Conditions: Breast Neoplasms
Keywords: Hormone Therapy Resistant Estrogen Receptor-Positive Estrogen Receptor-Negative
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 38
Healthy volunteers: no

Brief summary:
The investigators propose a randomized two arm trial, using Simon's 2-stage design, in ER+ patients with therapy resistant breast cancer to test the optimal sequence and dosing of epigenetic immune priming in hormone therapy resistance breast cancer. A third arm (Arm C) will include ER-negative patients who will follow the concurrent priming, but exclude tamoxifen. The two arms all include vorinostat, tamoxifen, and pembrolizumab to evaluate

* Sequential priming - begin pembrolizumab in Cycle 1 (Arm B and Arm C) and,
* Concurrent priming with maximal dosing of both epigenetic and immune modulators- begin pembrolizumab on day 1 in Cycle 2 (Arm A)

Detailed description:
Unique aspects of this study:

This is the first study to look at the response of hormone therapy resistance breast cancer to epigenetic immune priming. It is also the first study to look at the combination of an Histone deacetylase (HDAC) inhibitor (vorinostat), an anti-estrogen (tamoxifen) and a PD-1 inhibitor, pembrolizumab in pre or postmenopausal patients with ER+ advanced breast cancer with progression on multiple prior therapies.

Recent preclinical studies have further suggested that epigenetic priming may be even more effective in ER-negative tumors that do not respond to immune check point inhibitors or have low PD-1/PD-L1 expression. The goal of this study is to demonstrate that Vorinostat can increase PD-1 and PD-L1 expression.

In a third arm the study will evaluate the role of epigenetic priming in tumors that are ER-negative.

Arms:
arm 1: Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1) arm 2: Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2) arm 3: Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)

Interventions: intervention 1: Tamoxifen intervention 2: Vorinostat intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_001.pdf: 
Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.
Reversing Therapy Resistance with Epigenetic-Immune 
Modification
(Pembrolizumab, Vorinostat, Tamoxifen)
Protocol Number:  CC #147523   
Study Drugs: pembrolizumab, vorinostat, tamoxifen,
Version Number:  3.0
Version Date:  07/28/2016
IND Number: Exempt   
Principal Investigator (Sponsor-Investigator)    
Pamela N. Munster, MD
UCSF Helen Diller Family Comprehensive Cancer Center
Co-Investigators
Amy Jo Chien, MD
Michelle Melisko, MD
Mark Moasser, MD
John Park, MD
Anne Reinert, MD
Hope Rugo, MD
Melanie Majure, MD
Statistician
Joan F. Hilton, ScD, MPH 
UCSF Box 0560
Lead Clinical Research Coordinator
Amy Deluca
Revision History
NCT # 02395627


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Page 2 of 83
Version 3.0
Version 2.0
Version 1.3
Version 1.2
Version 1.1
Version 1.0
07/28/16
07/07/16
01/23/15
11/17/14
8/11/14




Protocol Signature Page
Protocol No.: 3.0    
Version Date:  07/28/16 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review
Committee (PRC), Committee on Human Research (CHR), and Data Safety Monitoring
Committee (DSMC).
2. I will conduct the study in accordance with applicable CHR requirements, Federal
regulations, and state and local laws to maintain the protection of the rights and welfare
of study participants.
3. I certify that I, and the study staff, have received the requisite training to conduct this
research protocol.
4. I have read and understand the information in the Investigators’ Brochure (or
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to conduct
the protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable
ethical principles, the Statement of Investigator (Form FDA 1572), and with local
regulatory requirements. In accordance with the FDA Modernization Act, I will ensure the
registration of the trial on the www.clinicaltrials.gov website.
5. I agree to maintain adequate and accurate records in accordance with CHR policies,
Federal, state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date
Principal Investigator
Site
Printed Name
Signature
Date


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Abstract
Title:
Reversing therapy resistance with epigenetic-immune modification: phase II trial of Vorinostat, 
Tamoxifen and Pembrolizumab in hormone receptor expressing advanced breast cancer.
Patient population:
Patients with ER+ hormone therapy resistant (HRT) and ER-negative breast cancer 
Rationale for study:
Background
More than two thirds of all advanced breast cancers are dependent on estrogen, and the 
introduction of selective estrogen receptor modulators (SERMs) has dramatically improved the 
survival of women with breast cancer. Unfortunately, the development of hormone therapy 
resistance in breast cancer is one of the most frequent causes of cancer death in women 
worldwide. This proposal is focused on the potential role of epigenetic immune priming to 
reverse therapy resistance in pre and postmenopausal breast cancer. Initially focused on 
hormone therapy positive tumors, recent preclinical studies have further suggested that 
epigenetic priming may be even more effective in ER-negative tumors that do not respond to 
Immune check point inhibitors or have low PD-1/PD-L1 expression. The goal of this study is to 
demonstrate that Vorinostat can increase PD-1 and PD-L1 expression. 
The goal of immune priming is to increase the number and composition of tumor infiltrating 
lymphocytes, which renders this a relevant approach to therapy resistant TNBC or ER-negative 
HER2-positive tumors
The role of HDAC inhibitors in breast cancer 
The role of epigenetic modulation has been studied extensively in breast cancer therapy. We 
have previously shown that epigenetic modulation with an HDAC inhibitor can reverse hormone 
therapy resistance and force cells into programmed cell death1. Based on these preclinical 
studies, we had proposed two clinical trials testing HDAC inhibitors with hormonal therapy in 
ER+ breast cancer. In a first clinical trial, we evaluated the role of vorinostat (VOR) in reversing 
therapy resistance in advanced breast cancer2. The objective response rate by RECIST criteria 
was 19%, the clinical benefit rate (response or stable disease >24 weeks) was 40%, and the 
median response duration was 10.3 months (confidence interval: 8.1–12.4). A second trial 
(ENCORE 301) evaluated entinostat and exemestane. The median overall survival in the 
combination arm was 28.1 months compared to 19.8 months in the exemestane only arm (HR = 
0.59; P = 0.036). 
Programmed cell death 1 (PD-1) and its ligand PD-L1 in breast cancer 
Inhibition of the PD-L1/PD-1 axis has been a major milestone in many cancer types. Clinically, 
epigenetic immune regulation has been implicated in priming lung cancer cells to PD-1 
inhibitors, which resulted in prolonged responses3,4. Increased PD-L1 expression has been 
observed in hormone therapy resistance, frequently reported with loss of progesterone receptor 
(PR) expression, a measure of hormone therapy resistance5. Hence, PD-1 inhibitors may have 
a role in hormone therapy resistant breast cancer, and PD-1 inhibitors may be more effective 
after epigenetic immune priming. Several investigators have shown that HDAC inhibitors have 
immune modulatory functions, including modulation of Tregs, FoxP3 expression, changes in 
tumor-infiltrating lymphocytes (TILs), induction of PD-L1 expression and blockage of PD-1 
signaling. Hence, the combination of HDAC inhibitors may potentiate the efficacy of PD-1 
inhibitors6.


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Optimal Epigenetic Immune priming (EIP) 
Based on the established role of HDAC inhibitors in reversing hormone therapy resistance to 
antiestrogens and aromatase inhibitors and therapy resistance in ER-negative tumors , and the 
provocative role of HDAC inhibitors in modulating tumor immunity, we propose to test the role of 
epigenetic immune priming (EIP) in acquired therapy resistance. In a three-arm Phase II trial, 
we will explore concurrent and sequential EIP, testing two principles: 

Sequential priming with optimal immune activation (Arm B and C) and, 

Concurrent priming with maximal dosing of both epigenetic and immune modulators (Arm 
A).
Primary objective: 
a) To define the optimal approach for epigenetic immune priming in breast cancer on the 
basis of overall response rate (ORR: CR+PR+SD at 24 weeks).
b) Safety and tolerability of vorinostat, tamoxifen and pembrolizumab
Secondary objectives:
a) To define the optimal approach for epigenetic immune priming in therapy –resistant 
breast cancer
b) Determine the impact of vorinostat on PD-L1 expression in ER-positive tumors and ER-
negative  tumors 
c)
To assess duration of response (DOR) 24 week landmark progression free survival 
(PFS:24) 
d) Median PFS and overall survival (OS) 
e) Tumor responses will also be calculated by Immune Related Response-Criteria (irRC). 
Exploratory objectives:
a) To evaluate changes in expression of immune checkpoint receptors / ligands 
(programmed death receptor-1 [PD-1]/programmed death ligand-1 [PD-L1]) in tumor 
biopsies pre- and post-therapy in tumor and immune cells.
b) To assess the ratio of effector T cells:  regulatory T cells in blood and tumor biopsies 
pre- and post-therapy.
c)
To evaluate inflammatory T cell signature changes in blood and tumor biopsies pre- and 
post-therapy.
d) To evaluate changes in number of myeloid-derived suppressor cells (MDSCs) in 
peripheral blood and tumor biopsies pre- and post-therapy.
e) To evaluate changes in histone acetylation in peripheral blood cells and tumor biopsies 
pre- and post-therapy
f)
Initial comparison to vorinostat induced PD-1 in lymphocytes, PD-L1 modulation in ER-
positive and ER-negative tumors 
Study design:


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We propose a randomized two-arm trial, using Simon’s 2-stage design, in ER+ patients with 
therapy resistant breast cancer to test the optimal sequence and dosing of epigenetic immune 
priming in hormone therapy resistant breast cancer. A third arm (Arm C) will include ER-
negative patients who will follow the concurrent priming, but exclude tamoxifen. 
The two arms all include vorinostat, TAM and pembrolizumab to evaluate 

Sequential priming – begin pembrolizumab in Cycle 1  (Arm B and Arm C) and,

Concurrent priming with maximal dosing of both epigenetic and immune modulators– 
begin pembrolizumab on day 1 in Cycle 2  (Arm A)
Drug combination: We propose an exploratory biomarker study to test the combination of 
pembrolizumab and vorinostat. 
Population:
We will test this combination in patients with tumors that may have unknown or low PD-L1 
expression by prior testing (e.g. prior Keynote study screen failures). Patients may have 
progressed on prior PD-1/PD-L1 checkpoint inhibitors. Tumor must have less than 1% ER 
expression (HER2 positive or negative) 
Schematic of the study design
 


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Figure 1. Schematic of dosing schedule 
Number of patients: 
20-87 patients
Duration of therapy:
Patients may continue treatment for 24 months from the time of study entry, and longer with 
permission of the sponsor and Merck. 
Duration of follow up:
Patients will be followed for 30 days after completion of treatment or removal from study, and 
serious adverse events will be collected for 30 days after the end of treatment.
Duration of study:
The study will conclude when all enrolled patients have been followed for more than 30 days 
following completion of therapy. The estimated duration of study, from start of enrollment to final 
study report is 4 years.


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Study drugs:
Tamoxifen (generic) is a non-steroidal selective estrogen receptor modulator (SERM) currently 
used in the prevention of breast cancer, for ductal carcinoma in situ, in women with early stage 
breast cancer and for those with metastatic cancer. It is extensively metabolized after oral 
administration, with N-desmethyl tamoxifen the major metabolite found in patients’ plasma.
Vorinostat (Suberoylanilide hydroxamic acid, SAHA; Merck) is a small molecule inhibitor of 
histone deacetylases (HDACs) that binds directly in the enzyme’s active site in the presence of 
a zinc ion. It targets most human Class 1 (related to the yeast transcriptional regulator Rpd3) 
and Class 2 (similar to the yeast Hda1) enzymes. It causes G1 or G2 phase cell-cycle arrest, 
apoptosis or differentiation in cultured transformed cells. Vorinostat is the most potent HDAC 
inhibitor that can be administered orally with excellent bioavailability.
Pembrolizumab (Merck) is a potent and highly selective humanized monoclonal antibody of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate 
tumor regression and ultimately immune rejection. Pembrolizumab is currently under clinical 
investigation. 
Safety assessments:
Safety will be assessed by reviewing adverse events (AEs), laboratory evaluations, physical 
examination, and spontaneous reports. Each patient will be assessed periodically for the 
development of any toxicity according to the MCI CTCAE v4.0. All AEs and serious AEs (SAEs) 
will be documented and reported. We will also pay particular attention to pembrolizumab 
adverse events of clinical interest, which will predominantly be of immune origin. 
Efficacy assessments:
For the primary endpoint, patients will be assessed for objective responses by RECIST criteria 
1.1. Secondary endpoints include immune response, progression free survival, and overall 
survival.  Monitoring of secondary endpoints will be performed via serial imaging and follow up 
for survival. Correlative endpoints include epigenetic modulation and immune modulation as 
well as their interaction. 
Unique aspects of this study:
This is the first study to look at the response of hormone therapy resistant breast cancer to 
epigenetic immune priming. It is also the first study to look at the combination of an HDAC 
inhibitor (vorinostat), an anti-estrogen (tamoxifen) and a PD-1 inhibitor (pembrolizumab) in pre 
or postmenopausal patients with ER+ advanced breast cancer with progression on multiple prior 
therapies. 
Recent preclinical studies have further suggested that epigenetic priming may be even more 
effective in ER-negative tumors that do not respond to Immune check point inhibitors or have 
low PD-1/PD-L1 expression. The goal of this study is to demonstrate that Vorinostat can 
increase PD-1 and PD-L1 expression. 
 In a third arm the study will evaluated the role of epigenetic priming in tumors that are ER-
negative. 


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List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical (Classification System)
AUC
area under the curve
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CHR
Committee on Human Research (UCSF IRB)
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CSF
cerebral spinal fluid
CT
computerized tomography
CTCEA
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTMS
Clinical Trial Management System
DFS
disease-free survival
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
ECI
event of clinical interest
FCBP
female of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBeAg
Hepatitis B “e” antigen
HBV
hepatitis B virus
HCT
hematocrit
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HGB
hemoglobin
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization
IND
investigational new drug application
IP
investigational product
IRB
Institutional Review Board


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List of Abbreviations
iwCLL
International Workshop on Chronic Lymphocytic Leukemia
IV
intravenous
LDH
lactate dehydrogenase
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NHL
non-Hodgkin’s lymphoma
ORR
overall response rate
PD
disease progression
PD-1
Programmed cell death 1
PK
pharmacokinetics
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
QOL
Quality of Life
RBC
red blood cell (count)
SD
stable disease
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
TIL
Tumor-infiltrating lymphocytes
ULN
upper limit of normal
WBC
white blood cell (count)


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Table of Contents
Protocol Signature Page........................................................................................................................2
List of Abbreviations ..............................................................................................................................8
1 Introduction..........................................................................................................................................13
1.1
Background on Indication ...................................................................................................13
1.1.1 Introduction to breast cancer ...............................................................................................13
1.2
Background on the Compounds........................................................................................15
1.3
Rationale for the Proposed Study .....................................................................................18
1.3.1 Rationale for Epigenetic Immune Priming (EIP):.............................................................18
2 Objectives of the Study.....................................................................................................................20
2.1
Primary objective:..................................................................................................................20
2.2 
Secondary objectives:..........................................................................................................20
2.4
Endpoints.................................................................................................................................21
2.4.1
Primary Endpoints.........................................................................................................21
a)
Overall response rate (CR+PR and SD at 24 weeks) ........................................................21
b)
Toxicity.......................................................................................................................................21
2.4.2
Secondary Endpoints ...................................................................................................21
a)
Duration of response rate .......................................................................................................21
b)
24 week landmark progression free survival (PFS:24),......................................................21
c)
Median PFS and overall survival (OS),.................................................................................21
d)
Tumor responses will also be calculated by Immune Related Response-Criteria (irRC)
21
e)
To test the response of PD-L1 expression to epigenetic modulation...............................21
2.5
Exploratory Endpoints......................................................................................................21
3 Study Design .......................................................................................................................................21
3.1
Characteristics .......................................................................................................................21
3.2
Number of Subjects...............................................................................................................22
3.3
Eligibility Criteria ...................................................................................................................22
3.3.1
Inclusion Criteria............................................................................................................22
3.3.2
Exclusion Criteria ..........................................................................................................23
3.4
Duration of Therapy ..............................................................................................................25
3.5
Duration of Follow Up...........................................................................................................26
lXs= Helen Diller Family Comprehensive Cancer Center 


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3.6
Randomization Procedures.................................................................................................26
3.7
Study Timeline........................................................................................................................26
3.7.1
Clinical Criteria for Early Trial Termination.............................................................26
4 Study Drugs .........................................................................................................................................27
4.1
Description, Supply and Storage of Investigational Drugs.........................................27
4.1.1
Investigational Drug Tamoxifen .................................................................................27
4.1.2
Investigational Drug Vorinostat (Zolinza, NSC 701852).......................................28
4.1.3
Investigational Drug MK-3475 (Pembrolizumab) ...................................................29
4.2
Drug Accountability ..............................................................................................................33
4.3
Drug Ordering.........................................................................................................................33
4.4
Packaging and Labeling of Study Drugs .........................................................................33
5 Treatment Plan ....................................................................................................................................33
5.1
Dosage and Administration ................................................................................................33
5.1.1
Dose Modifications and Dosing Delays ...................................................................35
5.2
Monitoring and Toxicity Management..............................................................................42
6 Study Procedures and Observations ............................................................................................43
6.2
Schedule of Procedures and Observations ....................................................................43
6.2.2
Long Term/Survival Follow-up Procedures ............................................................44
6.2.3
Discontinuation of Therapy.........................................................................................44
Analysis of Exploratory Endpoints: Tissue based endpoints.....................................................49
Analysis of Exploratory Endpoints: Immune endpoints ..............................................................50
6.3
Usage of Concurrent/Concomitant Medications............................................................52
6.3.2
Acceptable Concomitant Medications..........................................................................52
6.3.3
Prohibited Concomitant Medications ...........................................................................52
6.3.4
Rescue Medications & Supportive Care...........................................................................53
Supportive Care Guidelines ...........................................................................................................53
Contraception.................................................................................................................................54
7 Reporting and Documentation of Results....................................................................................55
7.1 Evaluation of Efficacy (or Activity).........................................................................................55
7.1.1. Antitumor Effect..................................................................................................................55
7.4
Evaluation of Safety ..............................................................................................................58
7.5
Adverse Events ......................................................................................................................58
7.5.2
Definition of Adverse Event ........................................................................................58
lXs= Helen Diller Family Comprehensive Cancer Center 


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7.5.3
Adverse reaction............................................................................................................59
7.6
Evaluation of an Adverse Event.........................................................................................60
7.7
Follow-up of Adverse Events..............................................................................................63
7.8
Adverse Events Reporting ..................................................................................................63
7.8.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
study PI and Merck..........................................................................................................................64
7.8.2
Serious Adverse Events..................................................................................................64
7.8.3
Reporting of Pregnancy and Lactation to the Sponsor and to Merck.......................65
7.9
Expedited Reporting .............................................................................................................65
8.0 Statistical Considerations and Evaluation of Results...................................................................66
8.1
Sample Size and Power Estimate .........................................................................................67
8.2
Interim Analyses.......................................................................................................................67
8.3
Analyses Plans.........................................................................................................................67
8.3.1
Analysis Population .........................................................................................................67
8.4
Evaluation of Safety.................................................................................................................67
9.0 Study Management...........................................................................................................................68
9.1
Pre-study Documentation....................................................................................................68
9.2
Institutional Review Board Approval................................................................................68
9.3
Informed Consent ..................................................................................................................68
9.4
Changes in the Protocol ......................................................................................................68
9.5
Handling and Documentation of Clinical Supplies .......................................................68
9.6
Case Report Forms (CRFs) .................................................................................................69
9.7
Oversight and Monitoring Plan ..........................................................................................69
9.8
Record Keeping and Record Retention ...........................................................................69
9.9
Coordinating Center Documentation of Distribution....................................................70
10 Protection of Human Subjects......................................................................................................70
10.1
Protection from Unnecessary Harm..................................................................................70
10.2
Protection of Privacy ............................................................................................................70
References ..............................................................................................................................................72
Appendices .............................................................................................................................................80
Appendix 1: Performance Status Criteria ........................................................................................80
Appendix 3: UCSF Policy/Procedure for Required Regulatory Documents for UCSF 
Investigator-Initiated Oncology Clinical Trials with an Investigator held Investigational 
New Drug (IND).......................................................................................................................................83
lXs= Helen Diller Family Comprehensive Cancer Center 


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Appendix 4 Multicenter Institutional Studies..................................................................................85
4.1Data and Safety Monitoring Plan for Multicenter Study (Phase 2 or 3 Institutional Study) .....85
lXs= Helen Diller Family Comprehensive Cancer Center 


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1
Introduction
1.1
Background on Indication
1.1.1 Introduction to breast cancer
Breast cancer is one of the most common cancers in the western hemisphere and the second 
most common cause of cancer death in women7. Endocrine therapy (including ovarian ablation, 
estrogen administration, and more recently, antiestrogen administration) has been a major 
component of antitumor therapy in breast cancer for more than a century8. Hormone sensitive 
metastatic breast cancer remains a therapeutic challenge despite the many recent advances in 
therapy as these tumors are frequently less sensitive to chemotherapy9. Barring a few 
exceptions, cure is not achieved in this disease. While hormonal interventions have clearly been 
shown to decrease tumor burden and to prolong life, the majority of patients eventually succumb 
to their disease due to disease recurrence.
1.1.2 Hormone-sensitive breast cancer
More than two thirds of all advanced breast cancers are dependent on estrogen. Estrogen 
withdrawal by physical removal of the ovaries or inhibition of their function has been one of the 
earliest successful interventions against breast cancer; however this intervention was limited to 
premenopausal women. The introduction of the SERMS (selective estrogen receptor 
modulators) has dramatically improved the survival of women with breast cancer, both pre and 
postmenopausal. The most prominent SERM is tamoxifen, which until recently has been the 
gold standard for first-line therapy in women with advanced hormone-sensitive breast cancer. 
The production of estrogen in postmenopausal women requires an enzyme called aromatase, 
which can be successfully blocked chemically. The introduction of several aromatase inhibitors 
(AIs) has added greatly to the arsenal against breast cancer and they have replaced tamoxifen 
as first-line therapy in the postmenopausal setting. The most commonly used aromatase 
inhibitors include letrozole, anastrozole and exemestane.
However, the AIs are reserved for women who have naturally entered menopause or have their 
ovarian function suppressed. For premenopausal women or women who are unable to tolerate 
AIs, tamoxifen remains the gold standard.
The response rate to first line hormonal therapy, determined from four pivotal randomized 
Phase III trials, ranges from 20-33%10,11,12,13. The response rate to second line hormonal therapy 
is considerably less (10-20%)10, suggesting a clear need for more effective therapy.14,15,16
1.1.3 Therapy resistance in breast cancer
Breast cancer has now been subclassified into several major subgroups: hormone therapy 
sensitive, hormone therapy resistant (HTR), HER2 positive (HER2+) and triple negative (TN). 
The treatment approaches to these clinical subtypes vastly differ. Hormone resistance has been 
attributed to a number of different mechanisms, namely loss of ER expression, alterations in 
apoptosis and cell signaling pathways, changes in ER coregulators, and the development of 
escape pathways17. Therefore, these women receive minimal benefit from endocrine therapy. 
The development of hormone therapy resistance is one of the most frequent causes of cancer 
death in women worldwide.
1.1.4 Immune surveillance and the role of the PD-1 pathway
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades18.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
lXs= Helen Diller Family Comprehensive Cancer Center 


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various malignancies19,20,21,22.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells correlates with improved prognosis and long-term 
survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  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 PDL2)23,24.  The structure of 
murine PD-1 has been resolved25. PD-1 and its 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, PD1 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 cascade14,15,16,23. 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 proteins26,27.  PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, 
B-cells, T regs and Natural Killer cells28,29. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells, as well as subsets of macrophages and 
dendritic cells30. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types, including non-hematopoietic tissues, as well as in various 
tumors26,31,32,33. 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.  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 tissues26. Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this 
T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects 
with melanoma (MEL)34. This suggests that the PD-1/PD-L1 pathway plays a critical role in 
tumor immune evasion and should be considered an attractive target for therapeutic 
intervention.
1.1.5 PD-1 and PD-L1 in breast cancer 
Inhibition of the PD-L1/PD-1 axis has been a major milestone in many cancer types. However, 
its relevance in breast cancer remains less clear. Expression and upregulation of PD-L1 is 
variable in breast cancer, and found to be high in TN and HER2+ disease. Increased PD-L1 
expression has been observed in hormone therapy resistance, frequently reported with loss of 
the progesterone receptor (PR), a measure of hormone therapy resistance5. Hence, PD-1 
inhibitors may have a role in hormone therapy resistant breast cancer. However, PD-1 inhibitors 
may be more effective after epigenetic immune priming. This proposal is focused on the 
potential role of epigenetic immune priming to reverse hormone therapy resistance (HTR) in pre 
and postmenopausal breast cancer.
Recent data suggests that PD-L1 expression is low in a majority of patients, which may confer 
poor response to PD-1 or PD-L1 check point inhibitors. Preclinical in vitro and in vivo studies, 
including ours, suggests that HDAC inhibition using vorinostat increases PD-L1 transcription 
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and cellular expression in breast cancer cells, including ER+ hormone sensitive and resistant as 
well as TN cells.
1.2
Background on the Compounds
1.2.1 Tamoxifen
Tamoxifen is the most commonly used anti-estrogen or SERM. It is currently being used for the 
prevention of breast cancer, for ductal carcinoma in situ, in women with early stage breast 
cancer and for those with metastatic cancer. It is generally well tolerated and due to its 
extensive use, its toxicities and long-term sequelae are well characterized. Women being 
treated with tamoxifen may experience flushing (similar to the flushing women experience 
during menopause), vaginal dryness and vaginal discharge. The most serious side effect is the 
slightly increased risk of thromboembolic events. In a trial involving 900 women treated with 
either tamoxifen or letrozole, 9 out of 455 patients experienced a thromboembolic event (2%), 
compared to 3 patients out of 455 in the group treated with letrozole (<1%). Other side effects 
included hot flashes (25%), headaches (5%), fatigue (5%) and nausea (8%)13. The observation 
of endometrial cancer (<0.5%) has been predominantly observed when used in the preventive 
or adjuvant setting35. Hence, the cumulative administration of tamoxifen is rarely hampered by 
toxicity, but rather by the emergence of resistance suggested by clinical progression while on 
the drug.
1.2.2 Histone Deacetylases (HDAC) and their inhibitors 
A promising new class of drugs showing activity in cancer is the histone deacetylase inhibitors 
(HDACi)36,37. While these agents may have single agent activity in cancer, they may also 
sensitize certain cancers to other types of therapeutic agents or overcome resistance. Histone 
deacetylases (HDAC) function to modulate gene expression by the removal of acetyl groups 
from histones38,39. The addition of acetyl groups to lysine residues on the N-terminal tail of 
histones by histone acetyl transferases (HAT) results in the weakening of the bond between 
histones and DNA39. In contrast, removal of acetyl groups by HDACs results in the 
condensation of the nucleosomes and has been correlated with gene silencing39. HDACs can 
be divided into at least three different classes, I-III. Each class contains several members of 
structurally and functionally variable HDACs40,41. Alterations in the regulatory function of HATs 
and HDACs have been associated with the development of certain cancers42. For example, 
mutations in the HAT gene CBP have been correlated with the development of certain colorectal 
and gastric cancers43, whereas altered HDAC function has been associated with the onset of 
acute promyelocytic leukemia (APL)42. There are several inhibitors of HDACs that show anti-
cancer activity in vitro and in vivo44. These include the short-chain fatty acids (sodium butyrate, 
valproic acid (VPA)), the hydroxamic acids (suberoylanilide hydroxamic acid (SAHA), 
trichostatin A), the cyclic tetrapeptides (depsipeptide (FK-228)) and the benzamides (MS-275). 
Vorinostat, FK-228, MS-275 and others are currently undergoing early clinical testing.  
1.2.3 Suberoylanilide hydroxamic acid (Vorinostat, SAHA)
Vorinostat (Suberoylanilide hydroxamic acid, SAHA; NSC 701852) is a small molecule inhibitor 
of histone deacetylase (HDAC) that binds directly in the enzyme’s active site in the presence of 
a zinc ion45. Because aberrant HDAC activity has been implicated in a variety of cancers, 
development of HDAC inhibitors is a rational approach to the design of targeted anticancer 
therapeutics. Several HDAC inhibitors from multiple chemical classes have been developed and 
are currently in clinical trials. Trichostatin A and butyric acid were among the first HDAC 
inhibitors to be administered to patients, but these were found to be clinically unsuitable due to 
potency and formulation issues46,47. Depsipeptide was originally selected for clinical study based 
on its antiproliferative effects; subsequently it was discovered to antagonize HDACs and was 
the first HDAC inhibitor to demonstrate clinical efficacy48. Of the three classes of HDACs, 
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vorinostat targets most human Class 1 (related to the yeast transcriptional regulator Rpd3) and 
Class 2 (similar to the yeast Hda1) enzymes37,49. The third class of HDACs (homologues of 
yeast sir2) requires NAD+ for activity and is not inhibited by vorinostat. Among those currently in 
clinical trials, vorinostat is the most potent HDAC inhibitor that can be administered orally with 
excellent bioavailability. Vorinostat was the first HDAC approved for CTCL in 2006.
Vorinostat was identified originally by its ability to induce differentiation of murine 
erythroleukemia cells at micromolar concentrations50. Subsequently, it was found to induce 
differentiation or arrest growth of a wide variety of human carcinoma cells. To date, vorinostat 
activity has been reported in transformed hematopoietic cells, including multiple myeloma (MM), 
acute promyelocytic leukemia (APL), acute lymphocytic leukemia, chronic myelogenous 
leukemia, Waldenstrom’s macroglobulinemia, and cutaneous T-cell lymphoma (CTCL)51-55. 
Activity has also been reported in cell lines representing other tumor types including bladder 
transitional cell carcinoma, breast cancer, prostate cancer, head and neck squamous 
carcinoma, and colon carcinoma56-61.
The antitumor activity of vorinostat was demonstrated in several in vivo models of cancer, 
including a xenograft model of human CWR22 prostate cancer cells57, a mouse model of APL 
containing the promyelocytic leukemia zinc-finger-retinoic acid receptor α fusion gene (PLZF-
RARα)62, and an N-methylnitrosourea-induced mammary tumor model in rodents63. Vorinostat 
has also showed activity when administered daily by intraperitoneal (IP) injections in the 
CWR22 and PLZF-RARα models and by oral (PO) administration in the carcinogen-induced 
mammary tumor model.
1.2.4 Pembrolizumab/MK-3475
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-3475.
Pembrolizumab (previously known as SCH 900475) 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.  
1.2.4.1 Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells / FoxP3+ regulatory T-cells correlates with improved prognosis and long-
term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  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) [7; 8].  The structure of 
murine PD-1 has been resolved [9].  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, 
lXs= Helen Diller Family Comprehensive Cancer Center 


V er si o n d at e: 0 7/ 2 8/ 1 6
Pr ot o c ol C C #: 1 4 7 5 2 3
P h a s e II – P e m br oli z u m a b, V ori n o st at,  T a m o xif e n,
P a g e 1 8 of 8 3
P K C θ  a n d Z A P 7 0 w hi c h ar e i n v ol v e d i n t h e C D 3 T- c ell si g n ali n g c a s c a d e [ 7; 1 0; 1 1; 1 2].  T h e 
m e c h a ni s m b y w hi c h P D- 1 d o w n m o d ul at e s T- c ell r e s p o n s e s i s si mil ar t o, b ut di sti n ct fr o m t h at 
of C T L A- 4 a s b ot h m ol e c ul e s r e g ul at e a n o v erl a p pi n g s et of si g n ali n g pr ot ei n s [ 1 3; 1 4].  P D- 1 
w a s s h o w n t o b e e x pr e s s e d o n a cti v at e d l y m p h o c yt e s i n cl u di n g p eri p h er al C D 4 + a n d C D 8 + T-
c ell s, B- c ell s, T r e g s a n d N at ur al Kill er c ell s [ 1 5; 1 6].  E x pr e s si o n h a s al s o b e e n s h o w n d uri n g 
t h y mi c d e v el o p m e nt o n C D 4- C D 8- ( d o u bl e n e g ati v e) T- c ell s a s w ell a s s u b s et s of m a cr o p h a g e s 
a n d d e n driti c c ell s [ 1 7].  T h e li g a n d s f or P D- 1 ( P D- L 1 a n d P D- L 2) ar e c o n stit uti v el y e x pr e s s e d 
or c a n b e i n d u c e d i n a v ari et y of c ell t y p e s, i n cl u di n g n o n- h e m at o p oi eti c ti s s u e s a s w ell a s i n 
v ari o u s t u m or s [ 1 3; 1 8; 1 9; 2 0].  B ot h li g a n d s ar e t y p e I tr a n s m e m br a n e r e c e pt or s c o nt ai ni n g 
b ot h I g V- a n d I g C-li k e d o m ai n s i n t h e e xtr a c ell ul ar r e gi o n a n d c o nt ai n s h ort c yt o pl a s mi c r e gi o n s 
wit h n o k n o w n si g n ali n g m otif s.  Bi n di n g of eit h er P D- 1 li g a n d t o P D- 1 i n hi bit s T- c ell a cti v ati o n 
tri g g er e d t hr o u g h t h e T- c ell r e c e pt or.  
P D- L 1 i s e x pr e s s e d at l o w l e v el s o n v ari o u s n o n-
h e m at o p oi eti c ti s s u e s, m o st n ot a bl y o n v a s c ul ar e n d ot h eli u m, w h er e a s P D- L 2 pr ot ei n i s o nl y 
d et e ct a bl y e x pr e s s e d o n a nti g e n- pr e s e nti n g c ell s f o u n d i n l y m p h oi d ti s s u e or c hr o ni c 
i nfl a m m at or y e n vir o n m e nt s.  P D- L 2 i s t h o u g ht t o c o ntr ol i m m u n e T- c ell a cti v ati o n i n l y m p h oi d 
or g a n s, w h er e a s P D- L 1 s er v e s t o d a m p e n u n w arr a nt e d T- c ell f u n cti o n i n p eri p h er al ti s s u e s [ 1 3].  
Alt h o u g h h e alt h y or g a n s e x pr e s s littl e (if a n y) P D- L 1, a v ari et y of c a n c er s w er e d e m o n str at e d t o 
e x pr e s s a b u n d a nt l e v el s of t hi s T- c ell i n hi bit or.  P D- 1 h a s b e e n s u g g e st e d t o r e g ul at e t u m or-
s p e cifi c T- c ell e x p a n si o n i n s u bj e ct s wit h m el a n o m a ( M E L)[ 2 1].  T hi s s u g g e st s t h at t h e P D-
1/ P D- L 1 p at h w a y pl a y s a criti c al r ol e i n t u m or i m m u n e e v a si o n a n d s h o ul d b e c o n si d er e d a s a n 
attr a cti v e t ar g et f or t h er a p e uti c i nt er v e nti o n.
M K- 3 4 7 5 ( pr e vi o u sl y k n o w n a s S C H 
9 0 0 4 7 5) i s a p ot e nt a n d hi g hl y s el e cti v e h u m a ni z e d 
m o n o cl o n al a nti b o d y ( m A b) of t h e I g G 4/ k a p p a i s ot y p e d e si g n e d t o dir e ctl y bl o c k t h e i nt er a cti o n 
b et w e e n P D- 1 a n d it s li g a n d s, P D- L 1 a n d P D- L 2 wit h o ut A D C C or C D C a cti vit y.
1. 2. 4. 2 Pr e- cli ni c al a n d Cli ni c al Tri al s
T h er a p e uti c st u di e s i n m o u s e m o d el s  h a v e s h o w n t h at a d mi ni str ati o n of a nti b o di e s bl o c ki n g P D-
1/ P D- L 1 i nt er a cti o n e n h a n c e s i nfiltr ati o n of t u m or- s p e cifi c C D 8 + T- c ell s a n d l e a d s ulti m at el y t o 
t u m or r ej e cti o n, eit h er a s a m o n o-t h er a p y or i n c o m bi n ati o n wit h ot h er tr e at m e nt m o d aliti e s.  
A nti- m o u s e P D- 1 or a nti- m o u s e P D- L 1 a nti b o di e s h a v e d e m o n str at e d a nti-t u m or r e s p o n s e s a s 
a 
m o n o-t h er a p y i n 
m o d el s of s q u a m o u s c ell c ar ci n o m a, p a n cr e ati c c ar ci n o m a, 
M E L a n d 
c ol or e ct al c ar ci n o m a.  
Bl o c k a d e of t h e P D- 1 p at h w a y eff e cti v el y pr o m ot e d 
C D 8 + T- c ell 
i nfiltr ati o n i nt o t h e t u m or a n d t h e pr e s e n c e of I F N- , gr a n z y m e B, a n d p erf ori n, i n di c ati n g t h at 
t h e m e c h a ni s m of a cti o n i n v ol v e d l o c al i nfiltr ati o n a n d a cti v ati o n of eff e ct or T- c ell f u n cti o n i n vi v o 
[ 2 2; 2 3; 2 4; 2 5; 2 6; 2 7].  E x p eri m e nt s h a v e c o nfir m e d t h e i n vi v o effi c a c y of P D- 1 bl o c k a d e a s a 
m o n o-t h er a p y a s w ell a s i n c o m bi n ati o n wit h c h e m ot h er a p y i n s y n g e n ei c m o u s e t u m or m o d el s 
( s e e t h e I n v e sti g at or’ s Br o c h ur e [I B]).
1. 2. 4. 3 Pr e- cli ni c al a n d Cli ni c al Tri al s
O n g oi n g cli ni c al tri al s ar e b ei n g c o n d u ct e d i n a d v a n c e d m el a n o m a, n o n- s m all c ell l u n g c a n c er, 
h e a d a n d n e c k c a n c er, ur ot h eli al tr a ct c a n c er, tri pl e n e g ati v e br e a st c a n c er, g a stri c c a n c er, a n d 
h e m at ol o gi c m ali g n a n ci e s. F or tri al d et ail s pl e a s e r ef er t o t h e I n v e sti g at or’ s Br o c h ur e.
P e m br oli z u m a b h a s b e e n a p pr o v e d i n m el a n o m a a n d l u n g c a n c er. 
1. 3  
R ati o n al e f or t h e Pr o p o s e d St u d y
1. 3. 1 R ati o n al e f or E pi g e n eti c I m m u n e  Pri mi n g ( EI P): 
Cli ni c all y, e pi g e n eti c i m m u n e r e g ul ati o n h a s b e e n  i m pli c at e d i n pri mi n g l u n g c a n c er c ell s t o P D-
1 i n hi bit or s w hi c h r e s ult e d i n pr ol o n g e d r e s p o n s e s 3, 4 . T h e effi c a c y of P D- 1 i n hi bit or s h a s n ot 
b e e n e st a bli s h e d; h o w e v er t h e e x pr e s si o n of P D- L 1 i n E R + br e a st c a n c er i s l o w. P D- L 1 
l X s = H el e n Dill er F a mil y C o m pr e h e n si v e C a n c er C e nt er 


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expression however has been shown to be a poor predictor of survival and PD-L1 expression 
has been suggested to increase as ER+ tumors become resistant to therapy. 
The role of epigenetic modulation has been studied extensively in breast cancer therapy. 
Several investigators have shown that HDAC inhibitors have immune modulatory functions, 
including modulation of Tregs, FoxP3 expression, changes in TIL expression, induction of PD-
L1 expression and blockage of PD-1. We have previously shown that epigenetic modulation 
with an HDAC inhibitor can reverse hormone therapy resistance and force cells into 
programmed cell death1. Based on these preclinical studies, we had proposed two clinical trials 
testing HDAC inhibitors with hormonal therapy in ER+ breast cancer. 
We hypothesize that pre-exposure of breast cancer cells to the HDAC inhibitor vorinostat (i.e., 
Arm A, sequential treatment) will result in down regulation of T-regulatory cells (Tregs) and 
FoxP3, which will increase the efficacy of PD-1 inhibitors, as measured by ORR, and prime cells 
to increased immune response. We therefore anticipate the schedule of administration may play 
an important role in the administration of this combination strategy. 
Recent preclinical studies have further suggested that epigenetic priming may be even more 
effective in ER-negative tumors that do not respond to Immune check point inhibitors or have 
low PD-1/PD-L1 expression. The goal of this study is to demonstrate that Vorinostat can 
increase PD-1 and PD-L1 expression. 
1.3.1.1 Prior studies with vorinostat in breast cancer:
In a Phase II clinical trial, we evaluated the role of vorinostat (VOR) in reversing hormone 
therapy resistance in advanced breast cancer2. In a single arm study, 43 patients (median age 
56 years (31–71)) were treated. A total of 25 patients (58%) received prior adjuvant tamoxifen 
(TAM), 29 (67%) progressed on at least one prior chemotherapy regimen, 42 (98%) progressed 
after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by RECIST 
criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. 
The median response duration was 10.3 months (confidence interval: 8.1–12.4). Histone 
hyperacetylation and higher baseline HDAC2 levels correlated with response and responses 
were mainly seen in the 56% of patients who had a meaningful change in acetylation with 
vorinostat. Preclinical studies have further suggested that hormonal therapy must be continued 
even in the presence of an HDAC inhibitor. 
1.3.1.2 Prior studies with other HDAC inhibitors in breast cancer:
 A second phase II (ENCORE 301) trial evaluated entinostat and exemestane, and treated 
patients with advanced estrogen receptor (ER)-positive breast cancer66. This study recently 
received Breakthrough Therapy designation from the FDA for its potential to reverse resistance 
to hormonal therapies. The median PFS was 4.3 months versus 2.3 months, for entinostat and 
placebo, respectively (HR = 0.73; P = 0.06). The median overall survival in the combination arm 
was 28.1 m compared to 19.8 m in the exemestane arm (HR = 0.59; P = 0.036). The objective 
response rate to the combination was 6.3%, while to exemestane alone was 4.6% (P = 0.58). 
While these two studies cannot be compared directly, the preclinical studies and the clinical 
studies, as well as the current landscape of standard of care, will make the combination with 
tamoxifen more likely effective. The combination with tamoxifen will also allow enrollment of 
premenopausal women.   
Hence the combination of HDAC inhibitors and PD-1 inhibitors may further result in an 
enhancement of anti-tumor efficacy of PD-1 inhibitors6,67. Based on the established role of 
HDAC inhibitors in reversing hormone therapy resistance to antiestrogens and aromatase 


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inhibitors and the provocative role of HDAC inhibitors in modulating tumor immunity, we propose 
to test the role of epigenetic immune priming (EIP) in acquired hormone therapy resistance. 
In a two arm Phase II trial, we will explore concurrent and sequential EIP testing two 
principles: Sequential priming with optimal immune activation (Arm A) and concurrent priming 
with maximal dosing of both epigenetic and immune modulators (Arm B). 
Figure 1.
Schematic of dosing schedule 
2
Objectives of the Study
2.1
Primary objective: 
a) To define the optimal approach for epigenetic immune priming in hormone refractory 
breast cancer on the basis of overall response rate (ORR: CR+PR+SD at 24 weeks).
  
b) Safety and tolerability of vorinostat, tamoxifen and pembrolizumab
2.2 
Secondary objectives:
a) To define the optimal approach for epigenetic immune priming in hormone –resistant 
breast cancer and ER-negative tumors 
b) To assess duration of response (DOR) 24 week landmark progression free survival 
(PFS:24) 
c)
Median PFS and overall survival (OS) 


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d) Tumor responses will also be calculated by Immune Related Response-Criteria (irRC). 
e) To test the response of tumor PD-L1 expression to epigenetic modulation
2.3
Exploratory objectives:
a) To assess for post-treatment changes in tumor-infiltrating lymphocyte (TIL) populations, 
PD-L1 expression and potential indicators of response. If tumor samples demonstrate 
that epigenetic therapy converts tumors from a low (baseline) to high TIL (post-
treatment) but without a corresponding increase in ORR, then we can confidently reject 
our hypothesis that enhancing TILs will increase pembrolizumab efficacy in this tumor 
type. 
b) Acetylation of histones in PBMCs as a pharmacodynamics response marker for 
vorinostat.
2.4
 Endpoints
Two arm study to determine the role of sequential versus epigenetic priming of ER+ 
breast cancer cells.  
A comparator arm in ER-negative tumors with biomarker endpoints
2.4.1
Primary Endpoints
a) Overall response rate (CR+PR and SD at 24 weeks)
b) Toxicity
2.4.2
Secondary Endpoints
a) Duration of response rate 
b) 24 week landmark progression free survival (PFS:24), 
c)
Median PFS and overall survival (OS), 
d) Tumor responses will also be calculated by Immune Related Response-Criteria (irRC)
e) To test the response of PD-L1 expression to epigenetic modulation
2.5
Exploratory Endpoints

To assess for post-treatment changes in TIL population, PD-L1 expression and potential 
indicators of response. If tumor samples demonstrate that the combination therapy 
converts tumors from a low (baseline) to high TIL (post-treatment) but without a 
corresponding increase in ORR, then we can confidently reject our hypothesis that 
enhancing TILs will increase pembrolizumab efficacy. Acetylation of histones in PBMCs 
as a response marker for vorinostat.
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3
Study Design
3.1
Characteristics
We propose a three arm, 20-87 patient trial in patients with hormone therapy resistant breast 
cancer to test the optimal sequence and dosing of epigenetic immune priming in hormone 
therapy resistant breast cancer. The two arms all include vorinostat, TAM and pembrolizumab to 
evaluate either sequential priming (Arm A) or, concurrent priming with maximal dosing of both 
epigenetic and immune modulators in ER+ (Arm B) and ER- (Arm C?) disease.  Stage 1 of the 
trial will evaluate 20 patients, 10 in each arm and randomly assigned. If the response rates are 
adequate, the trial will proceed to Stage 2 in order to evaluate 58 patients, 29 in each arm. 
Given the absence of responses in PD-L1 low patients to pembrolizumab, we will determine the 
benefits for vorinostat in reversing therapy resistance to pembrolizumab in ER-negative breast 
cancers (HER2-positive or negative)
Patients will be evaluated for response at 12 weeks by RECIST1.1 (using IR-RECIST) and will 
continue on therapy if they have stable disease or response at the time of disease evaluations.
Patients with progression on imaging, but are clinically stable, may stay on study but will require 
follow up staging after 4-6 weeks. Patients will be assessed continually for safety and tolerability 
as well as for any adverse events. If progression on therapy with pembrolizumab, patient may 
continue if clinical indicated and be re-evaluated after 4-8 weeks. 
We will follow AEs of clinical interest as defined by Merck and will dose modify pembrolizumab 
as per Merck guidelines. We have significant prior experience with vorinostat as an agent and 
are familiar with managing drug toxicities. In addition, we are experienced with immune-related 
toxicities as well.
Tissue biopsies of all patients will be collected prior to enrollment to assess for pre-treatment 
TIL and PD-L-1 expression. A limited number of patients with disease unamenable to biopsy will 
be allowed to enroll in the trial with prior approval from study PI. Follow up biopsies and 
peripheral blood collection will be taken from all patients post-treatment, prior to starting cycle 4, 
to characterize changes in local tissue effects and antigen-specific cellular and humoral immune 
responses in peripheral blood.
3.2
Number of Subjects
20-87 patients
3.3
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients enrolled onto the 
study unless otherwise specified.
3.3.1
Inclusion Criteria
1.
Pre and postmenopausal women or men with stage IV ER+ breast cancer histological or 
cytological confirmation
ER-positive tumors 
a.
Progressed after at least one line of hormonal therapy
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b.
Any number of prior chemotherapy in the metastatic setting
c.
Any number of prior hormonal therapies. 
d.
HER2 positive or negative
ER-negative tumors 
e.
PD-L1 low, high or unknown 
f.
Progression after prior PD-1 or PD-L1 inhibitors allowed 
g.
HER2 positive or negative
2.
18 years or older. 
3.
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. 
4.
Understand and voluntarily sign an informed consent prior to any study-related 
assessments or procedures are conducted and are able adhere to the study visit 
schedule and other protocol requirements.
5.
Consent to paired tumor biopsy, for accessible tumors
6.
Measureable tumor by RECIST criteria v.1.1
7.
Per Good Clinical Practice, any toxicity related to prior therapies that, in the opinion of 
the investigator, would potentially be worsened with anti-PD1 therapy should be resolved 
to less than Grade 1
8.
Adequate organ function within 14 days of study start:
o
Absolute neutrophil count (ANC) ≥ 1.5 X 109/L
o
Hemoglobin (Hgb) ≥9g/dL (may transfuse if clinically indicated)
o
Platelets (plt) ≥ 100 x 109/L
o
Potassium within normal range, or correctable with supplements;
o
AST and ALT ≤2.5 x Upper Limit Normal (ULN) or ≤5.0 x ULN if liver tumor is 
present;
o
Serum total bilirubin ≤ 1.5 x ULN
o
Serum creatinine ≤ 1.5 x ULN, or 24-hr clearance ≥ 60ml/min; and
9.
Females of child-bearing potential (defined as a sexually mature women who):
o
Has not undergone a hysterectomy (the surgical removal of the uterus) or 
bilateral oophorectomy (the surgical removal of both ovaries) or,
o
Has not been naturally postmenopausal for at least 24 consecutive months (i.e., 
has had menses at any time during the preceding 24 consecutive months).  
Must have negative serum pregnancy test within 7 days before starting study treatment 
in females of childbearing potential (FCBP) and willingness to adhere to acceptable 
forms or birth control (a physician- approved contraceptive method (oral, injectable, or 
implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier 
contraceptive with spermicide; or vasectomized partner). 
10. Male subjects with female partner of childbearing potential must agree to the use of a 
physician-approved contraceptive method throughout the course of the study
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3.3.2
Exclusion Criteria
1.
Any significant medical condition, laboratory abnormalities, which places the subject at 
unacceptable risk if he/she were to participate in the study.
2.
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent.
a.
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study.
b.
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy. 
c.
Patients may continue on ovarian suppression 
3.
Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.  
4.
Any condition that confounds the ability to interpret data from the study.
5.
Symptomatic central nervous system metastases. Subjects with brain metastases that 
have been previously treated with WBXRT and are stable for 6 weeks are allowed. 
Gamma or cyber knife treated lesions may enroll 2 weeks after completion if toxicities 
are resolved and no longer requiring steroids, patients with asymptomatic brain 
metastases are allowed after discussion with the study sponsor.) 
6.
Persistent diarrhea or malabsorption ≥ NCI CTCAE grade 2, despite medical 
management.
7.
Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) 
class 3 or 4 congestive heart failure.
8.
Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half-lives or 3 
weeks, whichever is shorter, prior to starting study drug or who have not recovered from 
side effects of such therapy (except alopecia). 
9.
Has an active auto-immune disease requiring systemic treatment within the past 3 
months or a documented history of clinical autoimmune disease in the past, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects with 
vitiligo or resolved childhood asthma/atopia would be an exception to this rule.  Subjects 
that require intermittent use of bronchodilators or local steroid injections would not be 
excluded from the study.  Subjects with hypothyroidism stable on hormone replacement 
or Sjorgen’s syndrome will not be excluded from the study.
10. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for the 
full duration of the trial, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.  
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
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14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. Pregnant women are excluded from this 
study because vorinostat, tamoxifen and PD-1 are drug classes with the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother, breastfeeding 
should be discontinued if the mother is treated with vorinostat, tamoxifen and PD-1 
inhibitors.
15. Active and ongoing steroid use, except for non-systemically absorbed treatments (such 
as inhaled or topical steroid therapy for asthma, COPD, allergic rhinitis).
16. Major surgery ≤ 2 weeks prior to starting a study drug or who have not recovered from 
side effects of such therapy.
17. Known hypersensitivity to pembrolizumab or any of its insipients.
18. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
3.4
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may continue for 24 
months or until:

Clearly documented disease progression

Inter-current illness that prevents further administration of treatment

Unacceptable adverse event(s)

Patients decides to withdraw from the study

Significant patient non-compliance with protocol

General or specific changes in the patients’ condition render the patient unacceptable for 
further treatment in the judgment of the investigator.

Patients may receive palliative radiation therapy for isolated symptomatic lesions
A subject must be discontinued from the trial for any of the following reasons:
·
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
·
Confirmed radiographic disease progression
Note: For unconfirmed radiographic disease progression, but clear clinical 
progression in the opinion of the treating physician or investigator, the patient should 
be withdrawn from study for progression. 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improving by 
symptoms or tumor markers. 
Unacceptable adverse experiences as described in Section 7.4
·
Intercurrent illness that prevents further administration of treatment
·
Investigator’s decision to withdraw the subject
·
The subject has a confirmed positive serum pregnancy test
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·
Noncompliance with trial treatment or procedure requirements
·
The subject is lost to follow-up
3.5
  Duration of Follow Up
Patients will be followed for 30 days after completion of treatment or removal from study  
Patients removed from study for unacceptable treatment related adverse event(s) will be 
followed until resolution or stabilization of all treatment related adverse events to Grade 2 or 
lower.
Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression each 
subject will be followed by telephone for overall survival until death, withdrawal of consent, or 
the end of the study, whichever occurs first.
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 6.2.7
3.6
  Randomization Procedures
This is an open-label randomized trial; therefore, the Sponsor, investigator and subject will know 
the treatment administered. Two arms will be tested, with each independent assessment. 
Patients will be randomized to either arm using a computerized randomization program by Dr. 
Scott Thomas. Patients will be further stratified by prior number of chemo- and hormonal 
therapies.  
No randomization is required for ER-negative patients (patients must have biopsiable disease)  
3.7
  Study Timeline
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 5.1). Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. All trial treatments will be administered on an outpatient basis. 
pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals may 
be increased due to toxicity as described in Section 5.2.1.2). Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min)
. 
3.7.1
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
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4. Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made.
4
Study Drugs
4.1
Description, Supply and Storage of Investigational Drugs
4.1.1
Investigational Drug Tamoxifen
Tamoxifen is available in the following doses for oral administration.
·
10 mg Tablets. Each tablet contains 15.2 mg of tamoxifen citrate, which is equivalent to 
10 mg of tamoxifen.
·
20 mg Tablets. Each tablet contains 30.4 mg of tamoxifen citrate, which is equivalent to 
20 mg of tamoxifen.
The administered dose will be 20 mg daily. 
Classification
Non-steroidal anti-estrogen
Mechanism of Action
Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 
ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in 
plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 
7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 
10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to 
patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 
ng/mL) for tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The 
average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after 
administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71-183 ng/mL) 
and 353ng/mL (range 152-706 ng/mL), respectively.
After initiation of therapy, steady state concentrations for tamoxifen are achieved in about 4 
weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 
weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady state, 
crossover study of 10 mg NOLVADEX tablets given twice a day vs. a 20 mg NOLVADEX tablet 
given once daily, the 20 mg NOLVADEX tablet was bioequivalent to the 10 mg NOLVADEX 
tablets.
Metabolism:
Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the 
major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen 
appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol 
derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a 
substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.
Excretion:
Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the 
administered dose was excreted from the body over a period of 2 weeks with fecal excretion as 
the primary route of elimination. The drug is excreted mainly as polar conjugates, with 


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unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal 
radioactivity.
Drug-drug Interactions:
In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively 
inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30
μM, respectively. The clinical significance of these in vitro studies is unknown.
How Supplied:
Tamoxifen (generic) is commercially available. (AstraZeneca has discontinued the commercial 
manufacture and distribution of branded NOLVADEX® tablets in the United States as
of June 2006)
Contraindications:
Tamoxifen is contraindicated in patients with known hypersensitivity to the drug or any of its 
ingredients.
Complete and updated adverse event information is available in the Investigational Drug 
Brochure and product package insert. 
4.1.2
Investigational Drug Vorinostat (Zolinza, NSC 701852)
Vorinostat is available in size 3 capsules containing 100 mg of Vorinostat for administration.
Classification
Antineoplastic
Mechanism of Action
Vorinostat, a histone deacetylase (HDAC) inhibitor.  Histone deacetylases (HDACs) are a family 
of enzymes that regulate chromatin remodeling and gene transcription via the dynamic process 
of acetylation and deacetylation of core histones.
Vorinostat, a potent inhibitor of HDAC activity, binds directly to the catalytic pocket of HDAC 
enzymes. It causes G1 or G2 phase cell-cycle arrest, apoptosis, or differentiation in cultured 
transformed cells
Storage:
Store vorinostat capsules at room temperature, 15 to 30 .C (59 to 86 .F). Do not store above
30.C.  Avoid exposure to excessive moisture.
Method of Administration:
Unless otherwise stated in the protocol, vorinostat capsules must be administered whole.
Administer doses of vorinostat with food, if possible.
Potential Drug Interactions:
The major pathways of vorinostat metabolism involve glucuronidation and β-oxidation. As
vorinostat is not eliminated via CYP450 pathways, no drug-drug interactions are expected with 
known CYP450 inhibitors or inducers. Although vorinostat was not a potent reversible CYP450 
inhibitor, studies performed to monitor gene expression changes indicated some potential for 
CYP2C9 and CYP3A4 activity suppression. However, these changes were observed at 
concentrations higher than the pharmacologically relevant concentration of 2 μM (Cmax).
Prothrombin time and INR prolongations have been reported in patients taking vorinostat 
concomitantly with coumarin derivative anticoagulants. Monitor these patients more frequently 
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Special Handling:
Vorinostat is an anticancer drug. If clean powder is spilt from broken or damaged vorinostat 
capsules care should be taken to minimize inhalation or direct contact with skin. Wash spill area 
at least 3 times with ethyl alcohol, followed by water.
Patient Care Implications:
Because vorinostat’s dose limiting toxicities are anorexia, dehydration, diarrhea, and fatigue, 
patients should maintain adequate fluid and food intake. Encourage patients to seek a 
nutritional consult. Treat diarrhea promptly with appropriate supportive care, including 
loperamide. Instruct patients to begin taking loperamide at the first signs of: 1) poorly formed or 
loose stool, 2) occurrence of more bowel movements than usual in one day, or 3) unusually high 
volume of stool. Loperamide should be taken in the following manner: 4 mg at first onset of 
diarrhea, then 2 mg after each unformed stool. Daily dose should not exceed 16 mg/day. 
Loperamide should not be taken prophylactically. Advise patients to drink plenty of clear fluids to 
help prevent dehydration caused by diarrhea. Avoid loperamide if there is the presence of blood 
or mucus in the stool or if diarrhea is accompanied by fever. If grade 3 or 4 diarrhea develops, 
discontinue further treatment with vorinostat. Patients should not have taken valproic acid, 
another histone deacetylase inhibitor, for at least 2 weeks prior to study enrollment.
How Supplied: 
Vorinostat is supplied by Merck & Co., Inc. Vorinostat will be provided in a 100-120 tablet bottle. 
For the purpose of this study, vorinostat will be given at 400 mg per day (4x 100 mg tablets), 5 
of 7 days. Please refer to complete prescribing information in the FDA packet insert for storage 
and handling. 
4.1.3
Investigational Drug MK-3475 (Pembrolizumab)
Pembrolizumab will be available in 100mg solution in a single use-vial for intravenous 
administration.
Classification
Antineoplastic
Mechanism of Action
Pembrolizumab (previously known as SCH 900475) 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. This blockade enhances functional activity of 
the target lymphocytes to facilitate tumor regression and ultimately immune rejection.
Contraindications
None
Availability
Pembrolizumab is an investigational agent supplied by Merck, for storage and application 
please refer to lab manual.
Summary
The programmed cell death 1 (PD-1) pathway represents a major immune control switch which 
may be engaged by tumor cells to overcome active T-cell immune surveillance.
MK-3475 (Pembrolizumab, previously known as SCH 900475) 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. This blockade enhances functional 
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Merck is studying pembrolizumab for various oncology indications.  An open-label Phase I study 
is being conducted to evaluate the safety and clinical activity of pembrolizumab when 
administered as monotherapy. The dose escalation portion of this study evaluated three dose 
levels of single agent pembrolizumab (1 mg/kg, 3 mg/kg, and 10 mg/kg), in patients with 
advanced solid tumors. All three dose levels were well tolerated and no dose-limiting toxicities 
(DLTs) were observed, therefore the maximum tolerated dose (MTD) has not been determined. 
The ongoing expansion part of this study is evaluating pembrolizumab in patients with 
melanoma (MEL) and non-small cell lung cancer (NSCLC).  
In a Phase II study, is also being conducted to evaluate the safety and clinical activity of 
pembrolizumab relative to standard of care chemotherapy in melanoma.
In a randomized, controlled, open-label, three-arm Phase III pivotal study is being conducted to 
evaluate two dosing regimens of pembrolizumab versus ipilimumab (IPI) in patients with 
unresectable or metastatic MEL who have not received IPI treatment. Protocol 010 (PN010), a 
randomized, adaptively designed Phase II/III trial is being conducted to evaluate two dosing 
schedules of pembrolizumab  (10 mg/kg Q3W or 2 mg/kg Q3W) versus docetaxel in patients 
with NSCLC with PD-L1 positive tumors who have experienced disease progression after 
platinum-containing systemic therapy. 
In an open-label, non-randomized, Phase I study is evaluating pembrolizumab alone in 
Japanese patients with advanced solid tumors and in combination with cisplatin/pemetrexed 
and carboplatin/paclitaxel in patients with advanced NSCLC. The combination therapy portion of 
the trial had not yet initiated as of 18-Oct-2013. 
In a nonrandomized, multi-cohort trial is evaluating pembrolizumab 10 mg/kg Q2W in patients 
with PD-L1 positive advanced solid tumors. Cohort A is enrolling patients with triple negative 
breast cancer, Cohort B is enrolling patients with squamous cell carcinoma of the head and 
neck, Cohort C is enrolling patients with urothelial tract cancer of the renal pelvis, ureter, 
bladder, or urethra. As of the cut-off date of 18-Oct-2013, Cohort D which will enroll patients 
with adenocarcinoma of the stomach or gastroesophageal junction had not yet initiated. Safety 
data are continuing to accumulate in the clinical development program across multiple 
indications; immune-related adverse events (irAEs) are expected based on the nature of the 
compound, its mechanism of action and reported experience with immunotherapies that have a 
similar mechanism of action.
Nonclinical Pharmacology
Pembrolizumab strongly enhances T-lymphocyte immune responses in cultured blood cells from 
healthy human donors, cancer patients, and primates. In T-cell activation assays using human 
donor blood cells, the EC50 (concentration where 50% of the maximum effect is achieved) has 
been ~0.1 to 0.3 nM. In addition to interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), 
interferon gamma (IFNΩ), and levels of other cytokines were modulated by pembrolizumab. The 
antibody potentiates existing immune responses only in the presence of antigen and does not 
nonspecifically activate T-cells.
Using an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to significantly 
inhibit tumor growth in a variety of syngeneic murine tumor models. In these experiments in 
mice, anti-PD-1 therapy is synergistic with chemotherapeutic agents such as gemcitabine and 
5-fluorouracil (5-FU) and combination therapy results in increased complete tumor regression 
rates in vivo.
Nonclinical Pharmacokinetics


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After intravenous (IV) administration of pembrolizumab to cynomolgus monkeys, systemic 
exposure to pembrolizumab independent of sex, increased with increasing dose. Systemic 
exposure for the 7-day dosing interval increased after repeated dosing from 40 to 200 mg/kg. 
Area under the concentration-time curve (AUC) for the 7-day dosing interval (AUC[0-7 days]) 
after one dose appeared to be dose-proportional from 0.3 to 200 mg/kg, suggesting dose-
independent pharmacokinetics (PK). Terminal half-life (t½) values from individual animals after 
repeated IV dosing ranged from 11.8 to 23.7 days (mean values ranged from 15.7 to 22.3 days) 
across the doses tested.
Safety Pharmacology/Toxicology
The potential for systemic toxicity of pembrolizumab was assessed in a 1-month repeat-dose 
toxicity study with a 4-month recovery in cynomolgus monkeys and in a 6-month repeat dose 
toxicity study with a 4-month recovery period in cynomolgus monkeys. In the 1- month toxicity 
study, cynomolgus monkeys were administered an IV dose of 6, 40, or 200 mg/kg once weekly 
for a total of five doses. Four monkeys/sex/group were euthanized during Week 5. The 
remaining two monkeys/sex/group were euthanized during Week 23, after a four-month post-
dose period. In this study, pembrolizumab was well tolerated in monkeys with the systemic 
exposure (AUC) up to approximately 170,000 μg/ day/mL over the course of the study. There 
was no test article-related mortality, and test article-related changes were limited to an 
increased incidence of inguinal swelling, and increased splenic weights in males receiving 200 
mg/kg. Both of these findings were not considered adverse and there was no histopathologic 
correlation. Splenic weights were normal at the post-dose necropsy. Anti-pembrolizumab 
antibodies were detected in seven (out of eight) animals in the 6 mg/kg dose group and one (out 
of eight) animal in the 40 mg/kg dose group, and were associated with an apparent increase in 
clearance of pembrolizumab. The presence of anti-drug antibodies (ADA) in monkeys in the 
low-dose group and in one monkey in the mid-dose group did not impact the pharmacodynamic 
response as sufficient target engagement was demonstrated for the duration of the study (with 
the exception of one low-dose monkey). Additionally, anti-pembrolizumab antibodies were not 
detected in any monkeys in the high-dose group, suggesting that potential toxicity has been 
evaluated at the highest exposure levels in the study. Based on the lack of adverse test article-
related findings in this study, the No Observable Adverse Effect Level (NOAEL) was ≥200 
mg/kg.
In the 6-month toxicity study, the potential for systemic toxicity was assessed in cynomolgus 
monkeys administered an IV dose of 6, 40, or 200 mg/kg once every other week for 
approximately 6 months (a total of 12 doses) followed by a 4-month treatment free period. Three 
animals/sex/group were designated for interim necropsy at the end of the 6-month dosing phase 
(3 days after receiving the last dose in Study Week 23); and the remaining monkeys were 
designated for final necropsy following the 4-month treatment-free period. Pembrolizumab was 
well tolerated at all dose levels. There were no test article-related antemortem findings. There 
were no test article-related electrocardiographic or ophthalmic findings. There were no test 
article-related changes at injection sites. There were no test article-related gross observations 
or organ weight changes at the interim or final necropsy. Since there were no test article-related
histomorphologic findings at interim necropsy, histomorphologic evaluation of tissues collected 
at final necropsy were not conducted. The presence of ADA was observed in five out of ten 
animals at 6 mg/kg/dose during the dosing phase, which correlated with an apparent increased 
rate of elimination of pembrolizumab in these animals. No anti-pembrolizumab antibodies were 
detected at 40 or 200 mg/kg/dose during the dosing phase, and no MK-3475 serum 
concentration profiles in these two groups suggested an effect of ADA on pembrolizumab 
elimination rate. During the treatment-free period, anti-pembrolizumab antibodies were detected 
in two animals at 6 mg/kg/dose, which already had ADA present during the dosing phase, and in 
two additional animals (one at 6 mg/kg/dose and one at 200 mg/kg/dose), which were ADA 
negative during the dosing phase. The detection of anti-pembrolizumab antibodies had a 
minimal effect on the mean group systemic exposure to pembrolizumab during the study and 


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did not impact the evaluation of potential toxicity of MK- 3475 for the duration of the 6-month 
study as there were no test article-related effects on any of the parameters examined and as no 
monkey in the mid- and high-dose groups developed ADA during the dosing phase. In 
conclusion, pembrolizumab administered once every other week over a 6-month duration to 
cynomolgus monkeys was well tolerated and the no observed effect level (NOEL) was ≥200 
mg/kg/dose (the highest dose tested). In addition, tissue cross-reactivity studies using monkey 
and human specimens were conducted to evaluate the potential cross reactivity of 
pembrolizumab with cryosections of cynomolgus monkey tissues and normal human tissues. 
Results demonstrated the expected on-target staining of the membranes of mononuclear 
leukocytes in both species. The off-target staining (cytoplasmic and stromal) that occurred in 
many tissues of both species was considered spurious binding inherent to the experimental 
conditions of the in vitro tissue cross reactivity studies with no in vivo toxicological significance.
Clinical Development
Clinical data from PN001 is presented in ths report with a visit cut-off date of 26-Jul-2013. As of 
26-Jul-2013, there have been 789 patients treated in PN001 with pembrolizumab as a 30-
minute IV infusion. Of these 789 patients, preliminary data are presented in this report from 479 
patients. Data from 200 patients in Part B3 and 110 patients in Part F that were treated as of the 
cut-off data were not included in the analyses yet. Based upon this safety database consisting 
of patients treated up to 10 mg/kg once every two to three weeks, pembrolizumab has been 
generally well-tolerated at doses up to 10 mg/kg every other week without DLTs. One (0.002%) 
patient assayed to date had samples confirmed positive for ADA, but no impact on safety has 
been observed. Five other clinical studies (PN002, PN006, PN010, PN011, and PN012) are 
ongoing however preliminary data analyses are not yet available. Important safety findings from 
these studies will be discussed in Section 5 of this report. For these 5 studies, the number of 
treated patients indicated in this report is based on a visit cut-off date of 18-Oct-2013 to allow for 
more mature enrollment data and align with the Development Safety Update Report data cutoff 
date.
Pembrolizumab PK results have been obtained from PN001 following the first dose at 1, 3 and
10 mg/kg IV of pembrolizumab administered to 17 patients with solid tumors. The observed 
pharmacokinetic profile of pembrolizumab was typical of other IgG mAbs with a half-life (t½) of 
approximately 2 to 3 weeks. There was no indication of dose dependency of half-life in the 3 
dose groups and a dose related increase in exposure was observed from 1 to 10 mg/kg. The 
long half-life supports a dosing interval of every 2 or 3 weeks. Exposure obtained with sparse 
sampling after dosing melanoma and non-small cell lung cancer (NSCLC) patients at 2 and 10 
mg/kg, every 2 or 3 weeks, is consistent with this profile.
As of 18-Oct-2013, PN002 has randomized 497 patients with metastatic melanoma (495 
patients were treated) across 3 treatment groups as follows, pembrolizumab 2 mg/kg Q3W,
pembrolizumab 10 mg/kg Q3W, and chemotherapy (investigator choice of treatment) in a 1:1:1 
ratio. PN006 has randomized 68 IPI-naïve patients with unresectable or metastatic melanoma 
across the 3 treatment groups: 10 mg/kg Q2W, 10 mg/kg Q3W, and ipilimumab in a 1:1:1 ratio. 
PN010 has randomized three patients with NSCLC across the 3 treatment groups: 10 mg/kg 
Q3W, 2 mg/kg Q3W, and docetaxel 75 mg/m2 Q3W in a 1:1:1 ratio. In PN011 10 patients have 
been treated. In PN012, 109 patients have been treated across the three cohorts as of 18-Oct-
2013.
4.2
 Drug Accountability
The Investigational Pharmacist will manage drug accountability records.


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4.3
Drug Ordering
UCSF will obtain pembrolizumab (MK-3475) directly from Merck as study supply.
4.4
Packaging and Labeling of Study Drugs
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable 
local and federal laws.
5
Treatment Plan
5.1
Dosage and Administration
The dose regimen of 200 mg Q3W of pembrolizumab is planned for all urothelial cancer trials. 
Available PK results in subjects with melanoma, NSCLC, and other solid tumor types support a 
lack of meaningful difference in PK exposures obtained at a given dose among tumor types. An 
open-label Phase 1 trial (PN001) in melanoma subjects is being conducted to evaluate the 
safety and clinical activity of single agent pembrolizumab.  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.  All three dose levels were well tolerated and no 
dose-limiting toxicities were observed.  This first in human study of pembrolizumab 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 maximum tolerated dose (MTD) has been 
identified.
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The clinical 
efficacy and safety data demonstrate a lack of clinically important differences in efficacy 
response or safety profile at these doses.  For example, in Cohort B2, advanced melanoma 
subjects who had received prior ipilimumab therapy were randomized to receive pembrolizumab 
at 2 mg/kg versus 10 mg/kg Q3W.  The overall response rate (ORR) was 26% (21/81) in the 
2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)).  The proportion 
of subjects with drug-related adverse events (AEs), grade 3-5 drug-related AEs, serious drug-
related AEs, death or discontinuation due to an AE was comparable between groups or lower in 
the 10 mg/kg group.  
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a given 
dose among tumor types.  Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to pembrolizumab to a clinically 
meaningful extent.  Taken together, these data support the use of lower doses (with similar 
exposure to 2 mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being evaluated in 
NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and 
neck cancer in PN012, which are expected to provide additional data supporting the dose 
selection.
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation 
results indicating that 200 mg will provide exposures that are reasonably consistent with those 
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within the 
exposure range established in melanoma as associated with maximal clinical response.  A 
population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 476 subjects from 
PN001.   The distribution of exposures from the 200 mg fixed dose are predicted to considerably 
overlap those obtained with the 2 mg/kg dose, with some tendency for individual values to range 
slightly higher with the 200 mg fixed dose.   The slight increase in PK variability predicted for the 
fixed dose relative to weight-based dosing is not expected to be clinically important given that 
the range of individual exposures is well contained within the range of exposures shown in the 
melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety.  The population PK 
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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 tumor types and indication settings. 
Table 5.1
Regimen Description
Arm A (Figure 1)
Study Drug
Dose
Route
Schedule
Cycle Length
Tamoxifen 
20 
mg 
Tablets
Oral
daily continuous All 
cycles
Vorinostat
400 mg
Oral
Days 5/7
All cycles
Pembrolizumab 200 mg 
Intravenous
Day 1, week 1
Cycles 1+
3 weeks (21 days)
Arm B (Figure 1)
Study Drug
Dose
Route
Schedule
Cycle Length
Tamoxifen 
20mg Tablets Oral
daily continuous
 All cycles
Vorinostat
400mg
Oral
Days 5/7
All cycles
Pembrolizumab 200mg 
Intravenous
Day 1, week 1
 Cycles 2+
3 weeks (21 days)
Arm C (Figure 1)
Study Drug
Dose
Route
Schedule
Cycle Length
Vorinostat
400 mg
Oral
Days 5/7
All cycles
Pembrolizumab 200 mg 
Intravenous
Day 1, week 1
Cycles 1+
3 weeks (21 days)
5.1.1
Dose Modifications and Dosing Delays 
The following dose modification rules will be used with respect to potential toxicity.  Toxicity will 
be assessed continuously according to the NCI Common Terminology Criteria for Adverse 
Events Version 4.0 (CTCAE v4.0) 
The following dose modifications should be made for febrile neutropenia, and blood counts 
obtained on day one of each cycle. If more than one of these conditions applies, use the most 
stringent (i.e., the greatest dose reduction). The AE may be due to pembrolizumab or 


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vorinostat alone in which case the respective agent should be reduced. If overlapping 
toxicity is suspected both drugs may be reduced with the potential to re-escalate the 
non-offending agent. Given the very different nature of pembrolizumab and 
vorinostat/tamoxifen toxicities, separate tables are shown for individual agents. 
No dose modification will be pursued for tamoxifen. 
5.1.1.1 Dose Modifications and Dosing Delays Tables for Drug Related Adverse Events 
Hematologic toxicity
Neutropenia:
Neutropenia
Febrile neutropenia
Vorinostat
Tamoxifen
ANC >1000
100%
100%
ANC: 500-1000
Hold for until <grade 2 #, 
Restart at 75%: 300 mg qd for all 
subsequent cycles
Second occurrence resume at 200 mg 
qd for all subsequent cycles
Third occurrence: remove from study
100%
ANC: 0-500
Hold for until <grade 2 or less#
Restart at 75%: 300 mg qd for all 
subsequent cycles
Second occurrence resume at 200 mg 
qd for all subsequent cycles
Third occurrence: remove from study
100%
#Patient with a dose delay for more than 3 weeks in the first 2 cycles will need to be replaced for 
toxicity and efficacy assessments.
Patients who developed a second episode of febrile neutropenia despite a dose modification 
will be removed from study.
Anemia
Hemoglobin
Vorinostat
Tamoxifen
>8 mg/dl
100 %: 400 mg qd
100%


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6.5-8 mg/dl
 75 %: 300 mg qd
100%
<6.5 mg/dl
 50 %: 200 mg qd
100%
An alternative to dose modification would be the use of PRBC transfusion. This is not allowed in 
cycle one, but may be used at the discretion of the treating physician for subsequent cycles. 
Thrombocytopenia
Platelets
Vorinostat
Tamoxifen
>75’000
100 %: 400 mg qd
100%
<75’000
100 %: 400 mg qd
100%
≤50’000/mm3
 Hold until <grade 2 or less
Restart at 75%: 300 mg qd for all 
subsequent cycles
Second occurrence resume at 
200 mg qd for all subsequent 
cycles
Third occurrence: remove from 
study 
100%
 ≤25’000/mm3
Hold until <grade 2 or less
Restart at 75%: 300 mg qd for all 
subsequent cycles
Second occurrence resume at 
200 mg qd for all subsequent 
cycles
Third occurrence: remove from 
study
100% 
Non-hematological toxicities
Laboratory abnormalities must be clinically relevant and dose and drug related to prompt dose 
modifications. 
Bilirubin
Vorinostat
Tamoxifen
≤1.5 mg/dl
100 %: 400 mg qd
100%
1.6  3.0 mg/dl
 75 %: 300 mg qd
100%


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>3.0 mg/dl
First occurrence: hold until <grade 2, 75 %: 
300 mg qd 
Second occurrence: Hold until grade 2 or 
less, 50 %: 200 mg qd
100% 
AST/ALT
Vorinostat
Tamoxifen
≤2.5 x ULN
100 %: 400 mg qd
100%
2.5-5 x ULN
First occurrence: 75 %: 300 mg qd
Second occurrence: 50 %: 200 mg qd
100%
> 5 x ULN
First occurrence: hold until <grade 2, 
resume at 75 %: 300 mg qd 
Second occurrence: Hold until grade 2 or 
less, 50 %: 200 mg qd
Third occurrence: remove from study
100% 
Hepatic Dysfunction: Any new increase in LFTs should raise the concern to rule out 
progressive metastatic disease. If the rise is not due to progressive metastatic disease, give the 
following dose based on lab values obtained on day 1 of each cycle:                                                                     
Effects on the liver: Tamoxifen has been associated with changes in liver enzyme levels, and 
on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, 
cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In 
most reported cases, the relationship to tamoxifen was uncertain. However, some positive 
rechallenges and dechallenges have been reported. If grade 3 or 4 liver toxicity is maintained 
after a temporary stopping of vorinostat, both drugs should be stopped. Any rechallenge should 
be discussed with the study chair. If treatment is delayed for more than 3 weeks, contact the 
Principle Investigator.
Gastrointestinal Toxicity
Nausea/Vomiting/Dehydration: 
In this protocol, the routine use of any and all anti-emetics 
is allowed as clinically appropriate; these include the use of dexamethasone and 5-HT3 receptor 
antagonists.
Patients should maintain adequate fluid and food intake because vorinostat’s dose-limiting 
toxicities are anorexia, dehydration, diarrhea, and fatigue.  In the setting of dysgeusia, popsicles 
and Gatorade have been found to be useful by some investigators to maintain adequate 
hydration. Patients should also be encouraged to seek a nutritional consult. 
Diarrhea: Treat diarrhea promptly with appropriate supportive care, including loperamide. Instruct 
patients to begin taking loperamide at the first signs of: 1) poorly formed or loose stool, 2) 
occurrence of more bowel movements than usual in one day, or 3) unusually high volume of stool.  
Loperamide should be taken in the following manner:  4 mg at first onset of diarrhea then 2 mg 
after each unformed stool.  The daily dose should not exceed 16 mg.  Loperamide should not be 
taken prophylactically.  Advise patients to drink plenty of clear fluids to help prevent dehydration 
caused by diarrhea.  Avoid loperamide if there is the presence of blood or mucus in the stool or if 


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diarrhea is accompanied by fever.  If diarrhea is suspected to be linked to pembrolizumab and is ≥ 
grade 3, hold dose until toxicity resolves to ≤ grade 1, then resume at dose given in prior cycle.
Other Non-hematological Toxicities: 
Laboratory abnormalities must be clinically relevant and dose and drug related to prompt dose 
modifications. 
Give the following dose based on the worst toxicity encountered during the previous cycle:
Fatigue
Vorinostat
Tamoxifen
Grade 1
100%
100%
Grade 2
Hold until toxicity is ≤grade 1, then resume at 
dose given in prior cycle.
100%
Grade 3, 4
Hold until toxicity is ≤ grade 1, then resume at 
75% (or less) of dose given in the prior cycle. 
If grade 3 toxicity recurs despite dose 
reduction, decrease to 50 % of initial dose.
100%.
Other 
Vorinostat
Tamoxifen
Grade 1
100%
100%
Grade 2
Hold until toxicity is ≤grade 1, then resume at 
dose given in prior cycle.
100%
Grade 3
Hold until toxicity is ≤grade 1, then resume at 
75% (or less) of dose given in the prior cycle. If 
grade 3 toxicity recurs despite dose reduction, 
decrease to 50 % of initial dose.
100%
Grade 4
Discontinue protocol therapy.
100%
Vorinostat may be reduced for grade II fatigue, asthenia, weight loss or other 
constitutional symptoms  if deemed in the best interest of the patient.  
Effects on the Eye: Ocular disturbances, including corneal changes, decrement in color vision 
perception, retinal vein thrombosis, and retinopathy has been reported in patients receiving 
tamoxifen. An increased incidence of cataracts and the need for cataract surgery have been 
reported in patients receiving tamoxifen. If grade 3 or 4 ocular toxicities occur, both drugs 
should be stopped. Any rechallenge should be discussed with the study chair.
5.1.1.2 Dose Modifications and Dosing Delays Tables for Specific Adverse Events 
for Pembrolizumab 


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Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below:

Diarrhea: Subjects 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).  In symptomatic 
subjects, infectious etiologies should be ruled out, and if symptoms are persistent and/or 
severe, endoscopic evaluation should be considered.
o
In subjects with severe enterocolitis (Grade 3), pembrolizumab will be 
permanently discontinued and treatment with systemic corticosteroids should be 
initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started and 
continued over at least 1 month.
o
In subjects with moderate enterocolitis (Grade 2), pembrolizumab should be 
withheld and anti-diarrheal treatment should be started. If symptoms are 
persistent for more than one week, systemic corticosteroids should be initiated 
(e.g., 0.5 mg/kg/day of prednisone or equivalent).  When symptoms improve to 
Grade 1 or less, corticosteroid taper should be started and continued over at 
least 
1 
month. 
Regarding 
guidelines 
for 
continuing 
treatment 
with 
pembrolizumab, see Section 5.2.
o
All subjects who experience diarrhea 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.

Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of prophylactic 
antiemetic therapy according to standard institutional practice.  Subjects should be 
strongly encouraged to maintain liberal oral fluid intake.

Anti-infectives: Subjects with a documented infectious complication should receive oral 
or IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice.

Immune-related adverse events: Please see Section 5.2.2 below and the separate 
guidance document in the administrative binder regarding diagnosis and management of 
adverse experiences of a potential immunologic etiology.  Specific immune-related 
adverse events (irAEs) will be collected and designated as immune-related events of 
clinical interest (ECIs) as described in Section 5.2.2.

Management of Infusion Reactions:  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion. Signs/symptoms 
may include: Allergic reaction/hypersensitivity (including drug fever); Arthralgia (joint 
pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue 
(asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle 
pain); 
Nausea; 
Pruritis/itching; 
Rash/desquamation; 
Rigors/chills; 
Sweating 
(diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to 
treatment); Urticaria (hives, welts, wheals); Vomiting.
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Table 5.1 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab.
Table 5.1
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication 
at 
subsequent dosing
Grade 1
Mild 
reaction; 
infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator.
None
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 
subject is deemed medically 
stable in the opinion of the 
investigator.
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 
subject 
should 
be 
premedicated 
for 
the 
next 
scheduled dose.
Subjects who develop Grade 2 
toxicity 
despite 
adequate 
premedication 
should 
be 
permanently 
discontinued 
from further trial treatment 
administration.
Subject 
may 
be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion 
of 
pembrolizumab with:
Diphenhydramine 
50 
mg po (or equivalent 
dose of antihistamine).
Acetaminophen 
500-
1000 
mg 
po 
(or 
equivalent 
dose 
of 
antipyretic).
Grades 3 or 4
Grade 3:
Prolonged 
(i.e., 
not 
rapidly 
responsive 
to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDS
No subsequent dosing


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NCI CTCAE Grade
Treatment
Premedication 
at 
subsequent dosing
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor 
or 
ventilatory 
support 
indicated
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization 
may 
be 
indicated.
Subject 
is 
permanently 
discontinued from further trial 
treatment administration.
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration.
For Further information, please refer to the Common Terminology Criteria for Adverse 
Events v4.0 (CTCAE) at http://ctep.cancer.gov
5.1.1.3 Supportive Care Guidelines for Pneumonitis
Subjects with symptomatic pneumonitis should immediately stop receiving pembrolizumab and 
have an evaluation.  The evaluation may include bronchoscopy and pulmonary function tests to 
rule out other causes such as infection.  If the subject is determined to have study drug 
associated pneumonitis, the suggested treatment plan is detailed in Table 5.12.
Table 5.12
Recommended Approach to Handling Pneumonitis
Study drug 
associated 
pneumonitis
Withhold/Discontinue 
pembrolizumab?
Supportive Care
Grade 
1 
(asymptomatic)
No action
Intervention not indicated
Grade 2
Withhold 
pembrolizumab, 
may 
return to treatment if 
improves to Grade 1 or 
resolves 
within 
12 
weeks
Systemic corticosteroids are indicated.  
Taper if necessary.
Grade 3 and Grade 
4
Discontinue 
pembrolizumab
Systemic corticosteroids are indicated. 
The use of infliximab may be indicated 
as appropriate.  Refer to the Event of 
Clinical Interest and Immune-related 
Adverse Event Guidance Document 
for additional recommendations.


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For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules should 
apply:

First episode of pneumonitis
o
May increase dosing interval by one week in subsequent cycles

Second episode of pneumonitis – permanently discontinue pembrolizumab if upon 
rechallenge subject develops pneumonitis  Grade 2
5.2
Monitoring and Toxicity Management
Each patient receiving pembrolizumab in combination with Tamoxifen and Vorinostat will be 
evaluable for safety.  The safety parameters include all laboratory tests and hematological 
abnormalities, physical findings, and spontaneous reports of adverse events reported to the 
investigator by patients.
Each patient will be assessed periodically for the development of any toxicity as outlined in 
Section 6 Study Procedures and Observations. Toxicity will be assessed according to the NCI 
CTCAE v4.0.  Dose adjustments will be made according to the system showing the greatest 
degree of toxicity. 
5.2.2 Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or 
is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, any 
ECI, or follow up to an ECI, whether or not related to the Sponsor’s product, must be reported 
within 24 hours to the Sponsor, either by electronic media or paper. Electronic reporting 
procedures can be found in the EDC data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
Events of Clinical Interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.8.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: 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. The trial site guidance for assessment and follow up of 
these criteria can be found in the Investigator Trial File Binder (or equivalent).


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6
Study Procedures and Observations
6.1 Treatment Duration
Eligible patients will receive treatment as described above, in consecutive 3-week cycles, until 
progression of disease or unacceptable toxicity. Patients are expected to receive treatment for 
at least 3 cycles, at which time the first evaluation for efficacy will occur. If there is continued 
safety and tolerability, treatment may continue. 
For Arm A: After the initial treatment with vorinostat and tamoxifen, regardless of response 
of the staging studies, PD-1 will be added to all patients. 
For Arm B: patients may remain on study if there is radiological progression however the 
clinical presentation shows improvement or benefit. 
All patients will be restaged during week 9 and 18 via imaging scans, staging will then be 
continued every 3 cycles until 6 months. After 6 months staging may be spaced out to 6 cycles if 
clinically indicated.
Patients will be followed for evaluation of safety for at least 30 days after the last dose of study 
drug. Any study drug-related serious adverse events will be followed until resolution, return to 
baseline grade, or deemed irreversible by the Investigator.
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from trial 
treatment.
6.2
Schedule of Procedures and Observations
The study-specific assessments are detailed in this section and outlined in Section 6 Schedule 
of Study Procedures and Assessments.  Screening assessments must be performed within 28 
days prior to the first dose of investigational product.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator. All on-study visit procedures are 
allowed a window of ± 5 days unless otherwise noted.  Treatment or visit delays for public 
holidays or weather conditions, or patient’s personal reasons that do not compromise safety do 
not constitute a protocol violation. Treatment delays may not exceed 3 weeks, unless discussed 
with the study team for patients with documented benefit. Patients with proven systemic benefit, 
who have localized progression in the sanctuary site, may receive localized treatment to that 
site, including but not limited to radiation therapy, gamma knife or surgery. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.  
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements.
6.2.2
Long Term/Survival Follow-up Procedures
Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an 


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AE of Grade > 1 deemed related to study drug, will be followed until the resolution of the AE to 
Grade 0-1, baseline or until the beginning of a new anti-neoplastic therapy.
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the follow-up phase and should be assessed every 12 weeks (± 7 days) by radiologic 
imaging to monitor disease status.  Every effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, end of 
the study or if the subject begins retreatment with pembrolizumab. Information regarding post-
study anti-neoplastic treatment will be collected if new treatment is initiated.
Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
6.2.3
Discontinuation of Therapy
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests.  Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 
request to end participation, or simply significant uncertainty on the part of the Investigator that 
continued participation is prudent.  There may also be administrative reasons to terminate 
participation, such as concern about a patient’s compliance with the prescribed treatment 
regimen.
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any adverse 
events which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
combination of vorinostat, tamoxifen or pembrolizumab may discontinue treatment with the 
option of restarting treatment if they may derive further benefit in the opinion of the study team. 
Tamoxifen should be continued.  After discontinuing treatment following assessment of CR, 
these subjects should return to the site for a Follow-up Visit every 12 weeks with staging studies 
as described for patients on active treatment. 
lXs= Helen Diller Family Comprehensive Cancer Center 


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Table 6.
Study Calendar
Test/Study
Baselinea
screening
Cycle 1
Cycle 2
Subsequent 
cyclesg
Restaging or 
off study
D1
D8
D10
-12
D15
D1
History 
X
X
X
X
X
X
Concomitant 
medication
X
X
X
X
X
X
Physical 
Exam, 
Vitals & ECOG
X
X
X
X
X
X
Height 
and 
weight
X
X
X
X
X
X
Toxicity 
Assessment
X
X
X
X
X
X
Xb
PK sample 
X or D1f
Xh
Xf 
(end 
of  
cycle 3)
Tumor 
FNA/Biopsy 
X or D1f
Xf 
(end 
of  
cycle 3)
PBMC
X or D1f
Xh
Xf 
(end 
of  
cycle 3)
Lymphocyte 
Subset
X or D1 f
Xh
Xf 
(end 
of  
cycle 3)
CBC w/diff
X
X
X
X
X
X
Comprehensive 
metabolic paneli
X
X
X
X
X
Xc
Thyroid Function
X
X
X(odd 
cycles)
CEA, Ca15-3, Ca 
125 
(If 
clinically 
indicated)
X
X
X
Xc
Pregnancy Test
Xd
Xd
Radiology
(CT scans, MRI)
Xe
Xe
Xe
Documentation of 
Response 
X
Vorinostat
400 mg once a day, 5 days on, 2 days off, weekly every cycle  
Tamoxifen
20 mg once a day continuously (for ER+ disease only)
Pembrolizumab
Arm A)
200 mg q every three weeks
start on day 1 of cycle 1
Pembrolizumab
Arm B)
200 mg q every three weeks
start on day 1 of cycle 2
a)
All screening procedures must be performed within 28 days unless otherwise indicated. Pre-study 
tests, History and Physical may be used for Day 1 tests if within 2 weeks 


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b)
Toxicity assessment must be performed until all treatment-related toxicities have been resolved 
or decreased to grade 1. Adverse events must be recorded up to 30 days after termination on 
study
c)
Every month for the first 6 cycles, then at least every 3 cycles thereafter, more frequently if 
clinically indicated 
d)
For women of childbearing potential, performed within 7 days of starting treatment. Pregnancy 
test will be repeated if clinically indicated. 
e)
Staging studies within 30 days prior to day of start, restaging after cycle 3 (week9), 6 (week 18), 
then 9, 12, then every 6 cycles if clinically indicated.  Partial and complete responses must be 
confirmed at least one month apart from the first documentation of objective response. Scans 
may be performed more frequently if clinically indicated.
f)
Pre-study within 14 days, and end of cycle 3 (preferably day 17-19) prior to cycle 4 day 1 
pembrolizumab infusion.  
g)
Cycle delays up to 5 days for non-medical reason (e.g. holidays) are acceptable without 
notification of regulatory agencies.
h)
On day 10-12 pre-dose. 
i)
Sodium, Potassium, Chloride, blood urea nitrogen, Creatinine, Non-fasting glucose, Calcium, 
Magnesium, Phosphorus, ALT, AST, Alkaline Phosphatase, Albumin, Total Bilirubin, Total Protein
j)
Therapy delay for palliative radiation should be based on discussion with the study sponsor and 
the treating physician, every effort should be made not to hold therapy, patients where vorinostat 
is being held for more than 4 weeks may stay on study if there is felt to be a benefit 
6.2.4
Logistics for Correlative studies
6.2.4.1 PK for vorinostat (vorinostat blood sample handling procedures)
Labeling:
1. Preprinted bar-coded PK sample labels with patient’s allocation number and 
prescribed collection time for the collection tubes.
2. Labels should be attached to the red-top Vacutainer tube and NUNC™ tube before 
the blood is collected.
Procedures:
1.
Label red-top Vacutainer tube (no anticoagulant) with preprinted bar-coded PK 
sample labels.
2.
Collect 5.0 mL whole blood in the labeled red-top vacutainer tube. If blood is being 
collected from a central or PIC line, collect a 10 mL discard sample first before 
collecting the actual PK samples.
3.
Invert the tube several times and allow the blood sample to clot at room temperature 
for 30 minutes.
4.
Centrifuge the clotted sample at 2,000 x g for 15 minutes at 4°C.
5.
Transfer the serum to 3.6 mL NUNC internal thread round bottom cryotubes (NUNC 
366524) with the bar-coded PK sample label attached.
6.
Samples will be stored at -70°C until processing
6.2.4.2 Histone Acetylation in peripheral blood mononuclear cells
Exposure to HDAC inhibitors results in inhibition of histone deacetylation. Histone acetylation 
(mainly histone H3) has been used as a biological marker of HDAC inhibitor activity. H3 
acetylation has been measured successfully in PBMCs in clinical trials using vorinostat and 
other HDAC inhibitors.  We will therefore measure H3 and H4 acetylation in peripheral blood 
mononuclear cells and in tumor samples of patients before and after treatment with vorinostat.


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Mononuclear cells will be obtained prior to treatment initiation and repeated on day 10 (+2) and 
at the end of cycle 3 (day 17-19). Cells will be isolated from patient blood by centrifugation at 
400 x g (Sorvall, HS4 rotor) for 30 min using a Ficoll-Paque gradient (Sigma, St. Louis, MO) as 
described by Sandor et al. Histone acetylation will be quantified by WB analysis of PBMCs 
using an acid extraction method to collect nuclear histone proteins.
6.2.4.3 Evaluation of vorinostat effects on tumor tissue acetylation and changes in 
estrogen receptor expression
Post-treatment tumor samples and PBMCs (as well as the vorinostat PK samples) will be 
obtained on cycle 3 (days 17-19) after the vorinostat morning dose. Fine needle aspirations 
(FNA) and core biopsies will be obtained either by an interventional radiologist (visceral disease, 
lymph node) or a cytopathologist (subcutaneous and skin lesions). Diff-Quick air-dry method 
(FNA) or touch prep analysis (core biopsies) at time of biopsy will be used to confirm the 
presence of tumor. Tumor samples will be divided and processed for specific techniques as 
listed below. An attempt for three cores will be made using the appropriate needle. Tissues will 
be evaluated for the effects of vorinostat on histone acetylation and estrogen expression (by 
IHC). For IHC, tumors will be fixed in formalin (1 hour/mm thickness), dehydrated, blocked in 
paraffin. Five-micron sections will be stained with the appropriate antibodies and visualized by 
light microscopy. Staining will be evaluated using Adobe Photoshop. As the tumor biopsies may 
contain a mixture of tumor and surrounding cells, cells will be stained (in addition to ER and H3) 
with specific antibodies used to distinguish tumor versus non-tumor tissues (e.g. cytokeratin 
(Keratin (5D3)) for breast cancers. PBMCs histone acetylation and ER expression will be 
quantified by Western blot.
6.2.4.4 Logistics on Immune modulation 
For immune assays we will collect 60cc of blood in green top tubes at baseline and day 10-12 in 
cycle 1 and on day 17-18 in cycle 3, at the time points specified above for tumor biopsies, FFPE 
for immune cell infiltrate and a frozen section will be obtained for TCR sequencing. 
Exploratory Objectives
1. To define the treatment-induced effects on circulating immune cells.
2. To assess the presence of antigen-specific immune responses to a broad panel of candidate 
tumor antigens.
At the prespecified endpoints: we will obtain

Immunohistochemistry and gene expression analysis for immune cell subset 
quantification and localization within tumors 

Flow cytometry to evaluate changes in intra-tumoral and circulating immune cells

T cell receptor (TCR) deep sequencing of tissue samples from pre-treatment biopsies and 
post-treatment biopsies, and post-treatment circulating T cells.

Immune response mRNA expression analysis to derive signatures associated with tumor 
response 

Identification of genomic mutations and gene copy aberrations associated with response 
and resistance to therapy 

Antigen array-base detection of circulating antibody responses 
These assays will be obtained in conjuction with Dr. Michael Rosenblum’s lab. 


6.3
Usage of Concurrent/Concomitant Medications
6.3.2
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.2.
Anti-diarrheal and anti-emetic treatment may be given as required, either therapeutically or 
prophylactically, after such events have occurred in conjunction with a prior dose given without 
anti-diarrheals or anti-emetics. If needed, efforts will be made to standardize such supportive 
regimens in agreement with participating Investigators.
Other examples of supportive care medications include prophylactic or therapeutic use of 
erythropoietin for anemia and bisphosphonates (e.g., pamidronate).
6.3.3
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Anti-cancer systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than Pembrolizumab

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with the study PI and Merck.   

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are 
live attenuated vaccines, and are not allowed.

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 study PI and Merck. 
lJCsF Helen Diller Family 
Comprehensive 
Cancer Center 


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Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
6.3.4
Rescue Medications & Supportive Care
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below:

Diarrhea: Subjects 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).  In symptomatic subjects, 
infectious etiologies should be ruled out, and if symptoms are persistent and/or severe, 
endoscopic evaluation should be considered.
o
In subjects with severe enterocolitis (Grade 3), pembrolizumab will be 
permanently discontinued and treatment with systemic corticosteroids should be 
initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started and 
continued over at least 1 month.
o
In subjects with moderate enterocolitis (Grade 2), pembrolizumab should be 
withheld and anti-diarrheal treatment should be started.  If symptoms are 
persistent for more than one week, systemic corticosteroids should be initiated 
(e.g., 0.5 mg/kg/day of prednisone or equivalent).  When symptoms improve to 
Grade 1 or less, corticosteroid taper should be started and continued over at 
least 1 month.  
Regarding guidelines for continuing treatment with 
pembrolizumab, see Section 5.2.
o
All subjects who experience diarrhea 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.

Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of prophylactic 
antiemetic therapy according to standard institutional practice.  Subjects should be 
strongly encouraged to maintain liberal oral fluid intake.

Anti-infectives: Subjects with a documented infectious complication should receive oral 
or IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice.

Immune-related adverse events: Please see Section 5.6.1.1 below and the separate 
guidance document in the administrative binder regarding diagnosis and management of 
adverse experiences of a potential immunologic etiology.  
lXs= Helen Diller Family Comprehensive Cancer Center 


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
Management of Infusion Reactions:  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion. Signs/symptoms 
may include: Allergic reaction/hypersensitivity (including drug fever); Arthralgia (joint 
pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue 
(asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle 
pain); 
Nausea; 
Pruritis/itching; 
Rash/desquamation; 
Rigors/chills; 
Sweating 
(diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to 
treatment); Urticaria (hives, welts, wheals); Vomiting.
Contraception
Pembrolizumab, tamoxifen and vorinostat may have adverse effects on a fetus in utero.  
Furthermore, it is not known if pembrolizumab has transient adverse effects on the composition 
of sperm.  Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 
methods of birth control or are considered highly unlikely to conceive.  Highly unlikely to 
conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years 
of age and has not had menses for greater than 1 year will be considered postmenopausal), or 
3) not heterosexually active for the duration of the study.  The two birth control methods can be 
either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Subjects should start using birth control from study Visit 1 throughout the study period up to 120 
days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), intrauterine device, sponge, or spermicide.  
Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
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 they must adhere to the contraception requirement (described above) for the duration of 
the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy and 
Lactation to the regulatory agencies and to Merck.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study.
7
Reporting and Documentation of Results
7.1 Evaluation of Efficacy (or Activity)
7.1.1. Antitumor Effect 
Response and progression in this study will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000] as well as Immune Related Response-Criteria (irRC).].  Changes in only 
the largest diameter (unidimensional measurement) of the tumor lesions are used in the 
RECIST v1.1 criteria (or International Workshop on Chronic Lymphocytic Leukemia [IWCLL]).


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7.1.2
Definitions
Evaluable for toxicity
All patients will be evaluable for toxicity from the time of their first treatment with the study drug.
Evaluable for objective response
Only those patients who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end of Cycle 1 will 
also be considered evaluable.)
7.1.3 Disease Parameters
Measurable disease
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a 
minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung).
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters.  
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy.
Target lesions
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions will be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as 
reference by which to characterize the objective tumor response.
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.  It is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”).  Bone lesions may be measureable if ≥ 1 cm on MRI.    Measurements of 
these lesions are not required, but the presence or absence of each will be noted throughout 
follow-up.
Non-measurable disease (Tumor Markers)
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan).  
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques are all non-
measurable. (e.g., PSA, CA-125, CA19-9, CEA)


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7.2.1
Methods for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment.
The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment.
7.2.2 Clinical Lesions:
Lesions will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is recommended. If measured by calipers, 
measurements have to be confirmed by two independent health care professionals. 
7.2.3 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. 
7.2.4 Conventional CT and MRI:
Imaging should be performed with cuts of 10 mm or less in slice thickness contiguously. Spiral 
CT should be performed using a 5 mm contiguous reconstruction algorithm. This applies to the 
chest, abdomen, and pelvis. 
7.3
Response Criteria
Evaluation of Target Lesions
Complete Response (CR)
Disappearance of all target lesions, determined by two separate observations conducted not 
less than 4 weeks apart.  Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes).  
There can be no appearance of new lesions.
Partial Response (PR)
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD.  There can be no appearance of new lesions.
Progressive Disease (PD)
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest 
sum SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or 
the appearance of one or more new lesions.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment started.
Evaluation of Non-Target Lesions
Complete Response (CR)


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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).
Incomplete Response/Stable Disease (SD)
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits.
Progressive Disease (PD)
Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions.
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 7 
Response Criteria
Target 
Lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
Best Response for this Category 
Also Requires
CR
CR
No
CR
> 4 weeks confirmation
CR
Non-CR/
Non-PD
No
PR
PR
Non-PD
No
PR
> 4 weeks confirmation
SD
Non-PD
No
SD
documented at least once > 4 
weeks from baseline
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
* In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression
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 recurrent 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. 
Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression.


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7.4
Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the CTCAE v4.0 for reporting of non-hematologic adverse events and modified 
criteria for hematologic adverse events, see Section 7.5.
For multicenter studies, the Principal Investigator at the UCSF Coordinating Center will hold the 
role of Study Chair.  The Study Chair is responsible for the overall conduct of the study and for 
monitoring its safety and progress at all participating sites.
7.5
Adverse Events
7.5.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0 (see Section 7.5).  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. 
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology 
(irAE).  
Please refer to section 7.5 for detailed information regarding the assessment and recording of 
AEs.  
7.5.2
Definition of Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
7.5.3
Adverse reaction
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event.
7.5.3.1
  Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction.


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7.5.3.2
  Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes.
7.5.3.3
  Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the study PI or Merck, it results in any of the following outcomes: 
•
Death
•
Life-threatening adverse event
•
Inpatient hospitalization or prolongation of existing hospitalization
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function
•
Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
7.5.3.4
  Life-threatening
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the study PI or Merck, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
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7.6
Evaluation of an Adverse Event
All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.  Data about these events and their severity 
will be recorded using the NCI CTCAE v4.0.  
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 
Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the 
intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related 
to 
investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions:
Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3:
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
7.6.1
NCI Common Terminology for Adverse Events (CTCAE) 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness
Table 7.6  Evaluating Adverse Events
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or 
diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention 


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indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-
threatening; 
hospitalization 
or 
prolongation 
or 
hospitalization indicated; disabling; limiting self-care ADL.
Grade 4
Life 
threatening 
consequences; 
urgent 
intervention 
indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or 
during any use of Merck product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the 
investigator, at immediate risk of death from the event as it occurred 
(Note: This does not include an adverse event that, had it occurred in a 
more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity 
(substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length 
of stay, even if the hospitalization is a precautionary measure for 
continued observation. (Note: Hospitalization [including hospitalization 
for an elective procedure] for a preexisting condition which has not 
worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking 
the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event 
associated with an overdose is considered a serious adverse event. An 
overdose that is not associated with an adverse event is considered a 
non-serious event of clinical interest and must be reported within 24 
hours to site UCSF CHR  and Merck
Other important medical events that may not result in death, not be 
life threatening, or not require hospitalization may be considered a 
serious adverse event when, based upon appropriate medical judgment, 
the event may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed previously 
(designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, 
indicate the appropriate length of time and units
Action taken Did the adverse event cause the Merck product to be discontinued?
Relationship 
to test drug 
Did the Merck product cause the adverse event? The determination of 
the likelihood that the Merck product caused the adverse event will be 
provided by an investigator who is a qualified physician. The 
investigator’s signed/dated initials on the source document or worksheet 
that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the 
investigator in assessing the likelihood of a relationship between the test 
drug and the adverse event based upon the available information. 
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relationship between the Merck product and the AE; the greater the 
correlation with the components and their respective elements (in 
number and/or intensity), the more likely the Merck product caused the 
adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to 
the Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
Time 
Course
Did the AE follow in a reasonable temporal sequence 
from administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-
induced effect (applies to trials with investigational 
medicinal product)?
Likely 
Cause
Is the AE not reasonably explained by another etiology 
such as underlying disease, other drug(s)/vaccine(s), or 
other host or environmental factors
7.7
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator.
7.8
Adverse Events Reporting 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above.
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 
the Committee on Human Research (CHR); and, when the study is conducted under an 
Investigational New Drug Application (IND), to the Food and Drug Administration (FDA) if it 
meets the FDA reporting criteria.
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s).
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at 
the Site Committee meetings. The Site Committee will review and discuss the selected toxicity, 
the toxicity grade, and the attribution of relationship of the adverse event to the administration of 
the study drug(s).
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
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For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 2 or 3 
Institutional Study at the Helen Diller Comprehensive Cancer Center please refer Appendix 4 
Multicenter Institutional Studies.\
7.8.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
study PI and Merck.
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by 20% over the prescribed dose. No specific information is available 
on the treatment of overdose of pembrolizumab. 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 adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 2 working 
days hours to Merck Global Safety. (
)
7.8.2
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is a new cancer (that is not a condition of the study);

Is associated with an overdose;

Is another important medical event 
Refer to Table X for additional details regarding each of the above criteria.
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 30 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
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Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck.
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. 
 
at the time of submission to FDA.
All subjects with serious adverse events must be followed up for outcome.
7.8.3
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
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 subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  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.
Such events must be reported within 2 working days to Merck Global Safety. 
 
7.9
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail.
Reporting to UCSF Committee on Human Research (Institutional Review Board)
The Principal Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) within 10 business days of his/her awareness of the event. 
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Any serious adverse event, that are unexpected and related,  or follow up to a serious adverse 
event, including death due to any cause other than progression of the cancer under study that 
occurs to any subject from the time the consent is signed through 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, whether or not 
related to the Sponsor's product, must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also must 
be reported immediately to the Sponsor.
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all 
three definitions: 
•
Suspected adverse reaction 
•
Unexpected 
•
Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
8.0 Statistical Considerations and Evaluation of Results
This trial will determine whether epigenetic priming may enhance the effects of PD-1 inhibitors 
in patients with ER+ metastatic breast cancer who have progressed on prior hormone therapy 
and chemotherapy. The trial will contain three arms. Within each arm we will determine whether 
epigenetic priming will required prolonged pre-exposure to epigenetic modulators or 
concomitant administration. 
Three arms will be tested, with each independent assessment. Patients will be stratified by prior 
number of hormonal therapy and chemotherapy, then randomized across arms by Dr. Scott 
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8.1
Response rates to chemotherapy in breast cancer are less than 20%. Historical 
response rates to pembrolizumab and MPDL3280A have been 18% and 19%, respectively, 
in patients whose tumors are PD-L1 positive. Hence, we expect the response rate for 
unselected patients and patients with no PD-L1 expression would be 10% or less. In 
contrast, we anticipate that vorinostat will increase the response rate to 30%Sample Size 
and Power Estimate
Response rates to hormonal therapy and MTOR or HDAC inhibitors have been reported as 5-
20% (19% for VOR-Tam, 6% for entinostat-exemestane, 12% for exemestane-everolimus). 
Given the recent additions to hormonal therapy this trial will treat a patient population that has 
received more lines of therapy than these trials, however we are interested in an ORR of >30%.  
8.2
For each arm:  Using an Optimal Simon's two-stage design (Simon, 1989), the null 
hypothesis (H_0) that the true response rate is 10% will be tested against a one-sided 
alternative. In the first stage, 10 patients will be accrued and a decision will be made to 
continue or stop accrual based on the observed objective response rate (ORR). If there 
are 0 or 1 objective responses at 24 weeks in these 10 patients, accrual to this arm of the 
study will be stopped.  Otherwise, 19 additional patients will be accrued for a total of 
n=29. We estimate that each regimen under evaluation will achieve ORR ≥ 30%. This 
study is designed to have an alpha of 0.0471, and a power of 80.5% to test the null 
hypothesis H_0: ORR = 10% against an alternative hypothesis, H_A: ORR = 30%, where 
ORR is defined as CR, PR, or SD > 24 weeks where arms are enrolled independently. 
Interim Analyses
In addition to the interim analysis for efficacy that is built into the Simon 2-stage design (see 
above), in each arm we will evaluate the need for dose modification after 6 patients have been 
enrolled. If 2 or more patients have a grade 3 non-hematologic toxicity that is clearly related to 
pembrolizumab, this agent will be reduced to 75%. Dose modification of vorinostat should be 
undertaken as per dose modification guidelines, a prior study with vorinostat and tamoxifen 
suggest that there is a high interpatient variability and tolerance and vorinostat will be adjusted 
per dose modification guidelines individually.
8.3
Analyses Plans
8.3.1
Analysis Populations
We will conduct an intention-to-treat analysis of efficacy. All patients who were randomized will 
be evaluated. 
For evaluation of safety, we will restrict the arm-specific samples to all patients who have 
received at least one dose of investigational therapy. 
8.3.2
Evaluation of Efficacy 
For each arm objective response rate (ORR) will be defined as the proportion of participants 
randomized to that arm whose status is SD or better (CR, PR) at 24 weeks’ follow-up. In 
addition to calculating the ORR, we will calculate the corresponding Agresti-Coull interval 95% 
confidence interval (CI) (Ref: Agresti, Alan; Coull, Brent A. (1998). "Approximate is better than 
'exact' for interval estimation of binomial proportions". The American Statistician 52: 119–126. 
doi:10.2307/2685469). If the lower bound of the 95% CI exceeds 10%, we will reject the null 


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hypothesis that the regimen is ineffective and conclude that it is sufficiently effective to warrant 
further study. 
8.3.3
Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the NCI CTCAE v4.0.
8.3.4
Analyses of Exploratory Endpoints
8.3.4.1   Tissue based endpoints
Note: Tissue will be used for multiple different exploratory assays. In the event that there is 
insufficient tissue to perform all assays for an individual subject, the tissue should be prioritized 
for assays as follows, in which the first assay described is the highest priority. 
Tumor PD-L1 assessment 
PD-L1 protein expression on tumor tissue from pre-treatment and post-Cycle-3 biopsies, and 
any other tumor biospecimens obtained, will be evaluated immunohistochemically and scored 
on a scale of 0, 1, 2, or 3. This scoring will be used for the determination of relationships 
between tumor PD-L1 expression and clinical responses described above. Specifically, in 
addition to hypothesizing that delayed pembrolizumab treatment (i.e., Arm A) will increase tumor 
response, we hypothesize that (i) PD-L1 expression will stimulate tumor response, (ii) but will 
not be associated with treatment (because PD-L1 is stimulated by vorinostat not 
pembrolizumab). 
For analysis, PD-L1 expression level, scored as {0,1,2,3}, will be classified as binary (0 
=negative; 1-3 =positive); across two time-points, this defines four types of PD-L1 participants: 
{0,0; 0,1; 1,0; 1,1}. We will use logistic regression to estimate Cycle-6 tumor response rate (95% 
CI) as a function of study arm and PD-L1 level at baseline and Cycle 3. Either time-point will be 
eliminated from the model if its effect is weak (p>0.2), leaving two types of PD-L1 participants: 
either {0,0; 1;1} or {0,0; 0,1}. 
Tissue immune subset quantification and localization
For all subjects, immune cell subsets and localization will be summarized by changes from 
baseline to after treatment using descriptive statistics.  
Immune cell mRNA signatures of response 
To identify individual genes whose expression levels at pre-treatment are associated with pCR, 
we will apply two-sample t tests to compare responders and non-responders. Adjusted P values 
controlling for false discovery rate (Benjamini and Hochberg method) will be derived. In addition, 
to assess association of pre-specified immune gene signature with response, the median 
expression level of the component genes will be used to represent the signature and two-
sample t tests will be used. For genes or signatures that emerge as significantly associated with 
response, logistic regression models will be used to assess their independent association with 
response after adjusting for known clinical prognostic factors. To identify pharmacodynamic 
markers, paired t-test will be carried out to examine immune gene expression differences 
between pre-treatment and post treatment samples. Additionally, association of gene 
expression levels after epigenetic priming with long term efficacy outcomes, such as PFS and 
DFS, will be explored using the Cox proportional hazards regression model. Hierarchical 
clustering superimposed with response status, relevant baseline or prognostic characteristics or 


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experimental factors will be performed using Spearman correlation and complete linkage to 
visualize the discriminating power of the immune gene expression and the correlative structure 
among the genes and the samples.
T cell receptor (TCR) deep sequencing
The change in tumor-infiltrating TCR between pre-treatment and post-epigenetic priming will be 
assessed by calculating the number of unique clonotypes comprising the top 25th percentile of 
cumulative reads after sorting by clone abundance. Repertoire change between sequencing 
experiments will be measured using Morisita’s distance. This analysis will also be performed in 
subjects receiving adjuvant chemotherapy using the same statistical techniques to evaluate the 
impact of adjuvant MPDL3280A on circulating T cell repertoire remodeling.
Genomic signatures of response
It is hypothesized that tumors with highly mutated or copy-aberrant genomes will either 
overexpress native proteins or express novel mutant proteins, both of which may be recognized 
by the immune system and serve as tumor-specific antigens. Therefore the effect of genomic 
mutations on the immune landscape will be investigated in each of the cohorts in this study as 
follows.
Tumor DNA will be isolated from pre-treatment tissue and from post-epigenetic priming 
specimens, and will be analyzed for copy number using the Human Genome CGH 244K 
Microarray (Agilent, Santa Clara, CA) and/or by next-generation sequencing. Results will be 
analyzed with DNA Analytics software (Agilent) and with the assistance of the UCSF Genome 
Core and the UCSF Biostatistics core. For copy number paired Wilcoxon signed-rank test will be 
applied to test difference of tumor gene copy number between pre and post treatment. Two-
sample Wilcoxon signed-rank test will be used to test the gene copy number between tumor 
responders and non-responders for pre-treatment, post-treatment and changes before and after 
the treatment, separately. Multiple testing adjustment will be done by controlling false positive 
rate. Next-generation sequencing will take place using appropriate methods and biostatistical 
analyses. Annotation will be based on NCBI and UCSC databases. Chi-square test will be 
applied to obtain the significant variants associated with the clinical response.
8.3.4.2   Immune endpoints
Immune cell activation 
For each arm individually, flow cytometry of circulating immune cell subsets will also be 
performed on pre-treatment blood and again after 9 weeks on vorinostat (post epigenetic 
priming). Established flow cytometry panels will examine T cell activation. Immune cell 
quantification will be summarized by changes from baseline to after treatment using descriptive 
statistics.  Furthermore, paired Wilcox on signed-rank test will be applied to test the pre-post 
treatment changes.  When available, immune cells digested from resected tumor tissues will 
also be assessed by flow cytometry.
Circulating antibody detection and characterization
Spotted antigen arrays will be used to detect circulating antibodies will be performed on sera 
derived from the pretreatment and after 9 weeks on vorinostat. . After standard preprocessing of 
the protein array data, Cluster and Treeview software will be used for unsupervised clustering of 
the data with Pearson correlation and complete linkage. For each array, an antigen is identified 
as being detected if its value is above the median. To determine the number of up- and 
downmodulated antibodies, the difference in log2 intensity values of pretreatment and post-
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differentially due to treatment. Number of antibodies with at least 2- or 4-fold difference between 
pretreatment and post-treatment samples will be compared between clinical responders and 
nonresponders by performing two-sided Wilcoxon rank sum test.
All correlative studies and assays will be performed in the Munster lab, in conjunction with 
Merck, with the help of Dr. Lawrence Fong and other experts in the field. 
9.0 Study Management
9.1 Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) will be reviewed and 
approved by the UCSF CHR (UCSF Institutional Review Board).  Prior to obtaining CHR 
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Site Committee and by the Protocol Review Committee (PRC).  The initial protocol and 
all protocol amendments must be approved by the IRB prior to implementation.  
9.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file. 
9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the CHR prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation.  The Study Chair and the UCSF study team will be responsible for updating any 
participating sites.
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9.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included.  The sponsor-
investigator will maintain written records of any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol.
9.6
Case Report Forms (CRFs)
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon as 
possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager.
9.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”.  The DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  See 
Appendix 2 Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional 
information.
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9.8
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data (e.g., signed and dated 
consent forms and medical records, such as progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall document that 
informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified.
9.9
Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
10
Protection of Human Subjects
10.1
Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the CHR mechanism and the process of informed consent. The 
CHR reviews all proposed studies involving human experimentation and ensures that the 
subject’s rights and welfare are protected and that the potential benefits and/or the importance 
of the knowledge to be gained outweigh the risks to the individual. The CHR also reviews the 
informed consent document associated with each study in order to ensure that the consent 
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document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits. 
10.2
Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document.
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Appendices
Appendix 1
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence of 
disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance without 
restriction
90
Able to carry on normal activity; minor 
signs or symptoms of disease
80
Normal activity with effort; some signs 
or symptoms of disease
1
Symptoms, but ambulatory
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but is 
able to care for most of his/her needs
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
50
Requires considerable assistance and 
frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours
30
Severely 
disabled, 
hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, fatal processes progressing 
rapidly
5
Dead
0
Dead


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Appendix 2
Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study include: 
•
Review of subject data
•
Review of suspected adverse reactions considered “serious”
•
Monitoring every six months (depending on study accrual)
•
Minimum of a yearly regulatory audit
Monitoring and Reporting Guidelines
Investigators will conduct continuous review of data and subject safety and discuss each 
subject’s treatment at monthly Site Committee meetings. These discussions are documented in 
the Site Committee meeting minutes. The discussion will include the number of subjects, 
significant toxicities in accordance with the protocol, and observed responses. 
All institutional Phase 2 or 3 studies are designated with a moderate risk assessment. The data 
is monitored twice per year with twenty percent of the subjects monitored (or at least three 
subjects if the calculated value is less than three). 
Adverse Event Review and Monitoring
All grade(s) 3-5 adverse events, whether or not unexpected, and whether or not considered to 
be associated with the use of the study drug, will be entered into OnCore®, UCSF’s Clinical 
Trial Management System.
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at 
the Site Committee meetings. The Site Committee will review and discuss the selected toxicity, 
the toxicity grade, and the attribution of relationship of the adverse event to the administration of 
the study drug(s). 
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
discussed at DSMC meetings, which take place every six weeks. 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Investigator or or the assigned designee must be 
notified within 1 business day from the participating site(s) and the Study Chair must then notify 
the DSMC Chair or qualified alternate within 1 business day of knowledge of this event. The 
contact may be by phone or e-mail. 
Increase in Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, a report should be submitted to 
the DSMC at the time the increased rate is identified. The report will indicate if the incidence of 
adverse events observed in the study is above the range stated in the Investigator Brochure or 
package insert. 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC 
must receive a formal letter within 10 business days and the CHR must be notified. 
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Data and Safety Monitoring Committee Contacts
DSMC Chair: 
DSMC Monitors 
Phone: 
Email:
Address: 
UCSF
San Francisco, CA 
UCSF Helen Diller Family Comprehensive 
Cancer Center
San Francisco, CA 94143
* DSMP approved by NCI 09/February2012


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Appendix 3
UCSF Policy/Procedure for Required Regulatory Documents for UCSF 
Investigator-Initiated Oncology Clinical Trials with an Investigator held Investigational 
New Drug (IND)
Purpose
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
Background
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
management of a clinical trial.
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well 
as paper files in the Regulatory Binders for both the Coordinating Site and the Participating 
Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
Procedures
1.   HDFCCC Essential Regulatory Documents
Documents Filed in iMedRIS:
·
CHR approvals for initial submission of application, all modifications, and continuing 
annual renewals
·
Current and prior approved protocol versions with signed protocol signature page(s)
·
Committee for Human Research (CHR) approval letters and Informed Consent Form(s) 
(ICF)
·
Current and prior versions of the Investigator Brochure (IB).
·
Serious Adverse Event Reporting
·
Protocol Violations and Single Patient Exception (SPE) Reports to CHR with supporting 
fax documentation
Documents Filed in OnCore®:
·
Package Insert (if the study drug is commercial) or Investigator Brochure
·
Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC)
·
Patient handouts
·
Screening/enrollment log
·
Data and Safety Monitoring Committee (DSMC) monitoring reports
·
OnCore® Case Report Form (CRF) completion manual


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Documents Filed in Regulatory Binder:
·
Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature
·
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.)
·
Site Initiation Visit (SIV) minutes and correspondence with participating site(s).
·
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center
·
Serious Adverse Event (SAE) reports to CHR.
·
MedWatch reporting to FDA 
·
Delegation of Authority Form
·
Drug Destruction Standard Operating Procedure (SOP)
·
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges
27 April 2012


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Appendix 4
Multicenter Institutional Studies
4.1
Data and Safety Monitoring Plan for Multicenter Study
(Phase 2 or 3 Institutional Study)
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study include: 
•
Review of subject data
•
Review of suspected adverse reactions considered “serious”
•
Monitoring every six months (depending on study accrual)
•
Minimum of a yearly regulatory audit
Monitoring and Reporting Guidelines
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk 
assessment. The data is monitored every six months, with twenty percent of the subjects 
monitored (or at least three subjects if the calculated value is less than three). 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate quarterly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters. 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites. The Study Chair will conduct continuous review of data 
and subject safety and discuss each subject’s treatment at monthly UCSF Site Committee 
meetings. The discussions are documented in the UCSF Site Committee meeting minutes. 
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate, at minimum, quarterly conference calls with the 
participating sites or more frequently as needed to discuss risk assessment. The following 
issues will be discussed as appropriate:
•
Enrollment information
•
Adverse Events (i.e. new adverse events and updates on unresolved adverse events 
and new safety information) 
•
Protocol Violations 
•
Other issues affecting the conduct of the study 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites. The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites. The data (i.e., 
copies of source documents) from the participating sites will be faxed over to the UCSF 
Coordinating Center prior to the monitoring visits in order for the DSMC to monitor the 
participating site’s compliance with the protocol, patient safety, and to verify data entry.
lXs= Helen Diller Family Comprehensive Cancer Center 


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Adverse Event Review and Monitoring
All grade(s) 3-5 adverse events, whether or not unexpected, and whether or not considered to 
be associated with the use of the study drug, will be entered into OnCore®, UCSF’s Clinical 
Trial Management System.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings. All clinically significant adverse events must be reported to the 
UCSF Coordinating Center by the participating sites within 10 business days of becoming aware 
of the event or during the next scheduled quarterly conference call, whichever is sooner. The 
UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s) from the 
UCSF Coordinating Center and the participating sites. 
In addition, all suspected adverse reactions considered “serious” must be entered in OnCore® 
and reported to the UCSF Coordinating Center within 1 business day. The suspected adverse 
reactions considered “serious” will be reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, which take 
place every six (6) weeks. 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or 
the assigned designee must be notified within 1 business day from the participating site(s) and 
the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of 
this notification. The contact may be by phone or e-mail. 
Increase in Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Study Chair at the UCSF 
Coordinating Center is responsible for notifying the DSMC at the time the increased rate is 
identified. The report will indicate if the incidence of adverse events observed in the study is 
above the range stated in the Investigator Brochure or package insert. 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC 
must receive a formal letter within 10 business days and the CHR must be notified. 
Data and Safety Monitoring Committee Contacts
DSMC Chair: 
DSMC Monitors 
Phone: 
Email:
Address: 
UCSF
San Francisco, CA 
UCSF Helen Diller Family Comprehensive 
Cancer Center
San Francisco, CA 94143
* DSMP approved by NCI 09/February2012


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4.2
UCSF Policy/Procedure for Required Regulatory Documents for a UCSF Multicenter 
Investigator-Initiated Oncology Clinical Trials with an Investigator held Investigational 
New Drug (IND)
Purpose
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
Background
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
management of a clinical trial.
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well 
as paper files in the Regulatory Binders for both the Coordinating Site and the Participating 
Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
Procedures
1.   HDFCCC Essential Regulatory Documents
Documents Filed in iMedRIS:
·
CHR approvals for initial submission of application, all modifications, and continuing 
annual renewals
·
Current and prior approved protocol versions with signed protocol signature page(s)
·
Committee for Human Research (CHR) approval letters and Informed Consent Form(s) 
(ICF)
·
Current and prior versions of the Investigator Brochure (IB).
·
Serious Adverse Event Reporting
·
Protocol Violations and Single Patient Exception (SPE) Reports to CHR with supporting 
fax documentation
Documents Filed in OnCore®:
·
Package Insert (if the study drug is commercial) or Investigator Brochure
·
Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC)
·
Patient handouts
·
Screening/enrollment log
·
Data and Safety Monitoring Committee (DSMC) monitoring reports
·
OnCore® Case Report Form (CRF) completion manual


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Documents Filed in Regulatory Binder:
·
Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature
·
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.)
·
Site Initiation Visit (SIV) minutes and correspondence with participating site(s).
·
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center
·
Serious Adverse Event (SAE) reports to CHR.
·
MedWatch reporting to FDA
·
Delegation of Authority Form
·
Drug Destruction Standard Operating Procedure (SOP)
·
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges
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ICF_000.pdf: 
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PAMELA MUNSTER, MD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
CC# 147523: Reversing Therapy Resistance with Epigenetic-Immune Modification 
(Pembrolizumab, Vorinostat, Tamoxifen)
This is a clinical trial, a type of research study.  Your study doctor, Pamela Munster, M.D., and 
her associates from UCSF Helen Diller Family Comprehensive Cancer Center at the University 
of California, San Francisco (UCSF) Medical Center will explain the clinical trial to you.
Clinical trials include only people who choose to take part.  Please take your time to make your 
decision about participating.  You may discuss your decision with your family and friends and 
with your health care team.  If you have any questions, you may ask your study doctor.
You are being asked to take part in this study because you have locally advanced or metastatic 
breast cancer.  Metastatic means the cancer has spread to areas of your body outside of your 
breast.
WHY IS THIS STUDY BEING DONE?
This is a research study to test a combination therapy in the treatment of patients with hormone 
receptor positive breast cancer. The study drug, pembrolizumab is an investigational drug.  This 
means pembrolizumab has not been approved by the U.S. Food and Drug Administration (FDA) 
for use in breast cancer.   In animal studies, lab experiments, and in some early human studies, 
pembrolizumab has been shown to prevent or slow the growth of cancer cells when used with 
other anti-hormonal therapy. It is now being tested in research studies in people with advanced 
cancer. 
The study drug pembrolizumab will be given in combination with two other drugs, tamoxifen 
and vorinostat.  Tamoxifen is an anti-hormonal drug that is United States FDA-approved to treat 
advanced breast cancer.  Vorinostat is a drug that prevents or slows the growth of cancer cells, it 
is FDA approved for treatment in patients with T-cell lymphoma but it is not FDA approved for 
use in breast cancer.  Vorinostat and pembrolizumab are therefore both investigational drugs in 
this study.  
The purpose of this study is to: 

Test how well the study drug pembrolizumab works to keep your cancer from growing,
when it is taken with tamoxifen and vorinostat. 

See which dose frequency of pembrolizumab is more effective in patients with breast
cancer, when given in combination with tamoxifen and vorinostat.
NCT#  02395627


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Merck & Co, and AVON Foundation for Women are providing funding to UCSF to conduct the 
study.  Merck & Co, the manufacturers of the study drugs, will also provide the study drugs at no 
cost to study participants.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 87 patients will be participating in this study, with 29 in each arm.  If any or both of the 
arms show no benefit in the first 10 patients, this arm will be closed before 29 patients are 
enrolled in that arm.
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY?
This study has three arms, Arm A, Arm B, and Arm C.  Your study doctor will tell you which 
arm and dose frequency group you will be participating in prior to your enrollment.
Arm A involves treatment with tamoxifen and vorinostat, and treatment with pembrolizumab 
every cycle. 
Arm B involves treatment with tamoxifen and vorinostat, and treatment with pembrolizumab 
starting in the second cycle.
Arm C involves treatment with vorinostat, and treatment with pembrolizumab every cycle.
WHAT WILL HAPPEN AND HOW LONG WILL YOU BE IN THE STUDY?
If you give your consent to be in this study by signing this form, you will have tests and 
procedures (called “screening”) done. These are done to reduce the risks of taking part in this 
study and to make sure it is okay for you to be in the study.
It is possible that after these tests are reviewed, you will not be able to be in the study. There may 
be other reasons why you cannot be in this study. These reasons will be discussed with you by 
your study doctor or the clinic staff.
Screening (before you begin the main part of the study)
After you have signed this consent, the screening tests listed below will be done within 28 days 
of your first dose of study drugs. Some of the tests listed below must be done within 4 days of 
your first dose of the study drugs.  You will need to have the following exams, tests or 
procedures to find out if you can be in the main part of the study.  Most of these exams, tests or 
procedures are a part of your regular cancer care (unless notes otherwise as Research Purposes). 
If you have had some of them recently, they may not need to be repeated. This will be up to your 
study doctor.  There may be reasons you are not allowed to take part in this study.  The study 
doctor or staff will discuss these with you.


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The total time to complete the screening tests and procedures is about 8 hours.  The screening 
procedures do not have to be completed in one day and you are allowed to take breaks if you 
have multiple procedures in one day.

Physical exam , including review of vital signs, height, and weight

Medical history including any past treatments or surgeries for your disease.

Blood draw (approximately 1-2 tablespoons)
Complete blood count (CBC) with differential and platelet count
o
Comprehensive metabolic panel
o
Blood chemistry assessment

Pregnancy test

Tumor assessment by MRI (Magnetic Resonance Imaging) or CT scan of chest,
abdomen, pelvis
o
A CT scan uses special x-ray equipment to make detailed pictures of body tissues and
organs.  For the CT scan, you may be given a "contrast material" (a special dye that 
makes it easier for doctors to see different tissues in your body).  The contrast material 
may be given orally, intravenously, or rectally (less likely).  Oral contrast material is 
given to you to drink and is used to help outline the stomach and intestines.  Intravenous 
(IV) contrast material is given to you by injecting the contrast material into a line which
is attached to a needle in your arm, and is used to get clearer pictures of your body 
cavity.  A rectal contrast fills up the loops of your lower bowel so the doctors can see 
your tumor better.  After you have been given the contrast material (either by mouth, 
by vein, or rectum), you will lie flat on a table that will move you into the CT scan 
machine.  You will be asked to lie still and may be asked to hold your breath for a few 
seconds.  The CT scan is done in the Radiology Department and takes about half an 
hour.
o
An MRI scan takes an image of your head or body to observe the location and size of
your tumor.  For the MRI scan, you may be given a "contrast material" (a special dye 
that makes it easier for doctors to see different tissues in your body).  Gadolinium is 
contrast material that causes some tumors to appear much brighter than normal tissue 
on MRI scans (these tumors may not be visible without gadolinium).  The contrast 
material may be given to you in your arm through an intravenous catheter (a tiny tube 
inserted into a vein).  You will then lie down on a narrow bed which will be placed in 
a tunnel that is 6 feet long by 22 inches wide and open at each end.  You will lie there 
quietly for about one hour, during which time you will hear a loud machine-like noise.  
The MRI scan is done in the Radiology Department and takes approximately an hour 
and a half to complete.
The following procedures will be done for research purposes:


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
Tumor biopsy
o
As part of this study, we will obtain a small piece of tumor tissue using a special
needle. This procedure will be done at the site where we can most easily get a piece
of the tumor and the biopsy can involve the lungs, liver, bone, lymph node, skin or
other. The biopsy needle will be inserted into tumor tissue and a small piece of the
tumor will be removed. 1-3 passes with this needle will be made. The tissue biopsy 
is used to confirm your diagnosis and make sure you are eligible to be in this 
research study. The tissue is also being used to help us determine if certain types of 
tumors might respond better to certain treatments.  This procedure takes about 30 
minutes.  You will sign a separate consent form for this procedure.  

Review of your medications (both prescription and over-the-counter) and side effects.

Blood draw (approximately 2-3 tablespoons)
o
Pharmacokinetics (PK) - These are blood tests that will help determine the levels
of study drug in your blood at different time points.
o
Test your  thyroid hormone levels
o
Assays to monitor immune suppression

ECOG performance status (Questions about how your disease is affecting your daily life).
During the main part of the study
This study will have three different treatment options which are referred to as Arm A, Arm B, 
and Arm C. You will be randomized to one of these treatment arms.  Randomization means that 
you are put into a group by chance. A computer program will place you in one of the groups. 
Neither you nor your study doctor can choose the group you will be in. You will have an equal 
chance of being placed in any of the groups.
Arm A involves treatment with a daily oral dose of 20mg tamoxifen and oral dose of 400mg of 
vorinostat which you take for 5 days of a seven day week.  The study drug pembrolizumab will 
administered to you intravenously in clinic starting cycle 1 and subsequent cycles. 
Arm B involves treatment with a daily oral dose of 20mg tamoxifen and oral dose of 400mg of 
vorinostat which you take for 5 days of a seven day week.  The study drug pembrolizumab will 
administered to you intravenously in clinic starting cycle 2 and subsequent cycles.
Arm C involves treatment with a daily oral dose of 400mg of vorinostat which you take for 5 
days of a seven day week.  The study drug pembrolizumab will administered to you
intravenously in clinic starting cycle 2 and subsequent cycles.
The study drugs will be given to you in 'cycles.'  Each cycle is 21 days or 3 weeks.
Treatment Period


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You will need the following tests and procedures. Each of the following study visits will take 
about 2 hours.
Cycle 1, Day 1
This visit will take about 2 hours 

Physical examination

Medical history

Blood draw (approximately 2-3 tablespoons)
o
Complete blood count (CBC) with differential and platelet count
Comprehensive metabolic panel
o
Blood chemistry assessment
The following procedures will be done for research purposes:

Review of the medications you are currently taking

Review of side effects

Tumor biopsy – if not done at the time of screening

Blood draw (approximately 2-3 tablespoons) – if not done at the time of screening
o
PK Sampling
o
Assays to monitor immune suppression – if not done at the time of screening

ECOG
Cycle 1 Day 10 to 12
This visit will take about 1 hour

Blood draw PK Samples (approximately 1 tablespoon)
Cycle 1 Day 8 and Day 15
This visit will take about 2 hours 

History and physical examination

Vital signs

Blood draw (approximately 1-2 tablespoons)
o
Routine safety tests including:
o
Complete blood count (CBC) with differential and platelet count
o
Blood chemistry assessment
The following procedures will be done for research purposes:

Review of the medications you are currently taking

Review of side effects

Blood draw (approximately 1 tablespoon) – Day 15 only
o
Assays to monitor immune suppression


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
ECOG
Cycle 2 Day 1
This visit will take about 2 hours 

History and physical examination

Vital signs

Blood draw (approximately 1-2 tablespoons)
Complete blood count (CBC) with differential and platelet count
Blood chemistry assessment
The following procedures will be done for research purposes:

Review of the medications you are currently taking

Review of side effects

Administration of pembrolizumab for study participants in Arm B (see pg 4 ‘During the
main part of the study’ for schedule’)

Blood draw (approximately 1 tablespoon)
o
Test your  thyroid hormone levels

ECOG
Cycle 3 Day 1 and every subsequent cycles +/- 5 days
This visit will take about 2 hours

History and physical examination

Vital signs

Blood draw (approximately 1-2 tablespoons)
o
Complete blood count (CBC) with differential and platelet count
o
Blood chemistry assessment

You will have a CT scan or MRI ( also cycles 6, 9 and 12 and then (and then every 6
cycles if clinically indicated)
The following procedures will be done for research purposes:

Review of the medications you are currently taking

Review of side effects

Administration of pembrolizumab for study participants in Arm A and B (see page 4,
During the main part of the study for schedule)

Blood draw (approximately 2-3 tablespoons)
o
PK sampling
o
Test your thyroid hormone levels (every odd cycle)

ECOG

Pregnancy test, if clinically indicated


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Cycle 3 Day 17 to 19
This visit will take about 2 hours

Blood draw samples (approximately 3 tablespoon)

Repeat tissue biopsy
Post treatment follow-up
Once you have discontinued all study treatments, your provider or study coordinator will give you 
a call within 30 days following the last dose of study treatment to see how you are doing (you will 
be asked about your health, any side effects, and any medications or treatments you might be 
taking); this is for research purposes). You don’t have to come back to the clinic.
Study location: All study procedures will be done at UCSF Helen Diller Family Comprehensive 
Cancer Center.
HOW LONG WILL I BE IN THE STUDY?
You will receive treatment as long as your disease is not getting worse and you do not have any 
bad side effects.  If treatment is stopped or you withdraw from treatment, you will be followed 
until any side effects from treatment have resolved.
CAN I STOP BEING IN THE STUDY?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely.  The study doctor 
may ask to do some end-of-study tests.
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
study drug combination can be evaluated by your doctor. Another reason to tell your doctor that 
you are thinking about stopping is to discuss what follow-up care and testing could be most 
helpful for you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, if the study is stopped, or for any other 
reason.
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE 
STUDY?
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don't know all the side effects that may happen.  
Side effects may be mild or very serious. Your health care team may give you medicines to help 


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lessen side effects. Many side effects go away soon after you stop taking the study drug 
combination. In some cases, side effects can be serious, long lasting, or may never go away. 
You should talk to your study doctor about any side effects you experience while taking part in 
the study.
Risks associated with pembrolizumab
As of 03-September-2016, pembrolizumab had been given to about 21,036 subjects with various 
cancers in clinical trials.  Men and women with cancer were treated, some for up to 
approximately 2 years.  Safety was studied across several cancers treated with different doses: 2 
mg/kg every 3 weeks, and 10 mg/kg every 2 or 3 weeks. The side effects seen were similar.
Very common side effects seen in more than 20% or more of patients, some may be serious 
(i.e. causing hospitalization, life-threatening or where noted, may cause death): 

Itching of the skin

Loose or watery stools

Cough
Common side effects seen in 5% to less than 20% of patients, some may be serious (i.e. 
causing hospitalization, life-threatening or where noted, may cause death): 

Joint pain

Back pain

Fever

Rash

Pain in your stomach

Loss of skin color

Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have
infrequent or hard stools

Low level of salt in the blood which may cause you to feel tired, confusion, have a
headache, muscle cramps and/or feel sick to your stomach
Less common side effects seen in 1% to less than 5% of patients, some may be serious (i.e. 
causing hospitalization, life-threatening or where noted, may cause death):

Inflammation of the lungs so you may feel short of breath and cough.  Sometimes this
might lead to death

Too much thyroid hormone so you may feel anxious, angry, have trouble sleeping, feel
weak or tired, tremble, sweat, have loose or watery stools

Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, have a fever, feel
short of breath at the time of receiving your infusion (IV) or just after, or pain at the site of 
infusion

Inflammation of the bowels/gut which may cause severe pain in your stomach with loose
or watery stools and black, tarry, sticky stools or stools with blood or mucus


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
Inflammation of the skin which may cause peeling of the skin, itchiness, and/or skin redness.
The skin inflammation (i.e. peeling, itching and redness) could also be widespread
throughout your body. More severe skin reactions may involve the inside of your mouth, the
surface of your eye and genital areas, and/or may cause the top layer of your skin to peel
from all over your body which can cause severe infection.  These severe conditions can
sometimes lead to death.
Rare side effects seen in less than 1% of patients, some may be serious (i.e. causing 
hospitalization, life-threatening or where noted, may cause death):

Inflammation of the bowels/gut so you may feel stomach pain with loose or watery stools

Inflammation of the nerves that may cause pain, weakness or tingling in the hands and
feet, and may spread to the legs, arms and upper body leading to severe muscle weakness 
and possible temporary paralysis

Inflammation of the muscles so you may feel weak or pain in the muscles

Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you
may have severe pain in the top part of your belly that may move to the back, sick to your 
stomach, and vomiting that gets worse when you eat

Inflammation of the eye so you may have eye redness, blurred vision, sensitivity to light,
eye pain, headaches, or see floaters

Inflammation of the liver that may make you feel sick to your stomach and vomit, feel
like not eating, feel tired, have a mild fever, have a pain in the right side of your stomach, 
yellow eyes and skin, and dark urine

Inflammation of the pituitary gland (a gland in the head), which may cause you to feel
sick to your stomach or have headaches, changes in behavior, double vision, few to no 
menstrual cycles, weakness, vomiting, dizziness or fainting. 

Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which
could cause tiredness, weight loss, muscle weakness, feeling faint, joint and muscle and 
stomach aches, nausea, vomiting, loose or watery stools, fever, salt craving, and 
sometimes darkening of the skin like a suntan.

Type 1 Diabetes, a condition that can cause too much sugar in your blood, feeling 
thirstier than usual, frequent urination and weight loss. You are likely to need regular 
insulin shots.

Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine,
swelling and low back pain

Inflammation of the middle layer of your heart wall (myocarditis) that may cause your
heart to have difficulty pumping blood throughout your body, which can cause chest 
pain, shortness of breath and swelling of the legs.  You may experience a fast or irregular 
heartbeat that may cause dizziness or fainting.  Sometimes this condition can lead to 
death.

Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This
condition may lead to change in your heart rate, blood pressure, body temperature, and the 
rate at which food is converted into energy.  


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
A condition that may make you feel weak and tired and might have drooping of the eyelids,
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and
legs, or difficulty breathing (myasthenic syndrome).

The formation of small clusters of immune cells (called granulomas) in parts of your
body, such as your lymph nodes, eyes, skin, or lungs (sarcoidosis).

Inflammation of the brain with confusion and fever (encephalitis). This may also include:
disorientation, memory problems, seizures, changes in personality and behavior, 
difficulty speaking, weakness or loss of movement in some parts of your body, and loss 
of consciousness
In addition to the above, if you have had an allogeneic stem cell transplant (a procedure in 
which a person receives blood-forming stem cells from a donor), you may experience graft 
versus host disease (GvHD), which may include diarrhea, skin rashes, and liver damage, after 
receiving pembrolizumab.  Sometimes this condition can lead to death.
In addition to what is specifically listed above, drugs that help stimulate the body’s immune 
response against tumor cells (immunotherapy drugs), such as pembrolizumab, can cause 
severe inflammation to every organ.
Risks associated with vorinostat:
Very common (experienced by 10% of patients or more):

Fatigue

Diarrhea

Nausea

Taste changes

Increased blood glucose level (hyperglycemia)

Increased creatinine level (transient)

Increased level of protein in the urine

Low platelet count (thrombocytopenia)
Common (experienced by between 1% and less than 10% of patients)

Loss of appetite (anorexia)

Weight loss

Muscle spasms

Hair loss (alopecia)

Dry mouth

Chills

Fever

Vomiting

Dizziness

Constipation

Low red blood cell count (anemia)

Headache

Itching


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
Swelling in hands or feet

Cough

Upper respiratory infection

Dehydration

Shortness of breath
Uncommon (experienced by less than 1% of patients):
A rare, but serious side effect of vorinostat is blood clots, including deep vein thrombosis (DVT) 
and pulmonary embolus.  You should seek emergency help and notify your health care provider 
immediately if you develop sudden chest pain and shortness of breath.  Notify your health care 
provider within 24 hours if you notice that one leg is swollen, red, painful and/or warm to touch 
and the other is not.
Risks associated with tamoxifen
Risks for tamoxifen can also be obtained from the package insert available for the drug.
Side effects you may experience from tamoxifen listed are:
Likely (side effects occurring in at least 20% of subjects):

Hot flushes

Nausea and vomiting

Fatigue

Vaginal discharge
Less likely (side effects occurring in 10-20% of subjects):

Blood clots

Changes in vision

Changes in liver functions
Uncommon (side effects occurring in less than or equal to 2% of subjects):

Cancer of the uterus
Other study related risks include:

Blood drawing (venipuncture) risks:  Drawing blood may cause temporary discomfort
from the needle stick, bruising, and infection.

IV line risks: may cause discomfort, irritation, mild bruising, bleeding, leakage of drug
solution, and rarely, infection, nausea, and lightheadedness. Because pembrolizumab is an 
antibody, there is the possibility that you may experience an acute infusion reaction. These 
are side effects that develop during or immediately after the administration of
pembrolizumab. Signs and symptoms may include:

Blood pressure changes (increase or decrease)

Headache


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
Cough

Dizziness

Fast heart beat

Feeling cold

Feeling that the tongue is swelling or your
airway is closing and you have trouble 
breathing
 
Fever

Joint pains

Muscle pains

Nausea

Rash, hives, or itching

Shortness of breath

Sweating

Tiredness

Vomiting

Electrocardiogram (EKG/ECG) risks: The ECG involves placing electrodes on the skin.
You may experience an allergic reaction to the adhesive used to attach the electrodes to the 
skin.  These symptoms are generally mild and clear up on their own.  Please let your doctor 
know if you are aware of any allergies.

Radiation (x-ray) risks: This research study involves exposure to radiation. Not all this
radiation exposure is necessary for your medical care and is for research purposes only. This 
amount of radiation may involve a low risk of cancer. However, we believe that this risk, given 
your overall medical condition is not clinically relevant. If you have any questions regarding 
the use of radiation or the risks involved, please consult your study doctor.

Bone scan risks:  Bone scan side effects are not common, and when encountered are usually
mild, such as nausea and vomiting, or you may become uncomfortable lying still for the 
duration of the examination.  The bone scan involves an injection, in the vein of your arm, of 
a radiotracer (radioactive compound that localizes in the bone).  The injection of the radiotracer 
may feel like a small sting and there may be possible bruising at the injection site.  You will 
be exposed to a limited and medically acceptable dose of radiation during the procedure.  There 
is always a slight risk of damage from being exposed to any radiation.

CT scan risks:  CT scans involve the risks of radiation (see above).  In addition, if contrast
material (iodine dye) is used, there is a slight risk of developing an allergic reaction, from mild 
(itching, rash) to severe (difficulty breathing, shock, or rarely, death).  The contrast material 
may also cause kidney problems, especially if you are dehydrated or have poor kidney 
function.  The study doctors will ask you about any allergies or related conditions before the 
procedure.  If you have any of these problems, you may not be allowed to have a CT scan.
Having a CT scan may mean some added discomfort for you.  In particular, you may be 
bothered by feelings of claustrophobia when placed inside the CT scanner, or by lying in one 
position for a long time.  If contrast material is used, you may feel discomfort when it is 
injected.  You may feel warm and flushed and get a metallic taste in your mouth. Rarely, the 
contrast material may cause nausea, vomiting or a headache.  

MRI risks:  Because the MRI machine acts like a large magnet, it could move iron-containing
objects in the MRI room during your examination, which in the process could possibly harm 
you.  Precautions have been taken to prevent such an event from happening; loose metal 
objects, like pocket knives or key chains, are not allowed in the MRI room.  If you have a piece 


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of metal in your body, such as a fragment in your eye, aneurysm clips, ear implants, spinal 
nerve stimulators, or a pacemaker, you will not be allowed into the MRI room and cannot have 
an MRI.
Having an MRI may mean some added discomfort for you.  In particular, you may be bothered 
by feelings of claustrophobia and by the loud banging noise during the study.  Temporary 
hearing loss has been reported from this loud noise.  This is why you will be asked to wear ear 
plugs.  At times during the test, you may be asked to not swallow for a while, which can be 
uncomfortable.
Contrast agent (gadolinium) risks: A few side effects of gadolinium injection such as mild 
headache, nausea, and local pain may occur. Rarely (less than 1% of the time) low blood 
pressure and lightheadedness occurs. This can be treated immediately with intravenous fluids. 
Very rarely (less than one in one thousand), patients are allergic to gadolinium. These effects 
are most commonly hives and itchy eyes, but more severe reactions have been seen which 
result in shortness of breath.
Patients with severe kidney disease sometimes have a bad reaction to gadolinium contrast. The 
condition is called nephrogenic systemic fibrosis (NSF). It can cause skin to tighten or scar 
and can damage internal organs. Sometimes it can be life-threatening. There are no reports of 
NSF in patients with normal kidney function. Before you have a MRI scan requiring an 
injection of gadolinium contrast, you will have a blood test in order to check the function of 
your kidneys. Based on your medical history and the results of the test, a doctor will decide 
whether it is safe for you to undergo the MRI scans.
try to take as little tissue as possible when we do the biopsy, and this means that sometimes 
the biopsy procedure can be unsuccessful and require a repeat biopsy to get enough tissue. 
Other potential risks will be described to you and discussed with you by doctors who conduct 
these biopsies.

Study Drug Combination: The side effects of the combination of pembrolizumab with
vorinostat and tamoxifen are not yet known.  It is possible that this combination of drugs will 
cause new or more serious side effects than taking these drugs separately. You will be 
monitored closely for side effects and your doctor may change your medications if it appears 
that this combination is causing serious side effects. You should tell your doctor about any side 
•
Tumor Biopsy: The biopsy has small but serious risks. While we make every effort to 
minimize the pain related to the procedure, the procedure is usually uncomfortable and 
sometimes painful. Wherever the biopsy is done in your body, it can lead to bleeding in that 
area, damage of organs near where the biopsy is done, or infection. While it is uncommon, 
sometimes bleeding or pain from the biopsy will reIquire you to stay overnight in the hospital  
or require you to go to the operating room to control any bleeding. We check your laboratory 
values before the biopsy to make sure that the procedure is as safe as possible and to minimize 
your chance of having a complication. Additionally, if the biopsy involves the lungs, it can 
cause the lungs to deflate and if this occurs, you might require treatment to correct this.  We 


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effects you experience while on this study.  When additional information about side effects is 
known, you will be notified of any further study drug related effects.  
If you are able to have a baby, you must avoid having sex (abstinence) or use reliable 
birth control methods during the study and for a period of 120 days after your last dose 
of pembrolizumab.  The following birth control methods are allowed during the study 
as per local regulations or guidelines:
Two (2) of the following barrier methods in combination:

Diaphragm

Condom

Copper intrauterine device (IUD)

Contraceptive sponge

Spermicide
OR
One (1) of the above barrier methods in combination with:

Hormonal contraceptives (including oral, subcutaneous, intrauterine, or intramuscular)
that are registered and marketed containing estrogen and/or a progestational agent
If you become pregnant during the study you must notify the study doctor right away.  The 
study drug will be stopped and you will be taken out of the study.
Male:
There may be risks if you are male and your partner is pregnant or trying to become 
pregnant. If you are male and your partner is able to have a baby, you and your partner must 
avoid having sex (abstinence) or use reliable birth control methods during the study and for a 
•
Reproductive Risks: You should not become pregnant while on this study because the drugs 
in this study can affect an unborn baby.  Women should not breastfeed a baby while on this 
study.  It is important to understand that you need to use birth control while on this study. 
Check with your study doctor about what kind of birth control methods to use and how long to 
use them.  Some methods might not be approved for use in this study.
•
 Female:
•
It is not known if the study drug(s) may affect an unborn or nursing baby. If you are 
pregnant, trying to become pregnant or breast-feeding, you may not be in the study.  
The study doctor will perform a blood or urine pregnancy test before the start of and during 
the study, if you are able to have a baby. 


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period of 120 days after your last dose of study drug pembrolizumab.  The following birth 
control methods are allowed during the study:
Two (2) of the following barrier methods in combination:

Diaphragm

Condom

Copper intrauterine device (IUD)

Contraceptive sponge

OR
One (1) of the above barrier methods in combination with:

Hormonal 
contraceptives 
(including 
oral, 
subcutaneous, 
intrauterine, 
or
intramuscular) that are registered and marketed containing estrogen and/or a 
progestational agent
If your partner becomes pregnant during the study you must notify the study doctor right 
away. If your partner is already pregnant when you begin the study you must use a 
condom (male) during the study and for a period of 120 days after your last dose of 
pembrolizumab. You must also agree to not donate sperm during the study and for a 
period of 120 days after your last dose of study drug.

Randomization Risks: You will be assigned to a treatment program by chance, and the
treatment you receive may prove to be less effective or to have more side effects than the 
other study treatment(s) or other available treatments.

Unknown Risks: The experimental treatments may have side effects that no one knows
about.  The researchers will let you know if they learn anything that might make you change 
your mind about participating in the study.

For more information about risks and side effects, ask your study doctor.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
Taking part in this study may or may not make your health better.  While doctors hope the study 
drug combinations will be more useful against cancer compared to the usual treatment, there is 
no proof of this.  We do know that the information from this study will help doctors learn more 
about the study drug combinations as a treatment for cancer.  This information could help future 
cancer patients.


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WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS 
STUDY?
Your other choices may include:

Getting treatment or care for your cancer without being in a study.

Taking part in another study.

Getting no treatment.

Getting comfort care, also called palliative care.  This type of care helps reduce pain,
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.
Please talk to your doctor about your choices before deciding if you will take part in this study.
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE?
We will do our best to make sure that the personal information in your medical record is kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given 
out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:

The study sponsor (Merck & co) or its representatives, including companies it hires to
provide study-related services

Researchers who are conducting this study at other research sites

Food and Drug Administration (FDA), National Cancer Institute (NCI), or other
government agencies involved in keeping research safe for people

The University of California
To ensure the scientific integrity of the study, you may not be able to review some of your 
records related to the study until after the study has been completed. When the study is over, you 
may write to the study doctor to ask to see health data about you that was collected during the 
study and to correct any errors.
Participation in research may involve a loss of privacy, but information about you will be 
handled as confidentially as possible.  A medical record will be created because of your 
participation in this study.  Your consent form and some of your research test results will be 
included in this record.  Therefore, your other doctors may become aware of your participation.  
Hospital regulations require that all health care providers treat information in medical records 
confidentially.


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WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for taking part in 
studies.  Check with your health plan/insurance company to find out what they will pay for.  
Taking part in this study may or may not cost you or your insurance company more than the cost 
of getting routine cancer treatment.
Pembrolizumab and vorinostat, will be provided free of charge while you are participating in this 
study.  However, the  pembrolizumab infusion , and certain other procedures associated with the 
administration of other drugs are considered routine care and will be billed to your insurance.
You will not be billed for any of the tests (such as optional biopsy, blood samples for biomarker 
testing) required specifically by the study.  These are procedures noted above as “research 
purposes” in this consent form.  Other procedures, which are also done in this study but are part 
of your routine care will be paid for by you or your insurance.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
WILL I BE PAID FOR TAKING PART IN THIS STUDY?
You will not be paid for taking part in this study.
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS 
STUDY?
It is important that you tell your study doctor, Pamela Munster, if you feel that you have been 
injured because of taking part in this study. You can tell the doctor in person or call her 
.
Treatment and Compensation for Injury:  If you are injured as a result of being in this 
study, the University of California will provide necessary medical treatment. The costs of 
the treatment may be billed to you or your insurer just like any other medical costs, or 
covered by the University of California, or the study sponsor Merck & Co depending on a 
number of factors. The University does not normally provide any other form of 
compensation for injury.  For further information about this, you may call the office of 
the Committee on Human Research at 415- 476-1814.  


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WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution.
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY?
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study.  Contact your study doctor(s) Pamela Munster 
.
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the Office of the Committee on Human Research at 415-476-1814
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
************************************************************
OPTIONAL RESEARCH
This section of the informed consent is about additional research studies that are being done with 
people who are taking part in the study.  You may take part in these additional studies only if you 
want to. Everyone who is taking part in the study is being asked to take part in this optional study. 
Your study doctor wants to use your blood and tissue samples to help better understand how 
pembrolizumab and vorinostat work in your body, in addition to helping develop new ways to 
monitor and treat diseases. We would like to use your previous biopsies of your tumor tissue 
(called archival tissue) and any remaining tissue from biopsies on this study, for immunological 
testing and to use some of your blood collected during your immune monitoring tests to be stored 
for future tests. If you decide to participate, your archived tissue will be collected at any time while 
you are on study and your blood sample will be collected during your already scheduled study 
blood draws.  


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What will happen if I agree to donate my specimens?
If you agree to let researchers collect and store your blood and tissue samples for future research, 
the following will happen:

After all routine tests required for your care are finished, instead of discarding your leftover
specimens we will save them in what is called a “tissue bank” for possible future research.
We also will collect and save information from your medical record, including things like 
results of physical examinations, diagnostic tests, medical questionnaires and histories, and 
cancer diagnoses and treatments. We do not know for sure if your specimens or medical 
record will be used, but they might be used in research about breast cancer.  

We may give your specimens and certain medical information about you (for example,
diagnosis, blood pressure, age) to other scientists or companies not at UCSF, including to a 
government health research database, but we will not give them your name, address, phone 
number, or any other information that would identify you. Reports about any research will 
not be given to you or your doctor.

Your specimens will be kept for indefinitely. If you decide later that you do not want your
specimens and information to be used for future research, you can notify the investigator in 
writing and we will destroy any remaining identifiable specimens and information if they are 
no longer needed for your care. However, if any research has already been done using 
portions of your specimens, the data will be kept and analyzed as part of those research 
studies.
What risks are involved with donating specimens for research?

Any extra blood we take will come through already scheduled blood draws done during this
study, and should not cause you any added risk, discomfort, or pain beyond what we normally 
expect from blood draws.

Confidentiality: Donating specimens may involve a loss of privacy, but information about
you will be handled as confidentially as possible. Study data will be physically and 
electronically secured.  As with any use of electronic means to store data, there is a risk of 
breach of data security.  Your name will not be used in any published reports from research 
performed using your specimen. The study doctor, Pamela Munster, MD and select tissue 
bank staff members will have access to information about you but they will not release any 
identifying information about you to researchers using your specimen. The UCSF Committee 
on Human Research and other University of California personnel also may see information 
about you to check on the tissue bank. 
Things to Think About
The choice to let us keep the left over tissue for future research is up to you. No matter what you 
decide to do, it will not affect your care.
If you decide now that your tissue can be kept for research, you can change your mind at any time. 
Just contact the study doctor Pamela Munster, M.D at the address below, and let us know that you 
do not want us to use your tissue. Then any tissue that remains will no longer be used for research.


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PAMELA MUNSTER, MD
Pamela Munster, M.D.
University of California, San Francisco
San Francisco, CA 94143
Participation in this optional research is voluntary, and if you choose not to allow the tumor 
tissue samples to be collected for research or to use your blood for future tests, it will in no 
way affect your care or participation in the main study. 
Previous tumor tissue - If you provide your consent, your tumor tissue previously removed during 
surgery or from old biopsies will be requested. The tumor tissue will be sent to a laboratory where 
tests will be performed.  Researchers will be performing tests that may provide additional 
information that may be helpful in understanding your response to pembrolizumab and vorinostat.  
The results from these tests will not have any effect on your treatment.  
_______
I do allow for previously collected tissue to be collected and used for 
Initials
the research purposes as described above.   
_______
I do not allow for previously collected tissue to be collected and used
Initials 
research purposes as described above.
Additional blood - If you provide your consent, additional blood taken during your study blood 
draws will be collected. The blood will be sent to a laboratory where it will be stored and tests 
will be performed.  Researchers will be performing tests that may provide additional information 
that may be helpful in understanding your response to pembrolizumab and vorinostat, and for 
future research about breast cancer.  
The results from these tests will not have any effect on your treatment.  
_______
I do allow additional blood to be collected and used for the research purposes
Initials 
described above.
_______
I do not allow additional blood to be collected and used for the research
Initials 
purposes as described above.


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CONSENT
You will be given a signed and dated copy of this consent form and a copy of the Experimental 
Subject's Bill of Rights to keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled.
By signing below, you agree that you have read or have been read this consent form and that you 
have had the chance to ask questions and they have been answered.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Participant's Printed Name 
Date
Person Obtaining Consent
Date
Witness – Only required if the participant is a non-English speaker