Clinical trial NCT04190056
Conditions: Anatomic Stage IV Breast Cancer AJCC v8 Prognostic Stage IV Breast Cancer AJCC v8
Sponsor: University of California, San Francisco
Start date: 2021-03-11; Completion date: 2023-06-15
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well pembrolizumab and tamoxifen with or without vorinostat work for the treatment of estrogen receptor positive breast cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Estrogen can cause the growth of breast cancer cells. Hormone therapy with tamoxifen may may fight breast cancer by blocking the use of estrogen by the tumor cells. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This trial is being done to find a drug combination to better control estrogen receptor positive breast cancer and reduce the number of pills taken.

Detailed description:
PRIMARY OBJECTIVE:

I. To define the role of epigenetic immune priming in a biomarker enriched estrogen receptor (ER)+ breast cancer population on the basis of overall response rate.

SECONDARY OBJECTIVES:

I. To assess duration of response (DOR) 24-week landmark progression-free survival (PFS:24).

II. Median PFS and overall survival (OS). III. Tumor responses will also be calculated by Immune Related Response-Criteria (irRC).

EXPLORATORY OBJECTIVES:

I. Evaluation of biomarker target threshold on response rate (retrospective cut off of 20% versus \[vs\] 10%).

II. To assess the ratio of effector T cells: regulatory T cells in blood and tumor biopsies pre- and post-therapy.

III. To evaluate inflammatory T cell signature changes in blood and tumor biopsies pre- and post-therapy.

IV. To evaluate changes in number of myeloid-derived suppressor cells (MDSCs) in peripheral blood and tumor biopsies pre- and posttherapy.

V. To evaluate changes in histone acetylation in peripheral blood cells and tumor biopsies pre- and post-therapy.

VI. Initial comparison to vorinostat-induced PD-1 in lymphocytes, PD-L1 modulation.

VII. Nanostring and 10 x sequencing and single cell immune phenotyping (on stored tissue for successful arms only).

VIII. Impact of histone deacetylase (HDAC) inhibition of response to pembrolizumab vs. pembrolizumab in biomarker enriched population.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, vorinostat orally (PO) once daily (QD) for 4 days weekly, and tamoxifen PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression of unacceptable toxicity.

ARM B: Patients receive pembrolizumab IV over 30 minutes on day 1 and tamoxifen PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression of unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 12 weeks thereafter.

Arms: arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1, vorinostat PO QD for 4 days weekly, and tamoxifen PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression of unacceptable toxicity. arm 2: Patients receive pembrolizumab IV over 30 minutes on day 1 and tamoxifen PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression of unacceptable toxicity.
Interventions: intervention 1: Pembrolizumab intervention 2: Tamoxifen intervention 3: Vorinostat
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Given PO

Protocol documents:
Prot_SAP_000.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.
Epigenetic priming for Immune therapy in ER-positive breast 
cancer in biomarker select population
Protocol Number: CC# 197520
Investigational Product(s): pembrolizumab, vorinostat, tamoxifen
Version Number: 3.3
Version Date: 09/30/2021
IND Number: 144356
Principal Investigator (Sponsor-Investigator)
Pamela N. Munster, MD 
University of California San Francisco
E-mail: 
Statistician
Mi-Ok Kim, PhD 
Revision History
Version 3.3
09/30/2021
Version 3.2
04/15/2021
Version 3.1
01/28/2020
Version 3.0
07/23/2019
Version 2.1
06/26/2019
Version 2.0
06/07/2019
Version 1.0
02/12/2019
Version 00
07/01/2018
NCT# 04190056


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Protocol Signature Page
Protocol No.: CC# 197520
Version Date: 09/30/2021
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data and Safety Monitoring Committee 
(DSMC). 
2.
I will conduct the study in accordance with Good Clinical Practices (ICH-GCP) and the 
applicable IRB, ethical, federal, state, and local regulatory requirements. 
3.
I certify that I, and the study staff, have received the required training to conduct this 
research protocol. 
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, federal, 
state, and local laws and regulations.
UCSF Principal Investigator 
Printed Name
Signature
Date


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Abstract
Title
Epigenetic priming for Immune therapy in ER-positive breast cancer in 
biomarker select population (Pembrolizumab, Vorinostat, Tamoxifen)
Study Description
We propose a randomized two-arm trial, enrolling 65 patients with 
hormone therapy-resistant breast cancer (HTR) to test the role of 
epigenetic priming in a biomarker enriched patient population in HTR 
breast cancer.
Phase of Study
Phase II
Investigational 
Products
Pembrolizumab, Vorinostat, Tamoxifen
Study population
Pre- and postmenopausal women or men with stage IV ER+ breast 
cancer with histological or cytological confirmation, 18 years or older
Primary Objective
To define the role of epigenetic immune priming in a biomarker enriched 
ER+ breast cancer population on the basis of overall response rate 
(ORR: CR+PR+SD at 24 weeks). 
Secondary 
Objectives
a) To assess duration of response (DOR) 24-week landmark 
progression-free survival (PFS:24) 
b) Median PFS and overall survival (OS) 
c)
Tumor responses will also be calculated by Immune Related 
Response-Criteria (irRC).


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Exploratory 
Objectives
a) Evaluation of biomarker target threshold on response rate 
(retrospective cut off of 20% vs. 10%)
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 
g) Nanostring and 10x sequencing and single cell immune phenotyping 
(on stored tissue for successful arms only)
h) Impact of HDAC inhibition of response to pembrolizumab vs. 
pembrolizumab in biomarker enriched population
Sample Size
Arm A (pembro + vorinostat + TAM): A total of 35 patients will be 
accrued. Arm B (pembro + TAM): A total of 30 patients will be accrued. 
Total of 65 patients will be accrued. 
Duration of Study 
Treatment
Patients may continue treatment until development of toxicity or until the 
patient no longer experiences clinical benefit.
Duration of Follow 
up
Patients will be followed for 30 days after end of study participation or 
removal from study, and serious adverse events will be collected for 30 
days after the end of treatment should the patient be taken off therapy.
Unique Aspects of 
this Study
This is one of the first studies to look at the response of hormone 
therapy-resistant breast cancer to epigenetic immune priming and 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 in a biomarker-enriched 
population. 
The goal of this study is to demonstrate that HDAC induced epigenetic 
priming in a biomarker enriched study will increase the efficacy of 
pembrolizumab with patient selection based on exhausted CD8+ cells in 
blood or tumor in a small subset of (ER)+ breast cancer patients.


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List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CNS
central nervous system
CR
complete response
CRF
case report form
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
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
ECG/EKG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FLC
free light chain
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBeAg
hepatitis B “e” antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonization
IDS
Investigational Drug Services (UCSF)
IND
investigational new drug application
IP
investigational product


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List of Abbreviations
IRB
Institutional Review Board
IV
intravenous
LDH
lactate dehydrogenase
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
ORR
overall response rate
PD
disease progression
PK
pharmacokinetics
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase


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Table of Contents
Protocol Signature Page ...............................................................................................................2
Abstract
3
List of Abbreviations ......................................................................................................................5
Table of Contents ..........................................................................................................................7
1
Introduction......................................................................................................................10
1.1
Background on Indication ....................................................................................10
1.1.1
Introduction to breast cancer ............................................................................10
1.1.2
Hormone-sensitive breast cancer......................................................................10
1.1.3
Therapy resistance in breast cancer..................................................................10
1.2
Background on the Investigational Products and Associated Known Toxicities.11
1.2.1
Pembrolizumab/MK-3475................................................................................11
1.2.2
Suberoylanilide hydroxamic acid (Vorinostat, SAHA) ...................................12
1.2.3
Tamoxifen ........................................................................................................13
1.2.4
Histone Deacetylases (HDAC) and their inhibitors .........................................13
1.3
Rationale for the Proposed Study.........................................................................13
1.3.1
Rationale...........................................................................................................13
1.4
Rationale for the Dose Selection/Regimen ..........................................................16
1.5
Correlative Studies ...............................................................................................16
2
Study Objectives..............................................................................................................17
2.1
Hypothesis............................................................................................................17
2.2
Primary Objective and Endpoints.........................................................................17
2.3
Secondary Objective(s) and Endpoint(s)..............................................................17
2.4
Exploratory (Correlative) Objectives ...................................................................18
3
Study Design ...................................................................................................................18
3.1
Characteristics ......................................................................................................18
3.2
Sample Size ..........................................................................................................19
3.3
Eligibility Criteria.................................................................................................19
3.3.1
Inclusion Criteria..............................................................................................19
3.3.2
Exclusion Criteria.............................................................................................21
3.4
Inclusion and Recruitment of Women and Minorities .........................................21
3.5
Duration of Treatment..........................................................................................22
3.6
Duration of Follow Up .........................................................................................22
3.7
Randomization Procedures...................................................................................22
3.8
Primary Completion .............................................................................................22
3.9
Study Completion.................................................................................................23
4
Investigational Products ..................................................................................................23
4.1
Description, Supply, and Storage of Investigational Products.............................23
4.1.1
Investigational Product: Pembrolizumab (MK-3475)......................................23
4.1.2
Investigational Product: Vorinostat..................................................................24


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Table of Contents
4.1.3
Investigational Product: Tamoxifen .................................................................25
4.2
Accountability Records for Investigational Product(s)........................................26
4.3
Ordering Investigational Product(s) .....................................................................26
5
Treatment Plan ................................................................................................................26
5.1
Dosage and Administration..................................................................................26
5.2
Dose Modifications and Dosing Delays...............................................................28
5.2.1
Dose Modifications and Dosing Delays Tables for Specific Adverse Events 
for Pembrolizumab........................................................................................................31
5.2.2
Dose Modification and toxicity management for immune-related AEs 
associated with pembrolizumab....................................................................................32
5.2.3
Dose Modification and Toxicity Management of Infusion-Reactions Related 
to Pembrolizumab.........................................................................................................39
5.2.4
Second Course..................................................................................................41
5.2.5
Monitoring and Toxicity Management.............................................................42
5.3
Stopping Rules .....................................................................................................42
5.4
Discontinuation and Withdrawal..........................................................................43
5.4.1
Supportive Care Guidelines for Pneumonitis...................................................44
6
Study Procedures and Schedule of Events .....................................................................45
6.1
Study Calendar .....................................................................................................46
6.2
Schedule of Procedures and Observations ...........................................................48
6.2.1
Prescreening Period..........................................................................................48
6.3
Participant Registration ........................................................................................48
6.3.1
Pretreatment Period ..........................................................................................48
6.3.2
Treatment Period ..............................................................................................49
6.3.3
Survival Follow-up...........................................................................................51
6.4
Correlative Studies ...............................................................................................52
6.4.1
Histone Acetylation in peripheral blood mononuclear cells ............................52
6.4.2
Evaluation of vorinostat effects on tumor tissue acetylation and changes in 
estrogen receptor expression.........................................................................................52
6.4.3
Logistics on Immune modulation.....................................................................52
6.5
Use of Concurrent/Concomitant Medications......................................................52
6.5.1
Acceptable Concomitant Medications..............................................................52
6.5.2
Rescue Medications & Supportive Care ..........................................................53
6.6
Prohibited Medications.........................................................................................54
7
Reporting and Documentation of Results........................................................................55
7.1
Evaluation of Efficacy: Antitumor Effect – Solid Tumors ..................................55
7.1.1
Definitions........................................................................................................55
7.1.2
Disease Parameters...........................................................................................56
7.1.3
Methods for Evaluation of Measurable Disease...............................................57
7.1.4
Response Criteria .............................................................................................58
7.2
Evaluation of Safety .............................................................................................60
7.3
Definitions of Adverse Events .............................................................................60
7.3.1
Adverse Event ..................................................................................................60


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Table of Contents
7.3.2
Adverse Reaction .............................................................................................60
7.3.3
Suspected Adverse Reaction ............................................................................60
7.3.4
Recording of Adverse Events...........................................................................62
7.3.5
Follow-up of Adverse Events...........................................................................63
7.3.6
Adverse Events Reporting................................................................................63
7.3.7
Definition of an Overdose for this Protocol and Reporting of Overdose to 
the Study PI and Merck.................................................................................................64
7.3.8
Adverse Events Monitoring..............................................................................65
7.3.9
Expedited Reporting.........................................................................................65
8
Statistical Considerations and Evaluation of Results ......................................................67
8.1
Sample Size Considerations .................................................................................67
8.1.1
Sample Size and Power Estimate .....................................................................67
8.1.2
Randomization..................................................................................................68
8.1.3
Stratification Factors ........................................................................................68
8.1.4
Accrual Estimates.............................................................................................68
8.2
Interim Analyses and Stopping Rules ..................................................................68
8.3
Analyses Plans......................................................................................................68
8.3.1
Analysis Population..........................................................................................68
8.3.2
Primary Analysis (or Analysis of Primary Endpoints).....................................68
8.3.3
Secondary Analysis (or Analysis of Secondary Endpoints).............................69
8.3.4
Exploratory/Correlative Analysis/Assessments ...............................................69
9
Study Management .........................................................................................................71
9.1
Pre-study Documentation.....................................................................................71
9.2
Institutional Review Board Approval...................................................................71
9.3
Informed Consent.................................................................................................71
9.4
Changes in the Protocol........................................................................................72
9.5
Handling and Documentation of Clinical Supplies..............................................72
9.6
Case Report Forms (CRFs) ..................................................................................72
9.7
Oversight and Monitoring Plan ............................................................................72
9.8
Record Keeping and Record Retention................................................................73
10
References ......................................................................................................................74
Appendix 1
Performance Status Criteria ...............................................................................78
Appendix 2
Data and Safety Monitoring Plan for a Phase II or III Institutional Study............79
Appendix 3
Prohibited Medications List ................................................................................82


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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 women1. 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 century2. Hormone-sensitive 
metastatic breast cancer remains a therapeutic challenge despite the many recent advances in 
therapy as these tumors are frequently less sensitive to chemotherapy3. 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 
post-menopausal. 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%4-7. The response rate to second-line hormonal therapy is 
considerably less (10-20%)4, suggesting a clear need for more effective therapy8-10.
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 pathways11. 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.


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1.2
Background on the Investigational Products and Associated Known 
Toxicities
1.2.1 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. 
1.2.1.1 Pharmaceutical and Therapeutic Background of PD-1
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades12. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies13-17. 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)1,2. The structure of 
murine PD-1 has been resolved3. PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and 
a cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).
Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the 
ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules 
such as CD3ζ, PKCθ, and ZAP70 which are involved in the CD3 T-cell signaling cascade1,4-6. 
The mechanism by which PD-1 downmodulates T-cell responses is similar to, but distinct from 
that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins7,8. PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, 
B-cells, T regs and Natural Killer cells9,10. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells11. 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 
tumors7,18-20. 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 tissues7. 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)21. This suggests that the PD-1/PD-L1 pathway plays a critical role in 


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tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention.
1.2.1.2 Pre-clinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to 
tumor rejection, either as a monotherapy or in combination with other treatment modalities. Anti-
mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses as a 
mono-therapy in models of squamous cell carcinoma, pancreatic carcinoma, MEL, and 
colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of IFN-ɣ, granzyme B, and perforin, indicating that 
the mechanism of action involved local infiltration and activation of effector T-cell function in 
vivo22-27. Experiments have confirmed the in vivo efficacy of PD-1 blockade as a monotherapy 
as well as in combination with chemotherapy in syngeneic mouse tumor models (see the 
Investigator’s Brochure [IB]).
For trial details, please refer to the Investigator’s Brochure. Pembrolizumab has been approved 
in several indications, see FDA label and IB v 16.
1.2.2 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 ion28. 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 issues29,30. 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 efficacy31. Of the three classes of HDACs, 
vorinostat targets most human Class 1 (related to the yeast transcriptional regulator Rpd3) and 
Class 2 (similar to the yeast Hda1) enzymes32,33. The third class of HDACs (homologs 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 concentrations34. 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)35-39. 
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 carcinoma40-45.
The antitumor activity of vorinostat was demonstrated in several in vivo models of cancer, 
including a xenograft model of human CWR22 prostate cancer cells41, a mouse model of APL 
containing the promyelocytic leukemia zinc-finger-retinoic acid receptor α fusion gene (PLZF-
RARα)46, and an N-methylnitrosourea-induced mammary tumor model in rodents47. Vorinostat 
has also shown activity when administered daily by intraperitoneal (IP) injections in the CWR22 


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and PLZF-RARα models and by oral (PO) administration in the carcinogen-induced mammary 
tumor model.
1.2.3 Tamoxifen
Tamoxifen is the most commonly used selective estrogen receptor modulator, 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%)7. The 
observation of endometrial cancer (<0.5%) has been predominantly observed when used in the 
preventive or adjuvant setting48. 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.
1.2.4 Histone Deacetylases (HDAC) and their inhibitors
A promising new class of drugs showing activity in cancer is the histone deacetylase inhibitors 
(HDACi)32,49. 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 histones50,51. The addition of acetyl groups to lysine residues on the N-terminal tail of 
histones by histone acetyltransferases (HAT) results in the weakening of the bond between 
histones and DNA51.
In contrast, removal of acetyl groups by HDACs results in the condensation of the nucleosomes 
and has been correlated with gene silencing51. HDACs can be divided into at least three 
different classes, I-III. Each class contains several members of structurally and functionally 
variable HDACs52,53. Alterations in the regulatory function of HATs and HDACs have been 
associated with the development of certain cancers54. For example, mutations in the HAT gene 
CBP have been correlated with the development of certain colorectal and gastric cancers55, 
whereas altered HDAC function has been associated with the onset of acute promyelocytic 
leukemia (APL)54. There are several inhibitors of HDACs that show anti-cancer activity in vitro 
and in vivo56. 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. 
1.3
Rationale for the Proposed Study
1.3.1 Rationale
Immunotherapy responses have remained limited in ER+ breast cancer. Our preliminary and 
clinical data suggest that epigenetic priming may be a successful strategy to enhance immune 
response. However, epigenetic priming is predominantly successful in patients with tumors that 
have exhausted CD8 subpopulation. 
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 all hormone therapy 


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positive patients, data from our pilot study with epigenetic priming suggests that benefits are 
vastly different if the population is limited to those patients with a 20% or higher expression of 
CD8 cells with dual expression of PD-L1 and CTLA in tumors (or 10% in blood). The pilot study, 
therefore, has two objectives, 
a) to show that vorinostat can increase the efficacy of pembrolizumab in a select ER+ breast 
cancer patient population and 
b) a biomarker select patient population has a higher than expected response rate to 
pembrolizumab 
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 ER+ breast cancer. 
The goal of the biomarker selection is to enrich for a population who is immune responsive
1.3.1.1 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 responses14,15. 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 resistance16. 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 
inhibitors17.
1.3.1.2 Pilot Study – Exhausted CD8+ cells predict response to PD-1 therapy in 
ER+ hormone therapy-resistant breast cancer after epigenetic priming 
Our initial pilot study of 34 patients with ER+ positive patients suggests that vorinostat 
decreases T-reg with Foxp3 expression. However, these effects were only associated with 
clinical benefit in patients with high expression of CD8 (CTLA/PD-L1) in their blood or tumor 
samples. 
The pilot included 34 patients (median age 56, 88% ECOG 1) who had been treated with a 
median of 5 (2-12) prior regimens. A minority experienced grade 3-4 toxicity (autoimmune 
hepatitis, fatigue, thrombocytopenia), with each toxicity occurring in 2 out of 34 patients (6%). 
Grade 2 toxicities included fatigue (27%), thrombocytopenia (12%), colitis (3%), and 
pneumonitis (3%). Six patients did not receive Pembrolizumab due to rapid disease progression 
or toxicity. 18% (5/28) of patients experienced clinical benefit (defined as CR, PR, or stable 
disease >6 months). Tumor lymphocyte infiltration and PD-L1 expression were low. High 
expression of PD-1/CTLA-4 dual staining in CD8 cells (>15% in tumor or blood) was seen in 5 
patients, with 80% (4/5) of those patients experiencing benefit, and in one other patient who 
withdrew from the study in week 3 because of immune hepatitis. 95% (21/22) of patients with 
less than 20% dual expression had no response. Both tumor and peripheral blood CD8 PD-
1/CTLA-4 dual expression strongly correlated with time to progression. Furthermore, reduction 
in Foxp3+/CTLA-4high Treg population in was seen in most tumors treated with vorinostat, but a 
more significant reduction Foxp3+/CTLA-4high Treg was seen in responding patients. 
All patients in the prior study received vorinostat and pembrolizumab, and it is not clear whether 
the high response rate in the biomarker-enriched group is due to the biomarker expression 


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alone or the constellation of the presence of the biomarker in the setting of HDAC inhibitor-
induced downregulation of Tregs. 
Table 1.1 Duration of Response by percentage of dual positivity of PD-1/CTLA-4 (20%)
Table 1.2 Duration of Response by percentage of dual positivity of PD-1/CTLA-4 (10%)
1.3.1.3 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 cancer13. 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 


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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.
1.3.1.4 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 cancer57. 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). 
1.4
Rationale for the Dose Selection/Regimen 
The rationale and justification for pembrolizumab, vorinostat, and tamoxifen dosing, route of 
administration, planned maximum dosage, and regimen are as defined in the previously 
conducted pilot study (NCT02395627)58.
1.5
Correlative Studies
Immune checkpoint inhibitors have revolutionized cancer therapy, yet have limited efficacy in 
estrogen receptor (ER+) breast cancer. Implicated factors include scarcity of tumor-infiltrating 
lymphocytes (TILs), low PD-L1 expression, female gender, and liver involvement. In vitro and in 
vivo studies suggest that epigenetic modulation with HDAC inhibitors modulate regulatory T 
cells (Treg) and change TIL composition, which is further associated with the presence of a 
specific immune signature58.
Patients with ER+ metastatic breast cancer, who progressed on multiple prior therapies, were 
treated with tamoxifen in combination with vorinostat and pembrolizumab either immediately or 
after 3 weeks of epigenetic priming in a phase II trial. Comprehensive flow-cytometric 
immunophenotyping, PD-L1 staining, and histone acetylation were evaluated on tumor and 
blood cells58.
34 patients (median age 56 years (32-81), heavily pretreated with a median of 5 (2-13) prior 
regimens received at least one dose of vorinostat and evaluable for response. Grade ¾ 
toxicities in 2 pts each (6%) included immune hepatitis, fatigue, and thrombocytopenia. Grade 2 
toxicities were pneumonitis and colitis in 3%, fatigue in 27% and thrombocytopenia in 12% pts. 
Six patients did not receive pembrolizumab due to rapid progression or toxicity. Clinical benefits 
rate defined as CR, PR, and stable disease > 6m was seen in 5/28 (18%) of patients. Tumor 
lymphocyte infiltration and PD-L1 expression were low. High expression of PD-1/CTLA-4 dual 
staining in CD8 cells of >20% in tumor or blood was seen in 5 patients overall, 4/5 (80%) 
patients with benefit and in one other patient, who was withdrawn due to immune hepatitis in 
week 3. Both tumor and peripheral blood CD8 PD-1/CTLA-4 dual expression strongly correlated 
with time to progression and reduction in Foxp3+/CTLA-4high Treg population in tumors by 
vorinostat58.
Our data highlight the potential for patient selection based on exhausted CD8+ cells in blood or 
tumor to predict response to immune checkpoint inhibitors in a small subset of ER+ breast 
cancer patients (NCT02395627)58-69.


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2
Study Objectives 
2.1
Hypothesis
Given the above data, we hypothesize that HDAC induced epigenetic priming in a biomarker 
enriched study will increase the efficacy of pembrolizumab with patient selection based on 
exhausted CD8+ cells in blood or tumor in a small subset of (ER)+ breast cancer patients.
Biomarker threshold for exhausted CD8+ will be set at 10% to avoid under-enrollment of 
patients with potential response. 
Response further correlated with exhausted CD4 cells in blood (but not not tumors), thus we will 
allow enrollment of patients who have dual expression of PD-1 and CTLA4 on CD4 cells in 
blood only: biomarker threshold will be set at 5%. 
Based on the below described earlier study results, we hypothesize that the pembrolizumab and 
TAM arm even in the setting of biomarker selection will not pass the first stage and will be 
stopped early after 11 patients and not expanded to 30 patients, whereas the immune priming 
by vorinostat arm will proceed to the second stage enrolling a total of 35. Under this hypothesis, 
we will most likely enroll 46 evaluable patients (~65% chance), whereas the possible enrollment 
ranges from 24 to 65. For the comparison of the treatment arms, the proposed design will have 
72.53% power for the Z-test for two proportions conditioning on the study design, when the true 
response rates are 0.4 and 0.1 for the immune priming and the no immune priming treatment 
arm. 
2.2
Primary Objective and Endpoints
Primary Objective
Endpoint(s)
Time Frame
To define the role of epigenetic immune 
priming in a biomarker enriched ER+ breast 
cancer population on the basis of overall 
response rate
ORR: 
CR+PR+SD
From time of initial response to time of 
progression or death, whichever 
occurs first, assessed up to 24 weeks
2.3
Secondary Objective(s) and Endpoint(s)
Secondary Objective
Endpoint(s)
Time Frame
1.
To assess duration of response 
(DOR) 24-week landmark 
progression-free survival 
(PFS:24)
DOR (CR+PR) 
From initiation of study treatment to time of 
progression or death, whichever occurs first, 
assessed up to 24 weeks
2.
Median PFS and overall 
survival (OS)

Median PFS

overall 
survival (OS)
From initiation of study treatment to the time 
of death from any cause on study, assessed 
up to 48 months
3.
Tumor responses will also be 
calculated by Immune Related 
Response-Criteria (irRC)
Tumor responses 
(irRC)
Through study completion, assessed up to 
24 months


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2.4
Exploratory (Correlative) Objectives
Exploratory Objective
Endpoint(s)
1.
Evaluation of biomarker target threshold on 
response rate (retrospective cut off of 20% vs 
10%)
Biomarker target threshold on response rate
2.
To assess the ratio of effector T cells: regulatory 
T cells in blood and tumor biopsies pre- and 
post-therapy.
Ratio of effector T cells: regulatory T cells in 
blood and tumor biopsies pre- and post-therapy
3.
To evaluate inflammatory T cell signature 
changes in blood and tumor biopsies pre- and 
post-therapy.
inflammatory T cell signature changes in blood 
and tumor biopsies pre- and post-therapy
4.
To evaluate changes in number of myeloid-
derived suppressor cells (MDSCs) in peripheral 
blood and tumor biopsies pre- and post-therapy.
changes in number of myeloid-derived 
suppressor cells (MDSCs) in peripheral blood 
and tumor biopsies pre- and post-therapy
5.
To evaluate changes in histone acetylation in 
peripheral blood cells and tumor biopsies pre- 
and post-therapy
changes in histone acetylation in peripheral 
blood cells and tumor biopsies pre- and post-
therapy
6.
Initial comparison to vorinostat-induced PD-1 in 
lymphocytes, PD-L1 modulation
Comparison to vorinostat-induced PD-1 in 
lymphocytes, PD-L1 modulation
7.
Nanostring and 10x sequencing and single cell 
immune phenotyping (on stored tissue for 
successful arms only)
Completion of Nanostring and 10x sequencing 
and single cell immune phenotyping (on stored 
tissue for successful arms only)
8.
Impact of HDAC inhibition of response to 
pembrolizumab vs. pembrolizumab in biomarker 
enriched population
Impact of HDAC inhibition
3
Study Design
3.1
Characteristics
We propose a single site Phase II, two-arm, open-label unblinded, 65-patient trial in patients 
with hormone therapy-resistant breast cancer (HTR) to test the role of epigenetic priming in a 
biomarker enriched patient population in HTR breast cancer. The two arms include Arm A: 
pembrolizumab, vorinostat, and tamoxifen and Arm B pembrolizumab and tamoxifen.
Patients will be evaluated for response at 9 weeks (±1 week) 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 clinically indicated and be re-evaluated after 4-8 weeks. 


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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, tamoxifen, and 
pembrolizumab combination and are facile with managing drug toxicities. 
Tissue biopsies of all patients will be collected prior to enrollment to assess for pre-treatment of 
our immune signature and PD-L-1 expression. Follow up biopsies and peripheral blood 
collection will be taken from all patients post-treatment at 8-10 weeks to characterize changes in 
local tissue effects and antigen-specific cellular and humoral immune responses in peripheral 
blood.
Patients will be stratified by prior number of hormonal and chemotherapies.
3.2
Sample Size
We adopt a randomized two-arm trial with futility early stopping built-in within each treatment 
arm using a Simon’s two-stage design (Simon, 1989). The effect of vorinostat on 
pembrolizumab and the effect of pembrolizumab and tamoxifen in this biomarker-selected 
population of ER+ breast cancer patients will be first tested against the respectively chosen null 
rate in the first stage within the treatment arms and then compared between the treatment arms. 
65 patients to be treated under the study/enrolled in the investigational portion of the study 
(sample size for primary objective). 
For Arm A (vorinostat + TAM + pembro): The null hypothesis that the true response rate for 
pembrolizumab and vorinostat in ER+ pretreated patients alone without biomarker enrichment is 
0.15 which will be tested against the alternative that response rate of pembrolizumab in a 
biomarker select population is 0.40. In the first stage, 13 patients will be accrued. If there are 2 
or fewer responses in these 13 patients, the study will be stopped. Otherwise, 22 additional 
patients will be accrued for a total of 35. The null hypothesis will be rejected if 10 or more 
responses are observed in 35 patients. This design yields a type I error rate of 0.025 and power 
of 0.9 in this treatment arm when the true response rate is 0.4 in this patient subpopulation.
For Arm B (pembro + TAM): The null hypothesis that the true response rate for 
pembrolizumab in ER+ pretreated patients alone is 0.10 which will be tested against the 
alternative that response rate of pembrolizumab in a biomarker select population is 0.35. In the 
first stage, 11 patients will be accrued. If there are 1 or fewer responses in these 11 patients, 
the study will be stopped. Otherwise, 19 additional patients will be accrued for a total of 30. The 
null hypothesis will be rejected if 7 or more responses are observed in 30 patients. This design 
yields a type I error rate of 0.025 and power of 0.9 in this treatment arm when the true response 
rate of pembro + TAM treatment is 0.35 in this patient subpopulation.
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 in 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, 18 years of age or older.


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Because no dosing or adverse event data are currently available on the use of 
pembrolizumab, vorinostat, or tamoxifen in patients <18 years of age, children are 
excluded from this study but will be eligible for future pediatric trials.
2.
>10% expression of PD-1/CTLA-4 dual staining in CD8 cells in tumor or blood or >5% 
expression of PD-1/CTLA-4 dual staining in CD4 in blood (only).
3.
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1. 
4.
Understand and voluntarily sign an informed consent prior to any study-related 
assessments or procedures are conducted and are able to adhere to the study visit 
schedule and other protocol requirements.
5.
Consent to paired tumor biopsy
6.
Measurable tumor by RECIST criteria
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:
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 childbearing potential (defined as 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 14days 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. All female and male participants must agree to use approved contraception during the 
treatment period and for at least 18 weeks after the last dose of study treatment and 
refrain from donating sperm during this period.


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3.3.2
Exclusion Criteria
1.
Prior treatment with pembrolizumab or other PD-(L)1
2.
Any significant medical condition, laboratory abnormalities, which places the subject at 
unacceptable risk if he/she were to participate in the study.
3.
Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or current pneumonitis/ interstitial lung disease.
4.
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected)"
5.
Has a history of HBV
6.
Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator
7.
Symptomatic central nervous system metastases. Subjects with brain metastases that 
have been previously treated and are stable for 6 weeks are allowed.
8.
Persistent diarrhea or malabsorption ≥ NCI CTCAE grade 2, despite medical 
management.
9.
Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) 
class 3 or 4 congestive heart failure.
10. Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half-lives or 4 
weeks, whichever is shorter, prior to starting study drug or who have not recovered from 
side effects of such therapy (except alopecia). 
11. Active autoimmune disease except for vitiligo or hypothyroidism
12. Active and ongoing steroid use, except for non-systemically absorbed treatments (such 
as inhaled or topical steroid therapy for asthma, COPD, allergic rhinitis).
13. Major surgery ≤ 2 weeks prior to starting a study drug or who have not recovered from 
side effects of such therapy.
14. Pregnant or breastfeeding.
15. Known Human Immunodeficiency Virus (HIV) infection 
16. Known history of tuberculosis
17. Known allergic reaction or intolerability to tamoxifen
18. Patients with prior history of DVTs must be on therapeutic or preventive anticoagulation 
3.4
Inclusion and Recruitment of Women and Minorities
Individuals of any sex/gender, race, or ethnicity may participate.


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The study recruitment strategy aims to achieve representation of minority groups that reflects 
the demographics of the affected population in the catchment area.
3.5
Duration of Treatment
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. 
All patients will be restaged during at 9 weeks (±1 week) and 18 weeks (±1 week) 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.
3.6
Duration of Follow Up
Patients will be followed for 30 days after end of study participation 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 5.4.
3.7
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.
3.8
Primary Completion 
The estimated primary completion is 36 months after the study opens to accrual.


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3.9
Study Completion
The expected study completion date is 48 months after the study opens to accrual.
The study will conclude when all enrolled patients have been followed for more than 30 days 
following completion of the study. The estimated duration of study, from start of enrollment to 
final study report is 4 years.
4
Investigational Products
4.1
Description, Supply, and Storage of Investigational Products
4.1.1 Investigational Product: Pembrolizumab (MK-3475)
Classification
Antineoplastic, Monoclonal antibody (mAb)
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.
Metabolism
Pembrolizumab is catalyzed into small peptides and single amino acids via general protein 
degradation, but it does not rely on metabolism for clearance.
Contraindications
None
Formulation, Appearance, Packaging, and Labeling
Pembrolizumab is supplied as 100 mg/4 mL solution in a single-use vial for intravenous 
administration. Pembrolizumab is manufactured by Merck. Supplies will be labeled in 
accordance with regulatory requirements. This trial is open-label; therefore, the participant, the 
trial site personnel, the Sponsor, and/or designee are not blinded to treatment. Drug identity 
(name, strength) is included in the label text; random code/disclosure envelopes or lists are not 
provided.
Availability
Pembrolizumab is being obtained as commercial supply provided by Merck. 
Storage and handling
Pembrolizumab is stored at the UCSF investigational pharmacy. Clinical supplies must be 
stored in a secure, limited-access location under the storage conditions specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. Clinical supplies may not be used for any purpose other than that stated in the protocol.
Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either:

At room temperature for no more than 6 hours from the time of dilution. This includes 
room temperature storage of the diluted solution and the duration of infusion. 


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
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time 
of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. 
Discard after 6 hours at room temperature or after 24 hours under refrigeration. 
Do not freeze. 
Side Effects
Complete and updated adverse event information is available in the Investigational Drug 
Brochure (IB) and/or product package insert. 
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines 
and procedures, and provided that appropriate records of disposal are kept.
4.1.2 Investigational Product: Vorinostat
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.
Metabolism
The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis, followed 
by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-
anilino4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. 
Compared to vorinostat, the mean steady-state serum exposures in humans of the O-
glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, 
respectively. In vitro studies using human liver microsomes indicate negligible biotransformation 
by cytochromes P450 (CYP).
Contraindications
None
Formulation, Appearance, Packaging, and Labeling


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Vorinostat is supplied as size 3 100 mg capsules for oral administration. Vorinostat will be 
supplied in a 100-120 capsule bottle. Vorinostat will be given at 400 mg per day (4x 100 mg 
tablets), 4 of 7 days. Vorinostat is manufactured by Merck & Co., Inc.
Availability
Vorinostat is being obtained as commercial supply provided by Merck & Co., Inc.
Storage and handling
Vorinostat is stored at the UCSF investigational pharmacy. 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. 
Vorinostat is an anticancer drug. If clean powder is spilled 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.
Side Effects
Complete and updated adverse event information is available in the current IB and/or product 
package insert. 
4.1.3 Investigational Product: Tamoxifen
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:


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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 
unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal 
radioactivity.
Contraindications
Tamoxifen is contraindicated in patients with known hypersensitivity to the drug or any of its 
ingredients.
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.
Formulation, Appearance, Packaging, and Labeling
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.
Availability
Tamoxifen is commercially available. It is being obtained as commercial supply.
Storage and handling
Tamoxifen is commercially available. Patients will obtain tamoxifen from their local pharmacy.
Side Effects
Complete and updated adverse event information is available in the current IB and/or product 
package insert. 
4.2
 Accountability Records for Investigational Product(s)
UCSF Investigational Drug Services (IDS) will manage drug accountability records for UCSF.
4.3
Ordering Investigational Product(s)
UCSF will obtain pembrolizumab and vorinostat directly from Merck & Co., Inc. Tamoxifen is 
commercially available.
5
Treatment Plan
5.1
Dosage and Administration
All trial treatments will be administered on an outpatient basis.


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Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks. 
Treatment cycle intervals may be increased due to toxicity, as described in Section 5.2. Every 
effort should be made to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution.
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 is 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 
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. 
As vorinostat and tamoxifen are oral, self-administered drugs, drug diaries will be provided for 
assessing compliance with treatment. The diary will be provided each time vorinostat and 
tamoxifen are provided to the study participant to take home. Missed doses will be noted and 
will not be replaced. The participant will proceed with the next scheduled dose at the next 
scheduled time.
Table 5.1
Trial Treatment
Drug
Dose/ 
Potency
Dose 
Frequency
Route of 
Administration
Regimen/ Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 3 
week cycle
Experimental
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned.
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 6.0). Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons.
Table 5.2
Arm A Regimen Description


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Investigational 
Product
Premedication; 
precautions
Dose
Route
Schedule
Cycle 
Length
Pembrolizumab
No premedications
No precautions
200 mg
Intravenous
Day 1, Week 
1
Cycles 1+
Vorinostat
Administer whole with 
food, if possible
400 mg
Oral
Days 4 of 7 
days
All cycles
Tamoxifen
No premedications
No precautions
20 mg 
(tablets)
Oral
Daily 
continuous
All cycles
3 weeks 
(21 days)
Table 5.3
Arm B Regimen Description
Investigational 
Product
Premedication; 
precautions
Dose
Route
Schedule
Cycle 
Length
Pembrolizumab
No premedications
No precautions
200 mg
Intravenous
Day 1, Week 
1
Cycles 1+
Tamoxifen
No premedications
No precautions
20 mg 
(tablets)
Oral
Daily 
continuous
All cycles
3 weeks 
(21 days)
Tamoxifen may be omitted in Arm B at the PI’s discretion
5.2
Dose Modifications and Dosing Delays
The following dose modification rules will be used with respect to potential toxicity. Toxicity will 
be assessed according to the NCI CTCAE version 5.0.
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 
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.


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Hematologic Toxicity*
Adverse Event:* Neutropenia
While dose hold may apply for all days of occurrence, dose modification will only apply if neutropenia 
persists for day 1, 8, and 15 of each cycle. Dose modifications are not required if labs are drawn on 
other days and counts have recovered upon retreatment on days 1, 8, 15. 
Neutropenia
Febrile neutropenia
Management/Next Dose for Vorinostat
ANC >1000
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
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: discuss with sponsor and principal investigator, consider 
omitting alternate weeks 
#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.
Adverse Event: Anemia
Hemoglobin
Management/Next Dose for Vorinostat
>8 mg/dl
100 %: 400 mg qd
6.5-8 mg/dl
75 %: 300 mg qd
<6.5 mg/dl
50 %: 200 mg qd
An alternative to dose modification in cases of anemia only would be the use of PRBC transfusion. 
Adverse Event: Thrombocytopenia
While dose hold may apply for all days of occurrence, dose modification will only apply if thrombocytopenia 
persists for day 1, 8, and 15 of each cycle. Dose modifications are not required if labs are drawn on other days and 
counts have recovered upon retreatment on days 1, 8, 15.
Platelets
Management/Next Dose for Vorinostat
>75’000
100 %: 400 mg qd
<75’000
100 %: 400 mg qd
≤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: discuss with sponsor and principal investigator, consider 
omitting alternate weeks 
≤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 
An alternative to dose modification in cases of anemia only would be the use of PRBC transfusion. 


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Adverse Event: Non-hematological toxicities
Laboratory abnormalities must be clinically relevant, and dose and drug-related to prompt dose 
modifications, in case of uncertainty doses may be re-escalated if toxicities recover.
Bilirubin
Management/Next Dose for Vorinostat
≤1.5 mg/dl
100 %: 400 mg qd
1.6 – 3.0 mg/dl
75 %: 300 mg qd
> 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
AST/ALT
Management/Next Dose for Vorinostat
≤2.5 x ULN
100 %: 400 mg qd
2.5-5 x ULN
First occurrence: 75 %: 300 mg qd
Second occurrence: 50 %: 200 mg qd
> 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
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 
Principal 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 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.


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Other Non-hematological Toxicities: 
Laboratory abnormalities must be clinically relevant, and dose and drug-related to prompt dose 
modifications, in case of uncertainty doses may be re-escalated if toxicities recover
Give the following dose based on the worst toxicity encountered during the previous cycle:
Fatigue
Management/Next Dose for Vorinostat
Grade 1
100%
Grade 2
Hold until toxicity is ≤grade 1, then resume at dose given in prior cycle.
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.
Other
Management/Next Dose for Vorinostat
Grade 1
100%
Grade 2
Hold until toxicity is ≤grade 1, then resume at dose given in prior cycle.
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.
Grade 4
Discontinue protocol therapy.
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.
5.2.1 Dose Modifications and Dosing Delays Tables for Specific Adverse Events 
for Pembrolizumab
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 


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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
5.2.2 Dose Modification and toxicity management for immune-related AEs 
associated with pembrolizumab
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic etiology. These immune-related AEs (irAEs) may 
occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment are critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab//combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation 
to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab/combination treatment are provided in Table 5.4.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult.  Therefore, while the investigator may attribute a toxicity 
event to the combination,  to Vorinostat or Tamoxifen alone, or to pembrolizumab alone, for 
adverse events listed in Table 5.4, both interventions must be held according to the criteria in 
Table 5.4 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse 
Events Associated with Pembrolizumab.
Holding Study Interventions:
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications.
Restarting Study Interventions:


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Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 5.4.

If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions.

If the toxicities do resolve and conditions are aligned with what is defined in Table 5.4, 
the combination of Vorinostat, Tamoxifen and pembrolizumab may be restarted at the 
discretion of the investigator. In these cases where the toxicity is attributed to the 
combination or to Vorinostat or Tamoxifen alone, re-initiation of pembrolizumab as a 
monotherapy may be considered at the PI’s discretion. 


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Table 5.4 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
monotherapy and IO Combinations
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold 
Pneumonitis 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Add prophylactic antibiotics for 
opportunistic infections
  Monitor participants for signs and symptoms of 
pneumonitis
  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Grade 2 or 3
Withhold
Diarrhea/Colitis 
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)
  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 


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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
substituted via IV infusion
Grade 2 a
Withhold
  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 3 b or 4 c
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold d
  Initiate insulin replacement therapy for 
participants with T1DM
  Administer antihyperglycemic in 
participants with hyperglycemia
  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)


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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
  Monitor for signs and symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
  Monitor for signs and symptoms of thyroid 
disorders
Grade 2
Withhold
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 3 or 4
Permanently 
discontinue
  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper
  Monitor changes of renal function
Grade 2
Withhold
Neurological 
Toxicities
Grade 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 1
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or 
DRESS
Withhold
  Based on severity of AE administer 
  Ensure adequate evaluation to confirm etiology 


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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Confirmed SJS, 
TEN, or 
DRESS
Permanently 
discontinue
corticosteroids
or exclude other causes
Persistent Grade 2 Withhold
Grade 3
Withhold or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (e.g., vasculitis and sclerosing cholangitis).


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5.2.3 Dose Modification and Toxicity Management of Infusion-Reactions Related 
to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions, including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 5.5.


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Table 5.5 Pembrolizumab Infusion Reaction Dose modification and 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 participant 
is deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr 
to 50 mL/hr). Otherwise dosing will be held until symptoms resolve, and the 
participant should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment
Participant 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 analgesic).
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 improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further study drug 
treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov


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Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should be 
placed back on study therapy within 3 weeks of the scheduled interruption unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
5.2.4 Second Course
All participants who stop study treatment with SD or better may be eligible for up to an additional 
17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after stopping 
study treatment from the initial treatment phase. This retreatment is termed the Second Course 
Phase of this study and is only available if the study remains open, and the participant meets 
the following conditions:
EITHER

Stopped initial treatment with study treatment after attaining an investigator-determined 
confirmed CR based on RECIST 1.1, and
o
Was treated with at least 8 cycles of study treatment before discontinuing 
treatment, and
o
Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared
OR

Had SD, PR, or CR and stopped study treatment after completion of 35 administrations 
(approximately 2 years) of study treatment for reasons other than disease progression or 
intolerability
AND

Experienced an investigator-determined radiographic disease progression by 
RECIST 1.1 after stopping initial treatment, and
o
Upon unblinding at the time of centrally verified disease progression were found 
to have received pembrolizumab, and
o
No new anticancer treatment was administered after the last dose of study 
treatment, and
o
The participant meets all of the safety parameters listed in the inclusion criteria 
and none of the safety parameters listed in the exclusion criteria, and
o
The study is ongoing
An objective response or disease progression that occurs during the Second Course Phase for 
a participant will not be counted as an event for the primary analysis of either endpoint in this 
study.
Note: patients must have measurable disease at the start of protocol treatment to be eligible for 
this provision.


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5.2.5 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 v5.0. Dose adjustments will be made according to the system showing the greatest 
degree of toxicity. 
5.2.5.1 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 7.3.7 - 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).
5.3
Stopping Rules
There is a futility early stopping built-in within each treatment arm. For Arm A (vorinostat + TAM 
+ pembro): In the first stage, 13 patients will be accrued. If there are 2 or fewer responses in 
these 13 patients, the study will be stopped. For Arm B (pembro and TAM): In the first stage, 11 
patients will be accrued. If there are 1 or fewer responses in these 11 patients, the study will be 
stopped. 


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Clinical Criteria for Early Trial Termination
1.
Early trial termination will be the result of the criteria specified below:
2.
Quality or quantity of data recording is inaccurate or incomplete
3.
Poor adherence to protocol and regulatory requirements
4.
Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects
5.
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 appropriate adjustments to subject treatment can be made.
5.4
Discontinuation and Withdrawal
Participants may discontinue study treatment at any time for any reason or be dropped from the 
study treatment at the discretion of the investigator should any untoward effect occur. In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative and/or 
other safety reasons. Specific details regarding procedures to be performed at study treatment 
discontinuation are provided in Section 6.3.2.6 – Study Procedures Restaging or Off-Study Visit.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to discontinue 
study treatment

Confirmed radiographic disease progression outlined in Section 3.5.

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

Unacceptable adverse experiences, as described in Section 7.3.5.

The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or sponsor, placed the participant at unnecessary risk from 
continued administration of study treatment.

The participant has a confirmed positive serum pregnancy test

Noncompliance with study treatment or procedure requirements

Recurrent Grade 2 pneumonitis

Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving [for monotherapy: at least 2 doses of pembrolizumab; for 
combination treatment: 2 cycles of the combination including 2 doses of pembrolizumab 
and at least 80% of the planned doses of vorinostat beyond the date when the initial CR 
was declared. These participants may be eligible for second-course treatment described 
in Section 5.3.


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
The participant is lost to follow-up

Completion of 35 treatments (approximately 2 years) with pembrolizumab. (Patients may 
continue vorinostat and tamoxifen.)
Note: The number of treatments is calculated, starting with the first dose. Participants who stop 
the combination or pembrolizumab after receiving 35 doses may be eligible for retreatment if 
they progress after stopping study treatment provided they meet the requirements detailed in 
Section 5.3. Participants may be retreated in the Second Course Phase (Retreatment) for up to 
an additional 17 cycles (approximately 1 year).
Note to Author:
-
Guidance on duration of pembrolizumab for solid tumors:
o
When there is disease present on imaging (i.e., metastatic, locally advanced, 
bulky disease NOS, etc.) – 24 months of pembrolizumab (35 cycles)
o
When there is no disease present on imaging (i.e., adjuvant, following resection, 
maintenance following induction chemo, etc.) – 12 months of pembrolizumab)
-
Guidance on duration of pembrolizumab for hematologic malignancies:
o
For widespread, recurrent disease – 24 months of pembrolizumab
When using pembrolizumab as consolidative therapy/ limited disease – 12 months.
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 7.3.5
·
Intercurrent illness that prevents further administration of treatment
·
Investigator’s decision to withdraw the subject
·
The subject has a confirmed positive serum pregnancy test
·
Noncompliance with trial treatment or procedure requirements
·
The subject is lost to follow-up
5.4.1 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 


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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 5.6.
Table 5.6
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.
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
6
Study Procedures and Schedule of Events
The study-specific procedures and assessments are detailed in this section and outlined in the 
Study Calendar – Section 6.1.
Screening assessments must be performed within 28 days prior to the first dose of 
investigational product unless otherwise noted. 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.


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6.1
Study Calendar
Period/
Procedure
Pre-
Screening
Screening1
Cycle 1
Cycle 2
Future 
Cycles2,3
Restaging or Off-Study Visit
Survival Follow-up
Study Day/Visit Day*
-365 to -28
-28 (±3)
1 (±3)
10-12 (±3)
15 (±3)
1 (±3)
1 (±3)
9 weeks Post Start of Tx (±7)
Study Treatment/Drug Administration
Pembrolizumab
200 mg q every 3 weeks; start on C1D1
Vorinostat
400 mg once a day, 4 days on, 3 days off, weekly every cycle
Tamoxifen
20 mg once a day continuously
Administrative Procedures
Prescreening ICF
X
Informed consent
X
Clinical Assessments
Physical exam
X
X
X
X
X
Vital signs
X
X
X
X
X
Performance status
X
X
X
X
X
Medical history
X
Concomitant medications
X
X
X
X
X
Toxicity Assessment4
X
X
X
X
X
X4
Drug Diaries5
X
X
X
Documentation of Response
X
X
1 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
2 Cycle delays up to 14 days for non-medical reason (e.g. holidays) are acceptable without notification of regulatory agencies
3 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
4 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
5 Drug diaries will be administered for vorinostat and tamoxifen (oral drugs) only on the first day of every cycle


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Period/
Procedure
Pre-
Screening
Screening1
Cycle 1
Cycle 2
Future 
Cycles2,3
Restaging or Off-Study Visit
Survival Follow-up
Study Day/Visit Day*
-365 to -28
-28 (±3)
1 (±3)
10-12 (±3)
15 (±3)
1 (±3)
1 (±3)
9 weeks Post Start of Tx (±7)
Laboratory Assessments
Hematology6
X
X
X
X
X
Comprehensive Metabolic Panel7
X
X
X
X
X
Thyroid Function8
X
X
X (odd cycles)
Tumor Markers9
X
X
X
X
Pregnancy test10
X
X
Lymphocyte Subset
X or C1D111
X12
X11 (end of C3)
PBMC11
X or C1D111
X12
X11 (end of C3)
PK testing
X or C1D1
X
X (end of C3)
Biomarker testing (prescreening)
X
Imaging Procedures
CT/MRI13
X
X
X
Tissue Collection/ Biopsy
Tumor FNA/Biopsy11
X or C1D1
X (end of C3)
6 Including CBC with differential and platelet count
7 Sodium, Potassium, Chloride, blood urea nitrogen, Creatinine, Non-fasting glucose, Calcium, ALT, AST, Alkaline Phosphatase, Albumin, Total Bilirubin, Total Protein
8 Including FT4 and TSH, TSH only for patients on thyroid replacement therapy
9 CEA, Ca15-3, Ca 125 (if clinically indicated)
10 For women of childbearing potential, performed within 14 days of starting treatment. Pregnancy test will be repeated if clinically indicated
11 Correlative studies: Pre-study within 14 days, and end of cycle 3 (preferably day 17-19 while on vorinostat) prior to cycle 4 day 1 pembrolizumab infusion
12 On day 10-12 pre-dose
13 Staging studies within 30 days prior to day of start, restaging after cycle 3 (week 9 +1w), 6 (week 18+1w), 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
*Note: Window for all study procedures is ±3 days except for scans which is ±7 days


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6.2
Schedule of Procedures and Observations
6.2.1 Prescreening Period

Prescreening ICF

Laboratory Assessments
o
Biomarkers testing (1 tbsp. blood draw)
6.3
Participant Registration
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 participants consented to the study 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.
6.3.1 Pretreatment Period
6.3.1.1 Screening Assessments 
The Screening procedures and assessments must be completed within 28 days of initiating 
study treatment. 

Clinical Assessments
o
Documentation of disease assessment (CT scan)
o
Physical examination
o
Vital signs
o
Performance status
o
Complete medical history
o
Concomitant medication review
o
Toxicity assessment
o
Documentation of response

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Comprehensive Metabolic Panel
o
Thyroid function
o
PK testing (or at C1D1)
o
Tumor markers
o
Pregnancy test
o
Lymphocyte Subset (or at C1D1)
o
PBMC (or at C1D1)

Imaging Procedures


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o
CT / MRI of breast 

Tumor Tissue Collection 
o
Tumor FNA/biopsy (or at C1D1)
6.3.2 Treatment Period
6.3.2.1 Study Procedures, Cycle 1, Day 1

Study Treatment/Drug Administration
o
Pembrolizumab (200 mg q every 3 weeks)
o
Vorinostat (400 mg once a day, 4 days on, 3 days off, weekly every cycle)
o
Tamoxifen (20 mg once a day continuously)

Clinical Assessments
o
Physical examination
o
Vital signs
o
Performance status
o
Concomitant medication review
o
Toxicity assessment
o
Drug diaries

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Comprehensive Metabolic Panel
o
PK testing (if not conducted at screening)
o
Tumor markers 
o
Lymphocyte Subset (if not conducted at screening)
o
PBMC (if not conducted at screening)

Tumor Tissue Collection 
o
Tumor FNA/biopsy (if not conducted at screening)
6.3.2.2 Study Procedures Cycle 1, Day 10-12

Study Treatment/Drug Administration
o
Pembrolizumab (200 mg q every 3 weeks)
o
Vorinostat (400 mg once a day, 4 days on, 3 days off, weekly every cycle)
o
Tamoxifen (20 mg once a day continuously)

Laboratory Assessments
o
PK testing
o
Lymphocyte Subset 
o
PBMC


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6.3.2.3 Study Procedures Cycle 1, Day 15

Study Treatment/Drug Administration
o
Pembrolizumab (200 mg q every 3 weeks)
o
Vorinostat (400 mg once a day, 4 days on, 3 days off, weekly every cycle)
o
Tamoxifen (20 mg once a day continuously)

Clinical Assessments
o
Physical examination
o
Vital signs
o
Performance status
o
Concomitant medication review
o
Toxicity assessment

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Comprehensive Metabolic Panel
6.3.2.4 Study Procedures Cycle 2, Day 1

Study Treatment/Drug Administration
o
Pembrolizumab (200 mg q every 3 weeks)
o
Vorinostat (400 mg once a day, 4 days on, 3 days off, weekly every cycle)
o
Tamoxifen (20 mg once a day continuously)

Clinical Assessments
o
Physical examination
o
Vital signs
o
Performance status
o
Concomitant medication review
o
Toxicity assessment
o
Drug diaries

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Comprehensive Metabolic Panel
o
Thyroid function
o
Tumor markers
6.3.2.5 Study Procedures Future Cycles

Study Treatment/Drug Administration
o
Pembrolizumab (200 mg q every 3 weeks)
o
Vorinostat (400 mg once a day, 4 days on, 3 days off, weekly every cycle)
o
Tamoxifen (20 mg once a day continuously)


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
Clinical Assessments
o
Physical examination
o
Vital signs
o
Performance status
o
Concomitant medication review
o
Toxicity assessment
o
Drug diaries
o
Documentation of response

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Comprehensive Metabolic Panel
o
Thyroid function (odd cycles)
o
PK testing (end of C3)
o
Tumor markers
o
Pregnancy test
o
Lymphocyte Subset (end of C3)
o
PBMC (end of C3)

Imaging Procedures
o
CT / MRI of breast 

Tumor Tissue Collection 
o
Tumor FNA/biopsy (end of C3)
6.3.2.6 Study Procedures Restaging or Off-Study Visit

Study Treatment/Drug Administration
o
Pembrolizumab (200 mg q every 3 weeks)
o
Vorinostat (400 mg once a day, 4 days on, 3 days off, weekly every cycle)
o
Tamoxifen (20 mg once a day continuously)

Clinical Assessments
o
Toxicity assessment

Imaging Procedures
o
CT / MRI of breast 
6.3.3 Survival Follow-up 
After completing the follow-up period, participants will be contacted by telephone every 12 
weeks to assess for survival/anti-cancer therapy status until death, withdrawal of consent, or the 
end of the study, whichever occurs first.


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6.4
Correlative Studies
6.4.1 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 tumor samples of patients before and after treatment with vorinostat.
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.
6.4.2 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.
6.4.3 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.
6.5
Use of Concurrent/Concomitant Medications
6.5.1 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 


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administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.3.
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 
antidiarrheals 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).
6.5.2 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 
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 5.2.1.
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 below and the separate 
guidance document in the administrative binder regarding diagnosis and management of 
adverse experiences of a potential immunologic etiology. 


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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 7.3.9 - Reporting of Pregnancy and 
Lactation to the regulatory agencies and 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.
6.6
Prohibited 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 


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o
Note: Radiation therapy to a symptomatic solitary lesion or 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. 
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.
7
Reporting and Documentation of Results
7.1
Evaluation of Efficacy: Antitumor Effect – Solid Tumors
Response and progression in this study will be evaluated using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)70. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
v1.1 criteria.
7.1.1 Definitions
Evaluable for toxicity
All participants will be evaluable for toxicity from the time of their first treatment with 
pembrolizumab, vorinostat, and tamoxifen.
Evaluable for objective response
Only those participants who have measurable disease present at baseline, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for response. These participants will have their response classified according to the definitions 
stated below. (Note: Participations who exhibit objective disease progression prior to the end of 
Cycle 1 will also be considered evaluable.)


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Evaluable Non-Target Disease Response 
Participants who have lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for non-target disease. The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions. 
7.1.2 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.
Malignant lymph nodes
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm (≥1.5 
cm) in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm [0.5 cm]). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease (Tumor Markers)
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm [<1 cm] 
or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions.
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition, should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 


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will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.
Non-target lesions
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline. 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 measurable 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).
7.1.3 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.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have 
slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline, and the lesions should be measured/assessed on the same pulse sequence. It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should 


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be used, and the image acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning techniques, if possible.
7.1.4 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 diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment started.
Evaluation of Non-Target Lesions
Complete Response (CR)
Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
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 participant’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria.


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Table 7.1 Response Criteria for Participants with Measurable Disease (i.e., Target 
Disease)
Target 
Lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
≥4 wks. Confirmation**
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not evaluated
No
PR
≥4 wks. Confirmation**
SD
Non-CR/Non-
PD/not evaluated
No
SD
Documented at least once ≥4 wks. 
from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
** Only for non-randomized trials with response as primary endpoint.
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression.
Note: Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment.
Table 7.2 Response Criteria for Participants with Non-Measurable Disease (i.e., Non-
Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised
Duration of Response
Duration of overall response
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.


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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 or death, whichever occurs first.
7.2
Evaluation of Safety
The safety parameters for this study include all laboratory tests and hematological 
abnormalities, physical findings, and spontaneous reports of adverse events reported to the 
investigator by participants.
Toxicity will be assessed according to the NCI CTCAE version 5.0. Safety analyses will be 
performed for all participants who have received at least one dose of study drug.
7.3
Definitions of Adverse Events 
7.3.1 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. 
7.3.2 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.
7.3.3 Suspected Adverse Reaction
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.
7.3.3.1
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 


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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 participants exposed to drugs in the 
angiotensin-converting enzyme 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.
7.3.3.2
Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, 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 participant 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.
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);


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
Is associated with an overdose;

Is another important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by 
Merck for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
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. 
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 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. 
 
 the time of submission to FDA.
All subjects with serious adverse events must be followed up for outcome.
7.3.3.3
Life-threatening
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the participant 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. 
7.3.4 Recording of Adverse Events
Refer to the Data Safety Monitoring Plan, located in Appendix 2.


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7.3.5 Follow-up of Adverse Events
All participants who experience adverse events will be followed with appropriate medical 
management until resolved or stabilized, as determined by the investigator, or until the initiation 
of new anti-cancer therapy, whichever occurs first. For selected adverse events for which 
administration of the investigational product was stopped, a re-challenge of the subject with the 
investigational drug may be conducted if considered both safe and ethical by the investigator.
7.3.6 Adverse Events Reporting
An adverse event is defined as any untoward medical occurrence in a patient, or clinical 
investigation participant administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can, therefore, be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events. Examples 
of this may include but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time.
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use.
Adverse events may occur during the course of the use of Merck product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
withdrawal.
All AEs, SAEs and other reportable safety events that occur after the consent form is signed but 
before treatment allocation/randomization must be reported by the investigator if the participant 
is receiving placebo run-in or other run-in treatment, if the event causes the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure. 

All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator. 

All AEs meeting serious criteria, from the time of treatment allocation/randomization through 
90 days following cessation of study treatment, or 30 days following cessation of study 
treatment if the participant initiates new anticancer therapy, whichever is earlier must be 
reported by the investigator. 

All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 
days following cessation of study treatment if the participant initiates new anticancer therapy 
must be reported by the investigator. 


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
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including death, at any 
time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study treatment or study participation, the investigator must 
promptly notify Merck.
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 
(IRB); 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 
discussed at DSMC meetings, which take place every six weeks.
For a detailed description of the Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional 
Study at the Helen Diller Comprehensive Cancer Center, please refer to Appendix 2.
7.3.7 Definition of an Overdose for this Protocol and Reporting of Overdose to 
the Study PI and Merck
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant 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.”


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All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. 
 
7.3.7.1 Event of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. 
 
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 participant must be 
reported within 2 working days to Merck Global Safety if it causes the participant 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 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 2 working days to Merck Global Safety.
Events of clinical interest for this trial include:
1.
an overdose of Merck product, as defined in Section - 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. 
7.3.8 Adverse Events Monitoring
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
7.3.9 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 Institutional Review Board
The UCSF PI must report events to the UCSF IRB according to institutional guidelines.
UCSF IRB website for guidance in reporting adverse events: https://irb.ucsf.edu/adverse-event


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Reporting to Sponsor – Merck & Co
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 FDA
If the study is being conducted under an IND, the Sponsor (or 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 Sponsor (or Sponsor-Investigator) must report in an IND safety report any suspected 
adverse reaction that is both serious and unexpected. The Sponsor 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)). 
Reporting to Industry Partners
Reporting of Pregnancy and Lactation to the Sponsor and Merck
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study.
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator if they 
cause the participant to be excluded from the trial, or are the result of a protocol-specified 


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intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 days 
following cessation of treatment if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator. All reported pregnancies 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 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. 
8
Statistical Considerations and Evaluation of Results
This is a randomized two-arm trial with futility early stopping built-in within each treatment arm 
using a Simon’s two-stage design71 (Simon, 1989). The effect of vorinostat on pembrolizumab 
and the effect of pembrolizumab and tamoxifen in this biomarker-selected population of ER+ 
breast cancer patients will be first tested against the respectively chosen null rate in the first 
stage within the treatment arms and then compared between the treatment arms. 
8.1
Sample Size Considerations
8.1.1 Sample Size and Power Estimate
For Arm A (pembro + vorinostat + TAM): The null hypothesis that the true response rate for 
pembrolizumab and vorinostat in ER+ pretreated patients alone without biomarker enrichment is 
0.15 which will be tested against the alternative that response rate of pembrolizumab in a 
biomarker select population is 0.40. In the first stage, 13 patients will be accrued. If there are 2 
or fewer responses in these 13 patients, the study will be stopped. Otherwise, 22 additional 
patients will be accrued for a total of 35. The null hypothesis will be rejected if 10 or more 
responses are observed in 35 patients. This design yields a type I error rate of 0.025 and power 
of 0.9 in this treatment arm when the true response rate is 0.4 in this patient subpopulation.
For Arm B (pembro + TAM): The null hypothesis that the true response rate for pembrolizumab 
in ER+ pretreated patients alone is 0.10 which will be tested against the alternative that 
response rate of pembrolizumab in a biomarker select population is 0.35. In the first stage, 11 
patients will be accrued. If there are 1 or fewer responses in these 11 patients, the study will be 
stopped. Otherwise, 19 additional patients will be accrued for a total of 30. The null hypothesis 
will be rejected if 7 or more responses are observed in 30 patients. This design yields a type I 
error rate of 0.025 and power of 0.9 in this treatment arm when the true response rate of 
pembro and TAM treatment is 0.35 in this patient subpopulation. 
Based on earlier results in Section 1.3 and hypothesized treatment effects, we will most likely to 
enroll 46 evaluable patients (~65% chance), whereas the possible enrollment ranges from 24 to 
65. For the comparison of the treatment arms, the proposed design will have 72.53% power for 
the Fisher’s exact test at 0.1 significance level when the true response rates are 0.4 and 0.1 for 
the immune priming and the no immune priming treatment arm.


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8.1.2 Randomization
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. 
Mi-Ok Kim.
8.1.3 Stratification Factors
Patients will be stratified by prior number of chemo- and hormonal therapies.
8.1.4 Accrual Estimates
Ten patients are expected to be eligible yearly based on prior accrual for a similar population.
8.2
Interim Analyses and Stopping Rules
This is a randomized two-arm trial with futility early stopping built-in within each treatment arm 
using a Simon’s two-stage design71.
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 Population
We will conduct an intention-to-treat analysis of efficacy. All randomized patients 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 Primary Analysis (or Analysis of Primary Endpoints)
Primary Endpoint 1 Analysis (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. Within 
each treatment arm, the observed ORR will be compared to the respective null (ineffective) rate 
using the decision rule provided by the Simon’s two-stage design. In addition to calculating the 
ORR, we will calculate the corresponding one-sided 95% confidence interval by appropriately 
accounting for the Simon’s two-stage design: given the observed response number (s), testing 
of the null hypothesis of H0:p≤p0 will reject the null if the probability of observing as many or 
less than the observed number of responses (s) is less than the significance level: Prob(S≤s│
p0)<α. Using this hypothesis inversely, we can construct a (1-α)100% one-sided confidence 
interval is given as a set 
{𝑝:𝑃𝑟𝑜𝑏(𝑆≤𝑠│𝑝0 = 𝑝) < 𝛼}


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where Prob(S≤s│p0=p)indicates the joint distribution of stage to stop and observed response 
number (s) as in Chang et al., 198972. Similarly, the observed rates will be compared between 
the treatment arms using the Z-test and appropriately accounting for the Simon’s two-stage 
design. 
8.3.3 Secondary Analysis (or Analysis of Secondary Endpoints)
We will use median (DOR, OS, PFS, computed by the Kaplan-Meier estimator) and 
percentages (% irRC) to summarize secondary endpoints. The respective confidence intervals 
will be computed as well.
8.3.4 Exploratory/Correlative Analysis/Assessments
8.3.4.1 Analysis of 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 


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DFS, will be explored using the Cox proportional hazards regression model. Hierarchical 
clustering superimposed with response status, relevant baseline or prognostic characteristics or 
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 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 the 
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 Analysis of 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 


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as being detected if its value is above the median. To determine the number of up- and down-
modulated antibodies, the difference in log2 intensity values of pretreatment and post-treatment 
samples will be taken for each patient to identify antigens that are detected 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
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 PI 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 participants before any protocol-related 
procedures are performed on any participants. 
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 FDA has determined that the 
study is exempt from IND requirements. 
The PI must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant-facing materials 
related to the study (e.g., advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB. Prior to obtaining IRB 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 IRB-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. 


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9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the PI and 
approved by PRC and the IRB prior to implementation. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the PI 
must then notify the IRB according to institutional requirements.
9.5
Handling and Documentation of Clinical Supplies
The PI will maintain complete records showing the receipt, dispensation, return, or other 
disposition of all investigational drugs at the site. The date, quantity, and batch or code number 
of the drug, and the identification of participants to whom the investigational product has been 
dispensed by participant number and initials will be included. 
The PI shall not make the investigational drug available to any individuals other than to qualified 
study participants. Furthermore, the PI will not allow the investigational product to be used in 
any manner other than that specified in this protocol.
9.6
Case Report Forms (CRFs)
The PI and/or 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. Study personnel 
will complete the CRFs; the PI 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 participant’s medical records maintained by 
study personnel. All source documentation should be kept in separate research files for each 
participant. 
In accordance with federal regulations, the PI 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. 
The PI 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 PI and the trial statistician.
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
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 


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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.
9.8
Record Keeping and Record Retention
The PI 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 PI 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 including, for example, signed and dated consent forms 
and medical records including, for example, 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, IRB correspondence and approval, signed participant 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 PI 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.


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10
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Thomas S, Thurn KT, Bicaku E, Marchion DC, Munster PN. Addition of a histone 
deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, 
which is opposed by the induction of autophagy. Breast Cancer Res Treat. 
2011;130(2):437-447.
13.
Munster PN, Thurn KT, Thomas S, et al. A phase II study of the histone deacetylase 
inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone 
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Wrangle J, Wang W, Koch A, et al. Alterations of immune response of Non-Small Cell 
Lung Cancer with Azacytidine. Oncotarget. 2013;4(11):2067-2079.


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and cancer: causes and therapies. Nat Rev Cancer. 2001;1(3):194-202.
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apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17). Br 
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Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone 
deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-
induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood. 
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Yu C, Rahmani M, Almenara J, et al. Histone deacetylase inhibitors promote STI571-
mediated apoptosis in STI571-sensitive and -resistant Bcr/Abl+ human myeloid leukemia 
cells. Cancer Res. 2003;63(9):2118-2126.
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deacetylase inhibition in human malignant B cells. Blood. 2003;101(10):4055-4062.
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Mitsiades CS, Mitsiades N, Richardson PG, Treon SP, Anderson KC. Novel biologically 
based therapies for Waldenstrom's macroglobulinemia. Semin Oncol. 2003;30(2):309-
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histone deacetylase inhibitors. Cancer Res. 2003;63(15):4460-4471.
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Butler LM, Agus DB, Scher HI, et al. Suberoylanilide hydroxamic acid, an inhibitor of 
histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. 
Cancer Res. 2000;60(18):5165-5170.
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Huang LL, Pardee AB. Suberoylanilide hydroxamic acid as a potential therapeutic agent 
for human breast cancer treatment. Mol Med. 2000;6(10):849-866.
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Said TK, Moraes RC, Sinha R, Medina D. Mechanisms of suberoylanilide hydroxamic 
acid inhibition of mammary cell growth. Breast Cancer Res. 2001;3(2):122-133.
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Munster PN, Troso-Sandoval T, Rosen N, Rifkind R, Marks PA, Richon VM. The histone 
deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human 
breast cancer cells. Cancer Res. 2001;61(23):8492-8497.
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Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor 
selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc 
Natl Acad Sci U S A. 2000;97(18):10014-10019.
46.
He LZ, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission in 
transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest. 
2001;108(9):1321-1330.
47.
Cohen LA, Amin S, Marks PA, Rifkind RA, Desai D, Richon VM. Chemoprevention of 
carcinogen-induced mammary tumorigenesis by the hybrid polar cytodifferentiation 
agent, suberanilohydroxamic acid (SAHA). Anticancer Res. 1999;19(6B):4999-5005.
48.
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast 
cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 
study. J Natl Cancer Inst. 2005;97(22):1652-1662.
49.
Marks PA, Richon VM, Breslow R, Rifkind RA. Histone deacetylase inhibitors as new 
cancer drugs. Current Opinion in Oncology. 2001;13(6):477-483.
50.
Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. J Cell 
Physiol. 2000;184(1):1-16.
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Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 
1997;389(6649):349-352.
52.
Yang WM, Tsai SC, Wen YD, Fejer G, Seto E. Functional domains of histone 
deacetylase-3. J Biol Chem. 2002;277(11):9447-9454.
53.
Yang WM, Yao YL, Sun JM, Davie JR, Seto E. Isolation and characterization of cDNAs 
corresponding to an additional member of the human histone deacetylase gene family. J 
Biol Chem. 1997;272(44):28001-28007.


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54.
Lin RJ, Nagy L, Inoue S, Shao W, Miller WH, Jr., Evans RM. Role of the histone 
deacetylase complex in acute promyelocytic leukaemia. Nature. 1998;391(6669):811-
814.
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Muraoka M, Konishi M, Kikuchi-Yanoshita R, et al. p300 gene alterations in colorectal 
and gastric carcinomas. Oncogene. 1996;12(7):1565-1569.
56.
Marks PA, Rifkind RA, Richon VM, Breslow R. Inhibitors of histone deacetylase are 
potentially effective anticancer agents. Clin Cancer Res. 2001;7(4):759-760.
57.
Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, 
placebo-controlled study of exemestane with or without entinostat in postmenopausal 
women with locally recurrent or metastatic estrogen receptor-positive breast cancer 
progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol. 
2013;31(17):2128-2135.
58.
Munster PN, Barberio MT, Pawlowska N, et al. Exhausted CD8+ cells (Tex) to predict 
response to PD-1 therapy in estrogen receptor (+) hormone therapy resistant breast 
cancer predictive of response to immune checkpoint inhibitors after epigenetic priming. 
Paper presented at: ASCO Annual Meeting; June 2, 2018, 2018; Chicago, IL.
59.
Terranova-Barberio M, Thomas S, Ali N, et al. HDAC inhibition potentiates 
immunotherapy in triple negative breast cancer. Oncotarget. 2017;8(69):114156-114172.
60.
Sabatier R, Finetti P, Mamessier E, et al. Prognostic and predictive value of PDL1 
expression in breast cancer. Oncotarget. 2015;6(7):5449-5464.
61.
Terranova-Barberio M, Thomas S, Munster PN. Epigenetic modifiers in immunotherapy: 
a focus on checkpoint inhibitors. Immunotherapy. 2016;8(6):705-719.
62.
Shen L, Ciesielski M, Ramakrishnan S, et al. Class I histone deacetylase inhibitor 
entinostat suppresses regulatory T cells and enhances immunotherapies in renal and 
prostate cancer models. PLoS One. 2012;7(1):e30815.
63.
Daud AI, Loo K, Pauli ML, et al. Tumor immune profiling predicts response to anti-PD-1 
therapy in human melanoma. J Clin Invest. 2016;126(9):3447-3452.
64.
Kestens L, Vanham G, Gigase P, et al. Expression of activation antigens, HLA-DR and 
CD38, on CD8 lymphocytes during HIV-1 infection. AIDS. 1992;6(8):793-797.
65.
Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the 
identification of high-risk breast cancer patients and those at risk of late relapse. J Clin 
Oncol. 2006;24(34):5373-5380.
66.
Bohling SD, Allison KH. Immunosuppressive regulatory T cells are associated with 
aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol. 
2008;21(12):1527-1532.
67.
Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K, Okada M. Possible 
involvement of regulatory T cells in tumor onset and progression in primary breast 
cancer. Cancer Immunol Immunother. 2009;58(3):441-447.
68.
Terranova-Barberio M, Thomas S, Munster PN. Host histone acetylation unlocks HDAC 
inhibitor potential. Oncotarget. 2017;8(63):106161-106162.
69.
Munster PN, Marchion D, Thomas S, et al. Phase I trial of vorinostat and doxorubicin in 
solid tumours: histone deacetylase 2 expression as a predictive marker. Br J Cancer. 
2009;101(7):1044-1050.
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
71.
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10.
72.
Chang MN, Wieand HS, Chang VT. The bias of the sample proportion following a group 
sequential phase II clinical trial. Statistics in Medicine. 1989;8(5):563-570.  


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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 II or III Institutional 
Study
Data and Safety Monitoring Plan for a Phase II or III Institutional Trial
1.         Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes: 

Semiannual auditing (depending on trial accrual)

Review of serious adverse events

Minimum of biennial regulatory auditing
2.
Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.  
All institutional Phase II and III therapeutic trials are audited on a semiannual basis, with all data 
from twenty percent of the enrolled participants audited by the DSMC Monitor/Auditor.  The 
assigned DSMC Monitor/Auditor will review no more than a total of 10 participant charts during 
the course of auditing this trial. DSMC Monitor/Auditors will send a follow-up report to the 
study team within 20 business days after the auditing visit is complete for the PI and the study 
team to resolve all action items from this report within 20 business days.  An abbreviated 
regulatory review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA logs, 1572 
forms, etc.) will occur at each participant monitoring review; however, a full regulatory review 
will occur on a biennially basis by the DSMC for regulatory compliance.
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.  
3.
Review and Oversight Requirements
3.1
Adverse Event Monitoring 
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the 


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investigational agent(s) or study procedure, will be entered into OnCore®, UCSF’s 
Clinical Trial Management System.  
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program 
(CTEP) of the National Cancer Institute.  Adverse events are further given an assignment 
of attribution or relationship to investigational agent or study procedure.  Attribution 
categories are:
•
Definite – The adverse event is clearly related to the investigational agent(s) or 
study procedure.
•
Probable – The adverse event is likely related to the investigational agent(s) or 
study procedure.
•
Possible – The adverse event may be related to the investigational agent(s) or 
study procedure.
•
Unrelated – the adverse event is clearly not related to the investigational agent(s) 
or study procedure.
All Grade 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 attribution assignment.
3.2
Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria:
•
Death.
•
Life-threatening (i.e., results in an immediate risk of death).
•
Requires inpatient hospitalization or prolongation of existing hospitalization,
•
Permanent or significant disability/incapacity
•
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed 
above. 
•
Event occurring in a gene therapy study.
•
Event that changes the risk/benefit ratio of a study.
•
Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported 
in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported 
on a Med Watch form.  
UCSF IRB website for guidance in reporting serious adverse events:


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https://irb.ucsf.edu/adverse-event 
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per 
IRB guidelines).  The SAEs are 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.  The date the SAE is sent to all required reporting agencies 
will be documented in OnCore®. 
If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, the event 
must be reported to the DSMC Chair (or Vice Chair) and DSMC Director within one 
business day.  
1.3
Review of 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 Principal 
Investigator will notify the DSMC via report 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 Investigator voluntarily holds enrollment or stops the study due to 
safety issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified 
within one business day and the IRB must be notified as per IRB reporting regulations.
Data and Safety Monitoring Committee Contacts:
  
 (DSMC Chair)
  
  
  Box 1705
  UCSF HDFCCC
  San Francisco, CA 94158
DSMC Director) 
Box 0981
UCSF HDFCCC
San Francisco, CA 94143


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Appendix 3 Prohibited Medications List 
Drug
Trade name (if applicable)
BCG (Intravesical or vaccine) - ok if on ARM B
Theracys. TICE-BCG
BuPROPion
Wellbutrin
Cladribine - ok if on ARM B
Mavenclad
Conivaptan
Vaprisol
Dacomitinib
Vizimpro
Deferiprone - ok if on ARM B
Ferriprox
Dexamethasone
Prozac
Fludrocortisone
FLUoxetine
Prozac
Hydrocortisone (topical is okay)
Cortef
Idelalisib
Zydelig
PARoxetine
Paxil
Methylprednisolone
Medrol
Ospemifene
Osphena
Prednisone
Deltisone
Tipranavir
Aptivus
Triamcinolone (topical, inhaled is ok)
Kenalog

ICF_001.pdf: 
CC#197520
ICF 11-15-2022
PAGE 1 OF 25PAMELA MUNSTER, MD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Study Title: Epigenetic priming for Immune therapy in ER-positive breast 
cancer in biomarker select population
Principal Investigator:
Pamela N. Munster, MD
Professor, Department of Medicine
University of California San Francisco
San Francisco, CA 
Telephone: 
This is a clinical research study. Your study doctor(s) Pamela Munster, MD from the 
UCSF Department of Medicine (Hematology/Oncology), will explain the study to you.
STUDY SUMMARY
Introduction: We are asking you to consider taking part in a research study being done 
by Dr. Munster at UCSF. You are being asked to take part in this study because you 
have stage IV estrogen-receptor positive (ER+) breast cancer.
The first part of this consent form gives you a summary of this study. We will give you 
more details about the study later in this form. The study team will also explain the study 
to you and answer any questions you have.
Research studies include only people who choose to take part. It is your choice whether 
or not you want to take part in this study. Please take your time to make a decision 
about participating. You can discuss your decision with your family, friends and health 
care team.
Purpose of the study: The researchers want to find whether a certain drug 
combination is better than another to control stage IV estrogen-receptor positive (ER+) 
breast cancer. This study will find out what effects, good and/or bad, pembrolizumab 
and tamoxifen and, for some individuals, vorinostat, have on patients and their breast 
cancer.
Study Procedures: If you choose to be in this study, you will be randomly assigned to 
one of two groups. One group will be asked to take one study drug daily for as long as 
their cancer does not get worse or progress. The other group will be asked to take two 
study drugs daily for as long as their cancer does not get worse or progress. In addition, 
everyone in this study, - regardless of their group - will need to come into UCSF Cancer 
Center for infusions of an additional study drug every 3 weeks for 30 minutes. Also, the 
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023
NCT#  04190056


CC#197520
ICF 11-15-2022
PAGE 2 OF 25PAMELA MUNSTER, MD
main study procedures include a physical exam, blood tests, CT scan, and tumor 
biopsy.
You will visit the research site approximately 7 times for each 9 week period (or for each 
3 cycles). You will be in this study for about as long as your cancer does not get worse 
or progress.
Possible Risks: There are risks to taking part in a research study. Some of the most 
likely risks of participation in this study include: 

Cough

Diarrhea

Fatigue

Hot flushes

Itching of the skin

Nausea
There are also rare but serious risks of participation, like: 

Type 1 Diabetes, a condition that can cause too much sugar in your blood, 
feeling thirstier than usual, frequent urination and weight loss.

Blood clots, including deep vein thrombosis (DVT) and pulmonary embolus.

Cancer of the uterus
We’ll tell you about the other risks later in this consent form.
Possible Benefits: You may benefit from participating in the study, but this cannot be 
guaranteed. 
Your Other Options: You do not have to participate in this study. Your other choices 
may include:

Getting treatment or care for your condition without being in a study. 

Taking part in another study.

Getting no treatment or receiving comfort care to relieve your symptoms and 
discomfort. 
Please talk to your doctor about your choices before agreeing to participate in this 
study.
Following is a more complete description of this study. Please read this description 
carefully. You can ask any questions you want to help you decide whether to join the 
study. If you join this study, we will give you a signed copy of this form to keep for future 
reference.
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


CC#197520
ICF 11-15-2022
PAGE 3 OF 25PAMELA MUNSTER, MD
DETAILED STUDY INFORMATION
This part of the consent form gives you more detailed information about what the study 
involves.
You are being asked to take part in this study because you have stage IV estrogen-
receptor positive (ER+) breast cancer.
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. There are 3 study drugs: pembrolizumab, 
vorinostat, and tamoxifen. Depending on which arm you are randomly selected to be in, 
you will receive a different combination of the study drugs.
Pembrolizumab is an investigational drug. This means pembrolizumab, while approved 
for other types of cancer, 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 and 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.
Vorinostat is an investigational drug. This means vorinostat has not been approved by 
the U.S. FDA for use in 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.
Pembrolizumab and vorinostat are therefore both investigational drugs in this study.
Tamoxifen is an anti-hormonal drug that is U.S. FDA-approved to treat advanced breast 
cancer.
The purpose of this study is to:

Find a drug combination to better control stage IV ER+ breast cancer and reduce 
the number of pills you take. This study will find out what effects, good and/or 
bad, pembrolizumab, vorinostat, and tamoxifen have on you and your stage IV 
ER+ breast cancer.
Merck, the manufacturer of pembrolizumab and vorinostat, is supplying pembrolizumab 
and vorinostat at no cost to study participants, and is providing funding to UCSF for this 
study.
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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How many people will take part in this study?
About 65 people will take part in this study.
About 35 people will be enrolled in Arm A, which will receive a combination of 
pembrolizumab, vorinostat, and tamoxifen. 
About 30 people will be enrolled in Arm B, which will receive a combination of 
pembrolizumab and tamoxifen.
What will happen if I take part in this research study?
Before you begin the main part of the study:
You will need to have the following tests and procedures to find out if you can be in the 
main part of the study. Some of these tests and procedures are part of regular cancer 
care and may be done even if you do not join the study. If you have had some of them 
recently, they may not need to be repeated. This will be up to your study doctor.

Clinical Assessments
o
You will have a physical examination that will include an assessment of vital 
signs, general appearance, skin, head and neck (including ears, eyes, nose and 
throat), respiratory, cardiovascular, abdomen, lymph nodes, thyroid, 
musculoskeletal (including spine and extremities), and neurological systems.
o
You will be asked how well you perform activities of daily living, like dressing 
yourself and getting out of bed.
o
You will be asked about your medical history, including history of prior treatments 
and any side effects related to prior treatment.
o
You will be asked what medications you are taking, including over-the-counter 
medicines, vitamins, or herbal treatments.
o
You will be asked about any side effects from your cancer or any prior treatments 

Laboratory Assessments
o
About 2 tablespoons of blood will be drawn by inserting a needle into a vein.

About 1 tablespoon of blood will be used for safety testing.

About 1 tablespoon of blood will be used for research biomarker testing. 
Biomarkers are substances in your tissues that may provide information 
on any changes to your genes or DNA, how your cancer cells are 
responding to study treatment and whether your cells are becoming 
resistant (no longer responding) to the study treatment.
o
If you are a woman of childbearing age, a blood test (less than ½ tsp) will be 
done to see if you are pregnant. (or at Cycle 1 Day 1)
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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
Imaging Procedures
o
You will have either a CT scan or an MRI scan of the breast. Whichever scan you 
have performed at screening, you will have performed throughout the remainder 
of the study.
o
CT SCAN: 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
MRI SCAN (if CT scan is not advised): 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.

Tissue Collection
o
FINE NEEDLE ASPIRATION (FNA) (or at Cycle 1 Day 1): This is a special type 
of biopsy. The doctor will insert a fine (very thin) needle through your skin and 
into your tumor and will remove a very small sample (less than ½ a teaspoon) of 
your tumor. Either an ultrasound or CT scan will be used to guide the placement 
of the needle. You will sign a separate consent form for this procedure. This 
procedure will take about 15-30 minutes.
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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During the main part of the study:
If the tests and procedures show that you can be in the main part of the study, and you 
choose to take part, then you will be "randomized" into one of the study arms described 
below. Randomization means that you are put into an arm by chance. A computer 
program will place you in one of the arms. Neither you nor your doctor can choose the 
arm you will be in. You will have an equal chance of being placed in any arm.

If you are in Arm A, you will receive a combination of pembrolizumab, 
vorinostat, and tamoxifen

If you are in Arm B, you will receive a combination of pembrolizumab and 
tamoxifen
Pembrolizumab

Pembrolizumab is given through the vein every 3 weeks of the 21-day cycle.

Please see last page of consent for complete List of Prohibited Medications.
Vorinostat (if you are randomly selected to be in Arm A)

Vorinostat is taken by mouth once a day for 4 days and then not taken for 3 days, 
weekly, every 21-day cycle.
o
We will ask you to keep a pill diary. In this diary, you will write the date, the 
time and the number of pills you take, and any new side effects you have. 
A side effect is an unwanted response to a medicine. If you miss any pills, 
you should also write that in the diary. Your study nurse will give you 
complete directions for how to keep the diary. This should take about 1-2 
minutes each week and will be collected by the study nurse at your clinic 
visits.

Please see last page of consent for complete List of Prohibited Medications.
Tamoxifen

Tamoxifen is taken by mouth once a day every day of the 21-day cycle.
o
We will ask you to keep a pill diary. In this diary, you will write the date, the 
time and the number of pills you take, and any new side effects you have. 
A side effect is an unwanted response to a medicine. If you miss any pills, 
you should also write that in the diary. Your study nurse will give you 
complete directions for how to keep the diary. This should take about 1-2 
minutes each week and will be collected by the study nurse at your clinic 
visits.

Please see last page of consent for complete List of Prohibited Medications.
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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The following tests and procedures will be done during the main part of the study:
Cycle 1, Day 1

Study Treatment/Drug Administration
o
You will receive pembrolizumab through a vein at UCSF.
o
You will be given enough vorinostat capsules to last you until your C2D1 (if you 
are randomly selected to be in Arm A). Each week you will take vorinostat for 4 
days and then not take it for 3 days.

You will be given a pill diary for vorinostat. 
o
You will begin taking tamoxifen. Tamoxifen will be prescribed by your study 
doctor and can be picked up at your normal pharmacy.

You will be given a pill diary for tamoxifen. 

Clinical Assessments
o
You will have a physical examination that will include an assessment of vital 
signs, general appearance, skin, head and neck (including ears, eyes, nose and 
throat), respiratory, cardiovascular, abdomen, lymph nodes, thyroid, 
musculoskeletal (including spine and extremities), and neurological systems.
o
You will be asked how well you perform activities of daily living, like dressing 
yourself and getting out of bed.
o
You will be asked what medications you are taking, including over-the-counter 
medicines, vitamins, or herbal treatments.
o
You will be asked about any side effects you’re having.

Laboratory Assessments
o
About 2 tablespoons of blood will be drawn by inserting a needle into a vein.

About 1 tablespoon of blood will be used for safety testing. 

About 1 tablespoon of blood will be drawn by inserting a needle into a vein to 
be used for research biomarker testing. 

Tumor Tissue Collection 
o
You will have a biopsy of your tumor tissue (fine needle aspiration) if you did not 
have one at screening.
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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PAGE 8 OF 25PAMELA MUNSTER, MD
Cycle 1, Day 10-12

Laboratory Assessments

About 1 tablespoon of blood will be drawn by inserting a needle into a vein to 
be used for research biomarker testing. 
Cycle 1, Day 15

Clinical Assessments
o
You will have a physical examination that will include an assessment of vital 
signs, general appearance, skin, head and neck (including ears, eyes, nose and 
throat), respiratory, cardiovascular, abdomen, lymph nodes, thyroid, 
musculoskeletal (including spine and extremities), and neurological systems.
o
You will be asked how well you perform activities of daily living, like dressing 
yourself and getting out of bed.
o
You will be asked what medications you are taking, including over-the-counter 
medicines, vitamins, or herbal treatments.
o
You will be asked about any side effects you’re having.

Laboratory Assessments
o
About 1 tablespoon of blood will be drawn by inserting a needle into a vein to be 
used for safety testing.
Cycle 2, Day 1

Study Treatment/Drug Administration
o
You will receive pembrolizumab through a vein at UCSF.
o
You will be given enough vorinostat capsules to last you until your C3D1 (if you 
are randomly selected to be in Arm A). Each week you will take vorinostat for 4 
days and then not take it for 3 days.
o
You will be given a pill diary for vorinostat. 
o
You will continue taking tamoxifen. Tamoxifen will be prescribed by your study 
doctor and can be picked up at your normal pharmacy.

You will be given a pill diary for tamoxifen.

Clinical Assessments
o
You will have a physical examination that will include an assessment of vital 
signs, general appearance, skin, head and neck (including ears, eyes, nose and 
throat), respiratory, cardiovascular, abdomen, lymph nodes, thyroid, 
musculoskeletal (including spine and extremities), and neurological systems.
o
You will be asked how well you perform activities of daily living, like dressing 
yourself and getting out of bed.
o
You will be asked what medications you are taking, including over-the-counter 
medicines, vitamins, or herbal treatments.
o
You will be asked about any side effects you’re having.
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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PAGE 9 OF 25PAMELA MUNSTER, MD

Laboratory Assessments
o
About 1 tablespoon of blood will be drawn by inserting a needle into a vein to be 
used for safety testing.
Future Cycles (Day 1)

Study Treatment/Drug Administration
o
You will receive pembrolizumab through a vein at UCSF.
o
You will be given enough vorinostat capsules to last you until the first day of your 
next cycle (if you are randomly selected to be in Arm A). Each week you will take 
vorinostat for 4 days and then not take it for 3 days.
o
You will be given a pill diary for vorinostat. 
o
You will continue taking tamoxifen. Tamoxifen will be prescribed by your study 
doctor and can be picked up at your normal pharmacy.

You will be given a pill diary for tamoxifen.

Clinical Assessments
o
You will have a physical examination that will include an assessment of vital 
signs, general appearance, skin, head and neck (including ears, eyes, nose and 
throat), respiratory, cardiovascular, abdomen, lymph nodes, thyroid, 
musculoskeletal (including spine and extremities), and neurological systems.
o
You will be asked how well you perform activities of daily living, like dressing 
yourself and getting out of bed.
o
You will be asked what medications you are taking, including over-the-counter 
medicines, vitamins, or herbal treatments.
o
You will be asked about any side effects you’re having.

Laboratory Assessments
o
About 2 tablespoons of blood will be drawn by inserting a needle into a vein.

About 1 tablespoon of blood will be used for safety testing. 

About 1 tablespoon of blood will be used for research biomarker testing. 
o
If you are a woman of childbearing age, a blood test (less than ½ tsp) will be 
done to see if you are pregnant.

Imaging Procedures
o
You will have a CT scan or an MRI of the breast.

Tumor Tissue Collection 
o
You will have a biopsy of your tumor tissue (fine needle aspiration) at the end of 
Cycle 3.
When you are finished receiving pembrolizumab, vorinostat, and 
tamoxifen:

Clinical Assessments
o
You will be asked about any side effects you’re having.
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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PAGE 10 OF 25PAMELA MUNSTER, MD

Imaging Procedures
o
You will have a CT scan or an MRI of the breast.
Study location: 
All study procedures will be done at Helen Diller Family Comprehensive Cancer Center.
How long will I be in the study?
You will be asked to take pembrolizumab, vorinostat, and tamoxifen for as long as your 
cancer does not get worse or progress. After you are finished taking pembrolizumab, 
vorinostat, and tamoxifen, the study doctor will ask you to visit the office for follow-up 
exams for at least 9 weeks post-start of treatment. We would like to keep track of your 
medical condition for the rest of your life. We would like to do this by calling you on the 
telephone once every 3 months to see how you are doing. Keeping in touch with you 
and checking on your condition every 3 months helps us look at the long-term effects of 
the study.
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. She will tell you how to stop your participation safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the pembrolizumab, vorinostat, and tamoxifen 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 she believes 
it is in your best interest, if you do not follow the study rules, or if the study is stopped.
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 lessen side effects. Many side effects go away soon after 
you stop taking the pembrolizumab, vorinostat, and tamoxifen. In some cases, side 
effects can be serious, long lasting, or may never go away. There also is a risk of death.
You should talk to your study doctor about any side effects you experience while taking 
part in the study.
Pembrolizumab, which is approved in the USA and some other countries, is available by 
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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PAGE 11 OF 25PAMELA MUNSTER, MD
prescription to treat several different cancers but may not be approved to treat your type 
of cancer.Pembrolizumab works by helping your immune system to fight your cancer. 
However, pembrolizumab can also cause your immune system to attack normal organs 
and tissues in your body and can affect the way they work, which can result in side effects. 
These side effects may be serious (i.e., causing hospitalization or be life-threatening), 
may result in death, and/or may occur after you stop taking pembrolizumab. These side 
effects can affect more than one of your normal organs and tissues at the same time.
Risks related to pembrolizumab
Very Common (out of 100 people, 20 or more people may have the following)

Itching of the skin

Loose or watery stools

Cough
Common (out of 100 people, at least 5 but less than 20 people may have the 
following)

Joint pain

Rash

Fever

Back pain

Pain in your belly

Loss of skin color 

Not enough thyroid hormone, so you may feel tired, gain weight, feel cold, or have 
infrequent or hard stools (hypothyroidism)

Low levels of salt in the blood that may cause you to feel tired, feel confused, have 
a headache, have muscle cramps, and/or feel sick to your stomach (hyponatremia)
Uncommon (out of 100 people, at least 1 but less than 5 people may have the 
following)

Inflammation of the lungs, so you may feel short of breath and cough (pneumonitis).

Too much thyroid hormone, so you may feel anxious, feel angry, have trouble 
sleeping, feel weak, tremble, sweat, feel tired, have loose and watery stools 
(hyperthyroidism)

Infusion reaction, where you may feel dizzy or faint, feel flushed, get a rash, have a 
fever, feel short of breath, experience a decrease in your blood pressure at the time 
of receiving your infusion (IV) or just after, or have pain at the site of infusion

Inflammation of the bowels/gut, which may cause severe pain in your belly with 
loose or watery stools, and black, tarry, sticky stools or stools with blood or mucus 
(colitis)
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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PAGE 12 OF 25PAMELA MUNSTER, MD

Inflammation of the skin so you may have 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 (Severe skin reactions, including Stevens-Johnson syndromeor toxic 
epidermal necrolysis)
Rare (out of 100 people, less than 1 person may have the following)

Inflammation of the nerves that may cause pain, weakness, or tingling in your 
hands and feet, and may spread to your legs, arms, and upper body, leading to 
severe muscle weakness and possible temporary paralysis (Guillain-Barre 
syndrome)

Inflammation of the muscles, so you may feel weak or have pain in your muscles 
(myositis)

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 your 
back, feel sick to your stomach, and have vomiting that gets worse when you eat 
(pancreatitis)

Inflammation of the eye, so you may have eye redness, blurred vision, sensitivity to 
light, eye pain, see floaters, or have headaches (uveitis) 

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 
belly, yellow eyes and skin, and dark urine (hepatitis)

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 your behavior, double 
vision, few to no menstrual cycles, weakness, vomiting and dizziness, or fainting  
(hypophysitis)

Adrenal glands (glands on top of the kidneys) that may not make enough hormone, 
which could cause tiredness, weight loss, muscle weakness, feeling faint, having 
joint, muscle, and bellyaches, nausea, vomiting, loose or watery stools, fever, salt 
craving, and sometimes darkening of the skin like a suntan (adrenal insufficiency)

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 (nephritis) 

Inflammation of the middle layer of your heart wall 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 (myocarditis)

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 (thyroiditis)
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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
A condition that may make you feel weak and tired and may cause drooping of the 
eyelids, blurred or double vision, difficulty swallowing, slurred speech, weakness in 
your arms and legs, or difficulty breathing (myasthenic syndrome/ myasthenia 
gravis including exacerbation)

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. This may also include: 
disorientation, memory problems, seizures (fits), changes in personality and 
behavior, difficulty speaking, weakness or loss of movement in some parts of your 
body, and loss of consciousness (encephalitis)

Inflammation of the spinal cord with pain, numbness, tingling, or weakness in the 
arms or legs, bladder or bowel problems including needing to urinate more 
frequently, urinary incontinence, difficulty urinating, and constipation (myelitis)

Inflammation of the blood vessels (vasculitis). Symptoms will depend on the 
particular blood vessels that are involved in the inflammatory process, for example; 
if it is your skin, you may get a rash. If your nerves are not getting enough blood, 
you could have numbness and weakness. You may also experience fever, weight 
loss, and fatigue.

Low levels of parathyroid hormone (a hormone made by 4 tiny glands in your neck) 
which may result in low blood calcium and cause muscle cramps or spasms; fatigue 
or weakness; numbness, tingling or burning in your fingertips, toes or lips 
(hypoparathyroidism)
Additionally, since pembrolizumab was approved (for melanoma) in September 2014, 
the following side effects have been reported by people receiving pembrolizumab. 
These side effects were voluntarily reported from a group of people of unknown size. It 
is not possible to estimate the frequency of these side effects:

Inflammation of the joints which may include joint pain, stiffness and/or swelling 
(arthritis)

Severe responses of the immune system that causes the body to attack its own 
blood cells, spleen, liver, lymph nodes, skin and brain. This may include fever, 
rash, inflammation of the liver, yellowing of the skin, an enlarged liver and spleen, 
low blood counts, and enlarged lymph nodes. The nervous system may also be 
affected and cause confusion, seizures, and even coma (hemophagocytic 
lymphohistiocytosis)

Changes in eyesight, eye pain, whitish patches on the skin and hearing loss 
(Vogt-Koyanagi-Harada syndrome)

Inflammation and scarring of the bile ducts (tubes that carry digestive fluid that is 
made in the liver). This can cause symptoms similar to those seen with 
inflammation of the liver (hepatitis) such as pain in the right side of your belly, 
yellow eyes and skin, feeling tired, and itching (sclerosing cholangitis).

Inflammation or swelling of the nerve fibers of the eye which send visual 
information from your eye to your brain. This health condition often has a sudden 
onset of vision loss, loss of color vision, pain when moving your eyes, and/or loss 
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IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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of peripheral vision. It may affect one or both eyes at the same time (optic 
neuritis).
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.
If you have had a solid organ transplant (for example, if you have received a kidney
or heart transplant), you may experience rejection of the transplanted organ. Your
doctor will monitor you and should tell you what signs and symptoms you should
report depending on the type of organ transplant that you have had.
Risks related to vorinostat
Likely (out of 100 people, 10 or more people may have the following)

Feeling tired, tiredness, weakness.

Diarrhea, which is frequent, loose watery stools, which can cause dehydration 
and may require hospitalization and treatment with intravenous fluids. Severe 
and prolonged diarrhea can be life-threatening.

Feeling sick to the stomach

Strange taste in the mouth.

Excess sugar in the blood, if severe may require hospitalization and urgent 
treatment. (diabetes)

Increased blood level of creatinine, a substance normally eliminated by the 
kidneys into the urine. This may mean that your kidneys are not functioning 
properly. 

Excess protein in the urine. This may cause fluid retention.

Low number of platelets, which may cause bleeding and bruising. Bleeding may 
be serious or life threatening and may require a blood transfusion.
Less Likely (out of 100 people, 1-9 people may have the following)

Loss of appetite (anorexia)

Weight loss

Muscle spasms

Hair loss (alopecia)

Dry mouth

Chills

Fever

Vomiting

Dizziness

Constipation
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023


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
Low number of red blood cells that can causes tiredness and shortness of 
breath. May require a blood transfusion.

Headache

Itching

Swelling in hands or feet

Cough

Upper respiratory infection

Dehydration

Shortness of breath
Rare but serious

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 related to tamoxifen 
Likely (out of 100 people, 20 or more people may have the following)

Hot flushes

Nausea and vomiting

Fatigue

Vaginal discharge
Less Likely (out of 100 people, 10-19 people may have the following)

Blood clots

Changes in vision

Changes in liver functions
Rare but serious

Cancer of the uterus
Risks related to Study Procedures
BLOOD DRAWS
The risks of drawing blood include temporary discomfort from the needle stick, bruising, 
and rarely, infection.
CT SCAN
CT scans involve the risks of radiation. In addition, if contrast material (iodine dye) is 
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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 with contrast. If you are taking metformin (or similar drugs by mouth to treat high 
blood sugar), such treatment will be stopped for 2-3 days around the time a scan is 
planned in order to avoid kidney side effects.
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 by vein. 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 SCAN
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 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 earplugs. At times during the test, you may be asked to not swallow for a 
while, which can be uncomfortable.
Because the risks to a fetus from MRI are unknown, pregnant women must not 
participate in this study. 
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 
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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.
TUMOR BIOPSY (FINE NEEDLE ASPIRATION – FNA)
The biopsy has small but serious risks. The general risks associated with this procedure 
are pain, discomfort, infection, and bleeding. 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 require 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 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.
DRUG INTERACTIONS 
You must also review with your study doctor all of your medications (including 
supplements and herbal or natural substances) at every visit, as well as notify your 
study doctor before starting any new medications, supplements, or herbal treatments 
while participating in the study because there is a risk of serious interaction with some 
kinds medications. Please go over the “Medications and Foods to Avoid” list at the end 
of this form with your study doctor and keep it for your reference. 
LOSS OF PRIVACY
There is a risk of loss of privacy. We will do our best to make sure that your personal 
information will be kept private. Your samples will be labeled with a code that cannot be 
used to identify you directly. The list that links your identity to the code on the sample 
will be kept separate from the samples. The researchers using your samples will never 
be given your identity. However, we cannot guarantee complete privacy.
RADIATION 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 result in a very small increased risk of future cancer. However, the UCSF 
Radiation Safety Committee believes that this risk, given your overall medical condition, 
is acceptable. If you have any questions regarding the use of radiation or the risks 
involved, please consult your study doctor.
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RANDOMIZATION
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.
REPRODUCTIVE 
You should not become pregnant or father a baby 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. 
RISK OF INADEQUATE TISSUE
Providing parts of your surgically-removed tissue for research could, in rare cases, 
result in too little tissue being available for your doctors to make a clinical diagnosis (or 
complete other clinically important tests). To minimize this risk, a Pathologist (or a 
pathology designee) carefully evaluates every tissue specimen at the time of surgery to 
decide if it can safely be provided for research. With this process in place, we believe 
the risk of negatively impacting your clinical care through providing tissue for research is 
extremely small (below 1%).
UNKNOWN
The experimental treatments may have side effects that no one knows about yet. 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 
pembrolizumab, vorinostat, and tamoxifen 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 pembrolizumab, vorinostat, and tamoxifen 
as a treatment for cancer. This information could help future cancer patients.
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.
Please talk to your doctor about your choices before deciding if you will take part in this 
study.
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How will my specimens and information be used? 
Researchers will use your blood and tissue specimens and information to conduct this 
study. Once the study is done using your specimens and information, we may share 
them with other researchers so they can use them for other cancer studies in the future. 
We will not share your name or any other personal information that would let the 
researchers know who you are. We will not ask you for additional permission to share 
the de-identified information and specimens.
Your blood and tissue specimens will be stored in a repository, also called a ‘tissue 
bank’, at UCSF. The manager of tissue bank and select tissue bank staff members will 
have access to your specimens and information about you, but they will not release any 
identifying information about you to researchers using your specimens. We may give 
your specimens and certain medical information about you (for example, diagnosis, 
blood pressure, age if less than 85) to other scientists or companies not at UCSF, 
including to an unrestricted or controlled-access government health research database, 
but we will not give them your name, address, phone number, or any other identifiable 
information. Your specimens and information will be kept indefinitely until they are used 
up or destroyed. 
Research results from these studies will not be returned to you and will not be put in 
your medical record. The research will not change the care you receive.
Researchers may use your blood and tissue specimens look at all of your DNA (this is 
called “whole genome sequencing. DNA contains information that determines things like 
eye color, height, or disease risk that are passed on from parent to child. Genetic 
information (also known as genotype data) and the medical record data (also known as 
phenotype data) may be shared broadly in a coded form for future genetic research or 
analysis. 
Donating data and 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. Genetic information that results from this study does not have 
medical or treatment importance at this time. However, there is a risk that information 
about taking part in a genetic study may influence insurance companies and/or 
employers regarding your health. Taking part in a genetic study may also have a 
negative impact or unintended consequences on family or other relationships. It is 
possible that future research could one day help people of the same race, ethnicity, or 
sex as you. However, it is also possible through these kinds of studies that genetic traits 
might come to be associated with your group. In some cases, this could reinforce 
harmful stereotypes.
There will be no direct benefit to you from allowing your specimens and data to be kept 
and used for future research. However, we hope we will learn something that will 
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contribute to the advancement of science and understanding of health and disease. If 
your specimens, the data or any new products, tests or discoveries that result from this 
research have potential commercial value, you will not share in any financial benefits. 
If you decide later that you do not want your information to be used for future research, 
you can notify the investigator in writing at,
Pamela N. Munster, MD
Professor, Department of Medicine
University of California San Francisco
and any remaining data will be destroyed. However, we cannot retract any data has 
been shared with other researchers.
How will information about me be kept confidential?
Participation in research involves some loss of privacy. We will do our best to make 
sure that information about you is kept confidential, but we cannot guarantee total 
privacy. Some information from your medical records will be collected and used for this 
study. If you do not have a UCSF medical record, one will be created for you. Your 
signed consent form and some of your research tests will be added to your UCSF 
medical record. Therefore, people involved with your future care and insurance may 
become aware of your participation and of any information added to your medical record 
as a result of your participation. Study tests that are performed by research labs, and 
information gathered directly from you by the researchers will be part of your research 
records and may be added to your medical record. 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.
Authorized representatives from the following organizations may review your research 
data for the purpose of monitoring or managing the conduct of this study:

Representatives of Merck & Co., Inc.

Representatives of the University of California

Representatives of the Food and Drug Administration (FDA) 
Are there any costs to me for taking part in this study?
Merck will provide pembrolizumab and vorinostat at no cost to you.
Two types of procedures will be done during this study. Some are part of your standard 
medical care and others are only for research. You or your insurer will be billed for the 
standard medical care. You will be responsible for your co-pays, deductibles, and any 
other charges that your insurer will not pay. There is a possibility that your insurer may 
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not cover all standard medical care costs if you are receiving medical services out of 
network. Any procedures done only for research will not be charged to you or your 
insurer.
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, Dr. 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, 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 Institutional Review Board at 415-476-1814.
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) Dr. Munster at 415-885-7810.
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 
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you may have about the study, please call the office of the Institutional Review Board 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. 
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************************************************************
OPTIONAL RESEARCH PARTICIPATION
This section of the informed consent is about optional future contact of 
participants in the main study. You can still be in the main study even if you say 
"no" to allowing optional future contact.
Future Contact 
We want to know if we may contact you in the future to see if you are interested 
in participating in other research studies.
If you agree and we contact you to tell you about a study, you have no obligation 
to actually participate in any study. You can decide when you are told about the 
study if you want to receive more information about the study. There would be a 
new consent process for that study. 
If at any time you decide you no longer want to be contacted about future 
studies, please let us know by calling 
Making Your Choice
Please read the sentence below and mark your choice by putting your initials in 
the "Yes" or "No" box. If you have any questions, please talk to your doctor or 
nurse, or call our research review board at 415-476-1814.
No matter what you decide to do, it will not affect your care or your participation 
in the main study.
1. Someone may contact me in the future about taking part in more 
research.
YES 
NO
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CONSENT
You have been given copies of this consent form and 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.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Date
Person Obtaining Consent
Date
Witness – Only required if the participant is a 
non-English speaker
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LIST OF PROHIBITED MEDICATIONS
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in biomarker select population
The following is a list of medications to avoid while you are on this study. If you go to 
any clinic or medical visit, please take this list with you for the doctor’s reference.
Before you begin treatment, Dr. Munster or one of her associates will review all 
medications you are taking. Make sure you talk with Dr. Munster before you start or stop 
taking any medications. This list contains only the most common drugs that are known 
to interact with the drugs used in this study. It is very important to discuss all 
medications that you are taking with your study doctor. This information will be reviewed 
at each study visit.
In addition to the listed medications, you should also avoid live vaccines including 
Zostavax, MMR (measles, mumps, rubella), but ultimately check with your provider.
The following is a list of prohibited drugs. You should not take these drugs while in this 
study.
Generic Name
Brand Names ®
BCG (Intravesical or vaccine) - ok if on ARM B
Theracys. TICE-BCG
BuPROPion 
Wellbutrin
Cladribine - ok if on ARM B
Mavenclad
Conivaptan
Vaprisol
Dacomitinib 
Vizimpro
Deferiprone - ok if on ARM B
Ferriprox
Dexamethasone 
Prozac
Fludrocortisone 
FLUoxetine
Prozac
Hydrocortisone (topical is okay) 
Cortef
Idelalisib
Zydelig
PARoxetine 
Paxil
Methylprednisolone 
Medrol
Ospemifene
Osphena
Prednisone 
Deltisone
Tipranavir 
Aptivus
Triamcinolone (topical, inhaled is ok)
Kenalog
IRB NUMBER: 19-28672
IRB APPROVAL DATE: 01/05/2023
IRB EXPIRATION DATE: 09/12/2023