Clinical trial NCT02971761
Conditions: Androgen Receptor Positive Estrogen Receptor Negative HER2/Neu Negative Metastatic Triple-Negative Breast Carcinoma Progesterone Receptor Negative Stage IV Breast Cancer AJCC v6 and v7
Sponsor: City of Hope Medical Center
Start date: 2017-06-01; Completion date: 2022-08-16
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects and how well pembrolizumab and enobosarm work in treating patients with androgen receptor positive triple negative breast cancer that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Androgen can cause the growth of breast cancer cells. Hormone therapy using enobosarm may fight breast cancer by blocking the use of androgen by the tumor cells. Giving pembrolizumab and enobosarm may work better than pembrolizumab alone in treating patients with androgen receptor positive triple negative breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety/tolerability of the combination regimen. II. To determine the response rate (complete response \[CR\] or partial response \[PR\] via Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) of the combination of pembrolizumab with enobosarm (GTx-024) in patients with advanced androgen receptor (AR) positive (+) triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. To evaluate clinical outcomes by RECIST 1.1 including clinical benefit rate (CBR) at 24 weeks, progression free-survival (PFS), duration of response (DOR), event free survival (EFS), time-to-treatment failure (TTF); and overall survival (OS).

II. To evaluate the role of immune-related response criteria (irRECIST). III. To evaluate the association of AR by immunohistochemistry (IHC) and clinical response.

EXPLORATORY OBJECTIVES:

I. To evaluate the association of an AR gene expression signature and clinical response.

II. To evaluate genomic and phenotypic status of breast tumor. III. To evaluate the effect of the combination therapy on peripheral blood circulating tumor cells (CTCs) and circulating tumor deoxyribonucleic acid (DNA) (ctDNA).

IV. To evaluate the effect of combination therapy on tumor-derived exosomes (TEX) and TEX associated immune biomarkers.

V. Immune correlatives:

Va. To evaluate pre-treatment programmed death ligand 1 (PD-L1) and tumor infiltrating lymphocytes (TILs) as a predictor of response to combination therapy.

Vb. To evaluate specific TIL subsets (e.g. CD4, CD8, regulatory T cell \[Treg\] distribution) and other immunological correlatives (e.g. T cell receptor \[TCR\] repertoire analysis) as possible predictors of response.

Vc. To evaluate change in TILs as a result of the combination therapy. Vd. To evaluate peripheral blood, immune biomarkers.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and enobosarm orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days, every 3 months, and bi-annually.

Arms: arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1 and enobosarm PO QD on days 1-21. Courses repeat every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Enobosarm intervention 2: Laboratory Biomarker Analysis intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
IRB #16131 
Title Page Version: 20 
 
07/22/2020 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
 
TITLE:  A Phase 2 Clinical Trial of the Combination of Pembrolizumab and Selective Androgen 
Receptor Modulator (SARM) GTx-024 in Patients with Metastatic Androgen Receptor 
(AR) Positive Triple Negative Breast cancer (TNBC) 
 
CITY OF HOPE PROTOCOL NUMBER: 16131 
 
 
 
 Title Page Version: 20 
 
              Initial Approval 
 
Protocol dated 12/08/16 v00 
 
 
Title Page Version 00 
 
COH Amendment 01 
Title page dated 02/02/2017 
 
 
Title Page Version 01 
 
COH Amendment 02 
Protocol dated 02/01/2017v01 
 
  
Title Page Version 02 
COH Amendment 03 
Protocol dated 04/03/2017v02 
 
  
Title Page Version 03 
COH Amendment 04 
Protocol dated 07/18/2017v03 
 
  
Title Page Version 04 
COH Amendment 05 
Protocol dated 08/15/2017v04 
 
 
Title Page Version 05 
COH Amendment 06 
Protocol dated 08/30/2017v05 
 
 
Title Page Version 06 
COH Amendment 07 
Protocol dated 09/20/2017v06 
 
 
Title Page Version 07 
COH Amendment 08 
Protocol dated 10/26/2017v07 
 
 
Title Page Version 08 
COH Amendment 09 
Personnel Update 12/04/2017 
 
 
Title Page Version 09 
COH Amendment 10 
Personnel Update 02/05/2018 
 
 
Title Page Version 10 
COH Amendment 11 
Personnel Update 02/27/2018 
 
 
Title Page Version 11 
COH Amendment 12 
Protocol dated 02/23/2018  
 
 
Title Page Version 12 
COH Amendment 13 
Personnel Update 03/16/2018 
 
 
Title Page Version 13 
COH Amendment 14 
Protocol dated 06/25/2018  
 
 
Title Page Version 14 
COH Amendment 15 
Protocol dated 09/19/2018  
 
 
Title Page Version 15 
COH Amendment 16 
Personnel Update 11/6/18  
 
 
Title Page Version 16 
COH Amendment 17 
Protocol dated 04/05/19 
 
 
 
Title Page Version 17 
COH Amendment 18 
Protocol dated 04/30/19   
 
 
Title Page Version 18 
COH Amendment 19 
Protocol dated 07/03/19 
 
 
 
Title Page Version 19 
COH Amendment 20 
Personnel Update 07/22/2020 
 
 
Title Page Version 20 
 
 
SPONSOR/IND NUMBER: 
City of Hope/ 132754 
DISEASE SITE: 
Breast 
STAGE (if applicable): 
IV 
MODALITY: 
Immunotherapy and Selective Androgen Receptor Modulator  
PHASE/TYPE: 
Phase 2 with Safety lead-in 
 
PRINCIPAL INVESTIGATOR: 
 
CO-INVESTIGATOR(S): 
 
 
PARTICIPATING CLINICIANS: 
 
BIO-STATISTICIAN: 


IRB #16131 
Title Page Version: 20 
 
07/22/2020 
 
 
 
RESEARCH STAFF:: 
 
           


Page 1 of 113 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
A Phase 2 Clinical Trial of the Combination of Pembrolizumab and Selective 
Androgen Receptor Modulator (SARM) GTX-024 in Patients with Metastatic 
Androgen Receptor (AR) Positive Triple Negative Breast cancer (TNBC)  
 
Version Date: 7/3/19 
Protocol Version: 19 
City of Hope #: 16131 
Agents:  Pembrolizumab (MK-3475) 
GTX-024 (SARM) 
IND #: 132754  
Sponsor: City of Hope 
 
Industry Partner: Merck & Co. 
GTx Inc. 
Funding Support: Merck & Co. 
NCT #: NCT02971761 
 
 
 
 
 
 


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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 


Page 3 of 113 
 
PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2 Clinical Trial of the Combination of Pembrolizumab and Selective Androgen Receptor Modulator (SARM) 
GTX-024 in Patients with Metastatic Androgen Receptor (AR) Positive Triple Negative Breast cancer (TNBC) 


Page 4 of 113 
Study Detail 
Indication(s) 
Androgen receptor (AR) positive metastatic triple negative breast cancer 
(TNBC) 
Phase 
2  
Number of participants 
29 evaluable 
Estimated Accrual Duration 
18 months  
Estimated Duration of the Study 
Approximately 36 months  
Participating Sites 
 City of Hope (Duarte), CA 
  
Study Agents 
Pembrolizumab - (Merck & Co.)  
GTX-024 - (GTx Inc.)  
Brief Protocol Title for the Lay 
Public 
Pembrolizumab and GTx-024 in AR positive (+) for Metastatic Triple 
Negative Breast Cancer. 
Sponsor 
City of Hope 
Industry Partners 
Merck & Co. 
GTx Inc. 
Rationale for this Study 
 Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers. Due to the lack of specific markers 
for effective targeted therapy, chemotherapy is the only therapeutic option for TNBC in the metastatic setting. 
Thus, novel targeted therapies are desperately needed for this devastating disease. One of the potential 
therapeutic targets is the androgen receptor (AR). In TNBC, up to 30% of cancers may express AR. In mRNA-based 
sub-classification of TNBC, luminal AR subtype accounts for approximately 10% of TNBC. Efficacy of AR targeted 
therapy such as enzalutamide was observed in patients with AR + TNBC.  
As a nonsteroidal selective androgen receptor modulator (SARM), GTx-024 demonstrates selective anabolic 
activity, weak anti-progestin activity and cannot be converted to estrogenic metabolites. The ability of GTx-024 to 
act as an AR agonist and a weak progesterone receptor antagonist may provide multiple mechanisms to inhibit 
breast cancer cell growth and by decreasing bone turnover, prevent bone metastases and skeletal related events 
in women with metastatic breast cancer. Currently there are two phase II clinical trials evaluating the clinical 
benefit of GTx-024 and the importance of the AR as a therapeutic target in women with ER positive metastatic 
breast cancer who have responded to previous hormonal therapy and in women with AR +, triple negative breast 
cancer (AR+ TNBC). 
Pembrolizumab is a highly selective humanized monoclonal antibody of the IgG4/kappa isotype that is believed to 
block the interaction between PD-2 and its ligands, PD-L1 and PD-L2. Pembrolizumab demonstrated sustained 
tumor regression with a response rate of approximately 24% in melanoma. Single agent pembrolizumab has a 
reported response rate in a cohort of 27 selected PD-L1+ TNBC patients of 19% [46], with the 5 responses were 
seen in patients with 8, 6, 6, 3, 1 lines of prior therapy for metastatic disease.  ~47% had 3+ lines in that study.  In a 
subsequent study presented after the initiation of this study,  a response rate of 5% was observed in 170 mTNBC 
patients , 44% with 3+ lines and no previously untreated patients. The 5% RR  was consistent between PD-L1 
positive and negative patients [67].   The combined RR for the two studies is approximately 7%, and the upper 
confidence interval for the larger study is 9%, so we have modified the discouraging response rate to reflect the 
more recent and larger study and selected 9% for our updated discouraging response rate of the combination (see 
statistical considerations). 
Immunotherapy and AR targeted therapy representpromising therapeutic strategies for TNBC. Despite the 
encouraging finding of recent phase II trials of AR targeted therapy such as enzalutamide, single agent AR targeted 
therapy is not adequate to induce durable clinical benefit. The complementary modes of action and low potential 
of overlapping toxicity profiles of these two modalities make the combination therapy of AR targeted agent and 
anti-PD-1 therapy potentially promising. This study is designed to test the efficacy of combining SARM GTx-024 
with pembrolizumab in patients with metastatic AR+ TNBC. 


Page 5 of 113 
 
Study Design 
 
Following a successful lead-in, we originally proposed an open-label Simon’s MiniMax two-stage Phase 2 study for 
metastatic Androgen Receptor (AR) positive Triple Negative Breast Cancer (TNBC). Eligible participants will receive 
pembrolizumab in combination with GTx-024.  This has been modified as noted in the statistical considerations 
due to the need to incorporate the more recent literature on the single agent Pembrolizumab response rate. 
A 3 at risk design will be utilized for the first 6 participants to assess toxicity for the combination therapy with 
pembrolizumab and GTx-024. The starting dose will be Dose Level 1. If there are DLTs at Dose Level 1, attributed to 
protocol therapy then Dose level -1 will be tested as the starting dose. 
 
Maximum cycles = 35 cycles 
 
Dose Levels 
Pembrolizumab  
(IV infusion over 30 minutes; 
on Day 1 of each 21-day cycle) 
GTx-024  
(Orally, once daily on Days 1-21 of 
each 21-day cycle) 
 
Dose Level -1 
200 mg  
9 mg  
Initial starting 
dose level 
Dose Level 1 
200 mg  
18 mg  
Subsequent participants enrolled on to the study will be treated at the tolerable dose defined during the safety 
lead-in. 
Participants will receive up to 35 cycles of treatment. If one agent is discontinued due to toxicity, then the 
participant may continue to receive single agent protocol therapy. 
Objectives 
 
Primary Objective 
 
To evaluate the safety/tolerability of the combination regimen 
 
To determine the response rate (CR or PR via RECIST 1.1) of the combination of pembrolizumab with GTx-024 
in patients with advanced AR + TNBC 
Secondary Objectives 
 
To evaluate clinical outcomes by RECIST 1.1 including clinical benefit rate (CBR) at 24 weeks, progression 
free-survival (PFS), duration of response (DOR), event free survival (EFS), time-to-treatment failure (TTF); and 
overall survival (OS);  
 
To evaluate the role of immune-related response criteria (irRECIST); 
 
To evaluate the association of AR by IHC and clinical response;  
Exploratory Objectives 
 
To evaluate the association of an AR gene expression signature and clinical response: 
 
To evaluate genomic and phenotypic status of breast tumor 
 
To evaluate the effect of the combination therapy on peripheral blood circulating tumor cells (CTCs) and 
circulating tumor DNA (ctDNA) 
 
To evaluate the effect of combination therapy tumor-derived exosomes (TEX) and TEX associated immune 
biomarkers 
 
Immune Correlatives: 
- 
To evaluate pre-treatment programmed death ligand 1 (PD-L1) and tumor infiltrating lymphocytes (TILs) 
as a predictor of response to combination therapy; 


Page 6 of 113 
- 
To evaluate specific TIL subsets (e.g. CD4,CD8, Treg distribution) and other immunological correlatives 
(e.g. TCR repertoire analysis) as possible predictors of response; 
- 
To evaluate change in TILs as a result of the combination therapy;  
- 
To evaluate peripheral blood, immune biomarkers 
 
Endpoints 
Primary endpoints 
 
Toxicity will be assessed using CTCAE v 4.0 
 
DLT is defined as any of the following that occur during the first cycle that are attributed as possibly, 
probably, or definitely related to protocol therapy for the safety lead-in: 
 Delay > 14 days in initiating Cycle 2 
 Planned dose of GTx-024 is < 75% during Cycle 1  
 Death not clearly due to underlying disease or extraneous causes 
Hematologic 
 Grade ≥ 3 thrombocytopenia with bleeding requiring transfusion 
 Grade 4 thrombocytopenia  
 Grade 4 neutropenia that persists more than 5 days 
 Grade 3 or 4 febrile neutropenia 
o 
Grade 3 febrile neutropenia: defined as single temperature of >38.3°C (101°F) or a sustained 
temperature of ≥38°C (100.4°F) for more than one hour 
Non-Hematologic 
 Any  ≥ Grade 3 non-hematologic toxicity with the following exceptions: 
o 
Grade 3 rash that resolves to ≤ Grade 1 within 14 days with appropriate supportive therapy 
o 
Grade 3 myalgia, fatigue, or constipation that resolves to ≤ Grade 1 within 72 hours  
o 
Grade 3 electrolytes abnormality that lasts < 72 hours that is not clinically complicated, and resolves 
spontaneously or responds to conventional medical interventions 
o 
Grade 3 nausea, vomiting, or diarrhea that lasts < 72 hours with adequate antiemetic and other 
supportive care. 
o 
Grade 3 hypersensitivity and injection site reactions  
o 
For patients with liver metastases who began treatment with Grade ≤ 2 hepatic transaminase: 
transaminase level ≥ 10x ULN lasting ≤ 7 days 
 Hy’s law: concurrent ALT/AST > 3.0 x ULN AND total bilirubin > 2.0 x ULN without initial findings of 
cholestasis and in the absence of any alternative cause 
 Response will be assessed using RECIST v 1.1  
Secondary endpoints 
 The following efficacy endpoints will be assessed using RECIST v 1.1 
 
Endpoint 
Patients 
Definition 
Progression-free survival 
(PFS) 
All patients 
Time to disease progression/ relapse or death as a result 
of any cause 
Clinical benefit rate (CBR) 
All patients 
Lack of progression at 24 weeks 
Duration 
of 
response 
(DOR) 
In CR or PR 
patients 
Time to progression or death 
Overall survival (OS) 
All patients 
Time to death as a result of any cause 
Time to treatment failure 
(TTF) 
All patients 
Time 
to 
treatment 
termination 
for 
any 
reason 
(progression, toxicity, death, patient preference) 
Event-free survival (EFS) 
All patients 
Failure of treatment or death as a result of any cause 
 
 
Response and clinical benefit will be assessed using irRECIST 


Page 7 of 113 
 
Statistical Considerations 
 
A Simon’s MiniMax two-stage Phase 2 design was the original design based on the initial reported response rate of 
19% with single agent pembrolizumab [46]. However, this was based on only 27 patients.  Subsequently, a study of 
170 patients observed a response rate of only 5%.[67] While the original protocol design stated a 19% response 
rate (the single agent response rate in the first reported study) as the discouraging rate for the combination and 
required >2/15 responses in the first stage to continue, these rules must be changed to reflect the data from the 
larger and more recent study that showed a response rate of only 5% for single agent Pembrolizumab (with that 
same response rate applying to both PD-L1 positive and negative tumors).  The later study had an upper 95% 
confidence limit of 9% RR, and the combined data from the two studies would result in a response rate of 
approximately 7%. As a result, we have determined that 9% would be a more appropriate discouraging response 
rate given the more recent and larger report on single agent Pembrolizumab and we consider a promising 
response rate a 20% increment, or a 29% response rate.  With the updated information, we will continue to accrue 
if at least 2/15 patients response (representing a RR of at least 13.3%).  We will maintain the total sample-size at 
29 patients.  Considering the impact of mid-design changes on hypothesis testing, and the variability of outcomes 
from the two relevant historical studies, the updated design is based on having at least 2 out of the first 15 
patients with a response, and then adding an additional 14 patients to better estimate the response rate of the 
combination. With 2+/15 with a response to continue, this is better than the upper 95% CI for the response rate 
reported in the larger and more recent study,  and satisfies the rule for continuing based on the SWOG planned 
versus attained design of Dahlberg (Green SJ and Dahlberg S (1992). Planned Versus Attained Design in Phase II 
Clinical Trials. Statistics in Medicine 11:853-862) for >1/15 responses based on a type I error of 5% and power of 
85% for distinguishing between a 9% and a 29% response rate.  With 29 total patients the SE of the response rate 
will be 9% or less.  
All eligible patients who start treatment will be considered in the calculation of the response rate. 
While both drugs are well-tolerated with non-overlapping toxicities, the initial 6 patients will be followed in a 
safety lead-in to observe if a dose adjustment is appropriate. If in the first 6 patients we observe 2 or more 
patients with dose limiting toxicities (DLTs) in the first cycle, this will mandate a reduction in the starting dose for 
all subsequent patients. If dose level -1 has 2 patients with DLTs in the first 6 patients, the study will hold accrual. 
During the safety lead-in, we will permit only 3 patients to be at risk for first cycle toxicities at any one time. 
With approximately 29 patients, we expect to have to obtain at least 12 patients with pre- and post- treatment 
biopsy material adequate for evaluation for AR pathway activity (AR by IHC and gene expression array) and 
immune profiling. The correlative studies will be used to potentially refine patient selection for future studies, and 
understand the role of AR pathway activities and immune changes on the activity of the combination of 
pembrolizumab plus GTx-024. These correlative studies are considered exploratory in the context of this limited 
Phase II study; however, 12 samples provide 80% power to detect an effective size of 0.8 (80% of the standard 
deviation), with a one-sided type I error of 5%. 
Safety/tolerability 
The safety and tolerability of the combination of pembrolizumab and SARM GTx-024 will be evaluated via a safety 
lead-in. In addition, the CBR will be evaluated at 32 weeks (by RECIST 1.1), the PFS will be evaluated, and the 
duration of response (time from documentation of tumor response to disease progression or death) will be 
evaluated. 
Abbreviated Eligibility Criteria 
Inclusion Criteria 
 Adult patients with AR+ TNBC  
 Measurable disease per RECIST v 1.1 


Page 8 of 113 
 ANC ≥ 1,500/mm3 
 Platelets ≥ 100,000/mm3 
 Total serum bilirubin ≤ 1.5 x ULN 
 Albumin ≥ 2.5 mg/dL 
 AST and ALT ≤ 2.5 x ULN OR ≤ 5.0 x ULN if liver metastases present 
 Creatinine clearance of ≥ 60 mL/min or serum creatinine ≤ 1.5 x ULN 
Exclusion Criteria 
 Any of the following prior therapies  
 Anti-PD-1, PD Ligand-1 (PD-L1), PD Ligand-2 (PD-L2) agent or an antibody targeting other immuno-
regulatory receptors or mechanisms  
 AR targeted agents (including GTx-024, enzalutamide or other AR targeted therapies). 
 Radiotherapy within 14 days prior to first dose of study treatment  
 Investigational agent within 21 days of study entry 
 Hormone replacement therapies within 14 days prior to the first dose of study treatment (estrogens, 
megesterol acetate) 
 Live-virus vaccination within 30 days of planned treatment start. 
 Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 3 weeks of the first 
dose of trial medication. 
 Currently taking or have previously taken testosterone or  testosterone-like agents (methyltestosterone, 
oxandrolone, oxymetholone, danazol, fluoxymesterone, dehydroepiandrosterone, androstenedione) other 
androgenic compounds or anti-androgens 
 Chronic systemic steroid therapy or on any other form of immunosuppressive medication. 
 History of pneumonitis (non-infectious) that requires steroids or current pneumonitis  
Investigational Product Dosage and Administration 
Pembrolizumab 200mg iv every 3 weeks iv and GTx-024 18 mg oral daily. The dose of GTx-024 may be reduced to 9 
mg orally daily. 
Clinical Observations and Tests to be Performed 
 Medical history and physical exam 
 Safety assessments (CBCs with differential, comprehensive chemistry panel, and thyroid function) 
 CT/ MRI scans  
 Correlative tumor tissue and blood sample 
 
 


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TABLE OF CONTENTS 
Protocol Team ................................................................................................................................................ 2 
Experimental Design Schema ......................................................................................................................... 2 
Protocol Synopsis............................................................................................................................................ 3 
Table of Contents ........................................................................................................................................... 9 
List of Tables and Figures .............................................................................................................................. 11 
Abbreviations ................................................................................................................................................ 12 
1.0 
Objectives ....................................................................................................................................... 13 
1.1 
Primary Objective ............................................................................................................. 13 
1.2 
Secondary Objectives ....................................................................................................... 13 
1.3 
Exploratory Objectives ..................................................................................................... 13 
2.0 
Background..................................................................................................................................... 14 
2.1 
Introduction/Rationale for Development ........................................................................ 14 
2.2 
Preclinical Studies ............................................................................................................ 18 
2.3 
Human Studies ................................................................................................................. 19 
2.4 
Overview of Proposed Study ............................................................................................ 22 
2.5 
Study Endpoints ............................................................................................................... 24 
3.0 
Eligibility Criteria ............................................................................................................................ 26 
3.1 
Inclusion Criteria .............................................................................................................. 26 
3.2 
Exclusion Criteria .............................................................................................................. 28 
4.0 
Participant Enrollment ................................................................................................................... 30 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures ........................................ 30 
4.2 
Registration Requirements/Process ................................................................................ 30 
4.3 
Screen Failures and Registered participants who do not Begin Protocol Therapy .......... 31 
5.0 
Treatment Program ........................................................................................................................ 32 
5.1 
Treatment Overview ........................................................................................................ 32 
5.2 
Treatment Cycle Definition .............................................................................................. 32 
5.3 
Treatment Plan ................................................................................................................ 32 
5.4 
Agent Administration ....................................................................................................... 32 
5.5 
Assessments and Special Monitoring ............................................................................... 33 
5.6 
Duration of Therapy and Criteria for Removal from Protocol Therapy ........................... 34 
5.7 
Follow Up ......................................................................................................................... 34 
5.8 
Duration of Study Participation ....................................................................................... 35 
5.9 
Supportive Care, Prohibited Treatments and Concomitant Medications ........................ 35 
6.0 
Anticipated Toxicities and Dose Delay/Modifications .................................................................... 41 
6.1 
Anticipated Toxicities ....................................................................................................... 41 
6.2 
Dose Delay/ Modification Guidelines .............................................................................. 42 
7.0 
Data & Safety Monitoring Plan, Adverse Event and Unanticipated Problem Reporting ................ 49 
7.1 
COH Data and Safety Monitoring ..................................................................................... 49 
7.2 
Events of Special Interest Requiring Expedited Reporting ............................................... 53 
7.3 
Reporting to Merck and GTx ............................................................................................ 54 
8.0 
Agent Information .......................................................................................................................... 56 
8.1 
Pembrolizumab ................................................................................................................ 56 
Prior to the destruction of Pembrolizumab, the DCC should be notified and an acknowledgement to 
proceed from the DCC should be received. ..................................................................... 58 
8.2 
GTx-024 ............................................................................................................................ 58 
Prior to the destruction of GTx-024, the DCC should be notified and an acknowledgement to proceed from 
the DCC should be received. ............................................................................................ 59 
9.0 
Correlative/Special Studies ............................................................................................................ 60 
9.1 
Tumor Tissue Studies ....................................................................................................... 60 
9.2 
Overview of Peripheral Blood Studies ............................................................................. 61 


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9.3 
Blood for immune correlatives ........................................................................................ 61 
9.4 
Bacteriomic profiling ........................................................................................................ 66 
16S Gut Microbiome rRNA Analysis ............................................................................................... 66 
Stool Specimen Collection .............................................................................................................. 66 
10.0 
Study Calendar ............................................................................................................................... 67 
11.0 
Endpoint Evaluation Criteria/Measurement of Effect .................................................................... 70 
11.1 
Primary Endpoints ............................................................................................................ 70 
11.2 
Secondary Efficacy Endpoints .......................................................................................... 70 
11.3 
Correlative Endpoints ....................................................................................................... 70 
12.0 
Statistical Considerations ............................................................................................................... 72 
12.1 
Dose-limiting toxicities ..................................................................................................... 72 
12.2 
Evaluable Participants ...................................................................................................... 72 
12.3 
Study Design..................................................................................................................... 73 
12.4 
Sample Size Accrual Rate ................................................................................................. 73 
12.5 
Statistical Analysis Plan .................................................................................................... 73 
13.0 
Data Handling, Data Management, Record Keeping ...................................................................... 75 
13.1 
Source Documents ........................................................................................................... 75 
13.2 
Data Capture Methods and management ....................................................................... 75 
13.3 
Case Report Forms/ Data Submission Schedule .............................................................. 75 
13.4 
Regulatory Records .......................................................................................................... 76 
14.0 
Adherence to the Protocol ............................................................................................................. 77 
15.0 
Study Oversight, Quality Assurance, and Data & Safety Monitoring ............................................. 78 
15.1 
All Investigator Responsibilities ....................................................................................... 78 
Site Lead Investigator Responsibilities ........................................................................................... 78 
15.2 
Study Principal Investigator Responsibilities ................................................................... 79 
15.3 
Protocol Management Team (PMT) ................................................................................. 79 
15.4 
Monitoring/Auditing ........................................................................................................ 79 
15.5 
City of Hope Data and Safety Monitoring Committee ..................................................... 79 
16.0 
Ethical and Regulatory Considerations ........................................................................................... 80 
16.1 
Ethical Standard ............................................................................................................... 80 
16.2 
Regulatory Compliance .................................................................................................... 80 
16.3 
Institutional Review Board ............................................................................................... 80 
16.4 
Informed Consent ............................................................................................................ 81 
16.5 
Participant Withdrawal .................................................................................................... 81 
16.6 
Special and Vulnerable Populations ................................................................................. 81 
16.7 
Participant Confidentiality ............................................................................................... 82 
16.8 
Future Use of Specimens Collected for this Trial ............................................................. 83 
16.9 
Conflict of Interest ........................................................................................................... 83 
16.10 
Financial Obligations, Compensation, and Reimbursement of Participants .................... 83 
16.11 
Publication/Data Sharing ................................................................................................. 83 
17.0 
References ...................................................................................................................................... 84 
Appendix A: ECOG Performance Status ........................................................................................................ 88 
Appendix B: Contraception guidelines ......................................................................................................... 89 
Appendix C: GTx-024 Pill Diary ..................................................................................................................... 90 
Appendix D: RECIST Criteria V1.1 ................................................................................................................. 93 
Appendix E: Immune Related Response Criteria .......................................................................................... 99 
Appendix H: At Home Sample Collection Kit Contents ............................................................................... 108 
Appendix I: Registration Coversheet .......................................................................................................... 109 
Appendix J: Sample Shipping Guidelines .................................................................................................... 110 
 


Page 11 of 113 
 
LIST OF TABLES AND FIGURES 
Table 2.3.1 AEs from GTx-024 vs. Placebo cancer trials attributed to drug treatment arm with a frequency 
of ≥0.5% 21 
Table 5.3 Dosing regimen and schedule ....................................................................................................... 32 
Table 5.11 Potential Interactions with GTx-024 ........................................................................................... 36 
Table 6.2 Dose Delay/Modification Guidelines for AEs ................................................................................ 42 
Table 7.3 Expedited reporting to Merck and GTx ......................................................................................... 54 
Table 9.1 Tumor tissue studies overview ..................................................................................................... 60 
Table 9.2 Peripheral blood studies overview ............................................................................................... 61 
Table 10.0 Study Activity Calendar ............................................................................................................... 67 
Table 11.2 Secondary Efficacy Endpoints ..................................................................................................... 70 
Table 11.3 Exploratory Endpoints to Evaluate Candidate Biomarkers by Potential Role ............................. 70 
Table 13.3: Data Submission Schedule ......................................................................................................... 75 
Table D1: For Patients with Measurable Disease (i.e., Target Disease) ....................................................... 97 
Table D2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) ........................................ 98 
Table E1: Comparison WHO and irRECIST criteria ........................................................................................ 99 
Table E2. Derivation of irRECIST overall responses .................................................................................... 101 
 


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ABBREVIATIONS 
AE 
ANC 
AR 
CBR 
CFR 
COH 
CR 
CRA 
CRF 
CTC 
CTCAE 
ctDNA 
CTEP 
CTMS 
DCC 
DLT 
DOR 
DSMC 
EFS 
EOT 
FDA 
GCP 
IB 
ICF 
IDS 
IHC 
IND 
IRB 
irRECIST 
iv 
MTD 
OS 
PD 
PFS 
PI 
PMT 
PR 
RECIST 
SAE 
SARM 
SD 
TNBC 
TTF 
WHO 
Adverse Event 
Absolute Neutrophil Count 
Androgen Receptor 
Clinical Benefit Rate 
Code of Federal Regulations 
City of Hope 
Complete Response 
Clinical Research Associate 
Case Report Form 
Circulating tumor cells 
Common Terminology Criteria for Adverse Events 
Circulating tumor DNA 
Cancer Therapy Evaluation Program 
Clinical Trial Management System 
Data Coordinating Center 
Dose Limiting Toxicity 
Duration of Response 
Data Safety Monitoring Committee 
Event-Free Survival 
End of Treatment 
Food and Drug Administration 
Good Clinical Practice 
Investigator Brochure 
Informed Consent Form 
Investigational Drug Services 
Immunohistochemistry 
Investigational New Drug  
Institutional Review Board 
Immune related Response Evaluation Criteria in Solid Tumors 
Intravenous 
Maximum Tolerated Dose 
Overall Survival 
Progressive Disease 
Progression Free Survival 
Principal Investigator 
Protocol Monitoring Team 
Partial Response 
Response Evaluation Criteria in Solid Tumors 
Serious Adverse Event 
Selective Androgen Receptor Modulator 
Stable Disease 
Triple Negative Breast Cancer 
Time-to-Treatment Failure 
World Health Organization 
 
 
 


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1.0 OBJECTIVES  
1.1 Primary Objective 
o To evaluate the safety/tolerability of the combination regimen  
o To determine the response rate (CR or PR via RECIST 1.1) of the combination of pembrolizumab 
with GTx-024 in patients with advanced AR + TNBC 
1.2 Secondary Objectives 
o To evaluate clinical outcomes by RECIST 1.1 including clinical benefit rate (CBR) at 24 weeks, 
progression free-survival (PFS), duration of response (DOR), event free survival (EFS), time-to-
treatment failure (TTF); and overall survival (OS);  
o To evaluate the role of immune-related response criteria (irRECIST); 
o To evaluate the association of AR by IHC and clinical response;  
1.3 Exploratory Objectives 
o To evaluate the association of an AR gene expression signature  and clinical response 
o To evaluate genomic and phenotypic status of breast tumor 
o To evaluate the effect of the combination therapy on peripheral blood circulating tumor cells 
(CTCs) and circulating tumor DNA (ctDNA) 
o To evaluate the effect of combination therapy on tumor-derived exosomes (TEX) and TEX 
associated immune biomarkers 
o Immune Correlatives: 
 To evaluate pre-treatment programmed death ligand 1 (PD-L1) and tumor infiltrating 
lymphocytes (TILs) as a predictor of response to combination therapy; 
 To evaluate specific TIL subsets (e.g. CD4,CD8, Treg distribution ) and other immunological 
correlatives (e.g. TCR repertoire analysis) as possible predictors of response; 
 To evaluate change in TILs as a result of the combination therapy;  
 To evaluate peripheral blood, immune biomarkers 


Page 14 of 113 
2.0 BACKGROUND 
2.1 Introduction/Rationale for Development 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on MK-
3475 (pembrolizumab) and GTx-024. 
2.1.1 
Triple negative breast cancer (TNBC) 
TNBC accounts for 15–20% of all breast cancer and is characterized by a lack of expression of estrogen 
receptor (ER), progesterone receptor (PR), or HER2. TNBC occurs more frequently in younger patients (< 
50 years of age) and generally shows a more aggressive behavior[1]. Median survival for patients with 
advanced TNBC is 12 months, which is much shorter than the survival for patients with other advanced 
breast cancer subtypes. Due to the lack of specific markers for effective targeted therapy, chemotherapy 
is the only therapeutic option for TNBC in the adjuvant or metastatic setting. Thus, novel targeted 
therapies are desperately needed for this devastating disease.  
2.1.2 
AR positive breast cancer 
AR is the most abundantly expressed steroid receptor in breast cancer with up to 95% of ER+ breast 
cancers expressing AR. In TNBC, 12-55% of cancers express AR depending on the study [2, 3]. Across all 
subtypes of BC, AR expression is associated with a better overall survival and disease-free survival 
irrespective of co-expression of ERα in breast cancer [2, 4]. Emerging evidence has shown AR may serve 
as a therapeutic target for this subset of TNBC [4-6]. A recent phase II trial studying single agent 
enzalutamide in AR+ TNBC has demonstrated encouraging clinical benefit rate of 35% at 16 weeks follow 
up, with a median PFS of 14.7 weeks [7].  A novel gene expression array may predict sensitivity to 
enzalutamide treatment[3]. 
2.1.3 
Selective Androgen Receptor Modulator (SARM) 
 GTx-024 is an oral nonsteroidal selective androgen receptor modulator (SARM) that is being developed 
for clinical use because of its selectivity for anabolic activity with minimal androgenic activity (i.e., tissue 
selectivity). GTx binds to the AR with similar affinity as testosterone. However, GTx-024 is a nonsteroidal 
ligand that does not bind or activate ER or progesterone receptor and, unlike testosterone and other 
steroidal androgens, cannot be aromatized to estrogenic metabolites. The underlying hypothesis 
regarding the selectivity of GTx-024 is that this nonsteroidal molecule induces slight conformational 
changes in the AR upon binding. The altered conformational change in AR changes the interaction of AR 
with specific coactivator and corepressor proteins that exist in different tissues, thereby resulting in a 
different mix of genes being turned on and off and conferring more selective anabolic activities. 
Differences in intracellular signaling pathways (i.e., non-genomic effects) and/or interactions with 
steroid biosynthetic enzymes (e.g., 5 alpha(α)-reductase) between GTx-024 and the steroids may also 
contribute to differences in selectivity. GTx-024 is an anabolic agonist in muscle and bone while acting 
neutral or antagonistic in androgenic tissues like the skin. Preclinical data coupled with the early clinical 
success of androgens in breast cancer, support the clinical evaluation of GTx-024 and SARMs as novel 
targeted therapies to treat AR-positive breast cancer. There are two phase II clinical trials currently 
being conducted to test the efficacy of GTx-024 in AR+ advanced breast cancer (TNBC: NCT02368691; 
ER+HER2-BC: NCT02463032).  


Page 15 of 113 
2.1.4 
Rationale of GTx-024 dosing selection 
GTx-024 has been evaluated in 21 completed and ongoing clinical studies enrolling over 1,500 total 
subjects. GTx-024 has been generally well-tolerated, including single doses up to 100 mg and multiple 
doses up to 30 mg once daily for up to 14 days. In longer studies, GTx-024 has also been generally well 
tolerated, including 1, 3, and 9 mg daily doses for up to 184 days (GTx IB). Previous clinical studies 
demonstrated that daily doses up to 30 mg of GTx-024 were well tolerated in healthy male volunteers. 
Both 10 mg and 30 mg daily doses were for up to 14 days. Elevated alanine transaminase (ALT) (any 
elevation outside upper limit of normal [ULN]) was the most common adverse event (AE) experienced. 
None of the subjects in the 10 mg dose group were discontinued from the study due to ALT elevations. 
In the 30 mg dose group, six subjects experienced ALT increases above two times the ULN. 
GTx-024 3 mg given daily was evaluated in two completed Phase 3 trials, in over 600 subjects, for the 
prevention and treatment of muscle wasting (cachexia) in subjects with advanced non-small cell lung 
cancer receiving chemotherapy. GTx-024 3 mg increased lean body mass in both studies and was safe 
and well tolerated when dosed for up to 168 days. Subjects in the GTx-024 and placebo groups 
experienced similar AEs and these AEs were consistent with the background chemotherapy regimen. 
Although GTx-024 3 mg was chosen for its anabolic activity in muscle for the completed Phase 3 study, a 
dose of 9 mg once daily was selected for hormonal therapy in the ongoing Phase 2 trial in ER+ and AR+ 
metastatic breast cancer in order to achieve a higher exposure that is both safe and more likely to be 
efficacious in women with advanced breast cancer. Seven out of twenty-two subjects with advanced, 
heavily pretreated (hormonal therapy, radiation, and chemotherapy) breast cancer demonstrated 
clinical benefit (CB) (stable disease [SD]) at 6 months. In one subject with SD (by Response Evaluation 
Criteria in Solid Tumors [RECIST], Version 1.12), tumor regression of 27% was demonstrated. Consistent 
with the previous studies, GTx-024 remained safe and well tolerated. 
In TNBC, doses of 15–20 mg per day should provide saturation of the AR potentially providing better 
efficacy as opposed to a lower dose with partial occupancy of the AR and absence of any progesterone 
receptor inhibitory effect. In TNBC patients, the 18 mg dose is preferred over a lower dose due to the 
aggressive phenotype of the disease and poor prognosis. Based on preclinical data, the 18 mg dose is 
more likely to saturate the AR and may lead to better clinical outcomes than a lower dose without 
receptor saturation or progesterone receptor inhibition. Based on the safety data collected to date in 
both preclinical and clinical settings, 18 mg dose will be safe and generally well tolerated. Currently, an 
ongoing Phase II study is evaluating the efficacy of GTx-024 at a dose of 18mg po daily in patients with 
AR+ TNBC (NCT02368691). However, in the event that a subject has a Grade 3 or greater toxicity, the 18 
mg dose may be reduced to 9 mg until the AE resolves or for the remainder of treatment based on the 
Investigator’s discretion. The 9 mg dose has been previously studied in postmenopausal women with 
metastatic breast cancer and was safe and well tolerated. 
2.1.5 
PD-1 checkpoint inhibition and cancer treatment 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades [8]. Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies [9-20].  In particular, 
the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors [17, 21-26]. One of the 
major causes of immune tolerance is expression of inhibitory T cell co-receptors such as cytotoxic T- 
lymphocyte-associated protein 4 (CTLA-4) and programmed cell death1 (PD-1). Strategies reversing 
immune tolerance to promote anti-tumor immunity have been proven successful. These include anti-


Page 16 of 113 
CTLA-4 monoclonal antibody ipilimumab, which improves overall survival in melanoma [27, 28]. An 
alternative strategy is blocking PD-1.  
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control 
[29]. The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 
which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands 
(PD-L1 and/or PD-L2).  The structures of murine PD-1 alone [30] and in complex with its ligands were 
first resolved [31, 32]and more recently the NMR-based structure of the human PD-1 extracellular 
region and analyses of its interactions with its ligands were also reported [33]. PD-1 and family members 
are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding, and a cytoplasmic tail which is responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade [34]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins [35].   
PD-1 has been shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-
cells, B-cells, T regs and Natural Killer cells [36]. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells [37] as well as subsets of macrophages[38] and 
dendritic cells [39].  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types [40], including non-hematopoietic tissues as well as in various tumors. 
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs. Binding of 
either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments [40].  PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor [41]. PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) [42].  This suggests that the 
PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention [43]. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2[44]. Pembrolizumab demonstrated sustained tumor regression with a response rate of 
approximately 24% in melanoma, with mainly grade 1 or 2 toxicities in patients regardless of previous 
ipilimumab use[45]. Single agent activity of pembrolizumab is currently been studied for HER2 positive 
breast cancer (NCT01848834). Single agent pembrolizumab has a reported response rate in a cohort of 
27 selected metastatic PD-L1+ TNBC patients of 19% (ref 46), with the 5 responses seen in patients with 
8, 6, 6, 3, 1 lines of prior therapy for metastatic disease.  ~47% had 3+ lines in that study.  In a 
subsequent study presented after the initiation of this protocol,  a response rate of 5% was observed in 
170 mTNBC patients , 44% with 3+ lines and no previously untreated patients. The 5% RR  was 


Page 17 of 113 
consistent between PD-L1 positive and negative patients (ref YYY).   The combined RR for the two 
studies is approximately 7%, and the upper confidence interval for the larger study is 9%, so we have 
modified the discouraging response rate to reflect the more recent and larger study and selected 9% for 
our updated discouraging response rate of the combination (see statistical considerations). 
 
2.1.5.1 Rationale for including subjects with PD-L1 negative tumors 
The KN 012 TNBC proof-of-concept data was obtained in subjects with PD-L1 positive tumors (PD-L1 
staining in ≥1% tumor cells or in stroma) [46]. No data was originally available on the performance of 
pembrolizumab in breast cancer patients with PD-L1 negative tumors (i.e., PD-L1 staining in <1% tumor 
cells and no stromal staining), but KEYNOTE-86 Arm A suggests a 5% response independent of PD-L1 
status in metastatic TNBC. Combined with thelimited data using PD-L1 expression as a biomarker 
predicting response to pembrolizumab, and patients with PD-L1 negative tumors may benefit from 
pembrolizumab, PD-L1 expression will not be used for patient selection. Instead, analysis of PD-L1 
expression will be included as a correlative study. 
2.1.5.2 Rationale for Dose Selection of Pembrolizumab 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W. The dose recently 
approved in the United States for treatment of melanoma subjects is 2 mg/kg Q3W. Although the dose 
of pembrolizumab studied in KN 012, which established efficacy and safety in mTNBC, was 10 mg/kg 
Q2W, recent studies in other tumor types have indicated that 10 mg/kg Q2W and 200 mg Q3W are likely 
to be similar with regard to efficacy and tolerability. 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical activity 
of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 
3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors [47].  
All three dose levels were well tolerated and no dose-limiting toxicities were observed.  This first in 
human study of MK-3475 showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. 
10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, 
B, C and D of this protocol to test for initial tumor activity. Recent data from other clinical studies within 
the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 release assay) 
suggested that peripheral target engagement is durable (>21 days). This early PK and pharmacodynamic 
data provides scientific rationale for testing a Q2W and Q3W dosing schedule. 
A population pharmacokinetic analysis has been performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of MK-3475 
were found to be dependent on body weight. The relationship between clearance and body weight, with 
an allometric exponent of 0.59, is within the range observed for other antibodies and would support 
both body weight normalized dosing or a fixed dose across all body weights.   
MK-3475 has been found to have a wide therapeutic range based on the melanoma indication.  The 
differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 for MK-
3475 in the melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher 


Page 18 of 113 
dose and exposure). The population PK evaluation revealed that there was no significant impact of 
tumor burden on exposure. In addition, exposure was similar between the NSCLC and melanoma 
indications. Therefore, there are no anticipated changes in exposure between different indication 
settings. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 
200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with 
the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range 
established in melanoma as associated with maximal efficacy response and 3) will maintain individual 
patients exposure in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. The pembrolizumab dose of 200mg Q3W has formed a 
foundation for ongoing combination therapeutic protocols. 
2.1.6 
Rationale for studying immunotherapy in combination with AR targeted therapy in AR+ TNBC 
Immunotherapy and AR targeted therapy represent the most promising therapeutic strategies for TNBC. 
Despite the encouraging finding of recent Phase 2 trials of AR targeted therapy such as enzalutamide, 
single agent AR targeted therapy is not adequate to induce durable clinical benefit. The complementary 
modes of action and low potential of overlapping toxicity profiles of these two modalities make the 
combination therapy of AR targeted agent and anti-PD-1 therapy potentially promising. 
2.2 Preclinical Studies 
2.2.1 
Preclinical Data for Pembrolizumab 
Refer to the Investigator’s Brochure for detailed preclinical data. 
2.2.1.1 PD-1 immune checkpoint inhibition 
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-1/PD-L1 
interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to tumor rejection, 
either as a monotherapy or in combination with other treatment modalities[41, 48, 49]. Anti-mouse PD-
1 or anti-mouse PD-L1 antibodies have demonstrated antitumor responses in models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia and colorectal carcinoma [49-53]. 
In such studies, tumor infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin 
expression were observed, indicating that the mechanism underlying the antitumor activity of PD-1 
checkpoint inhibition involved local infiltration and activation of effector T cell function in vivo[51]. 
Experiments have confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well 
as in combination with chemotherapy, in syngeneic mouse tumor models (see pembrolizumab IB). 
2.2.2 
Preclinical Data for GTx-024 in breast cancer  
The effects of GTx-024 on in vitro proliferation of breast cancer cell lines were examined.MDA-MB-231 
breast cancer cells and HCC-38 breast cancer cells stably transfected with the AR were treated with 
dihydrotestosterone (DHT), GTx-024, or the inactive R-isomer of GTx-024 in the presence and absence of 
bicalutamide, a known AR antagonist. DHT and GTx-024 inhibited the in vitro proliferation of the breast 
cancer cell lines with potencies ranging from approximately 1 to 100 nM. These effects were inhibited 


Page 19 of 113 
by co-treatment with bicalutamide and were not induced by the R-isomer of GTx-024, demonstrating 
dependence on the AR and the stereochemical configuration of the ligand.  
The ability of GTx-024 to stimulate AR action and inhibit progesterone receptor action may provide a 
dual mechanism to inhibit breast cancer cell growth. MDA-MB-231-AR cells were implanted 
subcutaneously in nude mice and were treated orally (PO) with vehicle or 30 mg/kg/day GTx-027, a 
close structural analog of GTx-024[54]. Tumor growth was reduced significantly, with greater than 75% 
tumor growth inhibition observed, compared with vehicle-treated tumors. The intratumoral expression 
of genes and pathways that promote breast cancer development through its actions on the AR were also 
suppressed. Similar tumor suppressive activity was observed in patient-derived xenograft models of 
TNBC (unpublished data). These data, coupled with the early clinical success of androgens in breast 
cancer, support the clinical evaluation of GTx-024 and SARMs as a novel targeted therapy to treat AR-
positive breast cancer. 
2.3 Human Studies 
2.3.1 
Clinical Data for Pembrolizumab 
Refer to the Investigator’s Brochure for detailed clinical data. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2. Pembrolizumab was recently approved in the US for the treatment of advanced, unresectable or 
metastatic malignant melanoma, and for use in melanoma subjects with disease progression after prior 
treatment with (a) ipilimumab or (b) a BRAF inhibitor, in the case of BRAF V600-mutant disease[55]. It is 
the first anti-PD-1 therapy to receive regulatory approval in the US, and is currently under regulatory 
review in the EU. Ongoing clinical trials of pembrolizumab are being conducted in advanced melanoma, 
non-small cell lung cancer, and a number of other advanced solid tumor indications and hematologic 
malignancies. For study details please refer to the IB.  
Preliminary data from a study of pembrolizumab in PD-L1-enriched selected patients with triple negative 
stage IV breast cancer suggest 18.3% potentially lasting clinical activity [46], while a larger subsequent 
study showed a response rate of 5% in mTNBC, with the same response rate for PD-L1-positive and 
negative patients.[67] Currently there are no completed studies completed evaluating the efficacy of 
pembrolizumab in ER+ breast cancer. Most common adverse reactions (reported in ≥20% of patients) 
with:  melanoma included fatigue, pruritus, rash, constipation, diarrhea, nausea, and decreased 
appetite; NSCLC included fatigue, decreased appetite, dyspnea and cough. In The P001 and P002 
melanoma and lung subjects, the most commonly reported drug related adverse event across the 
pembrolizumab dosing regimens are fatigue (27.9%), pruritus (19.0%), rash (14.0%), diarrhoea (12.3%), 
arthralgia (11.5%), and nausea (10.2%) (Pembrolizumab IB).  
2.3.1.1 Pembrolizumab Immune-Medicated Side Effects 
The most frequent potential immune-mediated adverse reactions reported in patients treated with 
pembrolizumab were hypo/hyperthyroidism, pneumonitis, colitis, hepatitis, nephritis, and hypophysitis 
(Pembrolizumab IB). Refer to Table 6 for dose modification for this immune-mediated side effects. 
Immune-Mediated Pneumonitis: Pneumonitis occurred in 32 (2.0%) of 1567 patients receiving 
KEYTRUDA in melanoma trials, including Grade 1 (0.8%), Grade 2 (0.8%), and Grade 3 (0.4%) 
pneumonitis. The median time to development of pneumonitis was 4.3 months (range: 2 days to 19.3 
months). The median duration was 2.6 months (range: 2 days to 15.1 months). Twelve (38%) of the 32 
patients received corticosteroids, with 9 of the 12 receiving high-dose systemic corticosteroids for a 


Page 20 of 113 
median duration of 8 days (range: 1 day to 1.1 months) followed by a corticosteroid taper. Pneumonitis 
led to discontinuation of pembrolizumab in 9 (0.6%) patients. Pneumonitis completely resolved in 21 
(66%) of the 32 patients. 
Immune-Mediated Colitis: Colitis occurred in 31 (2.0%) of 1567 patients receiving pembrolizumab in 
melanoma trials, including Grade 2 (0.5%), Grade 3 (1.1%), and Grade 4 (0.1%) colitis. The median time 
to onset of colitis was 3.4 months (range: 10 days to 9.7 months). The median duration of colitis was 1.4 
months (range: 1 day to 7.2 months). Twenty-one (68%) of the 31 patients received corticosteroids, all 
of whom required highdose systemic corticosteroids for a median duration of 6 days (range: 1 day to 5.3 
months) followed by a 5 corticosteroid taper. Colitis led to discontinuation of pembrolizumab in 14 
(0.9%) patients. Colitis resolved in 27 (87%) of the 31 patients. Colitis occurred in 4 (0.7%) of 550 
patients with NSCLC, including Grade 2 (0.2%) or Grade 3 (0.4%) colitis in patients receiving 
pembrolizumab. 
Immune-Mediated Hepatitis: Hepatitis occurred in 16 (1.0%) of 1567 patients with melanoma receiving 
pembrolizumab, including Grade 2 (0.1%), Grade 3 (0.7%), and Grade 4 (0.1%) hepatitis. The time to 
onset was 26 days (range: 8 days to 21.4 months). The median duration was 1.2 months (range: 8 days 
to 4.7 months). Eleven (69%) of the 16 patients received corticosteroids, with 10 of the 11 receiving 
high-dose systemic corticosteroids for a median duration of 5 days (range: 1 to 14 days) followed by a 
corticosteroid taper. Hepatitis led to discontinuation of pembrolizumab in 6 (0.4%) patients. Hepatitis 
resolved in 14 (88%) of the 16 patients. 
Immune-Mediated Endocrinopathies: Hypophysitis occurred in 13 (0.8%) of 1567 patients with 
melanoma receiving pembrolizumab including Grade 2 (0.3%), Grade 3 (0.3%), and Grade 4 (0.1%) 
hypophysitis. The time to onset was 3.3 months (range: 1 day to 7.2 months). The median duration was 
2.7 months (range: 12 days to 12.7 months). Twelve (92%) of the 13 patients received corticosteroids, 
with 4 of the 12 patients receiving high-dose systemic corticosteroids. Hypophysitis led to 
discontinuation of KEYTRUDA in 4 (0.3%) patients. Hypophysitis resolved in 7 (54%) of the 13 patients. 
Immune-Mediated Thyroid Disorders:  
o Hyperthyroidism occurred in 51 (3.3%) of 1567 patients with melanoma receiving 
pembrolizumab, including Grade 2 (0.6%) and Grade 3 (0.1%) hyperthyroidism. The median time 
to onset was 1.4 months (range: 1 day to 21.9 months). The median duration was 1.7 months 
(range: 1 day to 12.8 months). Hyperthyroidism resolved in 36 (71%) of the 51 patients. 
o Hypothyroidism occurred in 127 (8.1%) of 1567 patients with melanoma receiving 
pembrolizumab, including Grade 3 (0.1%) hypothyroidism. The median time to onset of 
hypothyroidism was 3.3 months (range: 5 days to 18.9 months). The median duration was 5.4 
months (range: 6 days to 24.3 months). Hypothyroidism resolved in 24 (19%) of the 127 
patients. 
2.3.2 
Clinical Data for GTx-024 
The clinical experience with GTx-024 comes from 21 Phase I, II and III clinical trials. The effect of food on 
the pharmacokinetics of GTx-024 3 mg is not clinically relevant. Therefore, GTx-024 may be 
administered without regard to food intake or the time of a meal.  
GTx-024 has generally been well tolerated in clinical trials conducted to date. Certain AEs associated 
with GTx-024 may occur. The most commonly reported side effects for GTx-024 in the previous 21 
clinical studies include: headache; back pain; diarrhea; pain in arm or leg; upset stomach; constipation; 
fatigue; dizziness; increases in liver enzymes; flu-like symptoms; anemia ; reduction in high density 
lipoproteins; visual disturbances. Dyspnea was observed more frequently in subjects that received 3 mg 


Page 21 of 113 
GTx-024 (~13%) as compared to placebo (~7%) in two Phase III trials in patients with stage III and IV 
NSCLC receiving chemotherapy consisting of a platinum doublet chemotherapy with a taxane or non-
taxane.  
GTx-024 treatment has been generally well-tolerated, including 1 mg, 3 mg and 9 mg daily doses. The 
important potential risks identified for GTx-024 are: 
o Dose-dependent, transient, asymptomatic increase in alanine aminotransferase (ALT) was 
observed in some of the Phase 1 and 2 studies. These increases were modest at doses up to 3 
mg/day. Most of the subjects studied to date had ALT levels that remained within normal limits. 
ALT levels returned to normal with continued exposure to GTx-024 in most cases and, when 
dosing was not continued, levels returned to normal. In the Phase 3 clinical studies (N=651) in 
subjects with NSCLC receiving chemotherapy, 6 subjects receiving GTx-024 had an ALT lab values 
≥ 5 times the ULN. None of these events were considered serious by the investigators, led to 
discontinuation of study drug or withdrawal of the subject from the study. No significant 
increases in total bilirubin, gamma-glutamyl transferase (GGT), alkaline phosphatase, or lactate 
dehydrogenase have been observed in patients with elevated ALT levels in the Phase 3 studies. 
There were no other consistent, clinically relevant, dose-related effects of GTx-024 on ECGs or 
vital sign measurements (blood pressure/heart rate). 
o Dose-dependent reduction in high density lipoprotein (HDL) of 27-31% were observed at a 3 mg 
dose in healthy male volunteers and postmenopausal females. This change is consistent with the 
effects of other orally administered anabolic agents. The clinical significance of these changes is 
unknown. There were no other consistent, clinically relevant, dose-related effects of GTx-024 on 
ECGs or vital sign measurements (blood pressure/heart rate). No reductions in HDL were 
reported during the Phase 3 clinical studies in patients with NSCLC (N=326 receiving GTx-024 3 
mg/day for up to 147 days). 
o Dyspnea was observed more frequently in subjects that received GTx-024 3 mg/day (42 subjects, 
~13%, 54 events reported) as compared to placebo (23 subjects, ~7%, 33 events reported) in 
two Phase 3 trials in patients with Stage III and IV NSCLC receiving chemotherapy consisting of a 
platinum doublet chemotherapy with a taxane (N=321) or non-taxane (N=330). Twelve of these 
events were serious, and were equally distributed among subjects receiving placebo and GTx-
024 3 mg/day. There was only one other serious event of dyspnea for a subject administered 
GTx-024 1 mg in a prior study. Dyspnea was observed in 3 subjects in the Phase 2 breast cancer 
study (GTx-024 9 mg/day), but none of these events were serious. 
In cancer trials, treatment-related AEs occurred at a similar frequency in each treatment group (Table 
2.3.1).  The most commonly occurring treatment-related events were those associated with the 
gastrointestinal system (nausea, vomiting, and diarrhea).  These events occurred in <3% of subjects 
(GTx-024 IB). 
Table 2.3.1 AEs from GTx-024 vs. Placebo cancer trials attributed to drug treatment arm with a 
frequency of ≥0.5%  
Treatment-related AEs  
GTx-024  
(N=432) 
Placebo   
(N=378) 
All subjects (N=810) 
n (%) 
n (%) 
n (%) 
Any treatment related adverse event  
67 (15.5) 
46 (12.2) 
113 (14.0) 
Nausea 
9 (2.1) 
8 (2.1) 
17 (2.1) 
Vomiting 
8 (1.9) 
4 (1.1) 
12 (1.5) 


Page 22 of 113 
Treatment-related AEs  
GTx-024  
(N=432) 
Placebo   
(N=378) 
All subjects (N=810) 
n (%) 
n (%) 
n (%) 
Diarrhoea 
5 (1.2) 
9 (2.4) 
14 (1.7) 
Headache 
5 (1.2) 
3 (0.8) 
8 (1.0) 
Alanine aminotransferase increased 
4 (0.9) 
2 (0.5) 
6 (0.7) 
Constipation 
4 (0.9) 
2 (0.5) 
6 (0.7) 
Fatigue 
4 (0.9) 
4 (1.1) 
8 (1.0) 
Abdominal pain 
3 (0.7) 
1 (0.3) 
4 (0.5) 
Anaemia 
3 (0.7) 
0 (0) 
3 (0.4) 
Dyspnoea 
3 (0.7) 
0 (0) 
3 (0.4) 
Hyperglycaemia 
3 (0.7) 
0 (0) 
3 (0.4) 
Polyneuropathy 
3 (0.7) 
1 (0.3) 
4 (0.5) 
Weight Increased 
3 (0.7) 
0 (0) 
3 (0.4) 
Alopecia 
2 (0.5) 
1 (0.3) 
3 (0.4) 
Aspartate aminotransferase increased 
2 (0.5) 
1 (0.3) 
3 (0.4) 
Deafness 
2 (0.5) 
0 (0) 
2 (0.2) 
Decreased appetite 
2 (0.5) 
0 (0) 
2 (0.2) 
Dehydration 
2 (0.5) 
0 (0) 
2 (0.2) 
Dermatitis allergic 
2 (0.5) 
0 (0) 
2 (0.2) 
Dizziness 
2 (0.5) 
0 (0) 
2 (0.2) 
Gastrooesophageal reflux disease 
2 (0.5) 
0 (0) 
2 (0.2) 
Insomnia 
2 (0.5) 
1 (0.3) 
2 (0.2) 
Leukopenia 
2 (0.5) 
0 (0) 
2 (0.2) 
Mucosal inflammation 
2 (0.5) 
0 (0) 
2 (0.2) 
Muscular weakness 
2 (0.5) 
0 (0) 
2 (0.2) 
Rash 
2 (0.5) 
0 (0) 
2 (0.2) 
Vision blurred 
2 (0.5) 
0 (0) 
2 (0.2) 
2.4 Overview of Proposed Study 
This is an open-label, Phase 2, single institutional trial of pembrolizumab in combination with GTx-024 
for patients with histologically proven diagnosis of metastatic AR+ TNBC who have measurable disease 
(per RECIST 1.1 Criteria). Patients will receive pembrolizumab at a dose of 200 mg iv once every 21 days 
in combination with GTx-024 at a dose of 18 mg orally with a safety lead-in. The first 6 participants will 
enroll at a 3 at risk safety lead-in to ensure the safety/ tolerability of the combination regimen. 
Patients may be therapy naïve or may have failed any number of prior therapies in the metastatic 
setting. Paraffin-embedded tumor tissue must be available for assessment of biomarkers and patient 
must be able to provide tissue for PD-L1 biomarker analysis from a newly obtained formalin fixed tissue 
or recent biopsy of a tumor lesion not previously irradiated. Patients may not have prior treatment with 
any other anti-programmed cell death protein-1 (anti-PD-1), or PD ligand-1 (PD-L1) or PD ligand-2 (PD-
L2) agent or an antibody targeting other immune-regulatory receptors or mechanisms. Patients may also 
not have previous treatment with AR targeted agents (including but not limited GTx-024, bicalutamide 
or enzalutamide). 
Since each agent may have its own anti-cancer properties if one agent is discontinued due to toxicity, 
then the participant may continue to receive single agent protocol therapy.   
Study treatment will continue until disease progression, unacceptable adverse event(s) (AEs), 
concurrent illness that prevents further administration of study treatment, investigator’s decision to 
withdraw the subject from study treatment or withdrawal.   


Page 23 of 113 
Since pembrolizumab is an immunotherapy agent, participants with confirmed radiographic progression 
per RECIST v1.1 who are clinically stable but do not meet irRECIST criteria for progression will continue 
to receive protocol therapy following consultation of the Study PI. 
Participants who discontinue treatment will be assessed for safety 30 days post-last dose of protocol 
therapy through to 90 days post last dose of protocol therapy or until initiation of a new anti-cancer 
therapy (whichever occurs sooner). 
Follow up response assessment for participants who end treatment and yet to progress will be every 3 
months until disease progression (verified by restaging imaging) or initiation of a new anti-cancer 
therapy. Participants who progress or initiated a new anticancer therapy will be followed biannually or 
as requested by the Study Principal Investigator (PI).  
2.4.1 
Correlatives and biomarker analysis 
2.4.1.1 Tumor tissue correlatives 
Previous research data suggested that CD8 T cell infiltration and PD-L1 expression within tumors may 
predict efficacy for pembrolizumab, but definitive biomarkers are not yet available [56-60]. To identify 
biomarkers to predict and/or follow efficacy for pembrolizumab in combination with GTx-024 in patients 
with metastatic TNBC, we propose the following correlative studies to analyze the immune and stromal 
cells within metastatic tumors, as well as immune cells in peripheral blood, before and after therapy:  
Biopsies of tumor tissue(s) prior to study initiation and at the end of study will be obtained. Key 
questions we will address include:  
o Immune and stromal cell characteristics before treatment that correlate with clinical response 
[56]. This includes PD-L1 expression levels. 
o Changes in immune and stromal cells after therapy that correlate with clinical response [57].  
The following methods will be utilized to address the above questions: 
o 12-color FACS analysis to enumerate/phenotype immune cell subsets and functional readouts, 
including cytokine production and signaling (phosflow).  
o TCR repertoire analysis via deep sequencing. Expansion of the T cell repertoire after therapy 
will be evidence for an immunological response and may indicate epitope spread.  
o Immunohistology using a novel quantitative, spatial image analysis system (Vectra, Perkin 
Elmer) that will enable us to analyze immune, stromal, and cancer cells in metastatic tumors via 
8-color histology.  
o Gene expression analysis of stromal cells via RNA-Seq or microarrays: Messenger RNA (mRNA) 
expression profiling in tumor specimens and peripheral blood will be completed to assess 
expression either by RNAseq or microarrays, to define a gene set critical for clinical response to 
pembrolizumab. The hypothesis to be tested is that pembrolizumab induces responses in 
tumors that reflect an inflammatory/immune cell-rich phenotype based on gene expression. 
Expression of individual genes related to the immune system may also be evaluated, such as 
immune signatures and critical cytokines. 
o Morphological / IHC TIL analysis of tumor biopsies: Tumor infiltrating lymphocytes have been 
shown to provide prognostic and potentially predictive value, particularly in TNBC and HER2-
overexpressing breast cancer. Hematoxylin and eosin (H&E)-stained breast tumor sections can 
be evaluated for TILs, according to a recently published standardized methodology [61]. We will 
evaluate: (1) pre-treatment TILS as a predictor of response to combination therapy; (2) specific 


Page 24 of 113 
TIL subsets (e.g. CD4, CD8, Treg distribution) and other immunological correlatives (e.g. TCR 
repertoire analysis) as possible predictors of response; (3) change in TILs as a result of the 
combination therapy. 
Sequencing technologies, such as whole genome sequencing or single cell RNA sequencing, allow global 
assessment of DNA mutations and gene expression profiles, which can provide molecular phenotyping 
that identifies distinct characteristics of tumors, including the ultimate outcome of disease. We will use 
single cell sequencing technology to characterize a given tumor for both its mutational profile and 
phenotypic status using fresh tumor tissue. 
2.4.1.2 Peripheral blood immune biomarkers (Serial cytokine measurements) 
Blood samples will be obtained to track the temporal dynamics of the host immune response.   
The 30 cytokine panel includes: epidermal growth factor (EGF), eotaxin, basic fibroblast growth factor 
(FGF-basic), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating 
factor (GM-CSF), hepatocyte growth factor (HGF), interferon alpha (IFN-α); IFN-gamma (γ), interleukin-1 
beta (IL-1β), interleukin-1 receptor antagonist (IL-1RA), IL-2; interleukin-2 receptor (IL-2R), IL-4, IL-5, IL-6, 
IL-7, IL-8, IL-10, IL-12p40/p70, IL-13, IL-15, IL-17, IFN-γ-inducible protein 10 (IP-10), monocyte 
chemoattractant protein-1 (MCP-1), monokine induced by IFN-γ (MIG), monocyte inflammatory protein-
1 alpha (MIP-1α), monocyte inflammatory protein-1 beta (MIP-1β), regulated upon activation, normal T 
cell expressed and secreted cytokine (RANTES), tumor necrosis factor (TNF)-α, and VEGF.  
2.4.1.3 Androgen Receptor Signaling 
Tumor specimen will be processed for mRNA extraction and AR signaling pathway will be analyzed. 
Association of AR signaling pathway and response to the combination therapy will be studied. 
2.4.1.4 Peripheral blood circulating tumor DNA (ctDNA) 
Circulating DNA fragments carrying tumor-specific sequence alterations (ctDNA) are found in the cell-
free fraction of blood, representing a variable and generally small fraction of the total circulating DNA. 
Advances in sequencing technologies have enabled the rapid identification of somatic genomic 
alterations in individual tumors, and these can be used to design personalized assays for the monitoring 
of ctDNA. Studies have shown the feasibility of using ctDNA to monitor tumor dynamics in a limited 
number of patients with various solid cancers, but few cases of breast cancer have been analyzed [62]. 
We will acquire serial peripheral blood and will examine the peripheral blood ctDNA and the effect of 
the combination of GTx-024 pembrolizumab on the ctDNA profiling. 
2.4.1.5 Tumor-derived exosomes 
Exosomes are small membrane-bound vesicles that present abundantly in peripheral blood. Tumor-
derived exosomes (TEX) are thought to carry immunosuppressive molecules and factors which can 
interfere with immune cell functions [63]. Through delivering suppressive cargos consisting of proteins 
similar to those in parent tumor cells to immune cells, TEX may influence the antitumor activities of 
immune cells. Hence, TEX may potential to serve as noninvasive biomarkers of tumor progression. In this 
study, we will evaluate TEX’s and TEX-associated immune biomarkers in association with patient’s 
response to AR targeted therapy and Pembrolizumab combination. 
2.5 Study Endpoints 
A primary endpoint is to evaluate the safety and tolerability of the combination therapy. Safety analysis 
will be carried out based on toxicities assessed by CTCAE version 4.0. Adverse events will be analyzed 


Page 25 of 113 
including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. Immune-related adverse 
events (irAEs) will also be collected.  
The other primary endpoint is to determine the response rate (CR or PR via RECIST 1.1) of the 
combination of pembrolizumab with GTx-024 in patients with AR positive advanced TNBC. 
Other secondary end points includes: clinical benefit rate (CBR) at 24 weeks; duration of response 
(DOR), PFS, EFS, TTF, OS to test the efficacy of therapy of the novel drug combination assessed by RECIST 
version 1.1. Any event (toxicity-related or progression) will be counted as “treatment failure”. Kaplan-
Meier estimates will be generated for PFS, failure-free survival and OS.  
Furthermore, secondary endpoint include assessing efficacy using irRECIST, an adaptation of RECIST 
version 1.1 to account for the unique tumor response characteristics to treatment with new 
immunotherapeutic agents, including pembrolizumab. 


Page 26 of 113 
3.0 ELIGIBILITY CRITERIA 
Patient MRN (COH Only): 
Patient Initials (F, M, L): 
Institution:   
 
Participants must meet the following criteria on screening examination to be eligible to participate in 
the study: 
3.1 Inclusion Criteria 
Informed Consent and Willingness to Participate 
__1. Documented informed consent 
__2. Willing to provide a sample from a recently obtained (within 42 days prior to initiation of 
Day 1) biopsy of a tumor lesion (See Section 9.1 for details).  
 
If recently-obtained samples are unavailable an archived metastatic specimen not 
previously irradiated may be submitted upon agreement from the study PI. 
Age Criteria, Performance Status and Life Expectancy 
__3. Age:  18 years  
__4. ECOG performance status of ≤ 1 (see Appendix A) 
__5. Life expectancy of > 3 months  
Nature of Illness and Treatment History 
__6. Metastatic triple negative breast cancer (TNBC) 
__7. Measurable disease per RECIST v1.1 criteria: At least 1 lesion of >10 mm in long axis 
diameter for non-lymph nodes or >15 mm in short axis diameter for lymph nodes that is 
serially measurable according to RECIST 1.1 using computerized tomography, magnetic 
resonance imaging, or panoramic and close-up color photography (see Appendix D). 
__8. Histologically proven diagnosis of TNBC per current ASCO/CAP guideline.  
 
ER negative (ER expression ≤ 10% positive tumor nuclei), PR negative (PR expression ≤ 
10% positive tumor nuclei) and HER2 negative breast cancer by IHC and/or FISH.  
__9. Androgen Receptor positive (AR+)  
 
Defined as ≥50% nuclear AR staining by immunohistochemistry (IHC) in either the primary 
or metastatic lesion 
 
NOTE: Research testing of AR status is available at COH Pathology. Refer to Section 10.0 
for details. 
__10. Resolution of grade 2 and above toxicities of most recent therapy except for stable 
sensory neuropathy (≤ Grade 2) and alopecia. 


Page 27 of 113 
Patient MRN: 
Patient Initials (F, M, L): 
Contraception 
__11. Female (childbearing potential): use an adequate method of birth control (except 
hormonal contraception) or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication. Refer to 
Appendix B. 
 
Childbearing potential defined as not being surgically sterilized or have not been free from 
menses for > 1 year.  
__12. Male: use an adequate method of contraception with the first dose of study therapy 
through 120 days after the last dose of study therapy. Refer to Appendix B 
 
 Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
 Laboratory Criteria (to be performed within 14 days prior to Day 1 of protocol therapy)  
__13. ANC ≥ 1500/mm3  
ANC: 
Date: 
__14. Platelets ≥ 100,000/mm3  
Plts: 
Date: 
__15. Hemoglobin ≥ 9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment) 
Hgb: 
Date: 
__16. Serum total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN if 
total bilirubin levels > 1.5 x ULN 
ULN: 
Bil: 
Direct Bil: 
Date: 
__17. Albumin ≥ 2.5 mg/dL 
Albumin: 
Date: 
__18. AST and ALT ≤ 2.5 x ULN OR ≤ 5.0 x ULN if 
liver metastases present 
ULN:           ALT: 
ULN:           AST: 
Date: 
Date: 
__19. Serum creatinine ≤ 1.5 x ULN OR Creatinine clearance* ≥ 60 
mL/min if creatinine levels > 1.5 x ULN 
* If measured or calculated per institutional standard. GFR 
can also be used in place of creatinine or CrCl 
 
 
ULN: 
Serum Cr: 
Cr Cl: 
 
Date: 
__20. Female of childbearing potential only: Negative urine or 
serum pregnancy test. 
If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required 
Urine test: 
 
Serum test: 
 
Date: 
 
 


Page 28 of 113 
Patient MRN: 
Patient Initials (F, M, L): 
 
3.2 Exclusion Criteria 
Prior Therapy and Concomitant Therapy 
__1.  Anti-programmed cell death protein-1 (anti-PD-1), PD Ligand-1 (PD-L1) PD Ligand-2 (PD-
L2) agent, an antibody targeting other immuno-regulatory receptors or mechanisms. 
__2.  Radiotherapy within 14 days prior to Day 1 of protocol therapy 
__3.  AR targeted agents (including GTx-024, enzalutamide or other AR targeted therapies). 
__4.  Investigational agent within 21 days prior to Day 1 of protocol therapy 
__5.  Hormone replacement therapies (estrogens, megesterol acetate) within 14 days prior to 
Day 1 of protocol therapy  
__6.  Live-virus vaccination within 30 days prior to Day 1 of protocol therapy. 
__7.  Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery 
within 21 days of the first dose of trial medication. 
__8.  Testosterone or testosterone-like agents (methyltestosterone, oxandrolone, 
oxymetholone, danazol, fluoxymesterone, dehydroepiandrosterone, androstenedione) other 
androgenic compounds or anti-androgens within 30 days prior to Day 1 of protocol therapy. 
__9.  Chronic systemic steroid therapy or on any other form of immunosuppressive 
medication. 
Other Illnesses and Conditions 
__10.  Unstable or untreated brain/leptomeningeal metastasis.  
__11.  Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, 
or abdominal carcinomatosis (known risks factors for bowel perforation). 
__12.  Active central nervous system metastases and/or carcinomatous meningitis. 
__13.  Severe hypersensitivity reaction to treatment with another monoclonal antibody 
__14.  Active autoimmune disease that has required systemic treatment in the past 2 years 
(replacement therapies for hormone deficiencies are allowed). 
__15.  Known history of HIV, Hepatitis B or Hepatitis C 
__16.  History of pneumonitis (non-infectious) that required steroids or current pneumonitis 
__17.  Diagnosed with or treated for cancer within the previous two years, other than breast 
cancer or non-melanoma carcinoma of the skin 
__18.  Unable to swallow capsules 
__19.  Currently on bisphosphonate or denosumab with elevated serum calcium levels  
corrected for albumin/ionized calcium levels outside of institutional normal limits 
__20.  Female: Pregnant or lactating 
 


Page 29 of 113 
Patient MRN: 
Patient Initials (F, M, L): 
 
__21.  Concomitant medical condition that precludes adequate study treatment compliance 
or assessment, or increases subject risk, in the opinion of the Investigator, such as but not 
limited to: 
 
Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline 
or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or 
a QTCB (corrected according to Bazett’s formula) interval > 470 msec; serious 
uncontrolled cardiac arrhythmia grade II or higher according to NYHA; uncontrolled 
hypertension (systolic > 150 and/or diastolic > 100 mm Hg) 
 
Acute and chronic active infectious disorders and non-malignant medical illnesses that are 
uncontrolled or whose control may be jeopardized by the complications of this study 
therapy 
 
Impairment of gastrointestinal function or gastrointestinal disease that may significantly 
alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome) 
Noncompliance 
__22.  Prospective participants who, in the opinion of the investigator, may not be able to 
comply with all study procedures (including compliance issues related to feasibility/logistics). 
Eligibility Confirmed* by 
(Choose as applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 
 
 
 


Page 30 of 113 
4.0 PARTICIPANT ENROLLMENT  
NOTE:  Sites must meet activation requirements prior to enrolling participants. 
4.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be done 
only after obtaining written informed consent.  Studies or procedures that were for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values or to evaluate suitability 
for treatment, even if the studies were done before informed consent was obtained. The informed 
consent process is to be fully documented (see Section 16.4), and the prospective participant must 
receive a copy of the signed informed consent document. Screening procedures are listed Study 
Calendar, Section 10.0. 
4.2 Registration Requirements/Process 
4.2.1 
COH DCC Availability and Contact Information 
Eligible subjects will be registered on the study centrally by the Data Coordinating Center (DCC) at City of 
Hope.  DCC staff are available between the hours of 8.00 am and 5.00 pm PST, Monday through Friday 
(except holidays). DCC contact information is as follows:  
o Phone: (626) 256-4673 ext. 83968 
o E-mail: DCC@coh.org 
4.2.2 
Slot verification and reservation 
Designated study staff should call the DCC to verify current slot availability, and to reserve a slot for a 
specific prospective subject.  Slots can only be held for a limited time. Refer to Section 5.3 for Safety 
Lead-in and Phase 2 treatment plan details. 
Eligible subjects must be registered prior to start of protocol therapy. Issues that would cause treatment 
delays should be discussed with the Principal Investigator. If a subject does not receive protocol therapy 
following registration, the subject’s registration on the study may be canceled after discussion with the 
PI. The Data Coordinating Center should be notified of cancellations as soon as possible. 
4.2.3 
Registration Process  
To register a participant the subsequent procedure is to be followed: 
1. The study team at City of Hope or the participating site should contact the DCC via telephone or 
email to provide notification regarding the pending registration and communicate desired 
timeline of the registration, especially if it must be completed promptly to meet the registration 
window.  
2. The data manager/coordinator/research nurse should then email copies to DCC@coh.org 
(participating site – please use #secure# in subject line) of the following documents: 
 
Registration Cover Sheet (Appendix X) 
 
Completed Eligibility Criteria List (printed from Section 3.0 of the protocol)  
 
Source documentation to support eligibility criteria** 
 
Signed Informed Consent document (participating sites – please send as per your 
institutional guidelines) 


Page 31 of 113 
 
Signed subject’s Bill of Rights (COH only) 
 
Signed HIPAA authorization form (if separate from the informed consent document) 
** For COH participants, provide copies of source documentation only if not readily 
available as a finalized record in the COH Electronic Medical Record (EMR). For participating 
sites, please include all source documentation and de-identify as per your institutional 
policy. 
3. After having received all transferred documentation, the DCC will complete the review the 
documents to verify eligibility, working with the study team as needed to resolve any missing 
required source elements. A participant failing to meet all protocol eligibility requirements will 
not be registered. 
4. Once eligibility has been confirmed, DCC staff will register the participant by: assigning a subject 
accession number, register the subject on study centrally into a COH clinical trials management 
system (e.g. MIDAS), and enter the subject into the eCRF system, Medidata RAVE. 
5. Once registration has been completed, DCC staff will send a Confirmation of Registration Form 
within 24 hours, including the participant study number to:  
 
The site study team: Principal Investigator, treating physician, protocol statistician, protocol 
nurse, CRC and COH IDS Pharmacy. 
 
the COH sponsor team designees 
4.3 Screen Failures and Registered participants who do not Begin Protocol Therapy 
The DCC is to be notified of all participants who sign consent but do not meet eligibility criteria or do not 
initiate protocol therapy.  For non-COH sites, the reason for screen failure will be documented in the 
registration coversheet (see Appendix X) and submitted to the DCC. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 32 of 113 
5.0 TREATMENT PROGRAM 
5.1 Treatment Overview 
This is an open-label Simon’s MiniMax two-stage Phase 2 trial for advanced Androgen Receptor (AR) + 
TNBC. The first 6 patients will be monitored as part of a safety lead-in in a 3 at risk design to determine 
safety and tolerability of the combination regimen- pembrolizumab and GTx-024.  
Participants will be administered protocol therapy in the outpatient setting in each 21-day cycle (see 
Section 5.3 and Section 5.4). Participants will receive up to 35 cycles of treatment. If one agent is 
discontinued due to toxicity, then the participant may continue to receive single agent protocol therapy. 
Participants who end protocol therapy (Section 5.6) will undergo follow-up (Section 5.7).  Windows for 
all assessments and treatments are detailed in Section 10.0. 
5.2 Treatment Cycle Definition 
Each cycle is defined as the administration of protocol therapy. 
In the absence of a delay of initiating a new cycle due to toxicity, each treatment cycle lasts 21 days, 
with a window of ± 3 days for participant convenience.  
Day 1 of each treatment cycle is defined by the administration of pembrolizumab. If pembrolizumab is 
permanently discontinued and GTx-024 is being continued, then each cycle will be 21 ± 3 days. 
5.3 Treatment Plan  
5.3.1 
Safety Lead-in Cohort 
Table 5.3 describes the combination regimen. A 3 at risk design will be utilized for the first 6 participants 
to assess toxicity for the regimen. Dose limiting toxicities (DLT) are defined in Section 12.1 and will be 
evaluated during Cycle 1.  
Table 5.3 Dosing regimen and schedule 
 
Dose Level 
Pembrolizumab  
(IV infusion over 30 minutes; 
on Day 1 of each 21-day cycle) 
GTx-024  
(Orally, once daily on Days 1-21 of 
each 21-day cycle) 
 
Dose Level -1 
200 mg  
9 mg  
Initial starting 
dose level 
Dose Level 1 
200 mg 
18 mg 
5.3.2 
Phase 2 Cohort 
Subsequent participants enrolled on to the study will be treated at the tolerable dose defined during the 
safety lead-in. Refer to Section 12.0 for details. 
5.4 Agent Administration 
5.4.1 
Pembrolizumab  
Pembrolizumab (200 mg) will be administered as a 30 minute IV infusion on Day 1 of each 21-day cycle.  
Every effort should be made to target infusion timing to be as close to 30 minutes as possible.  However, 


Page 33 of 113 
given the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
The pembrolizumab dose is fixed at 200 mg. There are no dose reductions. Management and dose 
delays associated with pembrolizumab AEs are outlined in Section 6.2.  
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion 
fluid and administration of infusion solution. 
On Day 1 of Cycle 1, pembrolizumab will be given first. 
5.4.2 
GTx-024 
GTx-024 should be taken daily (e.g. Days 1-21 of each 21-day cycle). Participant may be provided 
sufficient supply to include the 3 day cycle duration window (21 ± 3 days).  
On Day 1 of Cycle 1, GTx-024 should be taken after pembrolizumab. 
GTx-024 should be taken with water at approximately the same time each day with or without food.  
GTx-024 capsules should be swallowed whole.   
If a participant misses a dose and > 12 hours have passed since the scheduled dose time, the missed 
dose will be skipped and will not be made up.  Doses that are vomited will not be made up. 
Participants will be given a patient diary to document each dose of GTX-024 that is taken or missed 
(Appendix C). 
Management and dose modification associated with GTx-024 adverse events are outlined in Section 6.2.  
5.5 Assessments and Special Monitoring 
Refer to Section 10.0 summarizes the trial procedures to be performed. Note: Protocol therapy should 
be administered on Day 1 of each cycle after all procedures/safety assessments have been completed. 
It may be necessary to perform study procedures at unscheduled time points if deemed clinically 
necessary by the investigator.  
5.5.1 
Special Monitoring 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent 
an immunologic etiology. These adverse events may occur shortly after the first dose or several months 
after the last dose of pembrolizumab 
Diarrhea/colitis  
 Participants should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
Hyperthyroidism or hypothyroidism  
 Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 


Page 34 of 113 
Management of infusion reactions  
 Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.  
 Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
5.5.2 
Bone metastases and disease evaluation  
Bone scans will also be utilized to assess osseous metastases for participants with a known history of 
bone metastases or if clinically indicated during screening (see Section 10.0).  
A bone scan at follow up is required only if the participant develop new or worsening symptoms or if the 
investigator believes the participant has attained a Complete Response.   
Additionally, plain X-ray evaluation will be obtained for symptomatic sites with negative bone scan 
evaluations. 
5.5.3 
Brain metastases and disease evaluation  
Brain imaging should be performed in patients with known brain metastases at baseline and during the 
study. Imaging should occur as stated in Section 10.0.  
5.6  Duration of Therapy and Criteria for Removal from Protocol Therapy  
Participants will receive protocol therapy until one of the below criteria are met: 
o Confirmed disease progression 
 Note: Participants with confirmed radiographic progression per RECIST v1.1 who are clinically 
stable but do not meet irRECIST criteria for progression will continue to receive protocol 
therapy following consultation of the Study PI.  
o Completed 35 cycles of treatment (~24 months)  
o Participant is deemed intolerant to protocol therapy because of toxicity, despite dose 
modification/ delay  
 Note: If one agent is discontinued due to toxicity, then the participant may continue to 
receive single agent protocol therapy  
o General or specific changes in the patient's condition which render the patient unacceptable for 
further treatment in the judgment of the investigator 
o Withdrawal of consent for further protocol therapy (See Section 16.5) 
Once participants meet criteria for removal from protocol therapy, the participant should then proceed 
to End of Protocol Therapy assessments. 
Documentation of the reason for discontinuing protocol therapy and the date effective should be made 
in the source documentation and appropriate CRF. The COH DCC should be promptly notified of the 
change in participant status. 
5.7 Follow Up  
Following completion of protocol therapy, all participants will enter follow-up after ending protocol 
treatment.  This is comprised of: 


Page 35 of 113 
o Follow-up for safety, 30 days post-last dose of protocol therapy through to (a) 90 days post-last 
dose of protocol therapy or (b) until initiation of a new anticancer therapy (whichever occurs 
sooner) 
 Exception: If a participant received 4 cycles of GTx-024 monotherapy (~ 90 ± 7 days) beyond 
pembrolizumab discontinuation, then then the participant will only be followed for 30 days 
post last dose of protocol therapy. 
 Note the period for safety follow-up will be extended until stabilization or resolution for all 
reportable AEs (per the agreement of the Study PI) and accompanying follow-up safety 
report. 
o Follow-up for response for those who have yet to have disease progression. 
o Follow-up for survival for those who progressed or initiated a new anti-cancer therapy.  
 Follow-up for survival may be obtained by reviewing the medical record, contacting the 
participant or review of public records and the Social Security Index Registry. 
Assessment time points and windows are detailed in Section 10.0. 
5.8 Duration of Study Participation 
The reason(s) for discontinuing study participation should be documented and may include: 
o Completion of study activities (treatment and follow-up) 
o Withdrawal of consent (See Section 16.5) 
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for safety, behavioral, study termination or administrative 
reasons 
The reason for study completion and associated date must be documented in the source documentation 
and the study-specific case report form (CRF). The participant’s status is to be modified in the COH 
clinical trial management system once the participant completes the study. The COH DCC should be 
promptly notified of the change in participant status. 
5.9 Supportive Care, Prohibited Treatments and Concomitant Medications 
Participants must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator.. 
5.9.1 
Prohibited concomitant medication 
The following are prohibited until from Day 1 of protocol therapy until end of protocol therapy (last day 
of study agent or decision to end study agent(s) whichever occurs later): 
o Antineoplastic systemic chemotherapy or biological therapy  
o Immunotherapy not specified in this protocol 
o Chemotherapy not specified in this protocol 
o Other investigational agents other than pembrolizumab and GTx-024 
o Live vaccines  
o Testosterone or testosterone-like agents (methyltestosterone, oxandrolone, oxymetholone, 
danazol, fluoxymesterone, dehydroepiandrosterone, androstenedione) other androgenic 
compounds or anti-androgens 


Page 36 of 113 
o Hormone replacement therapy: estrogens and/or megesterol acetate 
o Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the PI. 
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.   
5.9.2 
Use with Caution 
The following medications (see Table 5.11) should be used with caution when co-administering GTx-024: 
o Potent CYP3A4 inducers may decrease the rate and extent of exposure of GTx-024 and its 
glucuronide metabolite 
o UDP inhibitors may increase GTx-024 and glucuronide exposure 
o Substrates of BCRP may increase exposure of the BCRP substrate  
Table 5.11 Potential Interactions with GTx-024 
Strong CYP3A4 
Inducers 
Strong CYP3A4 
Inducers 
BCRP 
Substrates 
UGT 
Inhibitors 
Barbiturates 
Phenobarbital 
Ofloxacin 
Gemfibrozil 
Carbamazepine 
Primidone 
Paratusin 
Ketoconazole 
Dexamethasone 
Rifabutin 
Pitavastatin 
 
Fosphenytoin 
Rifapentine 
Rosuvastatin 
 
Modafinil 
Rifampin 
Sulfasalazine 
 
Nafcillin 
Troglitazone 
 
 
Oxcarbazepine 
Herbals: 
 
 
Phenytoin 
Ginko Biloba 
 
 
Pioglitazone 
St John’s Wort 
 
 
5.9.3 
Other Considerations 
Refer to Appendix B for contraception related guidance. 
5.9.4 
Supportive Care Guidelines 
With the exception of therapies listed in Section 5.9.1, participants should receive appropriate 
supportive care measures as deemed necessary by the treating investigator.   
Suggested supportive care measures for the management of adverse events with potential immunologic 
etiology are outlined below. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral infection, which 
might require additional supportive care.  
The treatment guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 


Page 37 of 113 
5.9.4.1 Pneumonitis  
 Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
Grade 2 
 Administer systemic corticosteroids. 
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks. 
Grade 3 or 4 
 Immediately treat with IV steroids.  
 Administer additional anti-inflammatory measures, as needed. 
5.9.4.2 Diarrhea/colitis  
 All participants who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.   
 For Grade 2 or higher diarrhea, consider GI consultation and endoscopy to confirm or 
rule out colitis. 
Grade 2 diarrhea/colitis 
 Administer oral corticosteroids. 
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks. 
Grade 3 or 4 diarrhea/colitis 
 IV steroids followed by high dose oral steroids 
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks. 
5.9.4.3 Type 1 diabetes mellitus* OR ≥ Grade 3 hyperglycemia**  
o *if new onset, including diabetic ketoacidosis [DKA])  
o **if associated with ketosis (ketonuria) or metabolic acidosis (DKA)  
For T1DM or Grade 3-4 hyperglycemia 
 Insulin replacement therapy is recommended.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.  
5.9.4.4 Hypophysitis  
Grade 2 (i.e. symptomatic) 
 Treat with corticosteroids. 
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks. 
 Replacement of appropriate hormones may be required as the steroid dose is tapered. 


Page 38 of 113 
Grade 3 or 4 Treat with an initial dose of IV corticosteroids followed by oral corticosteroids  
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks. 
 Replacement of appropriate hormones may be required as the steroid dose is tapered. 
5.9.4.5 Hyperthyroidism or hypothyroidism  
Grade 2 Hyperthyroidism  
 Non-selective beta-blockers (e.g. propranolol) are suggested as initial therapy. 
Grade 3 or 4 Hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids.  
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks.  
 Replacement of appropriate hormones may be required as the steroid dose is tapered 
Grades 2-4 Hypothyroidism  
 Thyroid hormone replacement therapy, with levothyroxine or liothyroinine, is indicated 
per standard of care. 
5.9.4.6 Hepatic  
Grade 2 
 Monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 
 Treat with IV or oral corticosteroids 
Grade 3 or 4 
 Treat with intravenous corticosteroids for 24 to 48 hours.  
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks 
5.9.4.7 Renal failure or nephritis  
Grade 2 
 Treat with corticosteroids 
Grade 3 or 4 
 Treat with systemic corticosteroids.  
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks 
5.9.4.8 Management of infusion reactions  
 Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. 
Grade 1: Mild reaction; infusion interruption not indicated; intervention not indicated 
 Increase monitoring of vital signs as medically indicated until the participant is deemed 
medically stable in the opinion of the investigator. 


Page 39 of 113 
Grade 2: Requires infusion interruption but responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for < 
=24 hrs 
 Stop Infusion and monitor symptoms. 
 Additional appropriate medical therapy may include but is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
 
Acetaminophen 
 
Narcotics 
 Increase monitoring of vital signs as medically indicated until the participant is deemed 
medically stable in the opinion of the investigator. 
 If symptoms resolve within one hour of stopping drug infusion: 
i. 
May restart infusion at 50% of the original infusion rate (e.g., from 100 mL/hr to 
50 mL/hr).   
 If symptoms DO NOT resolve within one hour of stopping drug infusion: 
i. 
Hold the dose until symptoms resolve 
ii. 
Premedicate for the next scheduled dose 
 At subsequent dosing may premedicate 1.5h (± 30 minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine: 50 mg orally (or equivalent dose of antihistamine). 
 
Acetaminophen: 500-1000 mg orally (or equivalent dose of antipyretic). 
 Participants who develop Grade 2 toxicity despite adequate premedication should be 
removed from protocol therapy. 
Grade 3: Prolonged (i.e., not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae (e.g., renal impairment, pulmonary 
infiltrates) 
OR 
Grade 4: Life-threatening; pressor or ventilatory support indicated 
 Stop Infusion 
 Additional appropriate medical therapy may include but is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
 
Acetaminophen 
 
Narcotics 
 
Oxygen 
 
Pressors 
 
Corticosteroids 
 
Epinephrine 
 Increase monitoring of vital signs as medically indicated until the participant is deemed 
medically stable in the opinion of the investigator. 


Page 40 of 113 
 Hospitalization may be indicated. 
 Participant should not receive any further treatment with pembrolizumab. 
5.9.4.9 Myocarditis 
 For suspected immune-mediated myocarditis, ensure adequate evaluation to exclude 
other etiologies 
 Administer corticosteroids as appropriate 
 


Page 41 of 113 
6.0 ANTICIPATED 
TOXICITIES 
AND 
DOSE 
DELAY/ 
MODIFICATIONS  
6.1 Anticipated Toxicities 
6.1.1 
Pembrolizumab 
Per the IB (Edition 16, 2018) the expected toxicities for pembrolizumab are as follows (asterisk signifies ≥ 
10%, very common; no asterisk signifies 1-10%, common, † signifies 0.1- 1%, uncommon and ^ signifies 
0.01-0.1% rare). For percentage of subjects with adverse event of special interest by toxicity grade, refer 
to table 32 of IB. 
Blood and lymphatic system disorders Anemia, neutropenia†, thrombocytopenia†, leukopenia†, lymphopenia†, 
eosinophilia†, hemolytic anemia†, immune thrombocytopenic purpura† 
Cardio-Vascular  
Myocarditis†, hypertension † 
 
Endocrine 
Hyperthyroidism, hypothyroidism, hypophysitis †, secondary adrenal 
insufficiency †, thyroiditis† 
Eye 
Uveitis †, dry eye † 
Gastrointestinal  
Diarrhea*, nausea*, abdominal pain, vomiting, colitis, constipation, dry 
mouth, pancreatitis†, small intestinal perforation† 
General Disorders and Administration 
Site 
Fatigue*, asthenia, edema, pyrexia, influenza-like illness, chills  
Hepatobiliary 
Hepatitis† 
Immune system 
Infusion related reactions, severe infusion reactions† sarcoidosis†, solid 
organ transplant rejection^ 
Investigations (excluding hematologic) AST/ALT increased, blood alkaline phosphatase increased, blood 
creatinine increased, low sodium levels†, low potassium levels†, low 
calcium levels†, blood bilirubin increased†, amylase increased†, increased 
calcium† 
Metabolism and Nutrition 
Decreased appetite, Type 1 diabetes mellitus † 
Musculoskeletal and Connective Tissue Arthralgia, back pain, myositis, musculoskeletal pain, arthritis, pain in 
extremity, tenosynovitis^ 
Nervous system 
Headache, dizziness, dysgeusia, epilepsy†, lethargy†, Guillian-Barré 
syndrome †, encephalitis†, peripheral neuropathy†, myasthenic 
syndrome†, 
Psychiatric disorders 
Insomnia† 
Renal and urinary  
Nephritis † 
Respiratory, Thoracic and Mediastinal Cough, pneumonitis, dyspnea, penumonia † 
Skin and Subcutaneous Tissue  
Pruritus*, rash*, vitiligo, dry skin, erythema, lichenoid keratosis †, 
psoriasis†, dermatitis †, dermatitis acneiform †, papule†, hair color 
changes†, eczema†, alopecia†, severe skin reactions* , erythema 
nodosum ^,  Steven-Johnson Syndrome^ and toxic epidermal necrolysis^) 


Page 42 of 113 
6.1.2 
GTx-024  
Per the IB (Version 16, 2017) the expected toxicities for GTx-024 are listed below (no asterisk signifies ≥ 
10%; and * signifies 1-10%): 
Gastrointestinal 
Constipation 
Investigations 
Alanine aminotransferase increased*, blood creatinine increased* 
Nervous System 
Headache 
Respiratory, Thoracic and Mediastinal 
Dyspnea 
Skin and Subcutaneous Tissue 
Rash* 
Also reported on GTx-024 trials but with undetermined relationship to GTx-024 is: 
Metabolism and nutrition: Hypercalcemia. (This toxicity may be included in the consent, but is 
considered unexpected to the agent in terms of safety reporting classification). 
6.2 Dose Delay/ Modification Guidelines 
o Toxicities will be graded using the NCI CTCAE Version 4.0. 
o Baseline values are from the last values obtained prior to treatment. 
o If one agent is permanently discontinued, then the participant may continue treatment with the 
other agent treatment. 
o Guidelines for dose modification/ delays related to pembrolizumab and GTx-024 are stated in 
Table 6.2. 
o Participants already receiving 9 mg/day of GTx-024 and requiring further dose reduction must 
discontinue GTx-024. 
Table 6.2 Dose Delay/Modification Guidelines for AEs 
Toxicity 
Agent Most 
Likely 
Attributed to 
Dose delay/ modification guidelines 
Hematological 
Platelets Grade 3-4 
 
G3: 25,000-50,000/mm3 
G4: <25,000/mm3 
 
- 
 Hold study drugs until toxicity resolves to ≤ Grade 1. 
 Dose modify/ delay per investigator discretion based on 
attribution. 
 ANC Grade 4:  
<500/mm3 
 
Febrile neutropenia Grade 3-4 
 
G3: ANC< 1000/mm3 with a single 
temperature of > 38.3 oC or a 
sustained temperature of 
≥ 38 oC  for > 1 hour. 
 
G4: Life-threatening consequences; 
urgent intervention indicated 
Gastrointestinal (Diarrhea/Colitis)                                                     Follow supportive care guidelines in Section 5.9.4.2. 


Page 43 of 113 
Toxicity 
Agent Most 
Likely 
Attributed to 
Dose delay/ modification guidelines 
Diarrhea Grade 2-3 
G2: stool frequency of 4-6 over baseline 
per day 
G3: stool frequency of ≥7 over baseline 
per day 
Pembrolizumab 
(ir) 
GTx-024 
 Hold study drugs until toxicity resolves to ≤ Grade 1 and 
corticosteroid dose is < 10 mg/day. 
 Resume GTx-024 at the same dose or lower dose per 
investigator discretion following consultation with the 
Study PI. Resume pembrolizumab per protocol 
 Discontinue study regimen if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose or inability to 
reduce prednisone or equivalent to ≤ 10 mg per day 
within 12 weeks. 
Diarrhea Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
Permanently discontinue study regimen 
Colitis Grade 2-3 
G2: Abdominal pain; mucus or blood in 
stool 
G 3: Severe or persistent abdominal pain; 
fever; ileus; peritoneal signs 
Pembrolizumab 
(ir) 
 
 Hold pembrolizumab until toxicity resolves to ≤ Grade 1 
and corticosteroid dose is < 10 mg/day. 
 Discontinue pembrolizumab if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose or inability to 
reduce prednisone or equivalent to ≤ 10 mg per day 
within 12 weeks. 
Colitis Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
Permanently discontinue pembrolizumab. 
Hepatic (AST, ALT, or Increased Bilirubin)                                      Follow supportive care guidelines in Section 5.9.4.6 
Grade 2 
AST or ALT Grade2: >3.0 -5.0 x ULN 
Bilirubin Grade 2: >1.5 -3.0 x ULN 
Pembrolizumab 
(ir) 
GTx-024 
 Hold study drugs until toxicity resolves to ≤ Grade 1 and 
corticosteroid dose is < 10 mg/day.   
 Resume GTx-024 at the same dose or lower dose per 
investigator discretion. Resume pembrolizumab per 
protocol. 
 Discontinue study regimen if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose. 
Grade 3-4 
AST or ALT G3:  >5.0 -20.0 x ULN 
Bilirubin G3: >3.0 -10.0 x ULN 
 
AST or ALT G4:  >20.0 x ULN  
Bilirubin G4: >10.0 x ULN 
 
 Permanently discontinue study regimen. 
 For patients with liver metastasis who begin treatment 
with Grade 2 AST or ALT, if AST or ALT increases by ≥ 
50% relative to baseline and lasts for at least 14 days 
then patients should be discontinued from protocol 
therapy. 


Page 44 of 113 
Toxicity 
Agent Most 
Likely 
Attributed to 
Dose delay/ modification guidelines 
Metabolism and Nutrition                                                                       
Type 1 Diabetes Mellitus (if new onset) 
or Grade 3-4 hyperglycemia 
Hyperglycemia Grade 3: >250-500 
mg/dL; > 13.9-27.8 mmol/L; 
hospitalization indicated  
Hyperglycemia Grade 4: > 500 mg/dL; > 
27.8 mmol/L; life-threatening 
consequences 
Pembrolizumab 
(ir) 
 Hold pembrolizumab for new onset Type 1 diabetes 
mellitus or Grade 3-4 hyperglycemia associated with 
evidence of beta cell failure. 
 Follow supportive care guidelines in Section 5.9.4.3 
 Resume pembrolizumab when patients are clinically 
and metabolically stable 
Hypercalcemia Grade 2-4 
G2: Corrected serum calcium of > 11.5-
12.5 mg/dL; >2.9-3.1 mmol/L; ionized 
calcium > 1.5-1.6 mmol/L; 
symptomatic 
 
G3: Corrected serum calcium of > 12.5-
13.5 mg/dL; >3.1-3.4 mmol/L; ionized 
calcium > 1.6-1.8 mmol/L; 
hospitalization indicated 
 
G4: Corrected serum calcium of > 13.5 
mg/dL; >3.4 mmol/L; ionized calcium 
> 1.8 mmol/L; life-threatening 
consequences 
GTx-024 
 Hold GTx-024 until toxicity resolves to ≤ Grade 1.  
 Resume GTx-024 at the same dose or lower dose per 
investigator discretion.  
Hypophysitis                                                                                            Follow supportive care guidelines in Section 5.9.4.4 
Hypophysitis-Grade 2-4 
(i.e. Symptomatic) 
Pembrolizumab 
(ir) 
 Hold pembrolizumab until toxicity resolves to ≤ Grade 1 
and corticosteroid dose is < 10 mg/day. 
 Therapy with pembrolizumab can be continued while 
endocrine replacement therapy is instituted. 
 Discontinue pembrolizumab if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose or inability to 
reduce prednisone or equivalent to ≤ 10 mg per day 
within 12 weeks. 
Hyperthyroidism                                                                                       Follow supportive care guidelines in Section 5.9.4.5 
Hyperthyroidism-Grade 3 
Pembrolizumab 
(ir) 
 Hold pembrolizumab until toxicity resolves to ≤ Grade 1 
and corticosteroid dose is < 10 mg/day. 
 Discontinue pembrolizumab if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose or inability to 
reduce prednisone or equivalent to ≤ 10 mg per day 
within 12 weeks. 
Hyperthyroidism-Grade 4 
Permanently discontinue pembrolizumab 
Hypothyroidism                                                                                        Follow supportive care guidelines in Section 5.9.4.5 
Hypothyroidism- Any Grade 
Pembrolizumab 
(ir) 
 Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted.  
Infusion Reaction                                                                                      Follow supportive care guidelines in Section 5.9.4.8 


Page 45 of 113 
Toxicity 
Agent Most 
Likely 
Attributed to 
Dose delay/ modification guidelines 
Infusion Reaction-Grade 2 
Pembrolizumab 
(ir) 
 Hold pembrolizumab until toxicity resolves to ≤ Grade 
1. 
 If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate   (e.g., from 100 mL/hr to 50 
mL/hr).  
 Otherwise dosing will be held until symptoms resolve 
and the participant should be premedicated for the 
next scheduled dose.  
 Permanently discontinue pembrolizumab if toxicity 
develops despite adequate premedication. 
Infusion Reaction-Grade 3-4 
Permanently discontinue pembrolizumab. 
Pneumonitis                                                                                            Follow supportive care guidelines in Section 5.9.4.1 
Pneumonitis-Grade 2 
Pembrolizumab 
(ir) 
 
 Hold pembrolizumab until toxicity resolves to ≤ Grade 1 
and corticosteroid dose is < 10 mg/day.  
 Discontinue pembrolizumab if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose or inability to 
reduce prednisone or equivalent to ≤ 10 mg per day 
within 12 weeks. 
 Permanently discontinue protocol therapy if Grade 2 
pneumonitis recurs. 
Pneumonitis-Grade 3-4 
Permanently discontinue pembrolizumab 
Renal Failure or Nephritis                                                                       Follow supportive care guidelines in Section 5.9.4.7 
Grade 2 
Serum Creatinine>1.5-3.0X baseline; 
>1.5X-3.0 X ULN 
Pembrolizumab 
(ir) 
 
 Hold pembrolizumab until toxicity resolves to ≤ Grade 1 
and corticosteroid dose is < 10 mg/day.  
 Discontinue pembrolizumab if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose or inability to 
reduce prednisone or equivalent to ≤ 10 mg per day 
within 12 weeks.  
Grade 3-4 
Grade 3:  Serum Creatinine > 3.0 X 
baseline; >3.0-6.0 X ULN 
 
Grade 4: Serum Creatinine > 6.0 X ULN 
Permanently discontinue pembrolizumab 


Page 46 of 113 
Toxicity 
Agent Most 
Likely 
Attributed to 
Dose delay/ modification guidelines 
Cardiac                                                                                                       Follow supportive care guidelines in Section 5.9.4.9 
Myocarditis Grade 2 
Symptoms with mild to 
moderate activity or exertion 
Pembrolizumab 
(ir) 
 Hold pembrolizumab until toxicity resolves to ≤ Grade 1 
and if applicable, corticosteroid dose is < 10 mg/day.  
 Discontinue pembrolizumab if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose or if 
applicable, inability to reduce prednisone or equivalent 
to ≤ 10 mg per day within 12 weeks 
Myocarditis  ≥ Grade 3 
G3: Severe with symptoms at rest 
or with minimal activity or 
exertion; intervention 
indicated 
 
G4: Life-threatening 
consequences; urgent 
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic 
support) 
Permanently discontinue pembrolizumab 
Skin and subcutaneous  
Steven-Johnson Syndrome ≥ Grade 3 
G3: Skin sloughing covering <10% 
BSA with associated signs 
(e.g., erythema, purpura, 
epidermal detachment and 
mucous membrane 
detachment) 
 
G4: Skin sloughing covering 10 - 
30% BSA with associated 
signs (e.g., erythema, 
purpura, epidermal 
detachment and mucous 
membrane detachment) 
 
Pembrolizumab 
(ir) 
 
 Hold pembrolizumab. 
 Refer patient to specialized care for assessment and 
treatment. 
 If Steven-Johnson Syndrome is confirmed, permanently 
discontinue pembrolizumab. 
 
Toxic epidermal necrolysis ≥ Grade 4 
G4: Skin sloughing covering 
>=30% BSA with associated 
symptoms (e.g., erythema, 
purpura, or epidermal 
detachment) 
Pembrolizumab 
(ir) 
 
 Hold pembrolizumab and confirm toxic epidermal 
necrolysis.  
 Refer patient to specialized care for assessment and 
treatment. 
 If toxic epidermal necrolysis is confirmed, permanently 
discontinue pembrolizumab. 
 


Page 47 of 113 
Toxicity 
Agent Most 
Likely 
Attributed to 
Dose delay/ modification guidelines 
Other unspecified toxicities related to GTx-024 only 
≥ Grade 3 
GTx-024  
 Dose reduce (option 1) OR hold drug for up to 7 days 
(option 2) per investigator discretion 
Option 1: Dose reduction 
 Re-challenge with 18 mg or maintain at 9 mg per 
investigator discretion once the AE resolves to ≤ Grade 
1 
Option 2: Hold drug for 7 days 
 After 7 days rechallenge at the same or lower dose of 
GTX-024 OR discontinue GTx-024 
Other unspecified toxicities related to Pembrolizumab only 
Intolerable or persistent Grade 2 
Pembrolizumab 
 
 Hold pembrolizumab at physician discretion. 
 Permanently discontinue pembrolizumab for persistent 
Grade 2 adverse reactions for which treatment with 
pembrolizumab has been held, that do not recover to ≤ 
Grade 1 within 12 weeks of the last dose. 
Grade 3 or Severe  
 Non-irAE: Hold pembrolizumab until toxicity resolves to 
≤ Grade 1.  
OR 
 irAE: Hold pembrolizumab until toxicity resolves to ≤ 
Grade 1 and corticosteroid dose is < 10 mg/day. 
 Discontinue pembrolizumab if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose or inability to 
reduce prednisone or equivalent to ≤ 10 mg per day 
within 12 weeks.  
 Permanently discontinue for any severe or Grade 3 
drug-related AE that recurs, or any life- threatening 
event. 
Grade 4 
Permanently discontinue pembrolizumab 
Other unspecified toxicities related to both agents 
Intolerable or persistent Grade 2 
Pembrolizumab 
GTx-024 
 Hold study drugs at physician discretion. 
 Permanently discontinue study regimen for persistent 
Grade 2 adverse reactions for which treatment with 
study agents has been held, that do not recover to ≤ 
Grade 1 within 12 weeks of the last dose. 
Grade 3 or Severe  
 Non-irAE: Hold study drugs until toxicity resolves to ≤ 
Grade 1.   
OR 
 irAE: Hold pembrolizumab until toxicity resolves to ≤ 
Grade 1 and corticosteroid dose is < 10 mg/day. 
 Resume GTx-024 at the same dose or lower dose per 
investigator discretion. Resume pembrolizumab per 


Page 48 of 113 
Toxicity 
Agent Most 
Likely 
Attributed to 
Dose delay/ modification guidelines 
protocol. 
 Discontinue study regimen if toxicity does not resolve 
to ≤ Grade 1 within 12 weeks of last dose or inability to 
reduce prednisone or equivalent to ≤ 10 mg per day 
within 12 weeks.  
 Permanently discontinue for any severe or Grade 3 
drug-related AE that recurs, or any life- threatening 
event. 
Grade 4 
Permanently discontinue study regimen 
Other unspecified toxicities –UNRELATED to Protocol Therapy 
Any Grade 
UNRELATED 
 Maintain treatment with study agent(s).  
 Interruption of protocol therapy is permitted if the 
investigator consults with the Study PI to determine 
that this is in the best interest of the participant. 


Page 49 of 113 
7.0 DATA & SAFETY MONITORING PLAN, ADVERSE EVENT AND 
UNANTICIPATED PROBLEM REPORTING 
7.1 COH Data and Safety Monitoring  
Definition of Risk Level 
This is a Risk Level 4 study as defined in the City of Hope Institutional Data and Safety Monitoring Plan.  
This determination was made because the study involves a COH IND. 
Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) is responsible for monitoring the data and safety of this study.  
The PMT consists of the Principal Investigator (PI), Biostatistician, Research Protocol Nurse, and Clinical 
Research Coordinator. 
The PMT is required to submit periodic status reports (i.e., the PMT Report) according to the frequency 
prescribed in the City of Hope Institutional Data and Safety Monitoring Plan.  Important decisions made 
during PMT meetings (i.e., dose escalation, de-escalation, etc.) only need to be noted in the PMT Report 
submitted to the Data and Safety Monitoring Committee (DSMC). 
Adverse Events and Serious Adverse Events 
The PI will be responsible for determining the event name, assessing the severity (i.e., grade), 
expectedness, and attribution of all adverse events. 
Adverse Event (AE) - An adverse event is any untoward medical experience or change of an existing 
condition that occurs during or after protocol specific intervention, whether or not it is considered to be 
related to the protocol intervention.  
Reporting Non-serious Adverse Events – Adverse events will be collected after the patient is given the 
study treatment or any study related procedures.  Adverse events will be monitored by the PMT.  
Adverse events that do not meet the criteria of serious OR are not unanticipated problems will be 
reported only in the PMT Report. 
Serious Adverse Event (SAE) [per 21 CFR 312.32] - defined as any expected or unexpected adverse 
events that result in any of the following outcomes: 
 
Death 
 
Is life-threatening experience (places the subject at immediate risk of death from the event as it 
occurred) 
 
Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias of convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse). 
 


Page 50 of 113 
Reporting Serious Adverse Events - begins after study treatment or any study related procedures.  All 
SAEs occurring during this study, whether observed by the physician, nurse, or reported by the patient, 
will be reported according to the approved City of Hope’s Institutional policy.  Serious Adverse Events 
that require expedited reporting will be submitted electronically using iRIS. 
Adverse Event Name and Severity 
The PI will determine the adverse event name and severity (grade) by using the CTCAE version 4.0.  
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event, OR is an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor of 
the research participant experiencing the adverse event. 
Unexpected Adverse Event [21 CFR 312.32 (a)] – An adverse event is unexpected if it is not listed in the 
investigator’s brochure and/or package insert; is not listed at the specificity or severity that has been 
observed; is not consistent with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor of 
the research participant experiencing the adverse event. 
Adverse Event Attribution 
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
Definite - The AE is clearly related to the investigational agent or study procedure and unrelated to 
any other cause. 
Probable - The AE is likely related to the investigational agent or study procedure and unlikely 
related to other cause(s). 
Possible -The AE may be related to the investigational agent or study procedure and may be related 
to another cause(s). 
Unlikely -The AE is doubtfully related to the investigational agent or study procedure and likely 
related to another cause(s). 
Unrelated -The AE is clearly not related to the investigational agent or study procedure and is 
attributable to another cause(s). 
Expedited AE Reporting Guidelines 
Each AE will be assessed to determine if it meets the criteria for expedited reporting. Adverse event 
reporting is to occur according to the site’s specific IRB guidelines, and as outlined in this Section.  
Expedited Adverse Event Reporting to Local IRB 
Sites are to report to their local IRB per their site’s specific institutional and IRB guidelines.  As soon as 
possible, non-COH sites will provide to the DCC copies of the IRB submission and corresponding IRB 
response.   
Expedited Adverse Event Reporting to DCC/ Study PI 
o Adverse events that meet the specified guidelines below are to be reported to the DCC and 
Study PI within the timelines and per the procedures in the sections that follow.  


Page 51 of 113 
o Report the following per Table 7.8.2 to the DCC /Study PI within 24 hours of being aware that 
the event met reporting criteria: 
Expedited Reporting Guidelines 
Time point 
What to report expeditiously 
From the signing of the consent to 
study completion 
All unanticipated problems 
 
From time of signing of the consent 
to Day 1 of protocol therapy 
All SAEs related to protocol procedures  
From Day 1 of protocol therapy 
through (i) 30 days post-last dose 
visit AND (ii) 100 days post last dose 
visit or until initiation of a new 
anticancer therapy. 
  
 
All SAEs regardless of relationship to protocol therapy, study 
procedure, underlying disease or concomitant treatment. 
 
AEs that meet the definition of an unanticipated problem 
 
Potential drug induced liver injury  
 
Suspected transmission of an infectious agent (eg, pathogenic or 
nonpathogenic) via the study drug  
 
Secondary malignancy 
 
Pregnancy and lactation 
 
Overdose 
 
Grade 3/4 infusion reactions 
 
Discontinuation of protocol therapy due to unusual or unusually 
severe AE considered related to study agents. 
After the 100 days post last dose visit 
(i.e. follow-up) 
 
All SAEs that are considered possibly, probably, or definitely related 
to therapy. 
 
Pregnancy and lactation  (up to 7 months post last dose of 
nivolumab) 
Note: All reportable events will require follow up until stabilization or resolution per the agreement of the 
Study PI. 
 
7.1.1 
Expedited reporting to the DCC/Study PI – Non COH Sites 
1. Document/describe AE/UP on each of the following: 
a. MedWatch 3500A  or local IRB submission document* 
i. 
MedWatch 3500A is downloadable form at  
http://www.fda.gov/medwatch/getforms.htm 
 
ii. 
*The local IRB submission document may be used if the document template is 
approved by the DCC 
b. Expedited Reporting Coversheet 
i. 
The Expedited Reporting Coversheet is found in Appendix G.  A modifiable Microsoft 
Word document is also available from the DCC.  An electronic signature on the 
document will be accepted. 
2. Scan and email above documents to DCC@coh.org with the subject title as “Yuan Pembro GTX-
024 SAE”.   
a. All expedited reports received at this account are forwarded immediately to the Study PI, 
and to DCC personnel.  


Page 52 of 113 
b. While not required, if available and applicable, please also include the local IRB submission 
for this event in the submission.  
3. If an email receipt from DCC personnel is not received within one working day, please call 626-
256-4673 x 83968 and/or email DCC@coh.org. 
 
COH Held IND  
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report using the 
MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the Medwatch 3500A are: 
 
Any unexpected fatal or life threatening adverse experience associated with use of the drug 
must be reported to the FDA no later than 7 calendar days after initial receipt of the information 
[21 CFR 312.32(c)(2)] 
 
Any adverse experience associated with use of the drug that is both serious and unexpected 
must be submitted no later than 15 calendar days after initial receipt of the information [21 CFR 
312.32(c)(1)] 
 
Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
The COH PI or designee will be responsible for contacting the Office of IND Development and Regulatory 
Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  OIDRA will assist the PI 
with the preparation of the report and submit the report to the FDA in accordance with the approved 
City of Hope’s Institutional policy. 
Deviations and Unanticipated Problems 
 
Deviation - A deviation is a divergence from a specific element of a protocol that occurred without prior 
IRB approval.  Investigators may deviate from the protocol to eliminate immediate hazard(s) for the 
protection, safety, and well-being of the study subjects without prior IRB approval.  For any such 
deviation, the COH PI will notify the COH DSMC and COH IRB within 5 calendar days of its occurrence via 
iRIS in accordance with the Clinical Research Protocol Deviation policy.   
 
Single Subject Exception (SSE) 
An SSE is a planned deviation, meaning that it involves circumstances in which the specific procedures 
called for in a protocol are not in the best interests of a specific patient.  It is a deviation that is 
anticipated and receives prior approval by the PI and the IRB.  The SSE must be submitted as a “Single 
Subject Exception Amendment Request” via iRIS in accordance with COH IRB guidelines and the Clinical 
Research Protocol Deviation policy.  An IRB approved SSE does not need to be submitted as a deviation 
to the DSMC. 
Unanticipated Problem (UP) – Any incident, experience, or outcome that meets all three of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the characteristics of 
the subject population being studied; AND 


Page 53 of 113 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by the 
drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
 
Any UP that occurs during study conduct will be reported to the COH DSMC and COH IRB in accordance 
with the City of Hope’s Institutional policy using iRIS.  
COH Held IND 
The Office of IND Development and Regulatory Affairs (OIDRA) will assist the COH PI in reporting the 
event to the Food and Drug Administration (FDA). 
7.2 Events of Special Interest Requiring Expedited Reporting 
7.2.1 
Definition of an Overdose  
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or 
greater (≥5 times the indicated dose).  No specific information is available on the treatment of overdose 
of pembrolizumab. Appropriate supportive treatment should be provided if clinically indicated. In the 
event of overdose, the subject should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated. 
If an AE(s) is associated with (“results from”) the overdose of a pembrolizumab, the AE(s) is reported as 
a SAE, even if no other seriousness criteria are met. 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as “accidental or intentional 
overdose without adverse effect.” 
7.2.2 
Pregnancy and Lactation 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a participant (spontaneously 
reported to them) that occurs during the trial; See Table 7.3. 
Efforts must be made by the investigator to follow the outcome of pregnancy outcome per institutional 
policies.  
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  
If the pregnancy continues to term, the outcome (health of infant) must also be reported; weight and 
length of child, Apgar scores (with an explanation of score <10), and congenital abnormalities. If the 
new-born is healthy additional follow-up is not necessary. 
7.2.3 
Abnormal liver function tests 
Liver function tests that meet the following criteria as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing must be reported expeditiously to Merck and/or 
GTx. 


Page 54 of 113 
7.2.3.1 Merck:  
 An elevated AST or ALT ≥ 3X ULN in combination with total bilirubin ≥ 2X ULN and an 
alkaline phosphatase lab value that is < 2X ULN. 
7.2.3.2 GTx:  
 An elevated AST or ALT ≥  3X ULN in combination with total bilirubin ≥ 2X ULN 
 An elevated AST or ALT ≥  3X ULN in combination with clinical jaundice 
 Note: for participants with liver metastasis and elevated AST or ALT > 3X ULN at 
baselines, the values will not be reported as an SAE if ≤ 5X ULN. 
These criteria are based upon available regulatory guidance documents. The purpose of the criteria is to 
specify a threshold of abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology. 
 
7.3 Reporting to Merck and GTx  
The City of Hope PI or designee will forward reports to Merck and GTx in a timely fashion per below 
stated guidelines. 
7.3.1 
Reporting to Merck 
1. The following events will be reported using a MedWatch form in an expedited manner to Merck 
Global Safety within 24 hours of being aware of the event (via OIDRA) (Table 7.3).  
2. SAE reports and any other relevant safety information will be forwarded to the Merck Global 
Safety facsimile number 215 993-1220 (Attn: Worldwide Product Safety). 
3. Copies of all FDA reports cross-referencing the IND will also be submitted to Merck  (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at time of FDA submission (via OIDRA).  
4. Report to Merck aggregate safety information every 3 months at time of COH PMT report. 
5. Participating sites will report these events directly to the COH PI and the DCC who in turn will 
report to Merck. 
7.3.2 
Reporting to GTx 
1. The following events will be reported using a MedWatch form in an expedited manner to GTx 
Inc. within 24 hours of being aware of the event (via OIDRA) (Table 7.3).  
2. SAE reports and any other relevant safety information will be forwarded via facsimile or email 
(FAX: 001 866 966 2970 or email: sae@cmedresearch.com). 
3. Copies of all FDA reports cross-referencing the IND will also be submitted to GTx Inc. (FAX: 001 
866 966 2970 or email: sae@cmedresearch.com) at time of FDA submission (via OIDRA).  
4. Report to GTx Inc. aggregate safety information every 3 months at time of COH PMT report. 
5. Participating sites will report these events directly to the COH PI and the DCC who in turn will 
report to GTx. 
Table 7.3 Expedited reporting to Merck and GTx  
Time point 
What to report to Merck and GTx 
Screening up to Day 1 of protocol therapy 
 Pregnancy and lactation 


Page 55 of 113 
Time point 
What to report to Merck and GTx 
 Any reason for not starting Day 1 of protocol therapy  
For the time period beginning at treatment 
through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, 
whichever is earlier 
All reportable events will require follow up until 
stabilization or resolution per the agreement of 
the Study PI.  
 All SAEs regardless of relationship to protocol therapy, 
study procedure, underlying disease or concomitant 
treatment. 
 Death due to any cause other than progression of the 
cancer under study 
 All AEs that meet the definition of a UP 
 Overdose (Section 7.2.1) of either agent 
 Pregnancies and lactation (Section 7.2.2) 
 Abnormal liver function tests (Section 7.2.3) 
For participants yet to initiate anti-cancer therapy: 
From Day 1 of therapy up to 120 days post-last 
pembrolizumab dose 
 Pregnancies and lactation (Section 7.2.2) 
Post Safety follow-up to removal from study  
 All SAEs that are considered possibly, probably, or 
definitely related to pembrolizumab.  


Page 56 of 113 
8.0 AGENT INFORMATION  
8.1  Pembrolizumab 
Please refer to the IB for a detailed description. Pembrolizumab is FDA approved for metastatic 
melanoma, metastatic NSCLC whose tumors express PD-L1 and for patients with recurrent or metastatic 
HNSCC with disease progression on or after platinum-containing chemotherapy. 
8.1.1 
Other Names 
KEYTRUDA®, MK-3475. 
8.1.2 
Description and Molecular Weight 
Type IgG4 kappa monoclonal 
Source: Humanized (from mouse) 
Target: PD-1 receptor 
Molecular weight:  147 kDa 
8.1.3 
Mechanism of Action  
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell 
proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling 
through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. 
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with 
PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the 
anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in 
decreased tumor growth. 
8.1.4 
Pharmacokinetics 
Half-life elimination: 26 days (per package insert). 
8.1.5 
Human Toxicity 
See Section 6.1.1. 
8.1.6 
Formulation  
Pembrolizumab is provided in 50 mg lyophilized powder for reconstitution, or a 100 mg/4 mL solution, 
in single-use vials.  
8.1.7 
Storage and Stability 
8.1.7.1 Non-diluted product 
The 50 mg lyophilized product and 100 mg/4 mL solution should be stored between 2 oC -8oC. 
8.1.7.2 Reconstituted and diluted solutions  
Pembrolizumab contains no preservative, hence reconstituted, diluted solutions should not be stored at 
room temperature for more than 4 hours after preparation. This includes storage of reconstituted vials, 
storage of infusion solutions in the IV bag and the duration of infusion.  


Page 57 of 113 
Under refrigeration (2°C - 8°C) diluted solutions should not be stored for more than 24 hours from the 
time of preparation. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. Do not freeze. 
8.1.8 
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the agent. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
8.1.9 
Preparation 
Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial (not 
directly on the lyophilized powder), resulting in a concentration 25 mg/ml. Swirl the vial slowly. Allow up 
to 5 minutes for the bubbles to clear. Do not shake the vial. Visually inspect the reconstituted solution 
for particulate matter and discoloration prior to administration. Reconstituted pembrolizumab is a clear 
to slightly opalescent, colorless to slightly yellow solution. Discard reconstituted vial if extraneous 
particulate matter other than translucent to white proteinaceous particles is observed. Alternatively, 
Pembrolizumab solution provided at 100mg/4mL (25mg/mL) will be used.  
Withdraw the required volume from the vial(s) of pembrolizumab and transfer into an intravenous (IV) 
bag containing 0.9% Sodium Chloride Injection, USP. Mix diluted solution by gentle inversion. 
8.1.10 Administration 
The final concentration of the diluted solution should be 1 mg/mL - 10 mg/mL and administered IV over 
30 minutes, through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 
micron to 5 micron in-line or add-on filter.  
See also Section 5.4.1. 
8.1.11 Supplier 
The agent will be supplied free of charge by Merck. 
8.1.12 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using a drug accountability 
log. 
8.1.13 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 
or designee, the amount dispensed to participants, and the amount remaining at the conclusion of the 
trial.  
Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed 
according to applicable federal, state, local and institutional guidelines and procedures. Destruction will 
be documented in a drug accountability log. 


Page 58 of 113 
Prior to the destruction of Pembrolizumab, the DCC should be notified and an acknowledgement to 
proceed from the DCC should be received.  
8.2 GTx-024 
Please refer to the IB for a detailed description. GTx-024 has not been approved for any FDA indication. 
8.2.1 
Other Names 
Ostarine®, Enobosarm, MK-2866, S-22 
8.2.2 
Description and Molecular Weight 
Structural formula: 
Empirical formula: C19H14F3N3O3 
Molecular weight: 389.33 g/mol 
Chemical Name: (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-
methylpropanamide 
8.2.3 
Mechanism of Action 
GTx-024 is an oral nonsteroidal selective androgen receptor modulator (SARM). It is hypothesized that 
GTx-024 may alter the binding of coactivators and repressors to the androgen receptor in a tissue 
specific manner. Clinically, GTx-024 has been demonstrated to have potent muscle and bone anabolic 
activity with minimal androgenic effects.   
8.2.4 
Pharmacokinetics 
Refer to the IB. 
8.2.5 
Human Toxicity 
See Section 6.1.2. 
8.2.6 
Formulation  
GTx-024 3.0 mg Softgels will be supplied as opaque, white to off-white, size 5, oval Softgels with “GTx” 
imprinted in black ink on the outer shell containing 3.0 mg of GTx-024. The liquid Softgel fill is composed 
of GTx-024 dissolved in polyethylene glycol 400.  
8.2.7 
Storage and Stability 
Recommended storage will be at controlled room temperature 15oC-25oC (59oF-77oF), with excursions 
permitted to 30oC (86oF), protected from moisture. 
8.2.8 
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the agent. 


Page 59 of 113 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
8.2.9 
Administration 
See Section 5.4.2. 
8.2.10 Supplier 
The agent will be supplied free of charge by GTx Inc. 
8.2.11 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using a Drug Accountability 
Record. 
8.2.12 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from GTx 
Inc. or designee, the amount dispensed to participants, and the amount remaining at the conclusion of 
the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and procedures, and provided 
that appropriate records of disposal are kept. 
Prior to the destruction of GTx-024, the DCC should be notified and an acknowledgement to proceed 
from the DCC should be received.  
 
 
 
 
 
 
 
 
 
 
 
 


Page 60 of 113 
9.0 CORRELATIVE/SPECIAL STUDIES 
9.1 Tumor Tissue Studies  
An overview of collection, processing, and analysis details are shown in Table 9.1. 
Table 9.1 Tumor tissue studies overview 
Tissue Type 
Timepoint of 
collection 
Materials per 
timepoint 
Material 
Submitted  
Laboratory 
Performing the 
Analysis 
Type of Laboratory 
Analysis 
Formalin fixed 
(FFPE) tissue 
from core 
needle or 
surgical 
specimen or 
other 
procedure 
Baseline 
4 unstained slides 
ProbeOn 
Plus slides 
QualTek 
PD-L1 expression 
 Baseline  
 Optional: during 
treatment  
 End of protocol 
therapy  
 
5 unstained slides 
Slides 
Dr. Peter Lee at 
COH 
Changes in immune and 
stromal cells after therapy 
5 unstained slides 
 
 
10 unstained slides 
Slides 
 
 
Slides 
Holly Yin, COH 
 
 
Tempus 
Nanostring Expression 
analysis 
 
Tempus DNA + RNA 
sequencing 
Fresh tissue 
 Baseline 
 Optional: during 
treatment  
 End of protocol 
therapy 
2-3 cores of 18 
gauge needle 
biopsy specimen, or 
cancer cells 
collected from 
pleural 
fluid/ascites, or 
other biopsy 
/surgical samples. 
Fresh tumor 
in PBS or 
RPMI media 
on ice 
(See Section 
9.1.2) 
COH 
Biorepository 
Core  
Tumor heterogeneity and 
genomic  analysis 
 
o Baseline tissue:  
 FFPE (up to 42 days old from Day 1 of protocol therapy): A sample should be submitted within 
14 days post-registration. If a recently-obtained sample is unavailable an archived metastatic 
specimen not previously irradiated may be submitted upon agreement from the Study PI. 
 Fresh tissue (after consent): If a standard of care procedure is to be performed, attempts 
should be made to take extra tissue for research.  
o During treatment from partial responders (optional): Submit fixed and if available, fresh tissue 
for research if the participant is willing. 
o End of protocol therapy:  FFPE and if also available fresh tissue obtained for standard of care 
purposes to be submitted within 1 month of discontinuing therapy.  
9.1.1 
Labeling  
Label samples with COH protocol #, subject ID and timepoint of collection (e.g. baseline or EOT).  A 
sample manifest will be maintained by the PI or designee. 
9.1.2 
Distribution to laboratories for analysis 
Fresh tissue samples in PBS or RPMI media should be submitted to Karen Miller or designee at the COH 
Biorepository Core immediately on ice within 2 hours of collection. If possible, at least 1 day advance 
notice should be given to Karen Miller or designee.  


Page 61 of 113 
FFPE samples and PBMCs: If applicable, the COH Biorepository Core will distribute fixed tissue/ 
diagnostic tissue to internal and external laboratories for analysis (see Table 9.1). FFPE slides will be 
stored in locked 4
oC refrigerator in Beckman andPBMCs will be stored in locked -80oC freezer 
in Dr. Tim Synold’s lab until batch-shipped to Tempus. Tumor DNA and RNA sequenc
ing will 
be performed at Tempus. No identifiable information will be sent to Tempus and all unused 
specimen including DNA/RNA extract, FFPE slides and fresh frozen specimen will be returned 
to COH investigator. Tempus will not store nor conduct any other r
esearch with the unused or 
leftover tissue. Tempus: 15 FFPE +1 H&E for NGS and PD
-L1 (20% tumor --- ratio of tumor 
nuclei to benign nuclei; 5
-25mm2), plus normal sample (buffy coat from 1
-2 x 8 ml tubes whole 
blood). 
 
9.2 Overview of Peripheral Blood Studies 
Blood samples will be collected from an indwelling venous catheter or by venipuncture for the below 
stated analyses (see Table 9.2).  
Table 9.2 Peripheral blood studies overview 
Timepoint of 
collection 
Section 
Volume per 
Timepoint 
Tube Type 
Processing/ 
Receiving 
Laboratory 
Laboratory/ 
Vendor Performing 
the Analysis 
Type of 
Laboratory 
Analysis 
 Cycle 1 Day 1 
(Baseline) 
 Cycle 2 Day 1  
 Cycle 4 Day 1 
 Cycle 8 Day 1 
 End of treatment   
 
Section 
9.3 
 
30 mL 
Heparin green-top 
Analytical 
Pharmacology 
Core Facility 
(APCF) at COH 
Duarte campus 
Or Designated 
laboratory at 
each site 
Plasma cytokines: 
Dr. Tim Synold 
(APCF)  
 
PBMC: Dr. Peter Lee 
(COH Immuno-
oncology Core) 
Plasma and PBMC 
isolation to assess 
serial cytokines 
and immune 
response 
 
 
 
 
 
10 mL 
Purple-top 
COH APCF for 
initial 
processing 
Or Designated 
laboratory at 
each site 
 
Dr. Tim Synold 
 
Processing and 
storage for Flow 
cytometry and 
Tempus PMBC 
DNA sequencing 
(as a control for 
tumor DNA 
sequence) 
 
 
 
 
 
 
 
9.3 Blood for immune correlatives 
9.3.1 
COH APCF Notification, Blood Collection and Labeling 
NOTE: It is highly recommended that non-Duarte sites arrange for a courier prior to the participant’s 
clinic visit given the tight turnaround time for sample delivery to the COH APCF and COH Biorepository 


Page 62 of 113 
(Duarte Campus). For non COH sites, please notify the local blood sample processing laboratory for 
sample delivery. 


Page 63 of 113 
 
Notification to COH 
APCF of Pending 
Collection 
Tube 
Type 
Labeling and Collection Details 
Post-collection Instructions 
 Notify at least 
one day in 
advance) 
 Send calendar 
invite via e-mail: 
Leslie Smith-
Powell (Lsmith-
Powell@coh.org) 
or Dauhlian Chi 
(dchi@coh.org) 
 
Green-
top 
 
1. Label tubes with COH protocol # (For non-
COH sites,  local protocol #), subject ID, 
actual collection time in 24-hour format, 
institution (for CP sites), and timepoint of 
collection (e.g. D1C1 for Day1 of Cycle 1), 
and if applicable patient initials. 
2. Timepoints of collection are stated in 
Table 9.2. 
3. Blood samples will be collected from an 
indwelling venous catheter or by 
venipuncture  
4. Invert tubes eight times after collection.  
5. Green-top tube(s): Immediately place 
the tubes on ice. 
 
 
 Efforts should be made to promptly 
deliver the blood samples to the COH 
APCF, Shapiro room 1042 (Duarte 
Campus) for processing within 1-2 hours 
(± 30 minutes).  
- 
If delivery of samples fall outside 
of the above specified window, (1) 
a note should be made to the 
study regulatory binder and other 
applicable documents (and a 
reason provided) AND (2) the 
reason should also be 
communicated to the Study PI/ 
designee.  
 Deliver green top tubes on ice or 4oC. 
 For COH Community Practice sites and 
non-COH sites, courier deliveries should 
be made to the below address: 
Dr. Tim Synold 
Analytical Pharmacology Core Facility  
Shapiro 1042 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
 Notify at least 
one day in 
advance) 
Send calendar 
invite via e-mail:  
Biospecimen 
coordinator 
Purple-
top 
1. 
Label tubes with COH protocol # (For 
non-COH sites,  local protocol #), subject ID, 
actual collection time in 24-hour format, 
institution (for CP sites), and timepoint of 
collection (e.g. D1C1 for Day1 of Cycle 1), and 
if applicable patient initials. 
2. Timepoints of collection are stated in 
Table 9.2. 
3. Blood samples will be collected from an 
indwelling venous catheter or by 
venipuncture  
4. Invert tubes eight times after collection.  
5. Purple-top tube(s): Immediately place 
the tubes on ice. 
 Efforts should be made to promptly 
deliver the blood samples to the COH 
Biorepository Core (Duarte Campus) for 
processing within 1-2 hours (± 30 
minutes).  
 Deliver purple top tubes on ice or 4oC. 
 For COH Community Practice sites and 
non-COH sites, courier deliveries should 
be made to the below address: 
Shabnam Pathan 
COH Biorepository Core 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 


Page 64 of 113 
Notification to COH 
APCF of Pending 
Collection 
Tube 
Type 
Labeling and Collection Details 
Post-collection Instructions 
 
 
 
 


Page 65 of 113 
9.3.2 
Processing of samples  
Keep blood samples on a rocker set at low speed to mimic circulation and avoid clot formation until 
processing. Efforts should be made to process the samples within 4 hours of collection. 
Tube Type 
and Volume 
Processing Details 
Downstream 
assay 
Green-top 
(21 mL) 
  
 
Plasma  
1. For plasma preparation use 14 mL whole blood from green-top tubes. 
2. Centrifuge for 10 minutes at 1800 x g at 4 oC.  
3. The resulting upper plasma layer from each tube will be drawn up 
sequentially into a sterile 5 mL syringe and pushed through a sterile 
0.2/0.8 micron disposable filter.  
a. Save the plasma-depleted portion for isolation of PBMC (see 
below). 
4. The filtered plasma will then be transferred in 500 µL aliquots into 
multiple appropriately-labeled Starstedt microfuge tubes.  
5. To one aliquot, add 0.5 mL glycerol/0.02% sodium azide solution to 
dilute the plasma 50/50 v/v. Keep the diluted plasma sample at -20˚C 
and do not freeze.  
6. All the remaining plasma aliquots will be stored frozen at -80˚C until 
use. 
Cytokine 
analysis 
(COH APCF) 
Peripheral 
blood 
mononuclear 
cells (PBMC) 
 
7. Any blood remaining in the two green-top tubes used to prepare 
plasma above will be diluted 1:1 with Hank’s Balanced Salt Solution (or 
equivalent)  and combined with the whole blood from the unused 
green-top tube in a sterile 50 ml conical centrifuge tube. 
8. PBMC will then be isolated by Ficoll-gradient per COH APCF 
procedures. 
9. Isolated PBMC will be aliquoted and stored at -80˚C until use.   
FACS 
(COH 
ImmueOncolo
gy Core) 
 
 
 
 
Purple-top 
(~10 mL) 
Plasma and 
Plasma 
depleted 
whole blood 
cells (PDWB) 
1. Centrifuge for 10 minutes at 820 x g at room temperature.  
2. Remove the tubes from the centrifuge. Do not disturb the cellular layer.  
3. Extract plasma carefully. 
a. Do not disturb the buffy coat while pipetting plasma; leave ~3-
4mm of plasma behind to ensure the buffy coat is undisturbed.  
4. Freeze plasma at -80°C in 1-2 mL aliquots.  Do not fill tubes beyond 70% 
capacity.   
5. Mix the remaining PDWB.  
6. Freeze PDWB at -80°C in 1-2 mL aliquots. 
Sequencing-
cell free 
circulating 
tumor DNA 
and germline 
DNA 
(COH Dr. 
Synold’s Lab) 


Page 66 of 113 
9.3.3 
Sample maintenance and distribution/shipping to laboratories 
A sample manifest will be maintained by the PI or designee. Samples will be maintained at APCF until 
distribution to internal collaborators/external vendors. Samples will be batch shipped to non-COH 
vendors. 
Procedure for plasma/ buffy coat isolation from EDTA tubes: Collect blood in tube until filled. Mix tube 
by inverting 3-5 times and transport to Dr. Synold’s lab for processing. Samples must be processed 
within one hour of collection to minimize the possibility of white blood cell lysis. For processing, 
centrifuge the samples at 820g for 10 min at room temperature and transfer 1 mL aliquots of the plasma 
to sterile 2 mL microtubes. Freeze plasma aliquots at -80 °C. Remove the Buffy coat layer into a separate 
pre-labeled tube and store at -800C. Record corresponding information such as collection time, freezing 
time, and aliquot number.  
Flow Cytometry and single cell RNA sequencing: Peripheral blood mononuclear cells (PBMCs) will be 
isolated from the blood of patients per manufacturer protocol. For flow cytometry, cells will be 
stained for immune subtype markers and sorted by fluorescence-activated cell sorting (FACS) or 
CyTOF. For single cell sequencing, the cells will be loaded in Smarter ICELL8 single cell mRNA chip or 
the 10x, imaged via microscopy, and single cell libraries will be prepared per manufactures 
instructions.  Next generation sequencing will be performed.  
9.4 Bacteriomic profiling 
16S Gut Microbiome rRNA Analysis 
Gut microbiome has been associated with response to immune checkpoint inhibitors in patients with 
solid tumors. Fecal samples are relatively easy to collect and non-invasive. They provide an indication of 
the gut microbiome which may be an indicator of general health, impact drug availability, and indicate 
the presence of communities associated with inflammation, digestive inefficiencies, and pathogens. 
Monitoring the gut microbiome may allow us to predict the risk of possible side effects of immune check 
point inhibitors (colitis and decreased appetite) and therapeutic efficacy.  
 
The exploratory objective to monitor the gut microbiota at baseline, on treatment and end of treatment 
using fecal samples.  The differences in gut microbiota within and between fecal samples will be 
compared using alpha and beta diversity metrics based on 16S rRNA sequencing. 
Stool Specimen Collection 
Refer to Appendix F for more specific information on the planned analysis to be performed.  
Fecal material will be collected in a Zymo Research DNA/RNA Shield Fecal Collection Tube by patients as 
instructed.  A standard operating procedure (SOP) has been generated for stool collection, as outlined in 
Appendix F. A DIET and STOOL FREQUENCY LOG - GENERAL INSTRUCTIONS is listed in Appendix G.  
Stool collection kit contents are listed in Appendix H. A copy of this SOP will be provided to the patient 
and their understanding of the SOP will be documented by the PI.   
Samples will be collected pre-treatment (within 7 days of C1D1), C5 Day 1 (+/-7 days), every 4 cycles (+/-
7 days), and end of treatment (+/-7 days). Patient will bring samples on the scheduled study visits. 
All samples will be collected by participants at home or during study visit. Study team will collect the 
samples and transport to Biospecimen Coordinator in COH Biorepository. 


Page 67 of 113 
10.0 STUDY CALENDAR 
All procedures may increase in frequency if clinically indicated.  
Table 10.0 Study Activity Calendar  
Protocol Activity 
Screen-
ing a 
Protocol Therapy b, c 
EOT f 
Follow-up 
Cycle 1  
D1 d 
Cycle 2+  
D1 e 
Safety 
30 & 90-days 
post g  
Res- 
ponse h 
Survival i 
Informed Consent j 
X 
 
 
 
 
 
 
Eligibility Criteria k 
X 
 
 
 
 
 
 
Registration l 
X 
 
 
 
 
 
 
Medical History m 
X 
 
 
 
 
 
 
Physical Exam n 
X  
X 
X 
X 
X 
X 
 
Vital Signs o 
X 
X 
X 
X 
X 
X 
 
ECOG Status (Appx. A)  
X 
X 
X 
X 
X 
X 
 
Con-med review p 
X 
X 
X 
X 
X 
 
 
AE assessmentq 
Xq 
-----------------------------------Xr----------------------------------- 
 
 
Research AR testings 
X 
 
 
 
 
 
 
Pregnancy t 
X u 
 
 
 
 
 
 
CBC w/diff, plt  
X u 
X 
X 
X 
 
 
 
Serum chemistry v 
X u 
X 
X 
X 
 
 
 
Urinalysis w 
X u 
 
 
 
 
 
 
Fasting serum lipid profile x 
X u 
 
C3, C6 only 
X  
 
 
 
Thyroid function y 
X u 
 
C4 then every 
4 cycles 
 
 
 
 
Immune blood (green-top) z 
 
X  
C2, C4, C8 only 
X 
 
 
 
 
 
 
 
 
 
 
 
ctDNA blood aa 
 
X  
C2, C4, C8 only 
X 
 
 
 
Bacteriomic profilingll 
X 
 
C5 then every 
4 cycles 
X 
 
 
 
Tumor tissue  
X bb 
X cc 
X dd 
 
 
 
CT/MRI imaging ee 
X 
 
X ff 
X ee 
 
X 
 
Brain imaging gg 
X 
 
X ff 
X 
 
X 
 
Bone scan/ X-rayhh 
X  
 
X ff 
X 
 
X  
 
Responseii 
 
 
X ff 
X 
 
X  
 
Pembrolizumab jj 
 
Day 1 of each 21-day cycle 
 
 
 
 
GTx-024 kk 
 
Days 1-21 of each 21-day cycle 
 
 
 
 
Pill diary ll 
 
X 
X 
X 
 
 
 
Survival i 
 
 
 
 
 
 
X  
 
a. Screening evaluations will be performed within 28 days from start of protocol therapy, except laboratory 
assessments to be performed within 14 days prior to start of therapy (footnote u). 
b. Protocol therapy may last up to 35 cycles, until unacceptable toxicity or confirmed disease progression (see 


Page 68 of 113 
Section 5.6 for more comprehensive list). 
c. 
In the absence of a delay due to toxicity, each treatment cycle lasts 21 days ± 3 days. 
d. Day 1 of Cycle 1 is defined as the day of first administration of pembrolizumab. Screening evaluations performed 
within 14 days prior to start of protocol therapy may serve as Day 1 baseline evaluations. 
e. Activities (except imaging and response assessment- footnote gg) and safety assessment review to be performed 
within 72 hours prior to initiation of the new cycle.  
f. 
End of Treatment (EOT) assessments to be performed no later than 7 days after decision to end treatment 
(except tumor imaging- see footnote ff); assessments performed after last dose of study agent and within 7 days 
after the decision to end treatment may serve as End of Treatment assessments.  
g. Safety visits to occur (i) 30 (-2/+7) days post-last dose of protocol therapy AND (ii) 90 (± 7) days post-last dose of 
pembrolizumab or at initiation of a new anticancer therapy (whichever occurs first). Expedited reporting will 
occur during this period. Safety follow-up may be extended until resolution/ stabilization of reportable AEs. 
NOTE: If a participant received at least 4 cycles of GTx-024 monotherapy beyond pembrolizumab 
discontinuation, then the 90 post-last dose visit is waived. 
h. For participants who end protocol therapy but do not progress, Response Follow-up to occur ~ every 3 months 
(± 7 days) from the day of last response evaluation until progression or the initiation of a new anticancer 
therapy. 
i. 
Survival Follow-up:  For participants who progressed or initiated alternate anticancer therapy. Survival follow-up 
to occur bi-annually or as requested by the Study PI via medical record review, review of social security registry, 
or telephone call. 
j. 
Informed consent process to be fully documented (see Section 16.4). Informed consent must occur prior to any 
research only (non-SOC) screening procedures.  
k. 
Eligibility criteria are detailed in Section 3.0.  
 
l. 
Registration into the COH clinical trial management system (CTMS) (e.g. MIDAS). 
m. Medical history – to include a review of treatment history, any ongoing medical conditions and medical history 
pertaining to study eligibility and involvement.  
n. The investigator or qualified designee will perform a full physical exam during the screening period.  Directed 
physical exam should be performed as clinically indicated. 
o. Vital signs: Weight, heart rate, blood pressure, respiration rate, and temperature.  Height required only at 
baseline. 
p. Concomitant medication: All medications starting from 28 days of prior to start of protocol therapy through to 
the end of the Safety Follow-up visits should be recorded in the source documents. If concomitant therapy must 
be changed, including over-the-counter medications or alternative therapies, the reason and name of the 
agent/therapy should be recorded in the eCRF and source document(s). See Section 5.9 for concomitant 
medication/therapy restrictions and guidelines. 
q. Adverse event (AE) will be assessed using CTCAE v.4.0. SAEs related to study procedures will be recorded and 
reported from time of informed consent until Day 1 of protocol therapy. 
r. 
AE recording and reporting will continue until the completion of Safety follow up or until resolution or 
stabilization of any reportable AEs occurring during Safety Follow up period. For events of special interest 
requiring expedited reporting refer to Section 7.2. 
s. 
Participants who have undergone AR testing may use those results and do not have to have the test repeated. 
To request research AR testing at COH Pathology contact Dr. Daniel Schmolze (email: dschmolze@coh.org or 
phone: 626-256-4673 ext. 80727). 
t. 
Women of child bearing potential only: Serum or urine pregnancy test. 
u. Clinical labs to be performed within 14 days prior to initiating protocol therapy. 
v. 
Serum chemistry to include albumin, alkaline phosphatase, ALT, AST, CO2 or bicarbonate, calcium, chloride, 
glucose, phosphorus, potassium, sodium, magnesium, total bilirubin, direct bilirubin (if total bilirubin is elevated 


Page 69 of 113 
above the ULN), total protein, and blood urea nitrogen (BUN). 
w. Urinalysis to include glucose and protein. 
x. 
Fasting serum lipid profile to include low-density lipoprotein, high-density lipoprotein and triglycerides. 
y. 
Thyroid function- T3, free T4 and TSH. 
z. 
Immune blood Green-top tubes (30 mL per timepoint) should be placed on ice. See Section 9.2. NOTE: APCF 
notification instructions of a pending collection at least one day before collection should occur per Section 9.3.1. 
aa. ctDNA blood (10 mL per timepoint):  purple-top tube (10 mL per timepoint) should be placed on ice. See Section 
9.2. NOTE: COH Biorepository Core notification instructions of a pending collection at least one day before 
collection should occur per Section 9.3.1. 
bb. Fixed tissue (≤ 42 days old from Day 1) and if applicable, extra fresh tissue (Duarte Only) taken from a standard 
of care procedure to be submitted. If fixed tissue is unavailable, an archived metastatic specimen not previously 
irradiated may be submitted after consulting the Study PI. See Section 9.1 for details, notification of pending 
fresh tissue collection from Duarte participants and submission time frames. 
cc. Optional: Research tumor tissue (fixed and if applicable fresh (Duarte Only)) from partial responders; only if the 
participant is willing. See Section 9.1 for details, notification of pending fresh tissue collection from Duarte 
participants and submission time frames. 
dd. Fixed tissue and if applicable, extra fresh tissue (Duarte Only) taken from a standard of care procedure to be 
submitted within 1 month of discontinuing therapy. See Section 9.1 for details, notification of pending fresh 
tissue collection from Duarte participants and submission time frames. 
ee. CT/MRI: chest, abdomen, pelvis, any clinically indicated sites of disease, and of bone lesions. The same 
technique must be performed throughout the trial. NOTE: If imaging was obtained within 28 days prior to the 
date of discontinuation, then tumor imaging at treatment discontinuation is not required. 
ff. Imaging and response: end of Cycle 4 (- 7 days), then every 4 cycles (- 7 days). 
gg. Brain imaging: Only if known brain metastases or if clinically indicated. 
hh. Bone scans: Only if known history of bone metastases or if clinically indicated.  
ii. 
Response: Per RECIST v 1.1 (Appendix D) and irRECIST (Appendix E). NOTE: Participants with confirmed 
radiographic progression per RECIST v1.1 who are clinically stable and do not meet irRECIST criteria for 
progression will continue to receive protocol therapy following consultation of the Study PI. If a biopsy is 
indicated following progression per RECIST, attempts should be made to take extra tissue for research purposes 
per Section 9.1. 
jj. The dosing plan for the agents is described in Section 5.3; recommended supportive care is described in Section 
5.9.4. Refer to Section 6.2 for dose delay/ modification guidelines. 
kk. GTx-024 pill diary will be given to the participant and reviewed for adherence (Appendix C).  
ll. 
Stool samples must be collected within 7 days prior to cycle 1 day 1, cycle 5 day 1 (+/- 7 days), every 4 cycles (+/- 
7 days), and end of treatment (+/- 7 days). 


Page 70 of 113 
11.0 ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF 
EFFECT 
11.1 Primary Endpoints  
Safety lead-in: The safety and tolerability of the pembrolizumab plus GTx-024 combination. Safety 
analysis will be carried out based on toxicities assessed by CTCAE, version 4.0 criteria. AEs will be 
analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. Immune-related 
adverse events (irAE) will be collected (also see Section 12.3). See Section 12.1 for DLT definitions. 
Phase 2: The primary endpoint is to assess the response rate (CR or PR via RECIST 1.1) of the 
combination of pembrolizumab with GTx-024 in patients with AR+ advanced TNBC (see Appendix D). 
11.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints for the study are stated in Table 11.2. Since any event (toxicity-related 
or progression) will be counted as “progression”, the feasibility and efficacy endpoints will provide 
useful information for future trial designs. RECIST 1.1 will be used to assess response, EFS, TTF; Kaplan-
Meier estimates will be generated for overall survival (OS). Analysis to assess response and clinical 
benefit will be carried out using irRECIST (see Appendix E). 
Table 11.2 Secondary Efficacy Endpoints 
Endpoint 
Patients 
Definition 
Progression-free survival 
(PFS) 
All patients 
Time to disease progression/ relapse or death as a result of any cause 
Clinical benefit rate (CBR) 
All patients 
Lack of progression at 24 weeks 
Duration of response (DOR) 
In CR or PR 
patients 
Time to progression or death 
Overall survival (OS) 
All patients 
Time to death as a result of any cause 
Time to treatment failure 
(TTF) 
All patients 
Time to treatment termination for any reason (progression, toxicity, death, 
patient preference) 
Event-free survival (EFS) 
All patients 
Failure of treatment or death as a result of any cause 
11.3 Correlative Endpoints  
Proposed candidate biomarkers are listed in Table 11.3. These endpoints will be assessed at baseline 
and at selected timepoints during protocol therapy. Additional endpoints may be evaluated. 
Table 11.3 Exploratory Endpoints to Evaluate Candidate Biomarkers by Potential Role 
Tissue 
Biomarkers 
Pharmaco
-dynamic 
Predictive 
Response 
Tumor 
AR expression profile 
 
X 
X 
Tumor 
Programmed death ligand 1 (PD-L1) and tumor infiltrating lymphocytes 
(TILs) profile, immune signatures and genomic  analysis 
 
X 
X 
Fresh 
tumor 
Nanostring Expression  
Tumor heterogeneity and genomic  analysis 
 
X 
X 
Tumor/ 
blood 
Temporal profile of TIL subsets (e.g. CD4,CD8, Treg distribution) and other 
immunological correlatives (e.g. TCR repertoire analysis)  
X 
X 
X 
Tumor/ 
blood 
miRNA/mRNA profiling to evaluate changes in disease state and regulation 
of key immune checkpoint molecules  
X 
X 
X 
Blood 
Temporal profile of tumor-derived exosomes 
X 
X 
X 


Page 71 of 113 
Tissue 
Biomarkers 
Pharmaco
-dynamic 
Predictive 
Response 
Blood 
Number of circulating tumor cells (CTCs) and quantitation of circulating 
tumor DNA (ctDNA) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 72 of 113 
12.0 STATISTICAL CONSIDERATIONS 
12.1 Dose-limiting toxicities  
Dose limiting toxicity (DLT) is defined as any of the following that occur during the first cycle that are 
attributed as possibly, probably, or definitely related to protocol therapy for the safety lead-in: 
o Delay > 14 days in initiating Cycle 2 
o Planned dose of GTx-024 is < 75% during Cycle 1  
o Death not clearly due to underlying disease or extraneous causes 
Hematologic 
o Grade ≥ 3 thrombocytopenia with bleeding requiring transfusion 
o Grade 4 thrombocytopenia  
o Grade 4 neutropenia that persists more than 5 days 
o Grade 3 or 4 febrile neutropenia 
 Grade 3 febrile neutropenia: defined as ANC < 1000/ mm3 with a single temperature of > 38.3 
oC or a sustained temperature of ≥ 38 oC  for > 1 hour 
Non-Hematologic 
o Any  ≥ Grade 3 non-hematologic toxicity with the following exceptions: 
 Grade 3 rash that resolves to ≤ Grade 1 within 14 days with appropriate supportive therapy 
 Grade 3 myalgia, fatigue, or constipation that resolves to ≤ Grade 1 within 72 hours  
 Grade 3 electrolytes abnormality that lasts < 72 hours that is not clinically complicated, and 
resolves spontaneously or responds to conventional medical interventions  
 Grade 3 nausea, vomiting, or diarrhea that lasts < 72 hours with adequate antiemetic and 
other supportive care. 
 Grade 3 hypersensitivity and injection site reactions  
 For patients with liver metastases who began treatment with Grade ≤ 2 hepatic 
transaminase: transaminase level ≥ 10x ULN lasting ≤ 7 days. 
o Hy’s law: concurrent ALT/AST > 3.0 x ULN AND total bilirubin > 2.0 x ULN without initial findings 
of cholestasis and in the absence of any alternative cause 
12.2 Evaluable Participants  
Participants will be evaluable for toxicity from time of their first treatment. Participants who receive at 
least 1 dose of study drug will be evaluable for response.  
In order for participants to be evaluable for DLT during the safety lead-in (See Section 5.3) during Cycle 
1 participants must: 
o Receive ≥ 75% of the planned dose for GTx-024 and undergo all safety monitoring assessments 
for Cycle 1 OR 
o Experience a DLT. 
Participants who experience a Grade 3/4 pembrolizumab related infusion reaction during Cycle 1 of the 
safety lead-in will be replaced. 


Page 73 of 113 
12.3 Study Design 
This is a Phase 2 single institutional trial of pembrolizumab in combination with GTx-024 for patients 
with histologically proven diagnosis of adenocarcinoma of breast with evidence of metastatic AR+ TNBC 
who have measurable disease (per RECIST 1.1 Criteria). Patients must have confirmed AR+ TNBC. Eligible 
patients will receive pembrolizumab 200 mg IV every 3 weeks in combination with GTx-024 at a dose of 
either 18 mg po or 9 mg po daily as determined by the safety lead-in (see Section 5.3). 
Study treatment will continue until disease progression, unacceptable adverse event(s) (AEs), 
concurrent illness that prevents further administration of study treatment, investigator’s decision to 
withdraw the subject from study treatment, consent withdrawal, becoming lost-to-follow-up, death or 
for administrative reasons requiring cessation of treatment. 
After discontinuation of study treatment, each subject will be followed for 30 days for AE monitoring. 
Reportable adverse events will be collected for 90 days after the end of study treatment or until subject 
initiates new anticancer therapy  (whichever occurs earlier). 
Subjects who discontinue study treatment for reasons other than disease progression will have post-
treatment follow-up for disease status every 3 months until disease progression or initiation of a non-
study anticancer treatment.  
All subjects will be followed by biannually (or as requested by the Study PI) via medical record review, 
review of social security registry, or telephone call for overall survival until consent withdrawal, 
becoming lost to follow-up, death or end of the study. 
12.4 Sample Size Accrual Rate 
Sample-size: 29 patients. The estimated accrual rate will be one patient per month for a total of 18 
months. 
12.5 Statistical Analysis Plan 
12.5.1 Primary Objective: Response Rate 
A Simon’s MiniMax two-stage Phase 2 design was the original design based on the initial reported 
response rate of 19% with single agent pembrolizumab. However, this was based on only 27 patients.  
Subsequently, a study of 170 patients observed a response rate of only 5%. [67] While the original 
protocol design stated a 19% response rate (the single agent response rate in the first reported study) as 
the discouraging rate for the combination and required >2/15 responses in the first stage to continue, 
these rules must be changed to reflect the data from the larger and more recent study that showed a 
response rate of only 5% for single agent Pembrolizumab (with that same response rate applying to both 
PD-L1 positive and negative tumors).  The later study had an upper 95% confidence limit of 9% RR, and 
the combined data from the two studies would result in a response rate of approximately 7%.   As a 
result, we have determined that 9% would be a more appropriate discouraging response rate given the 
more recent and larger report on single agent Pembrolizumab and we consider a promising response 
rate a 20% increment, or a 29% response rate.  With the updated information, we will continue to 
accrue if at least 2/15 patients response (13.3%).  We will maintain the total sample-size at 29 patients.  
Considering the impact of mid-design changes on hypothesis testing, and the variability of outcomes 
from the two relevant historical studies, the updated design is based on having at least 2 out of the first 
15 patients with a response, and then adding an additional 14 patients to better estimate the response 
rate of the combination, rather than conduct a hypothesis test.   With 2+/15 with a response to 


Page 74 of 113 
continue, this is better than the upper 95% CI for the response rate reported in the larger and more 
recent study,  and satisfies the rule for continuing based on the SWOG planned versus attained design of 
Dahlberg (Green SJ and Dahlberg S (1992). Planned Versus Attained Design in Phase II Clinical 
Trials. Statistics in Medicine 11:853-862) for >1/15 responses based on a type I error of 5% and power of 
85% for distinguishing between a 9% and a 29% response rate.  With 29 total patients the SE of the 
response rate will be 9% or less. 
While both drugs are well-tolerated with non-overlapping toxicities, the initial 6 patients will be 
followed in a safety lead-in to observe if a dose adjustment is appropriate.  If in the first 6 patients we 
observe 2 or more patients with dose limiting toxicities (DLTs) (See Section 6.2) in the first cycle this will 
mandate a reduction in the starting dose for all subsequent patients. If dose level -1 has 2 patients with 
DLTs in the first 6, the study will hold accrual. 
During the safety lead-in, we will permit only 3 patients to be a risk for first cycle toxicities at any one 
time.  
With approximately 29 patients, we expect to have to obtain at least 12 patients with pre- and post- 
treatment biopsy material adequate for evaluation for AR pathway activity (AR by IHC and gene 
expression array) and immune profiling. The correlative studies will be used to potentially refine patient 
selection for future studies, and understand the role of AR pathway activities and immune changes on 
the activity of the combination of pembrolizumab plus GTx-024. These correlative studies are 
considered exploratory in the context of this limited Phase 2 study; however, 12 samples provide 80% 
power to detect an effective size of 0.8 (80% of the standard deviation), with a one-sided type I error of 
5%.  
12.5.2 Safety/tolerability 
The safety and tolerability of the combination of pembrolizumab and SARM GTx-024 will be evaluated 
via a safety lead-in. In addition, the CBR will be evaluated at 24 weeks (by RECIST 1.1), the PFS will be 
evaluated, and the duration of response (time from documentation of tumor response to disease 
progression or death) will be evaluated. 


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13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy 
dispensing records, recorded data from automated instruments, laboratory data) that are relevant to 
the clinical trial.  The Site Investigator or their designee will prepare and maintain adequate and 
accurate source documents.  These documents are designed to record all observations and other 
pertinent data for each patient enrolled in this clinical trial.  Source documents must be adequate to 
reconstruct all data transcribed onto the case report forms. 
13.2 Data Capture Methods and management 
Data for this trial will be collected using Medidata RAVE, City of Hope’s electronic capture system. 
Medidata RAVE is a web based, password protected system that is fully compliant with global regulatory 
requirements, including 21CRF Part 11 compliant.  
Study personnel at each site will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific electronic Case Report Form (eCRF). 
13.3 Case Report Forms/ Data Submission Schedule 
Study personnel at each site will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific electronic Case Report Form (eCRF) when the information corresponding to 
that visit is available.  
The investigator is responsible for all information collected on subjects enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy 
by the investigator. All case report forms must be completed by designated study personnel.  The 
completed case report forms must be reviewed, signed and dated by the Site Investigator or designee in 
a timely fashion. 
All data will be collected using electronic data collection system described in Section 13.2, and will be 
submitted according to the timelines indicated in Table 13.3. 
Table 13.3: Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 14 calendar days of treatment administration 
Adverse Event Report Forms 
Safety lead-in Cycle 1 only: within 7 calendar days of AE 
assessment/notification 
All other cycles of the safety lead-in and Phase 2: Within 14 
calendar days of the study visit 
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms (concomitant 
medications etc.) 
Within 10 calendar days of the assessment 
Off Treatment/Off Study Forms 
Within 10 calendar days of completing treatment or being taken 
off study for any reason 
Follow up/ Survival Forms 
Within 14 calendar days of the protocol defined follow up visit 


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Form 
Submission Timeline 
date or call 
13.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.0 ADHERENCE TO THE PROTOCOL 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. Protocol deviations may be on the part of the 
subject, the investigator, or study staff.   
All deviations from the protocol must be documented in study subject source documents and promptly 
reported.  The Study PI will report the deviation according to City of Hope’s deviation policy for 
reporting deviations (See Section 7.0).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & 
SAFETY MONITORING 
15.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
All investigators agrees to: 
o Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when necessary to protect the safety, rights or welfare of 
subjects.  
o Personally conduct or supervise the study (or investigation).  
o Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.  
o Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance 
with §21 CFR 312.64.  
o Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.  
o Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee).  
o Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible 
for initial and continuing review and approval of the clinical study.  
o Promptly report to the IRB and the Sponsor all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments and IND 
safety reports).  
o Seek IRB and Sponsor approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects.  
o Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
Site Lead Investigator Responsibilities 
The Site Lead Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations (CFR). The Site Lead Investigator must assure that all study 
site personnel, including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
It is the responsibility of the Site Lead Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events, 
deviations, and unanticipated problems.  
The Site Lead Investigator will be responsible for assuring that all the required data will be collected and 
entered onto the Case Report Forms at his/her site. For remote or onsite monitoring and auditing, the 
Site Lead Investigator will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all case report forms will be reviewed by the Site Lead 
Investigator and will require his/her final signature to verify the accuracy of the data. 


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An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of participants under the investigator's care; and for the control of drugs under 
investigation.  
15.2 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing 
that sponsor responsibilities as defined in § 21 CFR 312.  
15.3 Protocol Management Team (PMT) 
See Section 7.0. 
15.4 Monitoring/Auditing 
Clinical site monitoring/auditing is conducted to ensure that the rights of human subjects are protected, 
that the study is implemented in accordance with the protocol and regulatory requirements, and that 
the quality and integrity of study data and data collection methods are maintained. Monitoring/ auditing 
for this study will be performed by the City of Hope Office of Clinical Trials Auditing and Monitoring 
(OCTAM). 
Documentation of monitoring/auditing activities and findings by OCTAM will be provided to the study 
team, the PI, and the COH DSMC. 
15.5 City of Hope Data and Safety Monitoring Committee 
The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for all clinical 
trials that are sponsored by City of Hope. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. The committee reviews the 
progress and safety of all active research protocols that are not monitored by another safety and data 
monitoring committee or board. 
The COH DSMC will review and monitor toxicity and accrual data from this trial. Information that raises 
any questions about participant safety will be addressed with the PI, statistician and study team.  
Refer to Section 7.0 for details. 


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16.0 ETHICAL AND REGULATORY CONSIDERATIONS  
16.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
16.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the 
following considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 
Title 21 Part 312 – Investigational New Drug Application  
 
Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  
 
Section 801 of the Food and Drug Administration Amendments Act   
o State of California Health and Safety Code, Title 17 
o COH policies and procedures 
16.3 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the 
federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 
17,  must review and approve this protocol and the informed consent form prior to initiation of the 
study.  All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the IRB.  The 
IRB’s written unconditional approval of the study protocol and the informed consent document will be 
in the possession of the investigator before the study is initiated. 
The IRB will be informed of revisions to other documents originally submitted for review; serious 
unexpected or unanticipated adverse experiences occurring during the study, and any additional 
adverse experiences in accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; an annual 
update and/or request for re-approval; and when the study has been completed. 
Any amendment to the protocol document and accompanying informed consent document/template, 
as developed and provided by the PI, will require review and approval by the COH IRB before the 
changes are implemented in the study. 


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16.4 Informed Consent  
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and 
the HIPAA research authorization form.  Prospective participants will be informed that they may 
withdraw from the study at any time and for any reason without prejudice, including as applicable, their 
current or future care or employment at City of Hope or any relationship they have with City of Hope.  
Prospective participants will be afforded sufficient time to consider whether or not to participate in the 
research. 
After the study has been fully explained, written informed consent will be obtained from either the 
prospective participant or his/her guardian or legal representative before study participation. The 
method of obtaining and documenting the informed consent and the contents of the consent must 
comply with the ICH-GCP and all applicable regulatory requirements. 
Before implementing any study procedure, informed consent shall be documented by the use of a 
written consent form approved by the IRB and signed and dated by the prospective participant or 
his/her legally authorized representative at the time of consent. A copy of the signed informed consent 
will be given to the participant or his/her legally authorized representative. The original signed consent 
must be maintained by the investigator and available for inspection sponsor designated representatives, 
or regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 
16.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures and 
chart review and follow-up procedures. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review and 
follow-up procedures. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
16.6 Special and Vulnerable Populations  
16.6.1.1 
Inclusion of Women and Minorities 
The study is open anyone regardless of gender or ethnicity. Efforts will be made to extend the accrual to 
a representative population, but in a trial which will accrue approximately 29 participants, a balance 
must be struck between subject safety considerations and limitations on the number of individuals 
exposed to potentially toxic or ineffective treatments on the one hand and the need to explore gender, 
racial, and ethnic aspects of clinical research on the other. If differences in outcome that correlate to 
gender, racial, or ethnic identity are noted, accrual may be expanded or additional studies may be 
performed to investigate those differences more fully. 
Pregnant women are excluded because the study drugs may have adverse effects on a fetus in uterus. 


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16.6.1.2 
Exclusion of Children 
Children (< 18 years old of age) are excluded from this study because the disease does not primarily 
affect children.   
16.6.1.3 
Inclusion of HIV Positive Individuals 
Participants with a history of HIV are excluded from receiving protocol therapy due to concerns about 
inadvertent augmentation of infectious and/or inflammatory activity. 
16.6.1.4 
Vulnerable Populations 
45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, or economically or educationally disadvantaged persons as vulnerable 
populations.  
Adults lacking capacity to consent are not excluded from participation. This study does not pose 
additional risks for adults lacking capacity than for the general population.  In such instances, informed 
consent will be sought and documented from the prospective participant’s legally authorized 
representative in agreement with institutional policies and COH IRB approval. 
16.7 Participant Confidentiality  
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any 
study information relating to participants. 
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed participant authorization 
informing the participant of the nature of the PHI to be collected, who will have access to that 
information and why, who will use or disclose that information, ant the rights of a research participant 
to revoke their authorization for use of their PHI. In the event that a participant revokes authorization to 
collect or use PHI, the investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of participant authorization.  For participants 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 participant is alive) at the end of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out 
in accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used. 
Medical records of participants will be securely maintained in the strictest confidence, according to 
current legal requirements. Data will be entered, analyzed and stored in encrypted, password protected, 
secure computers that meet all HIPAA requirements.  All data capture records, drug accountability 
records, study reports and communications will identify the patient by initials and the assigned patient 
number. 
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring/ auditing, IRB reviews, and FDA/regulatory authority inspections. The participant’s 


Page 83 of 113 
confidentiality will be maintained and will not be made publicly available to the extent permitted by the 
applicable laws and regulations. 
16.8 Future Use of Specimens Collected for this Trial  
Left-over specimens will be stored for up to 10 years. 
16.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study.  All City of Hope investigators will follow the City of Hope conflict of interest policy. 
16.10 Financial Obligations, Compensation, and Reimbursement of Participants 
The study drugs pembrolizumab and GTx-024 will be provided by the manufacturer free of charge to 
study participants.  
The research participant nor the insurance carrier will be responsible for the research procedures 
related to this study.  
The research participant will be responsible for all copayments, deductibles, and other costs of 
treatment and diagnostic procedures as set forth by the insurance carrier.  The research participant 
and/or the insurance carrier will be billed for the costs of treatment and diagnostic procedures in the 
same way as if the research participant were not in a research study.   
In the event of physical injury to a research participant, resulting from research procedures, appropriate 
medical treatment will be available at the City of Hope to the injured research participant, however, 
financial compensation will not be available. 
The research participant will not be paid for taking part in this study. 
16.11 Publication/Data Sharing  
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the PI. Any investigator involved with this 
study is obligated to provide City of Hope with complete test results and all data derived from the study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among the City of Hope and 
participating institutions. The publication or presentation of any study results shall comply with all 
applicable privacy laws, including, but not limited to, the Health Insurance Portability and Accountability 
Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov and results will be 
reported on ClinicalTrials.gov within 12 months of the estimated or actual completion date of the trial, 
whichever date is earlier. 


Page 84 of 113 
 
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Nomi, T., et al., Clinical Significance and Therapeutic Potential of the Programmed Death-1 
Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer. Clinical Cancer Research, 2007. 13(7): 
p. 2151-2157. 
51. 
Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces 
regulatory T and myeloid cells within B16 melanoma tumors. Proceedings of the National Academy of 
Sciences of the United States of America, 2010. 107(9): p. 4275-4280. 
52. 
Zhang, L., T.F. Gajewski, and J. Kline, PD-1/PD-L1 interactions inhibit antitumor immune responses in a 
murine acute myeloid leukemia model. Blood, 2009. 114(8): p. 1545-1552. 
53. 
Pilon-Thomas, S., et al., Blockade of Programmed Death Ligand 1 Enhances the Therapeutic Efficacy of 
Combination Immunotherapy against Melanoma. Journal of Immunology, 2010. 184(7): p. 3442-3449. 
54. 
Narayanan, R., et al., Selective androgen receptor modulators (SARMs) negatively regulate triple-negative 
breast cancer growth and epithelial:mesenchymal stem cell signaling. PLoS One, 2014. 9(7): p. e103202. 
55. 
Poole, R., Pembrolizumab: First Global Approval. Drugs, 2014. 74(16): p. 1973-1981. 
56. 
Chang, A.Y., et al., Spatial organization of dendritic cells within tumor draining lymph nodes impacts 
clinical outcome in breast cancer patients. J Transl Med, 2013. 11: p. 242. 
57. 
Setiadi, A.F., et al., Quantitative, architectural analysis of immune cell subsets in tumor-draining lymph 
nodes from breast cancer patients and healthy lymph nodes. PLoS One, 2010. 5(8): p. e12420. 
58. 
Critchley-Thorne, R.J., et al., Applications of cellular systems biology in breast cancer patient stratification 
and diagnostics. Comb Chem High Throughput Screen, 2009. 12(9): p. 860-9. 
59. 
Critchley-Thorne, R.J., et al., Impaired interferon signaling is a common immune defect in human cancer. 
Proc Natl Acad Sci U S A, 2009. 106(22): p. 9010-5. 


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60. 
Critchley-Thorne, R.J., et al., Down-regulation of the interferon signaling pathway in T lymphocytes from 
patients with metastatic melanoma. PLoS Med, 2007. 4(5): p. e176. 
61. 
Salgado, R., et al., Harmonization of the evaluation of tumor infiltrating lymphocytes (TILs) in breast 
cancer: recommendations by an international TILs-working group 2014. Annals of Oncology, 2014. 
62. 
Dawson , S.-J., et al., Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer. New 
England Journal of Medicine, 2013. 368(13): p. 1199-1209. 
63. 
Whiteside, T.L., Exosomes and tumor-mediated immune suppression. The Journal of Clinical Investigation, 
2016. 126(4): p. 1216-1223. 
64. 
Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol, 1982. 5(6): p. 649-55. 
65. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
66. 
Hodi, F.S., et al., Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With 
Advanced Melanoma Treated With Pembrolizumab. Journal of Clinical Oncology, 2016. 
 67. Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, Cescon DW, Iwata H, Campone M, Nanda R, Hui R. 
Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast 
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Page 88 of 113 
APPENDIX A: ECOG PERFORMANCE STATUS 
ECOG Performance Status [64] 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all 
pre-disease performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited 
self-care, confined to bed or chair more than 50% 
of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot 
carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
 


Page 89 of 113 
APPENDIX B: CONTRACEPTION GUIDELINES 
Pembrolizumab and GTx-024 may have adverse effects on a fetus in uterus.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have azoospermia 
(whether due to having had a vasectomy or due to an underlying medical condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in 
women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.); OR  
 have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal 
ligation/occlusion, at least 6 weeks prior to screening; OR  
has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or impregnating a 
partner, respectively, while receiving study drug and for 120 days after the last dose of study drug by complying 
with one of the following:   
1. Practice abstinence† from heterosexual activity; OR  
2. Use (or have their partner use) acceptable contraception during heterosexual activity.   
Single method (one of the following is 
acceptable): 
o 
intrauterine device (IUD) 
o 
vasectomy of a female subject’s 
male partner  
o 
contraceptive rod implanted into the 
skin 
Combination method (requires use of two of the following): 
o 
diaphragm with spermicide (cannot be used in 
conjunction with cervical cap/spermicide) 
o 
cervical cap with spermicide (nulliparous women only)   
o 
contraceptive sponge (nulliparous women only)  
o 
male condom or female condom (cannot be used 
together)  
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies 
and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.   
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an 
acceptable method of contraception for subjects participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus (unborn 
baby) if pregnancy were to occur during the study.  In order to participate in the study subjects of childbearing 
potential must adhere to the contraception requirement (described above) from the day of study medication 
initiation (or 14 days prior to the initiation of study medication for oral contraception) throughout the study period 
up to 120 days after the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be entered into the 
study.  


Page 90 of 113 
 
APPENDIX C: GTX-024 PILL DIARY 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 
Study drug Instructions – When and How: 
o Take GTx-024 once a day with water 
o Swallow pills; do not chew them or crush them 
o Take the drugs at approximately the same time each day with or without food 
o Do not skip any doses 
 
What if I miss a scheduled dose? 
o If less than 12 hours have passed from the scheduled time, then take the missed dose as soon as 
you remember.   
o If more than 12 hours have passed from the scheduled time, then skip the missed dose. Wait for 
your next scheduled dose. Do not take extra medicine to make up the missed dose. 
 
What if I vomit a dose? 
o If you vomit your pills, write this down in your pill diary.   
o Wait until the next scheduled dose; do not take extra medicine to make up the vomited dose.  
 
Additional Instructions: 
o Keep your study drug in the original container until you take it. 
o Do NOT throw away empty pill bottles or unused pills. 
o Bring this diary, all pill bottles, and any unused pills to each clinic 
visit.  
o Contact your study doctor or nurse if you are having any new or 
worsening side effects. 
Contact Information for 
Study Doctor or Nurse 
 
Phone: 
Name: 
 
 
How to fill the Pill Diary (Example Only) 
To be filled by study team                           # of pills to take:  1 
 
Participant Only 
Week 1 
Cycle Day 
Week 
Day 
Date 
Time 
# of pills 
taken 
Comments 
1 
Mon 
4/10/17 
10:10 AM 
1 
 
2 
Tues 
4/11/17 
10:30 AM 
1 
 
 


Page 91 of 113 
 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 
 
To be filled by study team                                   # of pills to take:______ 
 
Week 1 
Cycle 
Day 
Week Day 
Date 
Time 
# of pills 
taken 
Comments 
1 
 
 
___:___AM/PM 
 
 
2 
 
 
___:___AM/PM 
 
 
3 
 
 
___:___AM/PM 
 
 
4 
 
 
___:___AM/PM 
 
 
5 
 
 
___:___AM/PM 
 
 
6 
 
 
___:___AM/PM 
 
 
7 
 
 
___:___AM/PM 
 
 
 
 
To be filled by study team                                  # of pills to take:______ 
 
Week 2 
Cycle 
Day 
Week Day 
Date 
Time 
# of pills 
taken 
Comments 
8 
 
 
___:___AM/PM 
 
 
9 
 
 
___:___AM/PM 
 
 
10 
 
 
___:___AM/PM 
 
 
11 
 
 
___:___AM/PM 
 
 
12 
 
 
___:___AM/PM 
 
 
13 
 
 
___:___AM/PM 
 
 
14 
 
 
___:___AM/PM 
 
 
 
Participant Signature (please sign when submitting your diary) 
 
____________________________________________________________   
Date: 
 
____/______/_____ 
 


Page 92 of 113 
 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 
 
To be filled by study team                                   # of pills to take:______ 
 
Week 3 
Cycle 
Day 
Week 
Day 
Date 
Time 
# of pills 
taken 
Comments 
15 
 
 
___:___AM/PM 
 
 
16 
 
 
___:___AM/PM 
 
 
17 
 
 
___:___AM/PM 
 
 
18 
 
 
___:___AM/PM 
 
 
19 
 
 
___:___AM/PM 
 
 
20 
 
 
___:___AM/PM 
 
 
21 
 
 
___:___AM/PM 
 
 
 
 
Participant Signature (please sign when submitting your diary) 
_____________________________________________________________  
  
Date: 
____/______/_____ 
 
Study Team ONLY:  # of Pill Bottles Returned: ________    # of Pills Returned: ________ 
Compare with drug diary entries made by participant/guardian.  If there is a discrepancy (in the # of bottles or the
pills returned), please reconcile (initials & date):____________________________ 
 


Page 93 of 113 
 
APPENDIX D: RECIST CRITERIA V1.1  
The following criteria describe RECIST Criteria V1.1 [65]. 
Disease Parameters 
Measurable disease  
Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be considered 
measurable.  If the investigator thinks it appropriate to include them, the conditions under which such 
lesions should be considered must be defined in the protocol. 
Malignant lymph nodes   
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis 
when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
Non-measurable disease   
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
Target lesions   
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of 
all involved organs, should be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters.  If lymph nodes are to be included in the sum, then only the short axis is added into the sum.  


Page 94 of 113 
The baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
Non-target lesions   
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
Clinical lesions   
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes) and 10 mm diameter as assessed using calipers (e.g., skin nodules).  In the case 
of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended.  
Chest x-ray   
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI   
This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g. 
for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable globally.  
As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should 
be optimized for the evaluation of the type and site of disease.  Furthermore, as with CT, the modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans.  Bodyscans should be performed with breath-hold scanning techniques, if 
possible. 


Page 95 of 113 
PET-CT  
At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of 
optimal diagnostic CT quality for use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and 
oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  Note, however, 
that the PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
Ultrasound   
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent review 
at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised.  If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy   
The utilization of these techniques for objective tumor evaluation is not advised.  However, such 
techniques may be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response (CR) or surgical resection is an 
endpoint. 
Tumor markers  
Tumor markers alone cannot be used to assess response.  If markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response.  Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin 
Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in first-line trials 
in ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology   
These techniques can be used to differentiate between partial responses (PR) and complete responses 
(CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual 
benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 


Page 96 of 113 
FDG-PET   
While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate 
the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible 'new' disease).  New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm:  
o Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
o No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at follow-
up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional follow-up CT  scans are 
needed to determine if there is truly progression occurring at that site (if so, the date of PD will 
be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
o FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET 
and biopsy resolution/sensitivity. 
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR):  
Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of 
one or more new lesions is also considered progressions). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study 
 


Page 97 of 113 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, 
not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
Table D1: For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented at least once >4 wks. from 
baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.”  
Every effort should be made to document the objective progression even after discontinuation of treatment. 
 


Page 98 of 113 
Table D2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised 
Duration of Response 
Duration of overall response:   The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since 
the treatment started). 
The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that progressive disease is objectively 
documented. 
 
Duration of stable disease:   Stable disease is measured from the start of the treatment until the criteria 
for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 


Page 99 of 113 
 
APPENDIX E: IMMUNE RELATED RESPONSE CRITERIA  
Immune related RECIST (irRECIST) is an adaptation of RECIST 1.1 to account for the unique tumor 
response characteristics to treatment with new immunotherapeutic agents, including pembrolizumab. 
RECIST 1.1 was developed based on treatment with cytotoxic agents. Immunotherapeutic drugs, such as 
pembrolizumab, may produce antitumor effects by potentiating endogenous cancer-specific immune 
responses. The response patterns seen with such an approach may extend beyond the typical time 
course of responses seen with cytotoxic agents, and can manifest as clinical responses after initial 
increases in tumor burden or even the appearance of new lesions. Standard RECIST 1.1 may not provide 
an accurate assessment of response to immunotherapeutic agents such as pembrolizumab [66], and will 
therefore be used with the adaptations referred to as irRECIST. 
Antitumor response based on total measurable tumor burden  
For the irRECIST, only index and measurable new lesions are taken into account (in contrast to 
conventional WHO criteria, which do not require the measurement of new lesions, nor do they include 
new lesion measurements in the characterization of evolving tumor burden). At the baseline tumor 
assessment, the sum of the products of the two largest perpendicular diameters (SPD) of all index 
lesions (five lesions per organ, up to 10 visceral lesions) is calculated. At each subsequent tumor 
assessment, the SPD of the index lesions and of new, measurable lesions (up to 5 new lesions per organ; 
10 visceral lesions) are added together to provide the total tumor burden: Tumor Burden = SPD index 
lesions + SPD new, measurable lesions. 
Table E1: Comparison WHO and irRECIST criteria 
 
  
WHO 
irRECIST 
New, measurable lesions 
Always represent PD  
Incorporated into tumor burden  
New, 
nonmeasurable lesions 
Always represent PD  
Do not define progression (but preclude irCR)  
Non-index lesions 
Changes contribute to defining BOR of CR, PR, 
SD, and PD  
Contribute to defining irCR (complete 
disappearance required)  
CR 
Disappearance of all lesions in two 
consecutive observations not less than 4 wk 
apart  
Disappearance of all lesions in two consecutive 
observations not less than 4 wk apart  
PR 
≥50% decrease in SPD of all index lesions 
compared with baseline in two observations 
at least 4 wk apart, in absence of new lesions 
or unequivocal progression of non-index 
lesions  
≥50% decrease in tumor burden compared with 
baseline in two observations at least 4 wk apart  
SD 
50% decrease in SPD compared with baseline 
cannot be established nor 25% increase 
compared with nadir, in absence of new 
lesions or unequivocal progression of non-
index lesions  
50% decrease in tumor burden compared with 
baseline cannot be established nor 25% increase 
compared with nadir  
PD 
At least 25% increase in SPD compared with 
nadir and/or unequivocal progression of non-
index lesions and/or appearance of new 
lesions (at any single time point)  
At least 25% increase in tumor burden compared 
with nadir (at any single time point) in two 
consecutive observations at least 4 wk apart  


Page 100 of 113 
Time-point response assessment using irRECIST  
Percentage changes in tumor burden per assessment time point describe the size and growth kinetics of 
both conventional and new, measurable lesions as they appear. At each tumor assessment, the 
response in index and new, measurable lesions is defined based on the change in tumor burden (after 
ruling out irPD). Decreases in tumor burden must be assessed relative to baseline measurements (i.e., 
the SPD of all index lesions at screening). The irRECIST were derived from WHO criteria and, therefore, 
the thresholds of response remain the same. However, the irRECIST response categories have been 
modified from those of WHO criteria as detailed in Table E1. 
Overall response using the irRECIST  
The sum of the products of diameters at tumor assessment using the immune-related response criteria 
(irRECIST) for progressive disease incorporates the contribution of new measurable lesions. Each net 
Percentage Change in Tumor Burden per assessment using irRECIST criteria accounts for the size and 
growth kinetics of both old and new lesions as they appear. 
Definition of Index Lesions Response Using irRECIST  
irComplete Response (irCR): 
Complete disappearance of all index lesions. This category encompasses 
exactly the same subjects as “CR” by the mWHO criteria. 
irPartial Response (irPR): 
Decrease, relative to baseline, of 50% or greater in the sum of the 
products of the two largest perpendicular diameters of all index and all 
new measurable lesions (i.e. Percentage Change in Tumor Burden).  
Note: the appearance of new measurable lesions is factored into the 
overall tumor burden, but does not automatically qualify as progressive 
disease until the SPD increases by ≥25% when compared to SPD at nadir 
irStable Disease (irSD): 
Does not meet criteria for irCR or irPR, in the absence of progressive 
disease. 
irProgressive Disease (irPD) 
At least 25% increase Percentage Change in Tumor Burden (i.e., taking 
sum of the products of all index lesions and any new lesions) when 
compared to SPD at nadir 
 
Definition of Non-Index Lesions Response Using irRECIST  
irComplete Response (irCR): 
Complete disappearance of all non-index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO 
criteria 
irPartial Response (irPR) or irStable Disease 
(irSD): 
Non-index lesion(s) are not considered in the definition of PR, 
these terms do not apply 
irProgressive Disease (irPD) 
Increases in number or size of non-index lesion(s) does not 
constitute progressive disease unless/until the Percentage 
Change in Tumor Burden increases by 25% (i.e., the SPD at nadir 
of the index lesions increases by the required amount) 


Page 101 of 113 
Impact of New Lesions on irRECIST  
New lesions in and by themselves do not qualify as progressive disease. However their contribution to 
total tumor burden is included in the SPD which in turn feeds into the irRECIST criteria for tumor 
response. Therefore, new non-measurable lesions will not discontinue any subject from the study. 
Definition of Overall Response Using irRECIST  
Overall response using irRECIST will be based on these criteria (Table E2): 
irComplete Response (irCR): 
Complete disappearance of all tumor lesions (index and non-index together with 
no new measurable/unmeasurable lesions) for at least 4 weeks from the date of 
documentation of complete response 
irPartial Response (irPR): 
The sum of the products of the two largest perpendicular diameters of all index 
lesions is measured and captured as the SPD baseline. At each subsequent tumor 
assessment, the sum of the products of the two largest perpendicular diameters 
of all index lesions and of new measurable lesions are added together to provide 
the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to 
baseline of the irSPD compared to the previous SPD baseline, of 50% or greater is 
considered an immune Partial Response (irPR). 
irStable Disease (irSD): 
irSD is defined as the failure to meet criteria for immune complete response or 
immune partial response, in the absence of progressive disease 
irProgressive Disease (irPD) 
It is recommended in difficult cases to confirm PD by serial imaging. Any of the 
following will constitute progressive disease:  
 
At least 25% increase in the sum of the products of all index lesions over 
nadir SPD calculated for the index lesions.  
 
At least a 25% increase in the sum of the products of all index lesions 
and new measurable lesions (irSPD) over the baseline SPD calculated for 
the index lesion. 
Table E2. Derivation of irRECIST overall responses 
Measurable response 
Nonmeasurable response 
Overall response 
Index and new, measurable 
lesions (tumor burden),*% 
Non-index lesions 
New, nonmeasurable 
lesions 
Using irRECIST 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
↓100 
Unequivocal progression 
Any 
irPR† 
↓≥50 
Absent/Stable 
Any 
irPR† 
↓≥50 
Unequivocal progression 
Any 
irPR† 
↓<50 to <25↑ 
Absent/Stable 
Any 
irSD 
↓<50 to <25↑ 
Unequivocal progression 
Any 
irSD 
≥25 
Any 
Any 
irPD† 
*Decreases assessed relative to baseline (scan prior to start of any protocol therapy), including measurable lesions only  
†Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 wk apart. 
 


Page 102 of 113 
Immune-Related Best Overall Response Using irRECIST (irBOR)  
irBOR is the best confirmed irRECIST overall response over the study as a whole, recorded between the 
date of first dose until the last tumor assessment before subsequent therapy (except for local palliative 
radiotherapy for painful bone lesions) for the individual subject in the study. For the assessment of 
irBOR, all available assessments per subject are considered.  
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks after 
the criteria for response are first met. 


Page 103 of 113 
 
Appendix F: Stool Collection Procedure 
STOOL COLLECTION KIT GENERAL INSTRUCTIONS 
As a part of your participation in the current study, we have some specific instructions related to 
collection of stool.  Please abide by these instructions, as they are essential for the proper conduct of 
the study. 
You are being asked to collect samples at the following times:
 
 7 days prior to Cycle 1 Day 1 
 Cycle 5 Day 1 (+/- 7 days), every 4 cycles (+/
- 7 days) and end of 
treatment (+/
-7 days) 
 
If you have any questions about sample collection, please call this number: ______________________ 
USING THE STOOL COLLECTION KIT 
Before you begin, review the following: 
a. Make sure you have a 
collection hat  and collection tube. 
b. Make sure you are able to deliver the sample to City of Hope
 within 1 week. 
 
STEP ONE: Please place the collection hat 
around the rim of your toilet seat for stool 
collection.  
 
 
STEP TWO: Unscrew the collection tube cap 
and use the spoon to scoop one spoonful of 
feces (about the size of a quarter) from a 
sample. Place the sample in the collection tube. 
Tighten the cap and shake to mix the contents 
thoroughly (invert 10 times) to create a 
suspension.  
Note: Some fecal material may be difficult to re-
suspend. As long as the material is suspended, the 
sample 
is 
stabilized. 
Foaming/frothing 
during 
shaking is normal.  
 


Page 104 of 113 
STEP THREE: Wash hands well, and write 
today’s date on the label. 
 
STEP FOUR: Place the plastic tube in the bag, 
and seal the back using the adhesive tape 
already present on the bag.  
 
 
STEP FIVE: Bring the sample to your City of 
Hope appointment.   
THANK YOU FOR YOUR PARTICIPATION! 
 
 


Page 105 of 113 
Appendix G:    Diet and Stool Frequency Log  
DIET and STOOL FREQUENCY LOG - GENERAL INSTRUCTIONS 
As a part of your participation in the current study, we are requesting that you complete a study log every day. 
General pointers: 
 
When you come to the clinic, bring your logs with you. 
 
Each page has room for seven days – one row should be completed for each day. 
 
Please avoid any intake of yogurt, yogurt-containing foods, or other bacteria-fortified foods.  
Example of how the top part of the log will look: 
 
A study team member will complete the information in this box before you leave the clinic. 
 
Example of how the information you enter might look:   
 
You or someone close to can complete the log for you, so long as the information is correct.  
 
List all prescription and non-prescription medications. 
 
The person who completes that day’s entry should write his or her initials in the last column. 
 
Example of the signature line: 
 
When you hand over the document to the study team, they will ask to sign and date at the bottom of each log if you agree that the 
information is complete and correct. 
 
COMPLETED BY STUDY TEAM                       Participant Initials:                                Participant Research Number:                            
 


Page 106 of 113 
Day 
and 
Date 
General description of food I ate: 
Did I eat 
yogurt or take 
probiotics? 
How was my stool frequency? 
Was a stool 
sample 
collected? 
Medications taken 
Initials of 
person filling 
information 
 
Eggs, toast, juice 
Ham sandwich, coke, potato chips 
Steak, mashed potatoes, wine 
⃝ Yes 
⃝ No 
⃝Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
Vitamin 
C, 
Lipitor 
 
JBC 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
X 
X 
X 


Page 107 of 113 
Day 
and 
Date 
General description of food I ate: 
Did I eat 
yogurt or take 
probiotics? 
How was my stool frequency? 
Was a stool 
sample 
collected? 
Medications taken 
Initials of 
person filling 
information 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
  
At the time of handing over the document   --   Participant Signature: __________________________________________ Date _____________________________
X 


Page 108 of 113 
 
APPENDIX H: AT HOME SAMPLE COLLECTION KIT CONTENTS 
 
Contents of each kit to be provided to participants for at home collection: 
[] Copy of Appendix F: Instructions for Stool Specimen Collection 
[] Stool collection hat 
[] Specimen tube with label attached 
Label should have participant identifier added; the participant will be asked to add the 
date himself/herself. 
[] Plastic sealable bag 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 109 of 113 
 
APPENDIX I: REGISTRATION COVERSHEET  
IRB 16131:  A Phase 2 Clinical Trial of the Combination of Pembrolizumab and Selective Androgen Receptor 
Modulator (SARM) GTX-024 in Patients with Advanced Androgen Receptor (AR) Positive Triple Negative Breast 
cancer (TNBC). 
Data Coordinating Center:   
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Tel:  626-256-4673 x 83968  
Email:  DCC@coh.org (use #secure# in subject line) 
Site Principal Investigator  
Name: 
 
Address: 
 
 
Phone:  
Fax:  
e-mail: 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
Medical Record No: 
Investigator/Treating Physician: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
 Hispanic 
Codes: 
 
Caucasian 
 Non-Hispanic 
01 Private 
06 Military or Veterans 
Adm. sponsored 
 
Asian 
 Other_________________ 
02 Medicare 
07 Self-pay (no 
insurance) 
 
American Indian 
 
03 Medicare & 
private ins. 
08 No means of 
payment  (no insurance) 
 
Native Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other_______________
____________________ 
05 Medicaid & Medicare 
Reason for Screen Failure:  
 
Reason for Failing to Initiate Protocol Therapy: 
 
 
 
 
 
 


Page 110 of 113 
 
APPENDIX J: SAMPLE SHIPPING GUIDELINES  
Follow the requirements for the proper packaging and shipping of biomedical material found in 42 CFR 
Part 72 - Interstate Shipment of Etiologic Agents Centers for Disease Control and Prevention, Office of 
Health and Safety Biosafety Branch. 
 
1. Samples must be de-identified with no PHI. Aim to ship samples on a Monday through 
Thursday. If this is not feasible, advance arrangements should be made with Dr. Yuan 
(yuyuan@coh.org) and Dr. Susan Yost (suyost@coh.org). Notify Dr. Yuan and Dr. Susan Yost of 
impending shipment. Billing information can be requested at that time. Also, on the day of 
shipment, please email recipient the sample shipment information and a sample manifest. 
2. Peripheral Blood Samples: For sample processing, please refer to section 9.3. Please ship to:  
Dr. Tim Synold 
Cc: Lesley Smith-Powell 
Analytical Pharmacology Core Facility (APCF) 
Shapiro 1042 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Tel: 626-218-2954 
tsynold@coh.org; Lsmith-Powell@coh.org 
 
3. Pathology Slides/Blocks: Batch ship with frozen gel ice-packs in order to prevent the melting of 
paraffin-embedded tissue blocks during transit to: 
Dr. Susan Yost 
Department of Medical Oncology & Therapeutic Research 
Building 51, City of Hope National Medical Center 
1500 East Duarte Rd, Duarte, CA  91010  
Direct: 626-218-0499  Internal x 80499 
suyost@coh.org 
 
4. Frozen samples: Batch ship on dry ice via FedEx. The shipment should contain enough dry ice to 
last at least 72 hours. When shipping frozen specimens from long distances, it is best to use a 
combination of dry ice and frozen gel ice-packs. 
 
Process tumor biopsy or large tumor tissue as follows: 
Materials Needed 
 
PBS 
 
Freezing media: 50% media (RPMI or DMEM), 40% FBS, and 10% DMSO 
a) Collect biopsy or large tumor tissue at time of surgery and place in PBS or RPMI media on 
ice.  Process samples as soon as possible. 
b) For available tissue biopsies, proceed directly to “step e”. 
c) For available large tumor tissue, quickly mince tissue into ~5mm3 (~1/4 inch) samples. 


Page 111 of 113 
 
d) Aliquot available tissue by placing one tumor tissue biopsy or two 5mm3 tumor samples per 
2mL labelled cryovial containing 1mL ice-cold freezing media. 
e) Immediately place vial in -80°C freezer overnight to cryopreserve at controlled rate of -
1°C/min using a rate controlled container.  
f) Send samples to Shabnam Pathan as follows:    
 
Ke Cui 
CC: Biospecimen Coordinator Shabnam Pathan 
COH Biorepository Core 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
626-218-1848; 626-218-0462 
kcui@coh.org; spathan@coh.org 
 
 
5. Microbiome specimens: See Appendix F for stool collection and ship samples to: 
Ke Cui 
CC: Biospecimen Coordinator Shabnam Pathan 
COH Biorepository Core 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
626-218-1848; 626-218-0462 
kcui@coh.org; spathan@coh.org 
Approximately 75-125 samples stool samples will be temporarily stored at -80oC in the Analytical 
Pharmacology Core Facility (APCF) in Shapiro 1042 (Dr. Tim Synold/Leslie Smith-Powell) until batch 
shipping to TGen: 
 
 
Sarah Highlander, PhD, Director 
TGen Clinical Microbiome Services Center 
Pathogen and Microbiome Division 
Translational Genomics Research Institute 
3051 W. Shamrell Blvd., Suite 106 
Flagstaff, AZ 86005 
shighlander@tgen.org | 928-213-6996 
 
 
 
6. DNA and RNA Sequencing 


Page 112 of 113 
 
Tumor DNA and RNA sequencing will be performed at Tempus. No identifiable information will 
be sent to Tempus and all unused specimen including DNA/RNA extract, FFPE slides and fresh 
frozen specimen will be returned to COH investigator. Tempus will not store nor conduct any 
other research with the unused or leftover tissue 
 
Tempus xT Panel (595 genes): 15 FFPE +1 H&E for NGS and PD-L1 (20% tumor --- ratio of tumor 
nuclei to benign nuclei; 5-25mm2), plus normal sample (buffy coat from 1-2 x 8 ml tubes whole 
blood).  
 
Ship to:  
 
Tempus 
600 West Chicago Ave. Ste 510 
Chicago, IL 60654 
800.739.4137 
 
 
 
 
 


Page 113 of 113 
 
APPENDIX K: EXPEDITED REPORTING COVERSHEET 
NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT 
For Use by Participating Institutions Only 
THIS FORM ALONG WITH A COPY OF THE MEDWATCH 3500 OR IRB REPORTING FORM MUST BE EMAILED TO DCC@COH.ORG 
WITHIN 24 HOURS OF KNOWLEDGE OF ONSET OF SERIOUS ADVERSE EVENT OR UNANCTICIPATED PROBLEM (Use #secure# in 
subject line) 
COH IRB #16131- Participating Site IRB # ___________ 
From: 
Date: 
Phone No.: 
Email: 
Reporting Investigator: 
Event:  
Participant ID: 
Institution: 
Date Event Met Reporting Criteria (as defined in protocol):   
 
Type of Report: 
 Initial    Follow-up 
CTCAE Grade:   
 G1/mild    G2/moderate     G3/severe    G4/life threatening   
 G5 
Attribution to Pembrolizumab: 
 Unrelated   Unlikely   Possible    Probable   Definite 
Attribution to GTx-024 
 Unrelated   Unlikely   Possible    Probable   Definite 
Historical/Known Correlation to 
pembrolizumab: 
 Expected    Unexpected 
Historical/Known Correlation to 
GTx-024: 
 Expected    Unexpected   
Meets Definition of Serious AE:      Serious      Non-serious 
Meets Definition of 
Unanticipated Problem: 
   UP      Not a UP 
Has the event been reported to 
the following institution’s IRB? 
   No      Yes; Date:_____/____/_____ 
 
Authorized Investigator Signature:   
Date:____/____/____