0 d a y s ( 1 2 w e e k s – 2 w e e k s) of tr e at m e nt.  
 
Ti m e t o P r o g r e s si o n ( T T P )  
 
T T P i s d efi n e d a s t h e ti m e fr o m d at e of r a n d o mi z ati o n t o t h e fir st d o c u m e nt e d 
o b s er v ati o n of di s e a s e pr o gr e s si o n i n r a di ol o gi c al e x a m w hi c h w a s d efi n e d i n t h e 
P C W G 2 crit eri a a s a b o v e. Ti m e t o s y m pt o m ati c pr o gr e s si o n a n d ti m e t o P S A 
pr o gr e s si o n will b e d efi n e d i n t h e s a m e m a n n er. P ati e nt wit h o ut pr o gr e s si o n will b e 
c e n s or e d o n l a st r a di ol o gi c al a s s e s s m e nt d at e.  
 
Ti m e t o P S A pr o gr e s si o n will b e d efi n e d i n t h e s a m e m a n n er a s P C W G crit eri a a s 
a b o v e. P ati e nt wit h o ut pr o gr e s si o n will b e c e n s or e d o n l a st P S A a s s e s s m e nt d at e.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 7  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
O v e r all S u r vi v al ( O S )  
 
O v er all S ur vi v al ( O S ) i s t h e ti m e fr o m d at e of r a n d o mi z ati o n t o d e at h d u e t o a n y 
c a u s e. If a p ati e nt h a s n ot di e d, o v er all s ur vi v al i s c e n s or e d at t h e l a st k n o w n ali v e 
d at e.  
 
P e r c e n t C h a n g e f r o m B a s eli n e i n P S A L e v el s  
 
T h e p er c e nt c h a n g e fr o m b a s eli n e i n P S A l e v el s aft er 1 2 w e e k s o n st u d y a n d t h e 
m a xi m u m p er c e nt c h a n g e fr o m b a s eli n e will b e s u m m ari z e d u si n g w at erf all pl ot s f or 
e a c h tr e at m e nt ar m. T o d efi n e t h e W e e k 1 2 vi sit, a vi sit wi n d o w of 8 4 + / - 1 4 d a y s 
will b e u s e d, h e n c e a n y P S A l e v el aft er 7 0 d a y s i s  c o n si d er e d a s P S A l e v el aft er 1 2 
w e e k s. F or p ati e nt s w h o di s c o nti n u e o n or b ef or e t h e 1 2 w e e k a s s e s s m e nt or f or 
w h o m t h e 1 2 w e e k a s s e s s m e nt i s mi s si n g, t h e l a st o b s er v ati o n pri or t o t h e w e e k 1 2 
a s s e s s m e nt will b e utili z e d. P ati e nt s wit h n o p o st - b a s eli n e P S A d at a will b e e x cl u d e d 
fr o m t h e s u m m ari e s. 
 
 
P h a r m a c o ki n e ti c s P a r a m e t e r s  
 
Lill y P K P D gr o u p will b e r e s p o n si bl e f or t h e P K a n al y si s. S C RI will b e r e s p o n si bl e f or 
pr o vi di n g t h e P K d at a s et ( at t h e i nt eri m a n al y si s i n p art B a n d f or t h e fi n al a n al y si s) 
a n d al s o pr o vi di n g Q C d at a fr o m t h e l a b ( at t h e e n d of t h e l e a d – i n s af et y c o h ort of 6 
t o 1 2 p ati e nt ). 
 
D uri n g P art A of t h e st u d y, P K bl o o d s a m pl e s will b e c oll e ct e d o n D a y - 1 (l a st d a y of 
L Y 3 0 2 3 4 1 4 m o n ot h er a p y w e e k tr e at m e nt ), at pr e - d o s e, 1. 5 , 3, a n d 6 h o ur s p o st 
L Y 3 0 2 3 4 1 4 d o s e; o n D a y 1 of c y cl e 1 at pr e - d o s e of L Y 3 0 2 3 4 1 4 a n d e n z al ut a mi d e; 
o n a n y d a y X of c y cl e 1 ( b et w e e n D a y 1 5 a n d D a y 2 8 ), at pr e - d o s e of L Y 3 0 2 3 4 1 4 
a n d e n z al ut a mi d e, 1. 5 , 3, a n d 6 h o ur s p o st L Y 3 0 2 3 4 1 4 d o s e ( n ot e : c y cl e d ur ati o n 
2 8 d a y s ) ; o n d a y 1 of c y cl e 2 a n d c y cl e 3 (i. e st u d y d a y 2 9 a n d 5 7 ) pr e - d o s e of 
L Y 3 0 2 3 4 1 4 a n d e n z al ut a mi d e a n d 1. 5 h p o st d o s e).  


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 8  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
T a ble 1 
P h ar m ac o ki netic S a m ple C ollecti o n Ti mes – P art A P atie nts  o nl y 
 
St u d y Visit  
C ollecti o n Ti m e ( ± 1 5 mi n utes)  
L Y 3 0 2 3 4 1 4 P K - 
D B S/ Pl as m a 
S a m ple  
E nz al ut a mi 
de P K 
Pl as m a 
S a m ple  
Wee k • 1, Da y - 1a 
Pre -d ose  
1. 5, 3, a n d 6 h o urs p ost L Y 3 0 2 3 4 1 4 d ose  
 
 
 
C ycle 1, Da y 1 a 
Pre -d ose of L Y 3 0 2 3 4 1 4 a n d e nzal uta mi de   
 
 
C ycle 1, Da y X ( Da y 
1 5 – Da y 2 8) b, c  
Pre -d ose of L Y 3 0 2 3 4 1 4 a n d e nzal uta mi de 
1. 5, 3, a n d 6 h o urs p ost L Y 3 0 2 3 4 1 4 d ose  
 
 
 
 
C ycle 1, Da y X + 1 b, c  
Pre -d ose of L Y 3 0 2 3 4 1 4 a n d e nzal uta mi de  
 
 
C ycle 2, Da y 1 b  
Pre - d ose of L Y 3 0 2 3 4 1 4 a n d 
e nzal uta mi de 
1. 5 h o urs p ost L Y 3 0 2 3 4 1 4 a n d 
e nzal uta mi de d ose  
 
 
C ycle 3, Da y 1 b  
Pre - d ose of L Y 3 0 2 3 4 1 4 a n d 
e nzal uta mi de 
1. 5 h o urs p ost L Y 3 0 2 3 4 1 4 a n d 
e nzal uta mi de d ose  
 
 
a: O n Da y -1, last da y of Wee k -1, t he m or ni n g L Y 3 0 2 3 4 1 4 d ose is gi ve n a n d P K sa m ples ta ke n t o esti mate 
t he e x p os ure of L Y 3 0 2 3 4 1 4 as m o n ot hera p y. O n Da y 1, a pre-d ose sa m ple is ta ke n pri or t o i nitiati o n of t he 
c o m bi nati o n treat me nt L Y 3 0 2 3 4 1 4 + e nzal uta mi de  (t his sa m ple is a b o ut 1 2 h o urs p ost t he Da y-1 e ve ni n g 
L Y 3 0 2 3 4 1 4 d ose)  
b: It is pla n ne d t hat t he m or ni n g d ose of L Y 3 0 2 3 4 1 4/ place b o will be ta ke n t o get her/c o nc o mita ntl y wit h t he 
dail y d ose of e nzal uta mi de.  
c: Da y X of C ycle 1 is a n y da y bet wee n Da y 1 5 a n d Da y 2 8.  
 
T h e Pl a s m a c o n c e ntr ati o n v er s u s ti m e pr ofil e s of L Y 3 0 2 3 4 1 4, e n z al ut a mi d e a n d it s 
m et a b olit e s will b e o bt ai n e d fr o m t h e a n al y si s of pl a s m a s a m pl e s. P h ar m a c o ki n eti c 
p ar a m et er s will b e c al c ul at e d f or e a c h p ati e nt i n t h e l e a d i n p h a s e p art A. 
P h ar m a c o ki n eti c p ar a m et er s f or L Y 3 0 2 3 4 1 4 will i n cl u d e b ut ar e n ot li mit e d t o A U C 0- 6 , 
C m a x , a n d Tm a x. at st e a d y st at e aft er 7 d a y s m o n ot h er a p y a n d at st e a d y st at e aft er at 
l e a st 1 5 d a y s c o m bi n ati o n t h er a p y wit h E n z al ut a mi d e. P h ar m a c o ki n eti c s p ar a m et er s 
f or e n z al ut a mi d e a n d it s m et a b olit e will i n cl u d e, b ut ar e n ot li mit e d t o, A U C 0- 6 , Cm a x , 
a n d T m a x at st e a d y st at e.  
 
F or p art B p ati e nt, o nl y s p ar s e s a m pli n g P K will b e c arri e d o ut a n d st e a d y st at e 
tr o u g h a n d C m a x L Y 3 0 2 34 1 4 c o n c e ntr at o n will b e r e p ort e d.  
 
A s st at e d i n s e cti o n 1. 6 of t hi s d o c u m e nt : t h e a n al y si s of t h e c o n c e ntr ati o n d at a a n d 
P K p ar a m et er s g e n er ati o n i s t h e r e s p o n si bilit y of Eli Lill y P K gr o u p a s p er t h e w or k 
pl a n. T h e P K p ar a m et er s will b e e sti m at e d u si n g W i n N o nli n® wit hi n P h o e ni x 6. 3 ( or 
hi g h er) ( P h ar si g ht. a C ert ar a T M C o m p a n y ) a n d a n y s oft w ar e, a p pr o v e d a n d v ali d at e d 
b y Eli Lill y gl o b al P K P D or g a ni s ati o n, t o a n al y s e t h e P K d at a u si n g n o n - li n e ar mi x e d 
eff e ct m o d elli n g t e c h ni q u e s. A s e p ar at e P K a n al y si s pl a n  i s d e v el o p e d b y Eli Lill y f or 
t h e P K a n al y si s. 


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 1 9  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
 
E x pl o r a t o r y E n d p oi n t s  
 
 
Bl o o d a n d ar c hi v al ti s s u e will b e c oll e ct e d f or e x pl or at or y st u di e s t o i d e ntif y p ot e nti al 
bi o m ar k er s pr e di cti v e of cli ni c al effi c a c y a n d di s e a s e pr o gr e s si o n i n t hi s p ati e nt 
p o p ul ati o n. A n al y si s m a y b e p erf or m e d o n bi o m ar k er v ari a nt s h y p ot h eti c all y pl a yi n g 
a r ol e i n PI 3 K p at h w a y s or e n z al ut a mi d e m et a b oli s m, i n cl u di n g, b ut n ot li mit e d t o, 
PI K 3 C A, P T E N, or A R - V 7, t o e v al u at e t h eir a s s o ci ati o n wit h o b s er v e d cli ni c al 
o ut c o m e s t o st u d y tr e at m e nt . 
A d diti o n al e x pl or at or y a n al y si s m a y b e p erf or m e d, if a p pr o pri at e a n d all o w e d b y t h e 
c oll e ct e d d at a. T h e d et ail s of t h e a n al y si s pl a n ar e d o c u m e nt e d i n a s e p ar at e 
d o c u m e nt. R e s ult s will b e i n cl u d e d i n a s e p ar at e r e p ort.  
 
 
G e n e r al R ul e s i n D e ri vi n g Ti m e T o E v e n t V a ri a bl e s  
 
T h e g e n er al r ul e f or ti m e t o e v e nt a n al y si s i s d e s cri b e d b el o w :  
 
Ti m e T o E v e nt = D at e of e v e nt wit h i nt er e st ( wit h e v e nt ) – St art D at e + 1 d a y, if 
t h er e i s a n e v e nt. 
Ti m e T o E v e nt = L a st D at e of e v e nt wit h i nt er e st ( n o e v e nt ) – St art D at e + 1 d a y, if 
t h er e i s n o e v e nt.  
 
If d at e s of e v e nt of i nt er e st s ar e n ot a v ail a bl e, t h e d at e of r a n d o mi z ati o n will b e u s e d 
a s e v e nt d at e (i e c e n s or e d o n d a y 1 ).  
 
S t a r t D a t e  
 
D at e of r a n d o mi z ati o n i s t h e st art d at e t o c al c ul at e t h e e v e nt.  
 
E v e n t D a t e s
 
F or O v er all S ur vi v al ( O S ), Pr o gr e s si o n - Fr e e S ur vi v al ( P F S ) a n d Ti m e T o Pr o gr e s si o n 
( T T P ) , m ulti pl e d at e s will b e u s e d t o d eri v e t h e e v e nt d at e s f or t h e s e e n d p oi nt s, wit h 
t h e f oll o wi n g r ul e s : 
•  
E v e nt s al w a y s t a k e pr e c e d e n c e t o  C e n s ori n g  
•  
If m ulti pl e e v e nt d at e s ar e a p pli c a bl e, t h e e arli e st d at e will b e  u s e d.  
•  
If m ulti pl e c e n s ori n g d at e s ar e a p pli c a bl e, t h e l a st d at e will b e  u s e d.  
 
C u t - off D a t e  
 
A n y E v e nt of i nt er e st aft er c ut - off d at e will n ot b e c o n si d er e d i n t h e pri m ar y 
a n al y s e s. If t h e fir st e v e nt of i nt er e st i s aft er c ut - off d at e, t h e ti m e t o e v e nt v ari a bl e  
will b e c e n s or e d t o t h e pr e vi o u s d at e a s s o ci at e d wit h t h e e v e nt of i nt er e st d at e.  
F oll o w - u p e v al u ati o n s of ti m e t o e v e nt m e a s ur e s m a y b e c o n d u ct e d at a l at er d at e 
a n d a p p e n d e d t o t h e C S R a s a p pr o pri at e.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 0  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
H a n dli n g of Mi s si n g Effi c a c y D a t a  
 
N o i m p ut ati o n will b e c o n d u ct e d f or t h e effi c a c y d at a.  
 
4  
S af e t y P a r a m e t e r s /  E n d p oi n t s  
 
A d v e r s e E v e n t s  
 
A d v er s e e v e nt s will b e c o d e d u si n g M e d D R A v er si o n 1 8. 0. P arti c ul ar pr ef err e d t er m s 
will b e s u m m ari z e d i n c o n s oli d ati o n w h e n a p pr o pri at e.  
 
F or e x a m pl e, a n a e mi a, h a e m at o crit d e cr e a s e d, h a e m o gl o bi n d e cr e a s e d, h y p o c hr o mi c 
a n a e mi a a n d r e d bl o o d c ell c o u nt d e cr e a s e d will b e s u m m ari e d a s a n e mi a.  
 
A tr e at m e nt - e m er g e nt a d v er s e e v e nt i s d efi n e d a s a n y a d v er s e e v e nt t h at h a s 
st art e d or w or s e n e d aft er t h e st art of t h e fir st d o s e of st u d y tr e at m e nt u p t o 3 0 d a y s 
aft er di s c o nti n u ati o n of st u d y dr u g. A d v er s e e v e nt s will b e gr a d e d u si n g t h e N CI - 
C T C A E v er si o n < 4. 0 3 > w h er e a p pli c a bl e, or u si n g t h e 5 - p oi nt s e v erit y s c al e:  
 
N C I - C T C A E G r a d e  
S e v e rit y s c al e  
1  
Mil d 
2  
M o d er at e  
3  
S e v er e  
4  
Lif e - T hr e at e ni n g  
5  
D e at h  
 
I n c a s e s of m ulti pl e o c c ur e n c e s of a d v er s e e v e nt, t h e m o st s e v er e gr a d e o b s er v e d i s 
t o b e r e p ort e d. 
 
L a b o r a t o r y P a r a m e t e r s  
 
L a b or at or y t o xi cit y gr a di n g will b e d eri v e d fr o m t h e l a b or at or y v al u e s u si n g N CI - 
C T C A E v er si o n < 4. 0 3 >.  
 
O t h e r  V a ri a bl e s  
 
T h e d u r a ti o n of  e x p o s u r e  
F or e a c h s u bj e ct, t h e L e n gt h of Ti m e o n d o u bl e - bli n d tr e at m e nt will b e c al c ul at e d i n 
d a y s, u si n g t h e f oll o wi n g f or m ul a :  
 
(‘ D at e l a st d o s e of st u d y dr u g’ # - ‘ D at e fir st d o s e* ) + 1  
 
T o t al D o s e C o n s u m e d  
F or e a c h s u bj e ct, t h e t ot al d o s e o n d o u bl e - bli n d tr e at m e nt will b e c al c ul at e d.  
 
D o s e I n t e n si t y  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 1  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
D o s e I nt e n sit y o n D o si n g D a y s will b e c al c ul at e d a s: 
[ T ot al D o s e C o n s u m e d ]  
[ S u m of all D o si n g I nt er v al s ]  
 
R el a ti v e D o s e I n t e n si t y  
 
D o s e I nt e n s it y will b e c al c ul at e d a s: 
[ T ot al D o s e C o n s u m e d ]  
[ L a st D o s e D at e - Fir st D o s e D at e + 1 ]  
 
C o m pli a n c e  
 
C o m pli a n c e will b e c al c ul at e d a s :  
 
[ T ot al D o s e C o n s u m e d ]  
   
* 1 0 0 % 
[ Pl a n n e d D o s e]  
 
Pri or a n d c o n c o mit a nt m e di c ati o n  
Pri or m e di c ati o n i s d efi n e d a s m e di c ati o n wit h a st o p d at e b ef or e t h e d at e of t h e fir st 
d o s e of st u d y dr u g.  
C o n c o mit a nt m e di c ati o n i s d efi n e d a s m e di c ati o n wit h at l e a st o n e d o s e t a k e n 
b et w e e n t h e d at e of fir st d o s e (i n cl u si v e) a n d t h e d at e of l a st d o s e (i n cl u si v e) of 
st u d y dr u g.  
 
 
 
H a n dli n g of Mi s si n g S af e t y D a t a  
 
If a p ati e nt’ s birt h d at e i s a p arti al d at e wit h m o nt h a n d y e ar a v ail a bl e, t h e 1 5 t h of t h e 
m o nt h will b e u s e d t o c al c ul at e t h e a g e. If a p ati e nt’ s birt h d at e i s a p arti al d at e wit h 
o nl y y e ar a v ail a bl e, t h e J ul y 1 st will b e u s e d t o c al c ul at e t h e a g e.  
 
W h e n d efi ni n g tr e at m e nt e m er g e nt a d v er s e e v e nt, if t h e a d v er s e e v e nt o n s et d at e i s 
mi s si n g  i n d a y, t h e l a st d at e of t h e m o nt h will b e u s e d. T h er ef or e, a n y a d v er s e e v e nt 
wit h o n s et i n t h e s a m e m o nt h of t h e fir st d o s e, i s c o n si d er e d a s tr e at m e nt e m er g e nt. 
If t h e a d v er s e e v e nt o n s et d at e i s mi s si n g i n b ot h d a y a n d m o nt h, t h e l a st d at e of 
t h e y e ar will b e  u s e d.  
 
F or a n y c o n c o mit a nt m e di c ati o n, if t h e fir st u s e d at e i s pri or t o t h e fir st d o s e of st u d y 
m e di c ati o n, t h e n t h e m e di c ati o n i s d efi n e d a s pri or m e di c ati o n. If t h e fir st u s e of 
c o n c o mit a nt m e di c ati o n i s mi s si n g i n d a y, t h e l a st d at e of t h e m o nt h will b e u s e d.  
T h er ef or e, a n y c o n c o mit a nt m e di c ati o n wit h fir st u s e i n t h e s a m e m o nt h of t h e fir st 
d o s e, i s c o n si d er e d a s t h e c o n c o mit a nt m e di c ati o n. If t h e fir st u s e d at e of  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 2  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
c o n c o mit a nt m e di c ati o n i s mi s si n g i n b ot h d a y a n d m o nt h, t h e l a st d at e of t h e y e ar 
will b e u s e d.  
 
Mi s si n g r el ati o n s hi p t o st u d y m e di c ati o n of a n y a d v er s e e v e nt, if t h e a d v er s e e v e nt 
o n s et d at e i s aft er t h e fir st d o s e of st u d y m e di c ati o n, t h e r el ati o n s hi p will b e 
c o n si d er e d a s pr o b a bl y r el at e d.  
 
 
5  
S t a ti s ti c al  M e t h o d s  
 
D efi ni ti o n of D a t e s / D a y s  
 
D e ri vi n g S t u d y D a y  
 
•  
D at e of fir st d o s e will b e u s e d i n all P art A  a n al y si s  
•  
D at e of r a n d o mi z ati o n will b e u s e d i n all P art B effi c a c y a n al y si s i n 
di s p o siti o n s, E C O G a n d effi c a c y r el at e d e n d p oi nt s t o e n s ur e t h e  c o n si st e n c y 
wit h t h e effi c a c y  a n al y si s.  
•
D at e of fir st d o s e will b e u s e d i n all P art B s af et y a n al y si s i n E x p o s ur e, 
A d v er s e  E v e nt s, L a b or at or y E v al u ati o n s, Vit al Si g n s, E C G, a n d P h y si c al 
e x a mi n ati o n  fi n di n g s 
 
G e n e r al C o n si d e r a ti o n  
 
F or c o nti n u o u s v ari a bl e s, d e s cri pti v e st ati sti c s will i n cl u d e t h e n u m b er of p ati e nt s 
( n ), m e a n, st a n d ar d d e vi ati o n, m e di a n, mi ni m u m a n d m a xi m u m. I n a d diti o n, f or 
c o nti n u o u s P K p ar a m et er s, t h e c o effi ci e nt of v ari ati o n will b e c al c ul at e d a n d f or  C m a x 
a n d A U C t h e g e o m etri c m e a n will al s o b e c al c ul at e d. Fr e q u e n ci e s a n d p er c e nt a g e s 
will b e di s pl a y e d f or c at e g ori c al d at a. P er c e nt a g e s b y c at e g ori e s will b e b a s e d o n t h e 
n u m b er of p ati e nt s wit h n o mi s si n g d at a, i. e. will a d d u p t o  1 0 0 %.  
All st ati sti c al c o m p ari s o n s will b e m a d e u si n g t w o si d e d t e st s at t h e al p h a = 0. 0 5 
si g nifi c a n c e l e v el u nl e s s s p e cifi c all y st at e d ot h er wi s e. All n ull h y p ot h e s e s will b e of 
n o tr e at m e nt diff er e n c e. All alt er n ati v e h y p ot h e s e s will b e t w o - si d e d u nl e s s 
s p e cifi c all y st at e d ot h er wi s e.  
All d at a pr o c e s si n g, s u m m ari z ati o n, a n d a n al y s e s will b e p erf or m e d u si n g S A S 
V er si o n 9. 4 or hi g h er. S p e cifi c ati o n s f or t a bl e, gr a p h s, a n d d at a li sti n g f or m at s c a n 
b e f o u n d i n t h e T L G s p e cifi c ati o n s f or t hi s st u d y.  
 
S t u d y P o p ul a ti o n  
 
Di s p o si ti o n of P a ti e n t s  
T h e f oll o wi n g p ati e nt d at a will b e s u m m ari z e d a n d pr e s e nt e d f or P art A, a n d e a c h 
tr e at m e nt gr o u p i n P art B : 
•  
N u m b er a n d p er c e nt a g e of p ati e nt s r a n d o mi z e d, a n d r a n d o mi z e d b ut  w er e 
n ot tr e at e d, b y tr e at m e nt gr o u p a n d  o v er all ;  
•  
N u m b er a n d p er c e nt a g e of p ati e nt s i n e a c h a n al y si s s et, b y tr e at m e nt  gr o u p, 
a n d  o v er all ;  
•  
N u m b er a n d p er c e nt a g e of p ati e nt s i n e a c h str at u m, b y tr e at m e nt gr o u p a n d 
o v er all f or t h e F A S, a n d S af et y  P o p ul ati o n ;  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 3  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
•  
N u m b er a n d p er c e nt a g e of p ati e nt s w h o pr e m at ur el y di s c o nti n u e d fr o m 
i n v e sti g ati o n al p eri o d, b y r e a s o n f or di s c o nti n u ati o n a n d b y tr e at m e nt gr o u p. 
R e a s o n s f or st u d y tr e at m e nt di s c o nti n u ati o n will b e s u m m ari z e d b y t h e 
f oll o wi n g c at e g ori e s : di s e a s e pr o gr e s si o n b a s e d o n R E CI S T v er si o n 1. 1, 
a d v er s e e v e nt ( A E ), m e di c al or et hi c al r e a s o n s, i n cl u di n g n o n - c o m pli a n c e, 
f oll o wi n g di s c u s si o n b et w e e n t h e i n v e sti g at or a n d s p o n s or, a n d s u bj e ct 
r e q u e st ( e x cl u di n g A E s ).  
P r o t o c ol Vi ol a ti o n s  
T h e n u m b er of pr ot o c ol d e vi ati o n s/ u n e v al u a bl e crit eri a a n d t h e n u m b er of p ati e nt s 
wit h at l e a st o n e pr ot o c ol d e vi ati o n or u n e v al u a bl e s u bj e ct s will b e s u m m ari z e d b y 
e a c h tr e at m e nt gr o u p a n d o v er all f or t h e F A S. T h e pr ot o c ol d e vi ati o n / u n e v al u a bl e 
crit eri a t y p e s will al s o b e s u m m ari z e d, w hi c h m a y i n cl u d e a n y of t h e f oll o wi n g : N ot 
D o n e, O ut si d e of Wi n d o w, E x cl u d e d Pri or T h er a p y, E x cl u d e d C o n c o mit a nt M e di c ati o n, 
V al u e O ut of R a n g e, S a m e M et h o d N ot U s e d, I n c orr e ct D o s e L e v el, D o s e N ot H el d, 
D o s e N ot R e d u c e d, I n c orr e ct Dr u g Di s p e n s e d, I n c orr e ctl y Str atifi e d, a n d Ot h er.  
M aj or pr ot o c ol vi ol ati o n s / u n e v al u a bl e crit eri a a s d efi n e d i n s e cti o n 2. 4 will al s o b e 
s u m m ari z e d b y vi ol ati o n t y p e/ u n e v al u a bl e crit eri o n a n d tr e at m e nt gr o u p f or t h e F A S.  
 
D e m o g r a p hi c a n d O t h e r B a s eli n e C h a r a c t e ri s ti c s  
 
 
D e m o gr a p hi c a n d ot h er b a s eli n e c h ar a ct eri st i c s will b e s u m m ari z e d b y d e s cri pti v e 
st ati sti c s f or e a c h tr e at m e nt gr o u p a n d o v er all f or t h e P K A S f or P art A, a n d f or F A S 
e a c h tr e at m e nt gr o u p i n P art B :  
D e s cri pti v e st ati sti c s f or a g e, w ei g ht, h ei g ht a n d Ti m e fr o m i niti al di a g n o si s at st u d y 
e ntr y will b e  pr e s e nt e d. A g e will b e c al c ul at e d a s t h e i nt e g er p art of ( D at e of 
R a n d o mi z ati o n – D at e of Birt h + 1 ) / 3 6 5. 2 5. A g e will al s o b e c at e g ori z e d u si n g t h e 
c at e g ori e s < 6 5 a n d ≥ 6 5 a n d will b e pr e s e nt e d u si n g fr e q u e n ci e s a n d p er c e nt a g e s. 
Fr e q u e n c y t a b ul ati o n s f or  r a c e a n d Ci g ar ett e S m o ki n g Hi st or y will b e pr e s e nt e d.  
 
Fr e q u e n c y t a b ul ati o n f or t h e r a n d o mi z ati o n str atifi c ati o n f a ct or will al s o b e 
pr e s e nt e d. T h e f a ct or s ar e:  
•  
vi s c er al di s e a s e st at u s ( pr e s e nt or  a b s e nt )  
•  
pri or c h e m ot h er a p y i n t h e h or m o n e - s e n siti v e s etti n g w h e n c o m m e n ci n g  A D T 
( y e s or  n o).  
 
 
 
C o n c o mi t a n t M e di c a ti o n  
Pr e vi o u s m e di c ati o n s ar e c o d e d wit h W H O Dr u g, V er si o n M ar c h 2 0 1 5 a n d will b e 
s u m m ari z e d b y t h er a p e uti c c at e g or y, A T C cl a s s ( 4t h l e v el, c h e mi c al s u b gr o u p ) a n d 
c o d e d t er m b y tr e at m e nt gr o u p f or t h e S A F.  
All m e di c ati o n s r e c ei v e d d uri n g t h e tr e at m e nt p eri o d (i. e. o v erl a p pi n g wit h t h e 
a d mi ni str ati o n of st u d y m e di c ati o n i n cl u di n g e n z al ut a mi d e) ot h er t h a n st u d y dr u g 
will b e c o n si d er e d c o n c o mit a nt m e di c ati o n s. A s wit h pr e vi o u s m e di c ati o n, 
c o n c o mit a nt m e di c ati o n will b e s u m m ari z e d f or e a c h tr e at m e nt gr o u p b y A T C cl a s s 
(l e v el 2 a n d 4 ) a n d W H O - D R L r ef er e n c e f or t h e S A F. P ati e nt s t a ki n g t h e s a m e 
m e di c ati o n m ulti pl e ti m e s will b e c o u nt e d o n c e p er m e di c ati o n a n d i n v e sti g ati o n al 
p eri o d. P ati e nt s w h o r e c ei v e d c o n c o mit a nt m e di c ati o n s will b e li st e d a s w ell.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 4  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
Effi c a c y A n al y si s  
 
A n al y si s of P ri m a r y V a ri a bl e  
 
I n or d er t o c o m p ar e t h e Pr o gr e s si o n Fr e e S ur vi v al ( P F S ) di stri b uti o n b et w e e n a n y of 
t h e 2 ar m s, t h e n ull h y p ot h e si s will b e c o n str u ct e d : 
 
H 0 : D ur ati o n of P F S i s e q u al b et w e e n L Y 3 0 2 3 4 1 4 a n d Pl a c e b o 
T h e a c c o m p a n yi n g alt er n ati v e h y p ot h e si s i s:  
H 1 : D ur ati o n of  P F S i s pr ol o n g e d i n L Y 3 0 2 3 4 1 4  
 
T h e o n e - si d e d p - v al u e s f or t h e a b o v e h y p ot h e si s t e st s will b e c al c ul at e d u si n g a n 
u n str atifi e d l o g - r a n k t e st. 
 
T h e h a z ar d r ati o of t h e tr e at m e nt eff e ct al o n g wit h 2 - si d e d, 6 0 %, 8 0 % a n d 9 5 % 
c o nfi d e n c e i nt er v al s will b e c al c ul at e d u si n g a C o x pr o p orti o n al h a z ar d m o d el.  
 
K a pl a n - M ei er s ur vi v al pl ot s will b e u s e d t o d e s cri b e t h e P F S i n e a c h tr e at m e nt ar m. 
M e di a n P F S a n d 6 0 %, 8 0 %, a n d 9 5 % c o nfi d e n c e i nt er v al s will b e e sti m at e d fr o m t h e 
K a pl a n - M ei er c ur v e.  
 
T h e s e c o n d ar y a n al y s e s of  pri m ar y effi c a c y v ari a bl e i n cl u d e:  
 
S e n siti vit y A n al y si s : A str atifi e d l o g - r a n k t e st b a s e d o n t h e str atifi c ati o n f a ct or s at 
r a n d o mi z ati o n will b e p erf or m e d if t h e d at a wit hi n e a c h str at u m i s s uffi ci e nt t o 
s u p p ort a str atifi e d a n al y si s. A C o x pr o p orti o n al h a z ar d m o d el str atifi e d b y t h e 
str atifi c ati o n f a ct or s at r a n d o mi z ati o n will al s o b e u s e d t o e sti m at e h a z ar d r ati o a n d 
t o cr e at e 6 0 %, 8 0 % a n d 9 5 % c o nfi d e n c e i nt er v al s f or t h e h a z ar d r ati o.  
S t r a tifi c a ti o n v a ri a bl e s will i n cl u d e: a, vi s c er al di s e a s e st at u s ( p r e s e nt or a b s e nt ) 
b, pri or c h e m ot h er a p y i n t h e h or m o n e - s e n siti v e s etti n g w h e n c o m m e n ci n g A D T ( y e s 
or n o).  
T h e pri m ar y v ari a bl e ( P F S b a s e d o n P C W G) of e a c h tr e at m e nt ar m c o m p ari s o n s will 
b e a n al y z e d a s d e s cri b e d a b o v e a n d t h e y will al s o b e di s pl a y e d i n t h e fi g ur e.  
T h e m e di a n of P F S ti m e, t h e p - v al u e of L o g - R a n k T e st, t h e h a z ar d r ati o a n d it s 8 0 % 
CI a n d n u m b er o f p ati e nt s at ri s k at e a c h ti m e p oi nt will b e di s pl a y e d i n t h e fi g ur e. 
T h e d eri v e d e n d p oi nt s f or t h e s e n siti vit y a n al y si s of t h e pri m ar y e n d p oi nt, s u c h a s, 
R a di ol o gi c al Pr o gr e s si o n - fr e e s ur vi v al (r P F S ) a n d Pr o gr e s si o n Fr e e S ur vi v al d efi n e d 
b y b ot h r a di ol o gi c al pr o gr e s si o n a n d s y m pt o m ati c di s e a s e pr o gr e s si o n d efi n e d b y 
P C W G 2, will b e a n al y s e d i n t h e s a m e m a n n er a s t h e pri m ar y effi c a c y e n d p oi nt.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 5  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
 
 
A n al y si s of S e c o n d a r y Effi c a c y V a ri a bl e s  
 
All s e c o n d ar y e n d p oi nt s will b e a n al y z e d i n t h e s a m e w a y a s t h e pri m ar y a n al y si s b y 
t h e s a m e t h e c ut- off d at e.  
r P F S, P F S b a s e d o n s y m pt o m ati c pr o gr e s si o n, P F S b a s e d o n P S A pr o gr e s si o n, P F S 
b a s e d o n R E CI S T crit eri a, ti m e t o Pr o gr e s si o n e n d p oi nt s, a n d O v er al l S ur vi v al will b e 
a n al y z e d i n t h e s a m e m a n n er a s t h o s e f or t h e pri m ar y effi c a c y v ari a bl e i n cl u di n g t h e 
gr a p hi c s, t h e u n str atifi e d a n al y si s a n d t h e str atifi e d s e n siti vit y a n al y si s b a s e d o n t h e 
str atifi c ati o n f a ct or s at r a n d o mi z ati o n. D u e t o t h e st u d y d e si g n, o n c e a p ati e nt 
e x p eri e n c e s P C W G 2 pr o gr e s si o n, t h e p ati e nt will b e di s c o nti n u e d fr o m t h e st u d y. T h e 
p ati e nt l o st - t o- f oll o w- u p p att er n c a n b e tr e at m e nt r el at e d, h e n c e a b o v e a n al y s e s ar e 
o nl y f or r ef er e n c e.  
R e s p o n s e r at e v ari a bl e s ( P S A R e s p o n s e, D C R, E P R a n d O R R ) will b e s u m m ari z e d f or 
e a c h tr e at m e nt gr o u p. T h e r e s p o n s e r at e al o n g wit h e x a ct 6 0 %, 8 0 % a n d 9 5 % 
c o nfi d e n c e i nt er v al s ( Cl o p p er - P e ar s o n ) will b e c al c ul at e d f or e a c h tr e at m e nt ar m.  
P er c e nt C h a n g e fr o m B a s eli n e i n P S A l e v el s will al s o b e s u m m ari z e d b y  e a c h 
tr e at m e nt gr o u p o v er ti m e. T h e m a xi m u m p er c e nt c h a n g e fr o m b a s eli n e aft er W e e k 
1 2 will b e s u m m ari z e d u si n g w at erf all pl ot s f or e a c h tr e at m e nt ar m. N o st ati sti c al 
t e sti n g will b e c o n d u ct e d. 
C at e g ori c al of c h a n g e i n E C O G will b e s u m m ari z e d b y s hift t a b l e. 
S u b g r o u p A n al y si s  
 
Pri m ar y a n al y s e s will b e c o n d u ct e d f or p ati e nt s u b gr o u p s a s d efi n e d b y t h e 
str atifi c ati o n f a ct or s a n d ot h er p ati e nt c h ar a ct eri sti c s. A C o x pr o p orti o n al h a z ar d 
m o d el will b e u s e d t o e sti m at e h a z ar d r ati o a n d t o cr e at e 6 0 %, 8 0 % a n d 9 5 % 
c o nfi d e n c e i nt er v al s f or t h e h a z ar d r ati o i n e a c h s u b gr o u p.  
 
 
A n al y si s of O t h e r V a ri a bl e s  
 
 
E x pl or at or y a n al y si s will b e c o n d u ct e d f or k e y effi c a c y e n d p oi nt s i n s u b gr o u p s i n 
a d diti o n t o t h e str atifi c ati o n f a ct or s or p ati e nt b a s eli n e c h ar a ct eri sti c s. V ari a bl e s t h at 
m a y b e c o n si d er e d i n cl u d e, b ut ar e n ot li mit e d t o a g e, di s e a s e hi st or y, a n d pr e vi o u s 
tr e at m e nt hi st or y. B ot h u ni v ari at e a n d m ulti v ari at e a n al y si s b y t h e C o x pr o p orti o n al 
h a z ar d m o d el will b e u s e d t o e x a mi n e t h e a s s o ci ati o n b et w e e n t h e k e y effi c a c y 
e n d p oi nt a n d pr o g n o s ti c s f a ct or. T h e l o gi sti c r e gr e s si o n a n al y si s m a y b e p erf or m e d 
t o e x a mi n e t h e a s s o ci ati o n b et w e e n t h e str atifi c ati o n f a ct or s, b a s eli n e v ari a bl e s a n d 
r e s p o n s e r at e s. All e x pl or at or y or p o st h o c a n al y s e s will b e i d e ntifi e d i n t h e 
a p pr o a pri at e s e cti o n s of t h e  cli ni c al st u d y r e p ort.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 6  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
S af e t y A n al y si s  
 
T h e pri m ar y a n al y si s p o p ul ati o n f or s af et y i s t h e s af et y p o p ul ati o n.  
 
All P art A S A F p ati e nt s will b e s u m m ari z e d f or s af et y a n al y si s a n d b a s eli n e 
c h ar a ct eri sti c s.  
All s af et y a n al y s e s will b e p erf or m e d o n t h e S A F, a n d all s af et y d at a will b e 
pr e s e nt e d b y c o h ort or tr e at m e nt gr o u p f or e a c h st u d y p eri o d.  
Tr e at m e nt - e m er g e nt a d v er s e e v e nt s ( T E A E s) ar e d efi n e d a s a d v er s e e v e nt s t h at 
b e gi n or w or s e n i n s e v erit y o n or aft er t h e d at e of t h e fir st d o s e of st u d y dr u g a n d 
wit hi n 3 0 d a y s of t h e d at e of t h e l a st d o s e of st u d y dr u g.  If d at e of l a st d o s e of 
st u d y dr u g i s mi s si n g b ut fir st d o s e d at e i s n o n - mi s si n g, A E s t h at b e gi n aft er t h e fir st 
d o s e of st u d y dr u g will b e c o n si d er e d a s T E A E s.  
 
A d v e r s e E v e n t s  
 
T h e c o di n g di cti o n ar y f or t hi s st u d y will b e M e d D R A V er si o n 1 8. 0 or hi g h er. It will b e 
u s e d t o s u m m ari z e A E s b y s y st e m or g a n cl a s s ( S O C ) a n d / or pr ef err e d t er m ( P T ).  
T o xi cit y gr a d e i s d efi n e d a c c or di n g t o t h e v er si o n 4. 0 3 or l at er of t h e N at i o n al C a n c er 
I n stit ut e C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s ( C T C A E ).  
T h e n u m b er a n d p er c e nt a g e of p ati e nt s wit h T E A E s, a s cl a s sifi e d b y S O C a n d P T, will 
b e s u m m ari z e d f or e a c h tr e at m e nt gr o u p. Si mil ar s u m m ari e s will al s o b e pr o vi d e d 
f or dr u g r el at e d T E A E s, tr e at m e nt- e m er g e nt S A E s, dr u g r el at e d s eri o u s T E A E s a n d 
T E A E s t h at l e a d t o st u d y dr u g di s c o nti n u ati o n or d e at h. T h e T E A E l e a di n g t o d e at h i s 
d efi n e d b y t h e C T C A E gr a d e = 5. A dr u g - r el at e d T E A E i s d efi n e d a s a n y T E A E r el at e d 
t o st u d y m e di c ati o n a s a s s e s s e d b y t h e i n v e sti g at or, or wit h mi s si n g a s s e s s m e nt of 
t h e c a u s alit y r el ati o n s hi p. 
T E A E s will al s o b e s u m m ari z e d b y s e v erit y i n C T C A E gr a d e. If a n a d v er s e e v e nt 
c h a n g e s i n s e v erit y, t h e n t h e a d v er s e e v e nt will b e c o u nt e d o nl y o n c e wit h t h e w or st 
s e v er it y. If C T C A E gr a d e i s mi s si n g, t h e a d v er s e e v e nt will b e s u m m ari z e d a s Gr a d e 
“ 3 ”.  
All A E s a n d S A E s o c c urri n g t hr o u g h o ut t h e c o n d u ct of t h e st u d y, i n cl u di n g all - c a u s e 
d e at h s, will b e s u m m ari z e d i n li sti n g s. Tr e at m e nt - e m er g e nt S A E s will b e 
s u m m ari z e d b y M e d D R A S O C a n d P T.  
 
 
T a bl e s will i n cl u d e t h e f oll o wi n g d et ail s:  
•  
N u m b er a n d p er c e nt a g e of p ati e nt s wit h  T E A E s  
•  
N u m b er a n d p er c e nt a g e of p ati e nt s wit h dr u g r el at e d  T E A E s  
•  
N u m b er a n d p er c e nt a g e of p ati e nt s wit h tr e at m e nt - e m er g e nt  S A E s  
•  
N u m b er a n d p er c e nt a g e of p ati e nt s wit h dr u g r el at e d tr e at m e nt - e m er g e nt  S A E s  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 7  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
•  
N u m b er a n d p er c e nt a g e of p ati e nt s wit h T E A E s b y m a xi m u m C T C A E  gr a d e  
•  
N u m b er of T E A E s l e a di n g t o p er m a n e nt di s c o nti n u ati o n of st u d y  dr u g.  
•  
N u m b er of dr u g r el at e d T E A E l e a di n g t o p er m a n e nt di s c o nti n u ati o n of st u d y 
dr u g.  
•  
N u m b er of  d e at h s.  
 
Cli ni c al L a b o r a t o r y E v al u ati o n  
 
 
 
T h e f oll o wi n g cli ni c al l a b or at or y p ar a m et er s will b e s u m m ari z e d :  
•  
H e m at ol o g y – f ull bl o o d c o u nt wit h h e m o gl o bi n, pl at el et s, 3- p art diff er e nti al, 
pr ot hr o m bi n ti m e ( P T ) a n d  I N R. 
•  
Bi o c h e mi str y – bl o o d gl u c o s e, H b A 1 c, el e ctr ol yt e s ( C a, Cl, M g, N a,  p h o s p h at e, 
a n d K ), B U N, cr e ati ni n e, t ot al bilir u bi n, al k ali n e p h o s p h at a s e, A S T, A L T, L D H, 
t ot al pr ot ei n, al b u mi n. 
•  
Uri n e A n al y si s.  
M e a n s, st a n d ar d d e vi ati o n, mi ni m u m, m a xi m u m a n d m e di a n f or n u m eri c r e s ult s will 
b e s u m m ari z e d at e a c h vi sit b y tr e at m e nt gr o u p.  
Bi o c h e mi str y a n d h e m at ol o g y l a b t e st s will b e gr a d e d a c c or di n g t o N CI C T C A E v 4 . 0 3 
or l at er w h er e a p pli c a bl e. S hift fr o m b a s eli n e t o t h e w or st gr a d e o n st u d y b y C T C A E 
gr a d e s will b e pr e s e nt e d. S hift s fr o m b a s eli n e t o w or st v al u e o n st u d y will b e 
pr e s e nt e d f or c at e g ori c al or or di n al l a b p ar a m et er s. I n ci d e n c e of p ati e nt s wit h 
l a b or at ory v al u e s o ut si d e l a b or at or y s u p pli e d n or m al r a n g e will al s o b e pr e s e nt e d.  
Mi cr o s c o pi c uri n al y si s r e s ult s will b e s u m m ari z e d b y c at e g ori c al s a n d will al s o 
pr e s e nt e d i n t h e li sti n g o nl y.  
T h e p ot e nti al f or dr u g - i n d u c e d li v er i nj ur y ( DI LI ) will b e e v al u at e d vi a li v er f u n cti o n 
t e st s a s o utli n e i n t h e F D A g ui d a n c e o n DI LI. S u m m ar y t a bl e s will b e pr e s e nt e d f or 
t h e f oll o wi n g:  
•  
S hift s fr o m b a s eli n e t o m a xi m u m p o st b a s eli n e v al u e a s a f u n cti o n of  t h e 
u p p er li mit of n or m al ( U L N ) a s f oll o w s:  
o  
A S T, A L T a n d eit h er A L T or A S T > = ( 3 x U L N, 5 x U L N, 1 0 x U L N,  2 0 x U L N, 
e x cl u si v el y )  
o  
T ot al bilir u n > = ( 1. 5 x U L N a n d 2 x U L N, e x cl u si v el y )  
o  
A L P > =  1. 5 x U L N.  
•  
T h e i n ci d e n c e of s u bj e ct’ s m e eti n g t h e crit eri a f or H y’ s L a w d efi n e d a s 
el e v ati o n s i n A L T a n d / or A S T of > = 3 x U L N wit h a c c o m p a n yi n g el e v ati o n s  i n 
t ot al bilir u bi n of > = 2 x U L N.  
 
 
 
Vi t al Si g n s  
 
Vit al si g n s a n d c h a n g e fr o m b a s eli n e f or vit al si g n s ( s y st oli c bl o o d pr e s s ur e, di a st oli c 
bl o o d pr e s s ur e, p ul s e r at e, t e m p er at ur e a n d w ei g ht ) will b e s u m m ari z e d u si n g m e a n,  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 8  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
 
st a n d ar d d e vi ati o n, mi ni m u m, m a xi m u m a n d m e di a n b y tr e at m e nt gr o u p a n d vi sit. 
A d diti o n all y, c h a n g e fr o m b a s eli n e at e n d of tr e at m e nt will b e s u m m ari z e d.  
 
 
P h y si c al E x a mi n a ti o n Fi n di n g s  
 
P h y si c al e x a mi n ati o n fi n di n g s will b e pr o vi d e d i n a li sti n g.  
 
 
El e c t r o c a r di o g r a m s ( E C G s )  
 
 
 
N u m b er a n d p er c e nt of s u bj e ct s wit h n or m al, n ot cli ni c all y si g nifi c a nt a b n or m al, a n d 
cli ni c all y si g nifi c a nt a b n or m al r e s ult s f or t h e 1 2 l e a d E C G will b e t a b ul at e d b y 
tr e at m e nt gr o u p at e a c h tr e at m e nt vi sit. A 2 x 3 s hift t a bl e s h o wi n g i n v e sti g at or’ s 
a s s e s s m e nt of c h a n g e s i n n or m al, a b n or m al, a n d a b n or m al a n d cli ni c all y si g nifi c a nt 
r e s ult s d uri n g t h e st u d y will b e di s pl a y e d. A b n or m al a n d cli ni c all y si g nifi c a nt r e s ult s 
will b e d o c u m e nt e d a s A E s.  
 
 
 
E x p o s u r e  
P ati e nt s will b e r a n d o mi z e d i n a 1 : 1 r ati o t o e n z al ut a mi d e 1 6 0 m g or all y Q D i n 
c o m bi n ati o n wit h L Y 3 0 2 3 4 1 4 2 0 0 m g or m at c hi n g pl a c e b o or all y BI D i n P art B.  
 
E x t e n t of E x p o s u r e  
D ur ati o n of e x p o s ur e of b ot h L Y 3 0 2 3 4 1 4 a n d e n z al ut a mi d e will b e s u m m ari z e d i n 
t w o w a y s. 
D e s cri pti v e st ati sti c s will b e pr e s e nt e d f or d ur ati o n of e x p o s ur e i n m o nt h s b y 
tr e at m e nt gr o u p f or t h e S A F. 
E x p o s ur e ti m e will b e c at e g ori z e d a c c or di n g t o t h e f oll o wi n g c at e g ori e s b y tr e at m e nt 
gr o u p :  
o  
< = 1 C y cl e  c o m pl et e d  
o  
2 C y cl e  c o m pl et e d  
o  
3 C y cl e  c o m pl et e d  
o  
4 C y cl e  c o m pl et e d  
o  
Et c  
C o u nt s a n d p er c e nt a g e s of s u bj e ct s i n e a c h of t h e s e c at e g ori e s will b e s u m m ari z e d 
f or e a c h tr e at m e nt gr o u p f or t h e S A F. 
 
T r e a t m e n t C o m pli a n c e  
O v er all c o m pli a n c e wit h t h e d o si n g s c h e d ul e will b e e x a mi n e d f or s u bj e ct s i n t h e S A F 
w h o s e t ot al st u d y dr u g c o u nt a n d fir st a n d l a st d a y s of tr e at m e nt ar e k n o w n.  
D e s cri pti v e st ati sti c s will b e pr e s e nt e d b y tr e at m e nt gr o u p f or c u m ul ati v e d o s e, 
d ur ati o n of e x p o s ur e, d o s e i nt e n sit y a n d r el ati v e d o s e i nt e n sit y.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 2 9  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
 
T r e a t m e n t M o difi c a ti o n s  
Tr e at m e nt m o difi c ati o n s will b e s u m m ari z e d b y e a c h tr e at m e nt gr o u p a n d o v er all  f or 
t h e S A F. T h e n u m b er of s u bj e ct s wit h d o s e i nt err u pti o n s a n d / or d o s e r e d u cti o n s will 
b e s u m m ari z e d b y tr e at m e nt gr o u p s u si n g fr e q u e n c y c o u nt s a n d  p er c e nt a g e s.  
 
 
P ri o r / C o n c u r r e n t M e di c a ti o n s a n d C o n c o mi t a n t M e di c a ti o n s  
 
All m e di c ati o n s will b e c o d e d u si n g t h e W H O Dr u g Di cti o n ar y < M ar. 2 0 1 5 >. T h e 
n u m b er of p ati e nt s r e c ei vi n g e a c h cl a s s of c o n c o mit a nt m e di c ati o n will b e 
s u m m ari z e d b y tr e at m e nt gr o u p b y A T C l e v el s a n d pr ef err e d t er m. M e di c ati o n s 
st o p p e d pri or t o i niti ati o n of st u d y dr u g a n d / or st art e d aft er di s c o nti n u ati o n of st u d y 
dr u g will b e s u m m ari z e d i n li sti n g s.  
 
P h a r m a c o ki n e ti c A n al y si s r e s p o n si bili t y of Lill y P K P D g r o u p  
 
P h ar m a c o ki n eti c A n al y si s wi ll b e p erf or m e d u n d er a s e p ar at e S A P writt e n b y Lill y P K 
s ci e nti st.  
 
 
 
P h a r m a c o d y n a mi c A n al y s e s  
 
N ot A p pli c a bl e.  
 
 
Q u ali t y of Lif e A n al y s e s  
 
N ot A p pli c a bl e.  
 
 
P h a r m a c o e c o n o mi c s A n al y s e s  
 
N ot A p pli c a bl e.  
 
5. 1 1 P h a r m a c o g e n e ti c s A n al y s e s  
 
T h e bi o m ar k er a n al y si s will b e p erf or m e d u n d er a s e p ar at e S A P writt e n b y Lill y t e a m.  
Pr e di cti v e bi o m ar k er s will b e s o u g ht b y i n cl u di n g t h e m, a n d t h eir i nt er a cti o n s wit h 
t h e Tr e at m e nt s, i n t h e effi c a c y m o d el s d e s cri b e d a b o v e,  a n d e x a mi n g t h eir i m p a ct o n 
t h e m o d el s’ fit. Bi o m ar k er s will i n cl u d e m ut ati o n s a n d a m plifi c ati o n s of 
PI 3 K / A K T / m T O R r el at e d g e n e s fr o m t ar g et e d e x o m e s e q u e n ci n g of ti s s u e a n d bl o o d 
s a m pl e s. F urt h er e x pl or at or y bi o m ar k er a n al y si s mi g ht b e d o n e if c o n si d er e d  of 
i nt er e st b y t h e s p o n s or. 
 
6
R ef e r e n c e s
 
Br o o k m e y er, R. a n d Cr o wl e y, J. ( 1 9 8 2 ) : A C o nfi d e n c e I nt er v al f or t h e M e di a n 
S ur vi v al Ti m e. Bi o m etri c s, 3 8, 2 9 - 4 1.  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 3 0  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
 
S A S I n stit ut e I n c. ( 2 0 0 1 ) : T h e S A S S y st e m, V er si o n 8. 2. C ar y, N C. S A S I n stit ut e 
I n c. 
 
F D A G ui d a n c e f or I n d u str y : Cli ni c al Tri al E n d p oi nt s f or t h e A p pr o v al of C a n c er Dr u g s 
a n d Bi ol o gi c s ( 2 0 0 7 ). U. S. D e p art m e nt of H e alt h a n d H u m a n S er vi c e, F D A. R o c k vill e, 
M D . 
 
P S A - b a s e d tr e at m e nt r e s p o n s e crit eri a i n c a str ati o n - r e si st a nt pr o st at e c a n c er: 
pr o mi s e s a n d li mit ati o n s  
Ur b a n E m m e n e g g er, M D C a n Ur ol A s s o c J. O ct 2 0 0 9 ; 3 ( 5 ) : 3 7 5 – 3 7 6.  
 
St ati sti c al R e vi e w a n d E v al u ati o n of Xt a n di ( e n z al ut a mi d e) o n M et a st ati c C a str ati o n - 
r e si st a nt pr o st at e c a n c er i n p ati e nt s h a v e h a v e pr e vi o u sl y r e c ei v e d d o c et a x el.  
C D E R, F D A M a y 2 1, 2 0 1 2  
 
 
 
7  
A p p e n di c e s  
 
A p p e n di x 1: S c h e d ul e of A s s e s s m e n t s  


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 3 1  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
 


[ G U 1 1 5/ 1 6 A -M C -C B B D]  
St atistic al A n al ysis  Pl a n  
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 3 2  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
 
 
 
 
 
 
a 
T he  p h ysical  e x a mi n ati o n,  me dical  hist or y,  c o n c o mita nt me dicati o ns  rec or d e d ≤3 0 d a ys  pri or  t o st u d y e ntr y, E C O G  P S,  C B C i ncl u di n g differe ntial  a n d  platelets,  C M P,  uri nal ysis,  a n d 
P T/I N R s h o ul d b e d o n e ≤7 d a ys pri or t o i nitiati o n of treat me nt. H o we v er, if t h ese i nitial e x a mi n ati o ns are o btai n e d wit hi n 7 2  h o urs pri or t o t he i nitiati o n of treat me nt t h e y d o n ot ha ve t o be 
re peate d. Sca ns t o d o c u me nt e v al u a ble disease (i.e., t u m or meas ure me nt), 1 2-lea d E C G, a n d P S A s h o ul d b e p erf or me d ≤4 wee ks pri or t o i nitiati o n of treat me nt. 
b  
P h ysical e xa mi n ati o n will i n cl u d e meas ure me nts of h ei g ht a n d wei g ht at t h e b as eli n e visit. P h ysical e x a mi n ati o ns ( P E) d o ne at all ot her ti mes d uri n g t he st u d y will i ncl u de o nl y  wei g ht.  
O nl y Part B patie nts will n ee d a p h ysical e x a m o n C y cle 1 Da y 1.  
c 
Vital si g ns i ncl u d e resti n g h eart rate, bl o o d press ure, oral  te m p erat ure 
d  
E C G perf or m e d l o call y at b aseli ne, pre d ose o n C y cles 1 -4, a n d at t h e E n d of Treat me nt visit. Re p eat if cli nicall y  i n dicate d. 
e 
Fasti n g C M P will i n cl u d e meas ure me nts of gl u c ose, B U N, creati ni n e, s o di u m, p otassi u m, c hl ori d e, calci u m, C O 2, A L P, A S T, A L T, t otal bilir u bi n, t otal pr otei n, al b u mi n, p h os p h or us, a n d 
L D H.  
f 
P T/I N R will o nl y n ee d t o b e re p eate d if a b n or mal at b aseli n e or if cli nicall y i n dicate d.  Patie nts re q uiri n g t h e i nitiati o n of a n a nti -c oa g ulati o n t hera p y d uri n g st u d y treat me nt s h o ul d ha ve 
t heir c oa g ulati o n test p erf or me d o n a wee kl y b asis.  
g  
Bi o mar ker  bl o o d sa m ples  will  b e  ta k e n at b aseli n e  a n d  pre-d ose  o n  Da y  1 of  C y cles  1, a n d 3  a n d e v er y  2 c y cles t h ereafter, a n d  at t he E n d  of  Treat me nt visit.  
h 
H b A 1c bl o o d sa m ple will b e ta k e n at b aseli n e, C y cle 3 a n d e v er y 2 c y cles t h ereafter, a n d at t h e E n d of Treat me nt  visit.  


[ G U 1 1 5/ 1 6 A-M C -C B B D]  
 
 
 
 
St atistic al A n al ysis Pl a n  
 
 
 
Sc he d ule of Assess m e nts (c o nti n ue d)  
i 
P K bl o o d sa m ples will h a v e a wi n d o w of ± 1 5 mi n utes. P K bl o o d sa m ples f or p atie nts w h o are p artici p ati n g i n Part A will be D a y - 1, pre-d ose, 1. 5, 3, a n d 6 h o urs p ost L Y 3 0 2 3 4 1 4 
d ose; C y cle 1 D a y 1 pre- d ose of L Y 3 0 2 3 4 1 4 a n d e n zal uta mi d e; C y cle 1 D a y X - a n y d a y b et wee n Da y 1 5 a n d Da y 2 8, pre -d ose of L Y 3 0 2 3 4 1 4 a n d e nzal uta mi de, 1. 5, 3, a n d 6 h o urs 
p ost L Y 3 0 2 3 4 1 4 d ose; a n d C y cle 1 D a y X + 1 - b et wee n Da y 1 6 a n d Da y 2 9, pre -d ose of L Y 3 0 2 3 4 1 4 a n d e n zal uta mi de. P K bl o o d sa m ples f or all patie nts will be ta ke n pre -d o se of 
L Y 3 0 2 3 4 1 4/ place b o a n d e n zal uta mi d e a n d 1. 5 h o urs p ost L Y 3 0 2 3 4 1 4/ place b o d ose o n C y cle 2 Da y 1 a n d C y cle 3 Da y 1  . 
j 
O n P K d a ys, pre -d ose meas ure me nts a n d d ose a d mi nistrati o n will be d o n e i n a faste d state. Patie nts s h o ul d re mai n faste d f or 1 h o ur p ost - d ose.  
k  
Patie nts will b e resta g e d pri or t o C y cle 3 a n d after e v er y 2 c y cles of treat me nt t h ereafter (e v er y 8 wee ks). Patie nts wit h pr o gressi ve disease or u nacce pta ble t o xicit y s h o ul d be 
disc o nti n u e d fr o m treat me nt; p atie nts wit h sta ble disease or res p o nse t o t h era p y will c o nti n u e  treat me nt. 
l 
P S A bl o o d sa m ples will b e ta k e n ≤4 wee ks pri or t o i nitiati o n of treat me nt, o n Wee k -1 Da y -7 f or Part A p atie nts, C ycle 1 Da y 1 ( u nless c ollecte d wit hi n t he pre vi o us 7 2 h o urs) Da y 1 
of e ver y c y cle, a n d at t h e E n d of St u d y  visit if n ot ta k e n i n t h e pre vi o us 4 wee ks. Patie nts wit h P S A pr o gressi o n are all o we d a n d e nc o ura ge d t o c o nti n ue treat me nt u n til s y m pt o matic or 
ra di o gra p hic pr o gressi o n.  
m  
B o ne sca ns - tec h n eti u m o nl y - ≤4 wee ks pri or t o i nitiati o n of treat me nt, pri or t o C y c le 3 a n d after e v er y 2 c y cle s of treat me nt t hereafter, a n d at t he E n d of St u d y visit if sca ns were n ot 
ta ke n i n t h e pre vi o us 8 wee ks. B o n e lesi o ns s h o ul d b e e v al u ate d usi n g P C W G 2 criteria a n d n ot R E CI S T v 1. 1.  
n  
C T sca ns of t h e c h est, a b d o me n a n d p el vis ≤4 wee ks pri or t o i nitiati o n of treat me nt. C T sca n of t h e c h est s h o ul d be re peate d o nl y if a b n or mal at baseli ne. C T sca ns of t he a b d o me n a n d 
pel vis s h o ul d b e ta k e n pri or t o C ycle 3 a n d after e v er y 2 c y cles of treat me nt t h ereafter, a n d at t h e E n d of St u d y visit (if sca ns were n ot ta ke n i n t he pre vi o us 8 wee ks). L y m p h n o des 
s h o ul d b e e v al u ate d usi n g P C W G 2 criteria a n d n ot R E CI S T v 1. 1.  
o 
Part A p atie nts d o n ot recei v e a  place b o.  
p  
O nl y Part A p atie nts c o me i n o n C y cle 1  Da y  1 5.  
q  
After p atie nts c o m plete t h era p y or are disc o nti n u e d fr o m treat me nt t h e y will visit t h e st u d y ce nter 3 0 d a ys ( + 3) after fi nis h i n g treat me nt f or e n d of treat me nt assess me nts. Patie nts m ust 
be f oll o we d f or A Es f or 3 0 cale n d ar d a ys after t h e last d ose  of st u d y  dr u g.  
r 
Patie nts w h o disc o nti n u e st u d y treat me nt pri or t o t h e o cc urre n ce of disease pr o gressi o n will b e f oll o we d e v er y 3 m o nt hs ( ± 1 m o nt h) fr o m t he date of last d ose of st u d y dr u g u ntil 
disease pr o gressi o n or f or u p t o 3 y ears w hic h e v er c o mes  first. 
 
 
 
 
 
 
 
 
 
 
 
 
 
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P:  C D S -0 1 0 2  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P  [ A] 
P a g e 3 3 of 3 5 
C o nfi d e nti al  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 3 4  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
A p p e n di x 2: T a bl e s, Fi g u r e s a n d Li s ti n g s S h ell s  
 
A p p e n di x 3: I n - T e xt T a bl e s a n d Fi g u r e s S p e cifi c a ti o n s  


[ G U 1 1 5/ 1 6 A -M C -C B B D]
St atistic al A n al ysis  Pl a n
V ersi o n 2. 0, A pr 1 7 2 0 1 7  
R E F E R E N C E S O P: C DS -0 1 0 2  
P a g e 3 5  of  3 5  
C o nfi d e nti al  
T e m pl at e I D: A SS O C -D O C -1 1 5 -S O P [ A]  
A p p e n di x 4: D e ri v e d V a ri a bl e s a n d D a t a s e t s S p e cifi c a ti o n s