A Phase I/II Study of Pembrolizumab and Vorinostat in Patients With Immune Therapy Naïve and Immune Therapy Pretreated Stage IV NSCLC
Phase: PHASE1
Conditions: Lung Cancer, Non-small Cell Lung Cancer
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Product:  Pembrolizumab, Vorinostat 
Protocol/Amendment No.:  18494/5 
 
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SPONSOR:  Moffitt Cancer Center 
 
TITLE:  A phase I/II study of pembrolizumab and vorinostat in patients with immune 
therapy naïve and immune therapy pretreated Stage IV NSCLC   
 
IND NUMBER: 128712. 
 
 
PI:  
Jhanelle Gray, MD 
 
12902 Magnolia Drive 
 
Tampa, FL 33612 
 
813-745-6895 
 
Jhanelle.Gray@moffitt.org 
 
 
 
Version 6 
  
June 27, 2019 
 
 
 
 

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1.0 
TRIAL SUMMARY .......................................................................................... 7 
2.0 
TRIAL DESIGN ............................................................................................... 8 
2.1 
Trial Design ................................................................................................ 8 
2.2 
Trial Diagram .............................................................................................. 8 
3.0 
OBJECTIVES & HYPOTHESES .................................................................... 9 
3.1 
Primary Objectives & Hypotheses ........................................................... 9 
3.2 
Secondary Objectives & Hypotheses ...................................................... 9 
4.0 
BACKGROUND & RATIONALE .................................................................. 10 
4.1 
Background .............................................................................................. 10 
4.1.1 Pharmaceutical and Therapeutic Background ....................................... 10 
4.1.2 Preclinical and Clinical Trial Data ........................................................... 11 
4.2 
Rationale .................................................................................................. 11 
4.2.1 Rationale for the Trial and Selected Subject Population ........................ 11 
4.2.2 Rationale for Dose Selection/Regimen/Modification .............................. 16 
4.2.3 Rationale for Endpoints .......................................................................... 18 
4.2.4 Methods for Evaluation of Measurable Disease ..................................... 20 
4.2.5 Response Criteria .................................................................................. 21 
4.2.6 Progression-Free Survival ...................................................................... 23 
4.2.7 Duration of Response ............................................................................ 23 
4.2.8 Objective Response Rate ...................................................................... 24 
4.2.9 Overall Survival ...................................................................................... 24 
4.2.10 Missing Assessments and Not Evaluable Designation ........................... 24 
4.2.11 Treatment Beyond Progression.............................................................. 24 
4.2.12 Biomarker Research .............................................................................. 25 

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4.3 
Biological sampling procedures ............................................................ 25 
4.3.1 Immunogenicity sampling and evaluation methods ................................ 25 
4.3.2 Biomarker/Pharmacodynamic sampling and evaluation methods .......... 26 
4.3.3 Archival Tumor Samples and Fresh Tumor Biopsies ............................. 27 
5.0 
METHODOLOGY .......................................................................................... 30 
5.1 
Entry Criteria ............................................................................................ 30 
5.1.1 Diagnosis/Condition for Entry into the Trial ............................................ 30 
5.1.2 Subject Inclusion Criteria ....................................................................... 30 
5.1.3 Subject Exclusion Criteria ...................................................................... 32 
5.2 
Trial Treatments ....................................................................................... 35 
5.2.1 Dose Selection/Modification ................................................................... 35 
5.2.2 Timing of Dose Administration ............................................................... 37 
5.2.3 Trial Blinding/Masking ............................................................................ 37 
5.3 
Randomization or Treatment Allocation ................................................ 37 
5.4 
Stratification ............................................................................................. 38 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ......... 38 
5.5.1 Acceptable Concomitant Medications .................................................... 38 
5.5.2 Prohibited Concomitant Medications ...................................................... 38 
5.6 
Rescue Medications & Supportive Care ................................................ 39 
5.6.1 Supportive Care Guidelines ................................................................... 39 
5.7 
Diet/Activity/Other Considerations ........................................................ 43 
5.7.1 Diet ......................................................................................................... 43 
5.7.2 Contraception ......................................................................................... 43 
5.7.3 Use in Pregnancy ................................................................................... 43 

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5.7.4 Use in Nursing Women .......................................................................... 44 
5.8 
Subject Withdrawal/Discontinuation Criteria ........................................ 44 
5.8.1 Discontinuation of Study Therapy after CR ............................................ 45 
5.9 
Subject Replacement Strategy ............................................................... 45 
5.10 Clinical Criteria for Early Trial Termination ........................................... 45 
6.0 
TRIAL FLOW CHART................................................................................... 46 
6.1 
Study Flow Chart* .................................................................................... 46 
7.0 
TRIAL PROCEDURES ................................................................................. 49 
7.1 
Trial Procedures ...................................................................................... 49 
7.1.1 Administrative Procedures ..................................................................... 49 
7.1.2 Assignment of Screening Number.......................................................... 50 
7.1.3 Assignment of Randomization Number .................................................. 50 
7.1.4 Clinical Procedures/Assessments .......................................................... 51 
7.1.5 Laboratory Procedures/Assessments .................................................... 52 
7.1.6 Other Procedures ................................................................................... 54 
7.1.7 Visit Requirements ................................................................................. 54 
7.2 
Assessing and Recording Adverse Events ........................................... 56 
7.2.1 Definition of an Overdose for This Protocol and Reporting of 
Overdose to the Sponsor and to Merck .................................................. 57 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ..... 57 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck .. 58 
7.2.4 Evaluating Adverse Events .................................................................... 60 
7.2.5 Sponsor Responsibility for Reporting Adverse Events ........................... 63 
8.0 
STATISTICAL ANALYSIS PLAN ................................................................. 63 
8.1 
Statistical Analysis Plan Summary ........................................................ 63 

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8.2 
Statistical Analysis Plan ......................................................................... 63 
8.2.1 Phase I dose escalation. ........................................................................ 63 
8.2.2 Definitions for Dose Limiting Toxicities. .................................................. 64 
8.2.3 Dose escalation. ..................................................................................... 65 
8.2.4 Operating characteristics. ...................................................................... 69 
8.2.5 Descriptive statistics ............................................................................... 73 
8.2.6 Sample size calculation. ......................................................................... 73 
8.2.7 Statistical plan for immunogenicity profiles in phase Ib and phase II: .... 75 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .................................................................................................... 76 
9.1 
Investigational Product ........................................................................... 76 
9.2 
Packaging and Labeling Information ..................................................... 76 
9.3 
Clinical Supplies Disclosure................................................................... 77 
9.4 
Storage and Handling Requirements ..................................................... 77 
9.5 
Returns and Reconciliation .................................................................... 77 
10.0 Data Safety Monitoring Plan ....................................................................... 77 
10.1 Risk to Subjects ....................................................................................... 77 
10.1.1 Human subject involvement and characteristics .................................... 77 
10.2 Recruitment and Informed Consent ....................................................... 77 
10.3 Protection Against Risk .......................................................................... 78 
10.4 Importance of the Knowledge to be Gained .......................................... 78 
10.5 Data Safety and Monitoring Plan ............................................................ 78 
10.6 Scientific Review Committee (SRC) ....................................................... 79 
10.7 PI Responsibility ...................................................................................... 79 
10.8 The Protocol Monitoring Committee (PMC) .......................................... 79 

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10.9 Suspension/Termination ......................................................................... 80 
10.10 Trial Discontinuation ............................................................................... 80 
10.11 Monitoring of the Study and Regulatory Compliance .......................... 80 
10.12 Internal Monitoring Plan.......................................................................... 80 
10.13 Protocol Modifications ............................................................................ 81 
10.14 The Institutional Review Board (IRB) ..................................................... 81 
10.15 Patient Privacy ......................................................................................... 81 
10.16 Records Retention ................................................................................... 81 
10.17 Compliance 
with 
Trial 
Registration 
and 
Results 
Posting 
Requirements ........................................................................................... 81 
11.0 APPENDICES ............................................................................................... 82 
11.1 ECOG Performance Status ..................................................................... 82 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ..... 82 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Criteria for Evaluating Response in Solid Tumors ............................... 82 
11.4 See Events of Clinical Interest Guidance Document ............................ 82 
12.0 REFERENCES .............................................................................................. 83 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
A phase I/II study of pembrolizumab and vorinostat in 
patients with immune therapy naïve and immune therapy 
pretreated Stage IV NSCLC   
Trial Phase 
I/II 
Clinical Indication 
Stage 
IV 
NSCLC, 
ECOG 
0-1 
patients 
who 
are 
immunotherapy naïve and immune- therapy pretreated. 
Second line or greater. 
Trial Type 
phase I/randomized phase II 
Type of control 
Pembrolizumab for the randomized phase II portion. 
Route of administration 
Pembrolizumab IV 
Vorinostat PO 
Trial Blinding 
Open Label  
Treatment Groups  
Phase I:  Vorinostat dose escalation. 
Phase Ib:  Vorinostat Ib expansion. 
Randomized Phase II: Arm A (pembrolizumab alone), Arm B 
(pembrolizumab plus vorinostat). 
Number of trial subjects 
Total=108 
Phase I dose escalation: 12 
Phase Ib: 18 
Randomized phase II: 78 
Estimated 
enrollment 
period 
18 months 
Estimated duration of trial 24 months 
Duration of Participation 
24 months 
 
 
 
 
 
 
 

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2.0 TRIAL DESIGN 
2.1 
Trial Design 
We propose a phase I/randomized phase II clinical trial of pembrolizumab and vorinostat in 
ECOG 0-1 patients with immune therapy naïve and immune therapy pretreated locally 
advanced or metastatic NSCLC who have progressed through one prior line of therapy 
(Figure 1).  The study would begin with a phase I dose escalation utilizing the modified 
continuous reassessment method (O'Quigley, Pepe, & Fisher, 1990).  This would be 
followed by a phase I expansion at the maximum tolerated dose (MTD) in 18 NSCLC 
patients who have been previously treated with anti-PD-1 or anti-PD-L1 therapy.  In parallel, 
a separate phase II arm will randomize 78 patients to a pembrolizumab alone group and a 
pembrolizumab plus vorinostat group.  
2.2 
Trial Diagram 
 
Figure 1. Clinical trial schema. *Pre-treatment and post-treatment biopsies will be 
obtained in both the phase Ib expansion and the randomized phase II patients. R 
(Randomization), P (Pembrolizumab), V (Vorinostat), MTD (maximum tolerated dose). 
N =78 

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3.0 OBJECTIVES & HYPOTHESES 
3.1 Primary Objectives & Hypotheses 
Phase 1 Escalation: 
Primary Objective:  To determine the safety, tolerability and feasibility of concurrent 
administration of vorinostat and Pembrolizumab. 
 
Hypothesis:  Concurrent administration of vorinostat and Pembrolizumab will be 
safe, tolerable, and feasible.  
 
Phase 1b Expansion (Single Arm, Pre-treated Cohort): 
Primary Objective:  To determine whether concurrent administration of vorinostat 
and Pembrolizumab will be effective in NSCLC patients who have been previously 
exposed 
to 
anti-PD-1 
or 
anti-PD-L1 
therapy. 
 
Hypothesis:  Concurrent administration of vorinostat and Pembrolizumab will be 
effective in NSCLC patients who have been previously treated with anti-PD-1 or anti-
PD-L1 therapy. 
 
Phase II (Randomized, Treatment Naïve Cohort): 
Primary Objective:  To determine whether concurrent administration of vorinostat 
and Pembrolizumab is more effective than Pembrolizumab alone. 
 
Hypothesis:  Concurrent administration of vorinostat and Pembrolizumab will result 
in a higher response rate and progression-free survival (PFS) than Pembrolizumab 
alone. 
 
3.2 Secondary Objectives & Hypotheses 
Secondary Objectives (Phase 1 expansion and phase II Arms A and B): 
1. To determine immunogenicity molecular profiles that correlate with outcome 
measures. 
2. To determine immunogenicity profiles that correlate with resistance to therapy. 
3. To examine and model the mechanisms of resistance to immunotherapy available to 
cancer cells and the eco-evolutionary dynamics that govern proliferation of the 
resistant phenotypes. 
 
Secondary Hypotheses (Phase 1 expansion and Phase II Arms A and B): 
1. High immunogenicity (High-IG) profiles in pre-treatment biopsies will predict for anti-
PD-1+/-vorinostat responsiveness in the Phase I expansion cohort. 
2. High or Low immunogenicity (High/Low-IG) profiles will result in a higher response 
rate in the anti-PD-1+vorinostat therapy group than in the anti-PD1 treatment alone 

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group in the phase II cohort. 
3. During/Post-treatment biopsies we will find that vorinostat combined with anti-PD1 
treatment will enhance IG profiles compared to anti-PD1 treatment alone in the 
Phase I expansion cohort and the phase II cohort. 
 
4.0 BACKGROUND & RATIONALE 
4.1 Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
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).  
The structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells.  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  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 tumors .  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in 
the extracellular region and contain short cytoplasmic regions with no known signaling 
motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the 
T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, 
most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed 
on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  

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PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific 
T-cell expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the 
United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
The World Health Organization estimated that 1.6 million people died of lung cancer in 2012 
(Ferlay et al., 2014).  Phase I clinical trials have shown that antibody mediated blockade of 
either PD-L1 or PD-1 can lead to durable tumor regression in about 20% of patients with 
advanced non-small cell lung cancer (NSCLC) (Brahmer et al., 2012; Edward B Garon, 
2013, 2014; Ghandi, 2014; Suzanne L. Topalian et al., 2012).  The pre-clinical and clinical 
data outlined below indicate that histone deacetylase inhibitors (HDACi) may enhance the 
efficacy of immune checkpoint inhibition (Juergens et al., 2011; Kelly et al., 2005; Kelly et 
al., 2003; Ma et al., 2013; Schrump et al., 2008; Vansteenkiste et al., 2008; Wrangle, 2013; 
Wrangle et al., 2013). 
Pembrolizumab (MK3475; Keytruda) in Lung  Cancer. 
Many studies have evaluated the PD-1/PD-L1 inhibitors in the treatment of advanced stage 
NSCLC.  In summary, overall response rates were ~18% with indications that (1) responses 
were durable and (2) PD-L1 positivity played a role in response (Brahmer et al., 2012; S. L. 
Topalian et al., 2012).  Immune-related toxicities were seen with both compounds, including 
pneumonitis at a rate of 3% with the PD-1 inhibitor (Brahmer et al., 2012). Most of these 
adverse 
events 
improved 
with 
drug 
cessation 
and 
treatment 
with 
glucorticocorticoids/endocrine therapy replacement where appropriate.  
In October 2013 and April 2014, respectively, Dr. Garon et al. and Dr. Leena Gandhi et al. 
presented the results of a phase I study of pembrolizumab (PD-1 inhibitor) in patients with 
advanced stage NSCLC refractory to 2 lines of prior treatment (Edward B Garon, 2013; 
Ghandi, 2014).  Thirty-eight patients were enrolled. The overall objective response rate was 
24% using investigator-assessed immune-related response criteria (irRC). Six of 9 (67%, 
95% CI 30-93%) patients with PD-L1 high tumors responded to therapy versus 0/22 (0%, 
95% CI 0-15%) patients with PD-L1 low tumors.  The most common drug-related adverse 

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events were rash, pruritus, and fatigue (16% each), and diarrhea (13%).  The only grade 3/4 
event was one patient who developed grade 3 pulmonary edema. There were no drug-
related deaths. 
In June 2014, Dr. Garon et al. presented preliminary results from KENOTE-001, a phase I 
study that randomized 217 patients with known PD-L1 status to pembrolizumab 10mg/kg 
every 2 weeks (Q2W) and pembrolizumab 10mg/kg every 3 weeks (Q3W) (Edward B 
Garon, 2014).  The overall response rate (ORR) in all patients was 18% (95% CI 13-24%) 
by irRC and 20% (95% CI 15-26%) by RECIST v1.1.  Patients with PD-L1 expressing 
tumors had ORR of 19% (95% CI 14-26%) by irRC and 23% (16-30%) by RECIST.  Patients 
with PD-L1 negative tumors had ORR of 13% (95% CI 4-27%) by irRC and 9% (2-23%) by 
RECIST.  At the interim analysis, there was no statistical difference in response rates in the 
different dosage groups.  The most common drug–related adverse events included fatigue 
(13%), decreased appetite (6.5%), arthralgia (6.1%), pruritis (5.4%), and pyrexia (3.6%) and 
most of these were grade 1/2.  Six percent of patients had grade 3/4 drug-related adverse 
events.  Four patients (2 patients in each schedule) developed grade 3/4 pneumonitis.   
Updated results of KEYNOTE-001 were recently published by Garon et al. and showed that 
the objective response rate among all patients was 19.4% (95% CI, 16.0-23.2) and the 
median duration of response was 12.5 months (range, 1.0-23.3), median PFS 3.7 months 
(95%CI, 2.9-4.1), and OS 12.0 months (95% CI, 9.3-14.7)(E. B. Garon et al., 2015).  The 
response rate in patients with at least 50% of tumor cells staining positive for PD-L1 was 
45.2% (95% CI, 33.5-57.3), median PFS 6.3 months (95% CI, 2.9-12.5), and median OS 
was not reached (95% CI, 13.7 to not reached).  PD-L1 expression in at least 50% of tumor 
cells correlated with better efficacy of pembrolizumab; however, it is important to note that 
16.5% (95% CI, 9.9-25.1) of patients with 1-49% PD-L1 staining responded and 10.7% 
(95% CI, 2.3-28.2%) of patients with <1% PD-L1 staining also responded. Of the 42 patients 
treated in the first-line setting, those with a TPS of 1-49%, 5/26 (19.2%) achieved an ORR 
while in the TPS ≥ 50% group, 8/16 (50%) achieved and objective response. 
Pembrolizumab was FDA approved in 2016 for first-line NSCLC PD-L1 ≥50 %.  
The phase 1/2 KEYNOTE 021 study comparing pembrolizumab plus chemotherapy to 
pembrolizumab alone was recently presented at ESMO 2016. It demonstrated an 
improvement in OS and PFS of the triplet compared to the doublet (Langer et al, ESMO 
2016). Based on these results carboplatin, pemetrexed plus pembrolizumab was submitted 
to the FDA as a regimen for first line, Non-squamous NSCLC regardless of PDL1 status. . 
Vorinostat in Lung Cancer. 
Suberoylanilide hydroxamic acid (SAHA, vorinostat) is an orally active, small molecule 
inhibitor of histone deacetylase (HDACi).  Clinical trials have shown that daily oral vorinostat 
is safe and tolerable and has a broad range of clinical activity in advanced solid tumors.   
Vansteenkiste et al. conducted a phase II trial of oral vorinostat in 16 patients with breast 
cancer (3 patients), NSCLC (10 patients), and colorectal cancer (3 patients).  Patients were 
treated with oral vorinostat 200mg BID, 300mg BID, or 400mg BID for 14 days on, 7 days off 
on a 21-day cycle.  Dose-limiting toxicities occurred in a total of 6 patients at both the 300mg 
BID and 400mg BID doses and included weight loss, asthenia, thrombocytopenia, nausea, 
vomiting, and anorexia.  Grade 3/4 toxicities included thrombocytopenia (50%), anemia 
(12%), asthenia (12%), nausea (12%), and anorexia (6%).  No dose limiting toxicities 

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occurred at the 200mg BID dose level.  Although treatment duration was short and TTP was 
33.5 days, 6/10 patients with NSCLC had a best response of stable disease by RECIST 
(Vansteenkiste et al., 2008).  Kelly et al. conducted a phase I study that enrolled 50 patients 
with solid tumors and 23 patients with hematologic malignancies.  The maximum tolerated 
dose was vorinostat 400mg daily or 200mg bid for continuous daily dosing and 300mg bid 
for 3 of 7 consecutive days.  In addition to the dose-limiting toxicities outlined in the prior 
trial, one patient had elevation of liver enzymes.  Only two patients with lung cancer were 
enrolled in that study; there were two patients with partial responses (laryngeal cancer and 
mesothelioma) (Kelly et al., 2005). Ma et al. studied vorinostat in a preclinical model with a 
window of opportunity trial in 15 patients with early-stage lung and esophageal cancers (Ma 
et al., 2013).  Vorinostat 400mg daily was given for 2-9 days and patients had pre-therapy 
and post-therapy biopsies of target lesions.  The study included 10 evaluable patients (8 
with lung adenocarcinoma, one with lung squamous cell cancer, and one with esophageal 
adenocarcinoma).  Eight of 9 lung cancer post-treatment biopsies exhibited either acute or 
chronic inflammation or necrosis when compared to pre-treatment biopsies.  Additionally, 
there was evidence of CD8 positive tumor infiltrating lymphocytes in the post-treatment 
tissue, supporting the theory that vorinostat acts as a biologic effector of tumor 
immunogenicity.  
Vorinostat has also been safely combined with chemotherapy.  For example, Ramalingam et 
al. combined vorinostat with carboplatin/paclitaxel in 28 patients with advanced 
malignancies including 19 patients with NSCLC (Ramalingam et al., 2007).  The maximum 
tolerated doses of vorinostat were 400mg daily for 14 of 21 days or 300mg bid for 7 of 21 
days.  Ten patients with NSCLC had partial responses and 4 had stable disease. 
These data show that the toxicities of vorinostat and pembrolizumab do not have substantial 
overlap.  Cytopenias occur in relation to vorinostat.  Low incidences of anorexia and nausea 
occur with both medications. 
HDAC inhibitors and PD-1 blockade– Preclinical experience. 
Previous studies have demonstrated that increased tumor expression of T cell chemokines, 
such as CCL5 and CXCL10, is associated with a better response to immunotherapy. 
Furthermore, expression of T cell chemokines is strongly and positively associated with 
increased T cell infiltration and improved patient survival (Beg, Khan, & Antonia, 2013; Ji et 
al., 2012; Ulloa-Montoya et al., 2013). Therefore, enhancement of expression of T cell 
chemokines may augment response to PD-1 blockade immunotherapy. Recent pre-clinical 
work in the laboratory of Amer Beg, Ph.D., at the Moffitt Cancer Center showed that HDACi 
emerged as the only class of agents in a 97-drug screen of FDA-approved oncology agents 
capable of inducing expression of multiple T cell chemokines, including CCL5, CXCL9, and 
CXCL10. The ability to induce T cell chemokines was evident with several HDACi, including 
romidepsin and vorinostat (Figure 2), and in multiple mouse and human lung cancer cell 
lines and primary tumor specimens (data not shown). HDACi’s ability to induce T cell 
chemokine expression was dependent on both JAK-STAT and NF-kB pathways. We used 
the HDACi romidepsin to study in vivo effects on lung tumor growth. HDACi treatment of 
mice bearing LKR tumors did not substantially cause tumor shrinkage but significantly 
reduced growth (p<0.0001; final tumor volume) (Figure 3).  Importantly, this effect of HDACi 
was completely T cell dependent (Figure 3). LKR tumor cells had low cell surface expression 
of PD-LI but which was substantially increased by IFN-g (not shown). PD-1 blockade with 
mAb reduced tumor growth but rarely induced rejection (Figure 3, 4).  However, when PD-1 

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blockade was combined with HDACi, 9 out of 11 
mice demonstrated complete tumor rejection 
(Figures 3 and 4). Importantly, HDACi anti-
tumor 
response 
correlated 
with 
T 
cell 
chemokine induction in tumors and greater 
presence of tumor-infiltrating lymphocytes (TILs). We next used a mouse tumor model 
(344SQ) that was resistant to anti-PD-1 treatment. Importantly, PD-1 blockade combined 
with HDACi significantly reduced growth of these tumors compared to untreated (p=0.0003), 
anti-PD-1 alone (p=0.01), or HDACi (p=0.004) alone treated mice. These results indicate 
that HDACi not only enhanced anti-tumor response against PD-1 blockade sensitive tumors 
(LKR), but also induced response against PD-1 blockade resistant tumors (344SQ). While 
in vivo pre-clinical data were generated with the HDACi romidepsin, based on virtually 
identical in vitro effects of different HDACi, we believe multiple HDACi are likely to have 
similar activity in vivo.   
HDAC inhibitors and PD-1 blockade: Clinical 
experience. 
In a phase I/II trial of 5-azacitadine in 
combination with entinostat in 19 patients with 
advanced NSCLC, one patient had a complete 
Figure 2: CXCL10 mRNA expression 
was determined in the human lung 
cancer 
cell 
line 
A549 
following 
treatment 
with 
30nM 
romidepsin, 
500nM 
MS275, 1μM 
MGCD0103, 
100nM LBH-589, and 10μM vorinostat 
for 24h. 
Figure 4: Combined results from 2-3 
independent experiments were used to 
determine significance of reject or no 
reject outcomes by Fisher Exact Test. 
The 
different 
treatment 
groups 
are 
indicated 
(LKR 
UT, 
n=20; 
LKR 
Romidepsin, n=21; LKR anti-PD1, n=13; 
LKR Romidepsin and anti-PD-1, n=11) 
and p values were determined compared 
to the untreated group; LKR Romidepsin: 
p=0.4878; LKR anti-PD-1: p=0.3939; LKR 
Romidepsin and anti-PD-1: p<0.0001. 
Figure 3: 129 mice were inoculated s.c. 
with 106 LKR, after which they were 
treated with 2mg/kg romidepsin on days 
14,16,18, with or without 300μg/mouse 
anti-PD-1 antibody on days 15,17,19 as 
indicated. Tumor growth over indicated 
time periods is shown.  Each line 
represents a single mouse. 

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response and another had a partial response.  Four patients had partial responses after 
subsequent therapy and one of those patients was treated with anti-PD-1 (Juergens et al., 
2011).  In a phase I study, 5 patients were treated with a combination of 5-azacitadine and 
entinostat prior to being treated with anti-PD-1 or anti-PD-L1 therapy. Three patients had 
partial responses and two had stable disease by RECIST criteria (Wrangle, 2013).  These 
data necessitate rationally designed clinical trials utilizing concurrent HDACi and immune 
therapy 
with 
engrained 
biomarker 
analysis.  
 
PD-L1 as a biomarker. 
Tumor PD-L1 expression by immunohistochemistry may enrich for response to anti-PD-1 
therapy; however, PD-L1 negative tumors also respond to anti-PD-1 therapy (Edward B 
Garon, 2014; Wolchok et al., 2013).  Interferon-gamma induces PD-L1 expression in tumor 
cells, and PD-L1 at the tumor cell surface co-localizes with TILs (Taube et al., 2012).  In 
patients with metastatic melanoma, expression of PD-L1 also predicts for longer overall 
survival (Taube et al., 2012).  The molecular underpinnings of PD-L1 expression on tumor 
cells are poorly understood and would likely provide insight into mechanisms of anti-PD-1 
therapy and potential predictive biomarkers.  Apart from PD-L1 status, more sensitive 
biomarkers are needed both to predict response and also to shed insight into the 
mechanism of anti-PD-1 resistance. As outlined below, a more robust assessment of 
immunotherapy-permissive tumor microenvironment may better predict response to anti-PD-
1 therapy than PD-L1 expression. 
An NF-kB gene expression signature is associated with an immune-active tumor 
microenvironment. 
The presence of T cells in tumors is associated with immune surveillance and improved 
patient survival. We recently investigated whether in addition to known pro-tumor functions, 
NF-kB activity in cancer cells is also associated with T cell-mediated anti-tumor responses 
(Hopewell et al., 2013). We found that, in tumors rendered immunogenic by model antigen 
expression or following administration of anti-tumor vaccines, high NF-kB activity leads to 
tumor rejection and/or growth suppression. NF-kB regulated T cell chemokines played a key 
role in lung tumor rejection in mice. To investigate NF-kB function in human lung tumors, we 
generated a novel gene expression signature to determine NF-kB activity in lung cancer 
cells (Hopewell et al., 2013). Importantly, overall lung tumor NF-kB activity was strongly 
associated with T cell infiltration but not with cancer cell proliferation. These results therefore 
indicate that a predominant effect of NF-kB activity in both murine and human lung cancer is 
to mediate immune surveillance and promote anti-tumor T cell responses (Hopewell et al., 
2013).  
While there are few, if any, reliable biomarkers available to predict the response to 
immunotherapy, many studies suggest that an “immune-active microenvironment” before 
therapy is associated with response (Ji et al., 2012; Ulloa-Montoya et al., 2013).  Based on 
our findings, we believe that high NF-kB activity in tumors can predict the presence of an 
immune-active microenvironment permissive to anti-PD-1 immunotherapy. Using the 
NanoString platform (see below), we will determine association between the NF-kB 
signature and response to PD-1 blockade alone and in combination with vorinostat.   
Nanostring Technology 

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Whereas microarrays require higher quality RNA that is not easily obtained from formalin-
fixed paraffin-embedded tissue (FFPET), the NanoString nCounter allows for high yield and 
efficient collection of gene expression data from FFPET without the need for a nucleotide 
amplification step (Geiss et al., 2008; Ullal et al., 2014).  Recently, a 20-gene expression 
profile called Lymph2Cx was used to accurately identify cell-of-origin categories in diffuse 
large B-cell lymphoma (DLBCL) using NanoString on FFPET (Scott et al., 2014). Another 
NanoString-based approach is the PAM-50 risk of recurrence score (proSigna), which is an 
FDA-approved prognostic tool that helps clinicians and patients prognosticate the 10-year 
risk of distant recurrence in early breast cancer (Dowsett et al., 2013; Gnant et al., 2014).  
The proSigna test can be performed within 72 hours at local qualified laboratories (package 
insert, http://prosigna.com/downloads/ ). Nanostring technology is therefore a clinically 
robust platform for molecular correlative studies. Importantly, NanoString allows 
simultaneous detection of expression of up to 800 genes. We will use NanoString to 
determine expression of key gene expression signatures and additional genes associated 
with an immune-active tumor microenvironment. Depending on biopsy tissue availability, we 
will perform RNA-sequencing analysis to answer many of the same questions discussed 
above in NanoString studies. The experiments will be run on the nCounter in the Moffitt 
Cancer Center Molecular Genomics Core facility.  
Summary 
The pre-clinical data from Amer Beg’s laboratory here at Moffitt, in addition to the clinical 
data summarized above, provide sound rationale for a clinical trial evaluating the 
combination of HDAC inhibition with PD-1 inhibitors in patients with NSCLC and the 
assessment of potential of predictive biomarkers that go beyond PD-L1 status in tumor 
tissue.  This will open the opportunity to improve the outcomes of patients with a terminal 
cancer.  
 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors.  All three dose levels were well tolerated and 
no dose-limiting toxicities were observed.  This first in human study of pembrolizumab 
showed evidence of target engagement and objective evidence of tumor size reduction at all 
dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  
10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule utilized 
in Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent data from 
other clinical studies within the pembrolizumab program has shown that a lower dose of 
pembrolizumab and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 
days).  This early PK and pharmacodynamic data provides scientific rationale for testing a 
Q2W and Q3W dosing schedule.  

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A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  Pembrolizumab has been found to have a wide 
therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab in the melanoma indication. The exposure margins are based on the notion 
of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen 
of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population  PK evaluation 
revealed that there was no significant impact of tumor burden on exposure. In addition, 
exposure was similar between the NSCLC and melanoma indications. Therefore, there are 
no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the 
assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab showing 
that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain 
individual patient exposures in the exposure range established in melanoma as associated 
with maximal efficacy response and 3) will maintain individual patients exposure in the 
exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
Thus, the phase I dose escalation will include a fixed dose of Pembrolizumab 200mg IV 
every 3 weeks and escalating doses of vorinostat (Table 1) to determine the MTD to be 
used in the expansion group and the randomized phase II portion of the trial.  Once a MTD 
is determined, patients can start on the phase Ib expansion and phase II portions of the trial.  
Cycle 1, day 1 will start with Pembrolizumab concurrent with continuous daily oral therapy 
with 
vorinostat. 
 
 
 

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Table 1: Vorinostat dose levels in phase I dose 
escalation phase. 
Dose Level 
Vorinostat Dose 
Pembrolizumab Dose 
-1 
100mg PO Daily 
200mg IV Q3 weeks 
1 
200mg PO Daily 
200mg IV Q3 weeks 
2 
400mg PO Daily 
200mg IV Q3 weeks 
 
4.2.3 Rationale for Endpoints 
Safety, tolerability, response rate, disease control rate, progression-free survival, duration of 
response, and overall survival will be interrogated as feasibility and efficacy endpoints. 
4.2.3.1 Efficacy Endpoints 
In addition to a baseline scan, confirmatory scans will be obtained 4-6 weeks following initial 
documentation of objective response. Response and progression will be evaluated in this 
study using the new international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1)(Eisenhauer et al., 2009).  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used (Schwartz et al., 2009).  
Patients who are found to have stable disease (SD), partial response (PR), or complete 
response (CR) will continue on study until evidence of disease progression, intolerance, or 
withdrawal from study. Response rate, overall survival, and progression-free survival will be 
determined. Subjects with progressive disease by RECIST 1.1 but without rapid clinical 
deterioration may continue to be treated at the discretion of the investigator. 
The efficacy analysis will be based on the treated Population which includes all subjects 
who receive any dose of either investigational product. The following efficacy endpoints 
will be analyzed. 
• 
Objective response is defined as confirmed CR or confirmed PR based on modified 
RECIST guidelines version 1.1. The ORR will be estimated by calculating the proportion 
of subjects who achieve OR; the 80% CI and 95% CI for the OR rate will be estimated 
using the exact binomial distribution. 
• 
Disease control is defined as CR, PR, or SD based on RECIST guidelines version 
1.1 with modifications. The disease control rate (DCR) will be estimated by the 
proportion of subjects who achieve DC, and its 80% CI and 95% CI will be estimated 
using the exact binomial distribution. 

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• 
Progression-free survival will be measured from the start of treatment with 
pembrolizumab and vorinostat until the documentation of disease progression or death 
due to any cause, whichever occurs first. For subjects who are alive and progression-
free at the time of data cut-off for analysis, PFS will be censored at the last tumor 
assessment date. The Kaplan-Meier method (Kaplan and Meier, 1958) will be used to 
estimate the PFS curve and the PFS rate at time points of interest. 
• 
Duration of response is defined as the duration from the first documentation of OR 
to the first documented disease progression or death due to any cause, whichever 
occurs first. For subjects who are alive and progression-free at the time of the data cut-
off for the analysis, DoR will be censored at the last tumor assessment date. The DoR 
will only be evaluated for the subgroup of subjects with an OR and will be calculated 
using the Kaplan-Meier method. 
• 
Overall survival will be determined as the time from the start of treatment with 
pembrolizumab and vorinostat until death due to any cause. For subjects who are alive at 
the time of data cut-off, OS will be censored on the last date when subjects are known to be 
alive. The Kaplan-Meier method will be used to estimate the OS curve and the OS rate at 
time points of interest. 
4.2.3.2 Disease Parameters 
• 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-nodal 
lesions and short axis for nodal lesions) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). Note:  Tumor lesions that 
are situated in a previously irradiated area might or might not be considered measurable. 
If the investigator thinks it appropriate to include them, only lesions that have clearly 
shown disease progression since prior irradiation will be considered or allowed. 
• 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
• 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable. Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. “Cystic lesions” thought to 
represent cystic metastases can be considered as measurable lesions, if they meet the 
definition of measurability described above. However, if non-cystic lesions are present in 
the same patient, these are preferred for selection as target lesions. 
• 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on 
the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does 

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

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4.2.5 Response Criteria 
4.2.5.1 Evaluation of Target Lesions 
 
• 
Complete Response (CR): 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have reduction 
in short axis to <10 mm. 
• 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum diameters. 
• 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progressions). 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
4.2.5.2 Evaluation of Non-Target Lesions 
• 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis). Note:  If tumor markers are initially 
above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
• 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
• 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion increase.     
• 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and 
the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator). 
 
4.2.5.3 Evaluation of Best Overall Response 
 

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The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
Table 2. For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented 
at 
least 
once 
>4 
wks. 
from 
baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**Only for non-randomized trials with response as primary endpoint. 
***In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
Table 3. For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions 

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can be measured is not advised 
 
4.2.6 Progression-Free Survival 
Progression free survival (PFS) is defined as the time from start of treatment (Cycle 1, Day 
1) until the date of objective disease progression or death (by any cause in the absence of 
progression) regardless of whether the patient withdraws from therapy or receives another 
anti-cancer therapy before progression. Clinical deterioration in the absence of radiographic 
evidence is not considered progression for purposes of determining PFS. Subjects who die 
without a reported prior progression will be considered to have progressed on the date of 
their death. Subjects who did not progress or die will be censored on the date of their last 
evaluable tumor assessment. Subjects who did not have any on study tumor assessments 
and did not die will be censored on the date they were first treated. Subjects who started 
any palliative local therapy or subsequent anti-cancer therapy without a prior reported 
progression will be censored at the last evaluable tumor assessment prior to initiation of the 
palliative local therapy or subsequent anti-cancer therapy, whichever procedure occurred 
first.  
The PFS time will always be derived based on scan/assessment dates not visit dates. 
 
RECIST version 1.1 assessments/scans contributing towards a particular visit may be 
performed on different dates.  The following rules will be applied: 
• 
Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression 
• 
When censoring a patient for PFS the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
4.2.7 Duration of Response 
• 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented. 
If a patient does not progress following a response, 
then their duration of response will use the PFS censoring time. 
• 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 

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4.2.8 Objective Response Rate 
ORR is defined as the number of subjects whose best confirmed objective response (BOR) 
is a CR or PR, divided by the number of subjects who received at least one dose. BOR is 
defined as the best response designation, as determined by the RECIST v1.1, recorded 
between baseline and the date of objectively documented progression per RECIST 1.1 or 
the date of initiation of palliative local therapy or the date of initiation of subsequent 
anticancer therapy, whichever occurs first. For subjects without documented progression or 
palliative local therapy or subsequent anti-cancer therapy, all available response 
designations will contribute to the BOR determination. The final analysis of ORR will take 
place at the time of PFS. 
4.2.9 Overall Survival 
OS is defined as the duration of time from the date for first treatment (Cycle 1 Day 1) to the 
date of death. A subject who has not died will be censored at last known date alive. 
4.2.10 Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements can be made at 
an assessment, the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
have changed the assigned time-point response. 
4.2.11  
Treatment Beyond Progression 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.   
Subjects will be permitted to continue treatment beyond initial RECIST v1.1 defined PD as 
long as they meet the following criteria: 
• 
Investigator-assessed clinical benefit and subject is tolerating study drug. 
• 
No evidence of significant clinical decline. 
• Subjects will be re-consented with an informed consent document describing 
any reasonably foreseeable risks or discomforts and other alternative 
treatment options. A follow-up scan should be performed within six 6 weeks 
+/- 7 days of original PD to determine whether there has been a decrease in 
the tumor size, or continued PD. The assessment of clinical benefit should be 
balanced by clinical judgment as to whether the subject is clinically 
deteriorating and unlikely to receive any benefit from continued treatment with 
Pembrolziumab ( + vorinostat for Arm B). If the investigator feels that the 
subject continues to achieve clinical benefit by continuing treatment, the 
subject should remain on the trial. The decision to continue treatment should 
be discussed with sponsor documented in the study records. **For the 
subjects who continue study therapy beyond progression, further progression 
is defined as an additional 20% increase in tumor burden from time of initial 

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PD. This includes an increase in all target lesions and any new measurable 
lesions. Study therapy should be discontinued if further progression is 
documented. New lesions are considered measureable at the time of initial 
progression if the longest diameter is at least 10mm (except for pathological 
lymph nodes which must have a short axis of at least 15 mm). Any new lesion 
considered non-measureable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest 
diameter increases to at least 10 mm (except for pathological lymph nodes 
which must have a short axis of at least 15 mm). The diameter(s) of any 
measurable new lesion(s) should be added to the target lesion sum of longest 
diameters in determining whether the criteria for further progression has been 
met. 
4.2.12 Biomarker Research 
 
4.3 Biological sampling procedures 
4.3.1 Immunogenicity sampling and evaluation methods 
Those enrolled on the Phase I (where Tissue allows) or the Phase II randomized study will 
be required to undergo a core biopsy of a target or nontarget lesion prior to starting 
treatment and between cycle 1 days 15-21.   
The pretreatment biopsy or archival sample needs to have occurred after the most recent 
line of therapy, and be either an FFPE sample or slide cut within 6 months of the assay for 
PD-L1 
Pharmacodynamic endpoints will then be assessed in the tumor tissue. We will determine 
whether tumor immunogenicity prior to treatment is associated with the response to 
pembrolizumab ± vorinostat, and whether vorinostat treatment leads to greater 
enhancement in immunogenicity after treatment. We broadly define tumor immunogenicity to 
include both T cell presence and the expression of immune response-promoting genes.  To 
this end, we will perform tumor biopsies prior to treatment and again at C1 Day15-21 after 
initiation of treatment (i.e. on-treatment).  NanoString assay will be used to determine 
expression of potentially important immune function genes, including a recently defined NF-
kB gene expression signature in lung cancer cells that is associated with greater T cell 
presence in human lung adenocarcinoma. An additional key goal is to determine association 
of pre- or on-treatment expression of other immune checkpoints genes (e.g. BTLA, LAG3, 
TIM3) with resistance to pembrolizumab ± vorinostat treatment. These important studies can 
provide a framework to assess how pembrolizumab ± vorinostat modulate the tumor 
microenvironment, characterize potential utility of biomarkers in response to treatment (e.g. 
NF-kB activity), and identify resistance mechanisms.  
 

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4.3.2 Biomarker/Pharmacodynamic sampling and evaluation 
methods 
Molecular studies. The following molecular test results including but not limited to ALK, 
EGFR, K-ras, ROS-1, PD-L1 status, RET, Met, PTEN, BRAF, PI3K and Her2 neu will be 
conducted when appropriate or collected when available in the medical record.  PD-L1 
status by immunohistochemistry and quantitation of tumor infiltrating lymphocytes will be 
determined on all biopsy specimens. 
PD-L1 expression will be measured in all fresh and archival biopsies using the IHC assay 
based on the anti-PD-L1 monoclonal antibody (most likely the Merck anti-PD-L1 clone 
22C3).  Positive staining with this assay is currently defined as tumor cell membrane 
staining at any intensity, analyzed with a cut-off value of ≥ 1% in a minimum number of 100 
evaluable cells. Baseline tumor PD-L1 expression will be evaluated for potential association 
with ORR, PFS, and overall survival (OS). 
Further, exploratory correlative studies may be completed based on the additional data 
obtained including utilization of an advanced DNA platform or additional immune based 
biomarker analyses. These results would also be correlated with patient outcomes and 
potentially help to address some of the critical barriers for effective personalized treatment. 
Histone acetylation studies on PBMC’s. Previous studies have indicated that HDAC 
inhibitors lead to the acetylation of many molecules including of histone 3 and 4. Biomarker 
assessments will be made on blood for assessment of pre and post-treatment effects on 
acetylated histone 3 (H3) and histone 4 (H4), total H3 and H4.  Correlative analysis will be 
performed on the peripheral blood mononuclear cells (PBMC) of all the patients enrolled in 
the study.  This will include flow cytometry based assessment of presence of suppressive 
cell types such as myeloid-derived suppressor cells (MDSC) and Tregs. In addition, we will 
determine expression of activation and resistance markers in lymphocytic lineages, 
including T cells, by flow cytometry and gene expression studies. Plasma will also be 
collected to determine levels of key cytokines and chemokines.  The blood draws will take 
place pretreatment (either during screening or on C1D1) and during treatment (C1D15+/- 7 
days). Peripheral blood mononuclear cells will be isolated from patient blood collected prior 
to and after initiation of therapy to measure H3 and H4 histone acetylation by western blot 
analysis by Dr. Amer Beg’s lab as previously described Gray et al, CCR, 2014(Gray et al., 
2014). 
 
4.3.3 Eco-evolutionary modeling methods 
Toward secondary objective #3, the following steps will be taken: 
The initial step will use available clinical and correlative data to examine (in the context of 
estimated immune response to therapy) the changes in frequency of subpopulations within 
each lung cancer on biopsies taken prior to therapy, during therapy, and (where available) at 
the time of tumor progression. This will be used to parameterize models using (non-spatial) 
Ordinary Differential Equations of the evolutionary dynamics. 
In the second step, we will apply image analytic methods to the existing pathology slides.  
This will allow development of spatially-explicit mathematical models including Partial 

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Differential Equation and Agent-based methods to capture the ecological as well as 
evolutionary dynamics. 
A final step involves testing model predictions or exploring hypotheses developed through 
model simulations by performing additional studies on available samples, for example, 
obtaining new IHC stains on the pathology slides. 
4.3.4 Archival Tumor Samples and Fresh Tumor Biopsies 
4.3.4.1  Archival tumor samples and Fresh tumor biopsies 
Archived tissue will be collected from all patients enrolled on the study. For those enrolled 
on the phase I escalation portion without available archival tissue, fresh tumor specimens 
will be collected by image-guided biopsy with onsite pathologic confirmation by a trained 
cytotech or board certified cytopathologist. Approximately 125 μL of tumor sample is 
required at baseline for PDL1 testing and to evaluate potentially predictive biomarkers and 
complete other correlative studies. In addition, patients enrolled on the phase I dose 
escalation, Phase Ib expansion and randomized phase II portions of the trial will undergo 
serial biopsies. More specifically, those enrolled on the  phase I dose escalation, Phase Ib 
expansion and Phase II randomized study will be required to undergo a core biopsy of an 
accessible lesion prior to starting treatment (or collection of archival tissue from after the 
most recent line of therapy where available) and between cycle 1 day 15-21.   The biopsies 
will be performed under image guidance (including but not limited to CT or ultrasound-
guided core biopsies) as determined by the location of tumor and risks associated with each 
procedure. Fresh tumor biopsies, on-site evaluations for tissue quality will be performed by 
the cytotechnologist to ensure viable tissue and for collection of adequate tumor sample. 
Four to 6 core biopsy samples will be collected.  At a minimum, 2 will be placed in neutral-
buffered formalin and embedded in paraffin wax and two core needle samples will be snap 
frozen and stored in liquid nitrogen. The tumor collected through these methods will be 
analyzed to explore whether positive vs negative biomarkers could predict response and 
resistance to the treatment. Samples will be retained after the clinical study report has been 
finalized.  
4.3.4.2 Molecular Analyses 
These correlates will be analyzed using descriptive statistics to compare disease outcome in 
biomarker positive and negative subsets. In addition, univariate and multivariate analyses 
will be performed to see whether the markers described above (both as continuous or 
dichotomous variable) predict for disease outcome (i.e., disease control rate, response and 
PFS after appropriate adjustment for other prognostic variables). 
4.3.4.3 Withdrawal of informed consent for donated biological 
samples 
If a subject withdraws consent to the use of donated samples, the unused samples will be 
disposed of/destroyed, and the action documented.   
The Principal Investigator: 
• 
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 

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• 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed, the action documented and 
the signed document returned to the study site 
• 
Ensures that the subject is informed about the sample disposal. 
 
Molecular studies 
The following molecular test results including but not limited to ALK, EGFR, K-ras, ROS-1, 
PD-L1 status, RET, Met, PTEN, BRAF, PI3K and Her2-neu will be conducted when 
appropriate or collected when available in the medical record.  PD-L1 status by 
immunohistochemistry and quantitation of tumor infiltrating lymphocytes will be determined 
on all biopsy specimens. 
 
Pharmacodynamic studies 
NanoString Analysis. We will use a customized panel of ~100 genes (Custom Immune 
Panel) which will include genes in the NF-kB signature (30 genes with highest Principal 
Component Analysis (PCA) weight), resistance genes, T cell chemokines, T cell genes, HLA 
genes, co-stimulatory molecules and housekeeping genes (Table 4). Using this panel, we 
will separately evaluate expression by PCA of the NF-kB signature and a 12-gene T cell 
chemokine signature, which was also generated at Moffitt Cancer Center using bioinformatic 
gene expression analysis of 14,492 distinct solid tumors.   
A key component of NanoString analysis will be to define resistance mechanisms in patients 
who fail to respond to treatment and those who progress after initially responding. A major 
mechanism of resistance may be the presence of other “driver” immunosuppressive 
mechanisms within the tumor microenvironment. These may include additional immune 
checkpoints (BTLA, LAG3, TIM3, A2AR), suppressive immune cells (Treg, TAMs), 
immunosuppressive enzymes (IDO, arginase), and/or immunosuppressive cytokines (TGFB, 
IL-10). NanoString studies will help determine whether pre-treatment and/or on-treatment 
expression of genes encoding for these additional immunosuppressive pathway 
components are associated with resistance to treatment. Depending on availability of biopsy 
samples, we will further determine protein expression of potentially important 
immunosuppressive molecules by IHC (see below). In patients who initially respond to 
therapy, there will be an option to also obtain a third biopsy upon progression of disease. 
Defining presence or emergence of resistance markers in these patients may therefore 
provide new insights into possible therapeutic strategies for this cohort of patients. 
RNA sequencing. RNA sequencing (RNA-seq) can be used for exome wide analysis of 
gene expression. Depending on biopsy tissue availability, we will perform RNA-seq analysis 
to answer many of the same questions discussed above in NanoString studies. In addition, 
RNA-seq can help define new genes that may be associated with response and synergy 
between pembrolizumab and vorinostat as well as genes whose expression is changed as a 
result of treatment. If sufficient fresh frozen tissue is available, we will perform RNA-seq 
instead of NanoString studies.  
 
IHC studies. Biopsy slides (FFPE) will be utilized to determine presence of CD8+ TILs and 
CD33+ myeloid cells. We will assess association of both cell types in pre-treatment biopsies 

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with patient response. In addition, we will determine changes in presence of these cell types 
as a result of treatment. We will also separately assess presence of these cell types in tumor 
beds and tumor stroma as they may differentially associate with response. Finally, if 
sufficient tissue is available, we will expand our studies to Vectra panels which rely on 
immunofluorescence to detect presence of multiple cell types. We will utilize panels which 
will include, but not limited to, FoxP3 (Treg marker), CK, CD3, CD4, CD8, Granzyme-B (to 
determine cytolytic activity of T cells), Ki67 (to determine T cell proliferation, which is 
associated with ongoing anti-tumor activity).  
 
Histone acetylation studies on PBMC’s and tumor biopsies. 
Previous studies have indicated that HDAC inhibitors lead to the acetylation many 
molecules including of histone 3 and 4. Biomarker assessments will be made on blood and 
tumor tissue for assessment of pre and post-treatment effects on but not limited to 
acetylated histone 3 (H3) and histone 4 (H4), total H3 and H4, and quantitative HDAC 
assay.  Assessments will be made by Western Blot.  Correlative analysis will be performed 
on the peripheral blood mononuclear cells (PBMC) of all the patients enrolled in the study. 
The blood draws will take place pretreatment (either during screening or on C1D1), during 
treatment (C1D15) and at progression. We will isolate peripheral blood mononuclear cells 
from patient blood collected prior to and after initiation of therapy to measure H3 and H4 
histone acetylation by western blot analysis. 
 
Shipping information for PBMC and Tissue samples: 
Moffitt Cancer Center 
Attn: Tissue Core ACQ 
12902 Magnolia Drive.  
MCC 3040 / Tissue Core 
Tampa, FL 33612 
813-745-57763 
 
 
 
Table 4. Genes in the custom immune panel. 
 
NF-kB 
Signature 
 
 
GBP1 
PSMB9 
IRF1 
TAP1 
TNFAIP3 
CCL5 
PSMB8 
IL32 
SH2B3 
NFKBIE 
T 
cell 
chemokines 
 
CCL2 
CCL3 
CCL4 
CCL5 
CCL8 
CCL18 
CCL21 
CXCL9 
CXCL10 
CXCL11 
CXCL12 
T 
cell 
marker 
genes 
CD8A 
CD4 
CD3E 
CD3G 
TRAC 
TRBC1 
 
DC/APC 
markers 
CD80 
CD83 
CD86 
HLA 
genes 
 
HLA-A 
HLA-B 
HLA-C 
HLA-
DMA 
HLA-
DMB 
HLA-
DOB 
HLA-
DPA1 
HLA-
DPB1 

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OPTN 
BIRC3 
PSME2 
ARNTL2 
GFPT2 
ITGA5 
HLA-B 
ITGAM 
TAP2 
IFIH1 
CYLD 
PLAUR 
CCL2 
MMP9 
LAMC2 
CTSS 
LXN 
RELB 
G0S2 
PARP12 
 
Resistance 
genes 
 
BTLA4 
LAG3 
HAVCR2 
ADORA2A 
IDO1 
ARG1 
TGFB1 
IL10 
FOXP3 
CTLA4 
PDCD1 
CD274 
PDCD1LG2 
 
 
 
 
Co-stimulation 
genes 
CD40 
CD40LG 
CD27 
CD28 
ICOS 
TNFRSF9 
FAS 
FASLG 
 
HLA-
DQA1 
HLA-
DQB1 
HLA-
DRA 
HLA-
DRB3 
HLA-
DRB4 
HLA-E 
HLA-G 
 
 
 
 
 
 
 
 
 
 
5.0 METHODOLOGY 
5.1 Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
1. Histologic or cytologic diagnosis of Stage IV NSCLC  
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1.   
4. Have archival tissue where available. Those patients enrolled on the phase 1 
escalation trial where archival tissue is not available will undergo a fresh biopsy 
where clinically feasible after discussion with the sponsor. 

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5. In addition, patients enrolled on the phase 1 dose escalation, phase 1 expansion or 
Phase II trial must be willing and able to provide tissue from a newly obtained core or 
excisional biopsy of a tumor lesion.  Newly-obtained is defined as a specimen 
obtained up to 3 months prior to initiation of treatment on Day 1, and must be 
obtained after most recent treatment.  Subjects for whom newly-obtained samples 
cannot be provided (e.g. inaccessible or subject safety concern) may submit an 
archived specimen only upon agreement from the Sponsor.) 
6. Randomized phase II: Tumor proportional score of PD-L1 ≥1%. 
7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
8. Demonstrate adequate organ function as defined in Table 5 all screening labs 
should be performed within 10 days of treatment initiation. 
9. Have a histologic or cytologic diagnosis of Stage IV NSCLC. 
10. Phase I/IB (Pre-treated): Have progression from at least one prior line of therapy. 
Maintenance therapy following platinum doublet-based chemotherapy is not 
considered as a separate regimen of therapy. Subjects who received platinum-
containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for 
locally advanced disease, and developed recurrent (local or metastatic) disease 
within 6 months of completing therapy are eligible for these arms. Subjects with 
recurrent disease ≥ 6 months after completing a platinum-containing adjuvant, 
neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, 
who also subsequently progressed during or after a systemic regimen given to treat 
the recurrence, must have received another treatment in the first-line metastatic 
setting. 
11. Randomized Phase II: Be treatment naïve in the stage IV setting, with the exception 
of patients whose tumors harbor an activating mutation (including but not limited to 
EGFR, ALK, ROS1) and were previously treated with targeted therapy. Subjects who 
received platinum-containing adjuvant, neoadjuvant or definitive chemoradiation 
therapy given for locally advanced disease, and developed recurrent (local or 
metastatic) disease < 6 months of completing therapy are ineligible for this arm. 
Subjects with recurrent disease ≥ 6 months after completing a platinum-containing 
adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally 
advanced disease, who also subsequently progressed during or after a systemic 
regimen given to treat the recurrence, are eligible for this arm. 
12. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
13. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference 
Section 5.7.2).  Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year.  

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14. Male subjects should agree to use an adequate method of barrier contraception 
starting with the first dose of study therapy through 120 days after the last dose of 
study therapy. 
Table 5. Adequate Organ Function Laboratory/Test Values 
System 
Laboratory/Test Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels 
> 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
Cardiac 
 
Left ventricular ejection fraction (LVEF) ≥45% 
aCreatinine clearance should be calculated per institutional standard. 
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating in and receiving study therapy or has participated in a study 
of an investigational agent and received study therapy or used an investigational 
device within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at 
doses ≥ 10 mg prednisone or any other form of systemic immunosuppressive 
therapy within 7 days prior to the first dose of trial treatment. Subjects are permitted 
to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with 
minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief 
course (≤28 days) of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by contact allergen) is permitted. 
 

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3. Has a known history of TB Disease  (Mycobacterium tuberculosis) 
 
4. Hypersensitivity to pembrolizumab, vorinostat or any of its excipients 
 
5. Patients enrolled on the phase II randomized trial, who have had prior treatment with 
a PD1 or PDL1 inhibitor, anti-CTLA 4 antibody or any other antibody or drug that 
specifically targets immune checkpoint pathway (i.e. not “immune therapy naïve”).  
 
-Note: For those enrolled in the phase I dose escalation, prior use of a PD1 or PDL1, 
anti-CTLA4 antibody or any other antibody or drug that specifically targets immune 
checkpoint pathway is allowed.  For those enrolled in the phase IB, prior use of a 
PD1 or PDL1, anti-CTLA4 antibody or any other antibody or drug that specifically 
targets immune checkpoint pathway is required.  For all patients in all phases, prior 
use of a vaccine for treatment of cancer is allowed. 
 
6. Patients enrolled in the phase Ib expansion who have never previously been treated 
with a PD1 or PDL1 inhibitor, anti-CTLA 4 antibody or any other antibody or drug that 
specifically targets immune checkpoint pathway in the past (i.e. not “pre-treated”) 
 
7. Patients who have received thoracic radiation >30Gy within six months of the first 
dose of pembrolizumab. 
 
8. Patients taking any HDACi other than vorinostat. 
9. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. 
10. Has had prior chemotherapy within 3 weeks, or targeted small molecule therapy or 
radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered 
agent.   
 
-Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study.  
-Note: Subjects with any grade alopecia are an exception to this criterion and may 
qualify for the study. 
11. If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.    
12. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy, or in situ cervical cancer. 
13. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 

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returned to baseline), have no evidence of new or enlarging brain metastases, and 
are not using steroids in doses greater than 10 mg of prednisone daily (or equivalent) 
for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
14. Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids in doses greater 
than 10 mg of prednisone daily (or equivalent) or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment. Subjects are permitted to enroll if they have vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger. 
15. Has an active infection requiring systemic therapy. 
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, that would substantially increase risk of 
incurring adverse events (AEs) from the study medications, that would interfere with 
the subject’s participation for the full duration of the trial, or is not in the best interest 
of the subject to participate, in the opinion of the treating investigator.   
17. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
21. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
22. Has a history of, or any evidence of activenon-infectious pneumonitis that required or 
requires steroids. 
23. Has evidence of interstitial lung disease 
24. Has a history of symptomatic (NYHA class II-IV) heart failure. 
 

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5.2 Trial Treatments 
The phase I dose escalation will include a fixed dose of Pembrolizumab 200mg IV every 3 
weeks and escalating doses of vorinostat (three dose levels) to determine the MTD to be 
used in the expansion group and the randomized phase II portion of the trial.  Once a MTD 
is determined, the phase Ib expansion and randomized phase two portions of the trial can 
begin accrual.  Cycle 1, day 1 will start with Pembrolizumab concurrent with continuous daily 
oral therapy with vorinostat. 
 
Table 6. Vorinostat dose levels in phase I dose escalation phase.  
Dose Level 
Vorinostat Dose, 
Route, Frequency 
Pembrolizumab Dose, 
Route, Frequency 
Use 
-1 
100mg PO Daily 
200mg IV Q3 weeks 
Experimental 
1 
200mg PO Daily 
200mg IV Q3 weeks 
Experimental 
2 
400mg PO Daily 
200mg IV Q3 weeks 
Experimental 
 
Trial treatment should begin within 3 days of randomization or as close as possible to the 
date on which treatment is allocated/assigned. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology.  These adverse events may occur shortly after the 
first dose or several months after the last dose of treatment. Pembrolizumab must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per Table 7 below. 
See Section 5.6.1 and Events of Clinical Interest Guidance Document for supportive care 
guidelines, including use of corticosteroids. 
 
 

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Table 7. Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 
diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-
4 hyperglycemia associated with 
evidence of beta cell failure.  
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidis
m  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the 
thyroid disorder is instituted 
Therapy with pembrolizumab can be continued while 
treatment for the thyroid disorder is instituted. 
Infusion 
Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure 
or Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicity2 
3 or 
Severe3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal 
to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose.   
3 Grade 3 drug-related amylase or lipase abnormality that is not associated with symptoms or clinical manifestations of pancreatitis 

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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
does not require dose delay. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects 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. 
5.2.2 Timing of Dose Administration 
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).  There is a ±7 day treatment window for Day 1 of each cycle. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
Vorinostat should be taken with food, at regular intervals regardless of pembrolizumab 
infusion time.  On days the pt receives pembrolizumab, the vorinostat should be taken prior 
to 
the 
pembrolizumab 
infusion.  
 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 Randomization or Treatment Allocation 
Patients who are enrolled on the phase II portion of the study and successfully complete the 
screening exams for initial registration will be randomized into one of two study arms. The 
study Biostatistician will generate a Flow Chart for Randomization. This Flow Chart will be 
held in confidence by the Biostatistician and the Clinical Trials Coordinator.  The individual 
randomization assignment will be released by the Clinical Trials Coordinator only after the 
patient signs the informed consent document and successfully completes the screening 
process.  
Treatment of patients on Arm A: Those patients randomized to Arm A will receive 
pembrolizumab alone. 

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Treatment of patients on Arm B: Those patients randomized to Arm B will receive 
pembrolizumab plus vorinostat. 
 
5.4 Stratification 
The patients will be stratified by histology and PD-L1 status, including the following three 
levels of PD-L1 membranous expression on tumor cells that have been scientifically 
justified: 1) Proportion Score (PS)1-49%, and PS≥50%. 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.5.1 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 in the source documentation 
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 source documentation. Only those 
concomitant medications which are considered immunosuppressive such as steroids will be 
recorded in the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs as defined in Section 7.2 and ECIs as per the ECI guidance document. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• 
Antineoplastic 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 to the brain may 
be allowed at the investigator’s discretion.   
• 
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, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology or to treat a comorbid 
condition as a standard of care (e.g. COPD exacerbation).  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
• 
HDAC inhibitors other than vorinostat. 
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. 
5.6 Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the ECI 
guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous corticosteroids as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids alone.   Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
• 
Pneumonitis:  

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o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
o A second episode of grade ≥ 2 pneumonitis mandates discontinuation of 
study therapy. 
 
 
• 
Diarrhea/Colitis:  
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).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer 
oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) 
or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• 
Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 

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taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
 
 
• 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
 
• 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
 
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  
 
• 
Management of Infusion Reactions: Signs and symptoms usually develop during 
or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
 
 

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Table 8 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 8. Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from further 
trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
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: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
 
 

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5.7 Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab 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. Male subjects should agree to 
use an adequate method of barrier contraception starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent that 
contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor and to Merck.  If there is any question that a 
subject will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 

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immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 Subject Withdrawal/Discontinuation Criteria 
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 7.1.4 – 
Other Procedures. 
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, please see Section 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, please 
see Section 7.1.2.7.1 
• 
Unacceptable adverse experiences as described in Section 5.2.1.2 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
Confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
Subject is lost to follow-up 
• 
Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. 
Subjects who stop pembrolizumab after 24 months may be eligible for up to one year 
of additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.7.3. 

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• 
Administrative reasons 
• 
A second episode of grade ≥ 2 pneumonitis mandates discontinuation of study 
therapy. 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the last dose of study drug, each 
subject will be followed for 30 days for adverse event monitoring (serious adverse events will 
be collected for 90 days after the end of treatment as described in Section 7.2.3.1).  
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. 
5.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of 
the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open.  Subjects will resume therapy at the same dose and schedule 
at the time of initial discontinuation.  Additional details are provided in Section 7.1.7.3. 
5.9 Subject Replacement Strategy 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 

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6.0 TRIAL FLOW CHART 
6.1 Study Flow Chart* 
Trial Period: 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
To be repeated beyond 
8 cycles 
Discon 
Safety 
Follow-
up 
Follow 
Up Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-27 to 
c1d1e 
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
At time of 
Discon 
30 days 
post last 
dose of 
study 
drug 
Every 8 
weeks 
post 
discon 
Every 
12 
weeks  
Screening Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vorinostat compliance review/Pill 
Diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Trial Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Survival Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Review Adverse Events 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Pregnancy Test – Urine or Serum 
b-HCG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 

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Trial Period: 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
To be repeated beyond 
8 cycles 
Discon 
Safety 
Follow-
up 
Follow 
Up Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-27 to 
c1d1e 
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
At time of 
Discon 
30 days 
post last 
dose of 
study 
drug 
Every 8 
weeks 
post 
discon 
Every 
12 
weeks  
PT/INR and aPTT 
X 
X 
(C1D15
-C1D21 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Comprehensive Serum Chemistry 
Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Magnesium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Echocardiogram g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging (CT 
Thorax/Abdomen) 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xd 
 
Brain MRI or Brain CT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Archival or Newly Obtained Tissue 
Collectiona,b 
X 
X 
(C1D15
-C1D21 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood 
Collectionc 
Xc 
Xc 
 
X 
 
X 
 
X 
 
X 
 
X 
 

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Trial Period: 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
To be repeated beyond 
8 cycles 
Discon 
Safety 
Follow-
up 
Follow 
Up Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-27 to 
c1d1e 
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
At time of 
Discon 
30 days 
post last 
dose of 
study 
drug 
Every 8 
weeks 
post 
discon 
Every 
12 
weeks  
*All clinic visits and tests (including labs, imaging studies and biopsies) will have a plus or minus 7 day window for completion. 
a All patients in the study are required to have a pre-treatment biopsy, where feasible, or archival tissue from after the most recent line 
of therapy, which will be tested for PD-L1 and nanostring analyses.   
b C1D15-21 biopsies will be done on patients in the phase I dose escalation, phase Ib and phase II parts of the study, where feasible. 
PD-L1 and Nanostring studies will be completed on all of these biopsy specimens. 
c Timepoints for the first two correlative study blood collection include first during Screening or on C1D1, and second on C1D15.  The 
remainder of the blood collections will occur with the reimaging scans. Histone acetylation studies will be run on serial PBMC 
draws in all patients (includes phase I dose escalation, phase Ib expansion and phase II).  The blood will be collected in five 10 
mL green top (sodium heparin) tubes for a total of about 50mL of whole blood. 
d Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up Phase and should 
be assessed every 8 weeks (56 ± 7 days) by radiologic imaging to monitor disease status.  After 1 year, the imaging time point will 
occur every 12 weeks (± 7 days).  
e The main study screening window will occur within 28 days prior to the first study treatment. Note additionally that screening 
laboratory blood and urine studies must be obtained within 10 days of C1D1, with the exception of pregnancy testing in applicable 
patients, which must be obtained within 72 hours of first treatment. 
f  Only serious adverse events will be collected during the screening window. 
g Echocardiogram will be performed at screening for baseline, and may be repeated if clinically indicated per the treating investigator. 
Echocardiogram should be performed within 30 days of treatment initiation. 

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7.0 TRIAL PROCEDURES 
7.1 Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor 
and/or Merck for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.  
The investigator is responsible for patient care and for obtaining consent by the patient.  
Written informed consent must be obtained prior to entry of any patient. The informed 
consent will adhere to IRB requirements, applicable laws and regulations and Sponsor 
requirements. 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   

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7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.2 Assignment of Screening Number 
Once a patient is enrolled in the study, he/she will be assigned a simple 3 digit number, with 
the first patient assigned to 001 and so on.  A separate spreadsheet with password 
protection will be maintained that contains the patient study number along with personally 
identifiable information.  Password protection will be maintained in order to keep patient 
information strictly confidential.  Upon signing the informed consent form, the patient will be 
assigned a subject number by the investigator or his/her designee. Once assigned to a 
patient, a subject number will not be reused. If the patient fails to be started on treatment for 
any reason, the reason will be entered on the Eligibility Tab in OnCore, and his/her 
demographic information will be entered on the Demography Tab in OnCore. All laboratory, 
radiologic, and pathologic data collected on trial participants will be assigned the unique 
treatment number and stored in the OnCore system database.  
 
7.1.3 Assignment of Randomization Number 
Patients who successfully complete the screening exams for initial registration will be 
randomized into one of two study arms. Randomization will be accomplished using the 
Moffitt Cancer Center web-based Subject Registration and Randomization System (SRAR). 
The SRAR program is accessed using an individual secure identification key that 
authenticates the user into the Moffitt network 

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 The study Biostatistician will generate a Flow Chart for Randomization. This Flow Chart will 
be held in confidence by the Biostatistician and the Clinical Trials Coordinator.  The 
individual randomization assignment will be released by the Clinical Trials Coordinator only 
after the patient signs the informed consent document and successfully completes the 
screening process.  
 
Treatment of patients on Arm A: Those patients randomized to Arm A will receive 
pembrolizumab alone. 
Treatment of patients on Arm B: Those patients randomized to Arm B will receive 
pembrolizumab plus vorinostat. 
7.1.3.1 Trial compliance (medication/diet/activity/other) 
The Principal Investigator and the Clinical Research Coordinator assigned to the case will 
be primarily responsible for maintaining all study related documents including the clinical 
research forms.  Oncore is the password protected, web-based electronic secure, database 
of record for all CRF entries and will be verified with source documentation. The review of 
medical records within the EMR will be done in a manner to assure that patient 
confidentiality is maintained.  Vorinostat compliance review will take place via a medication 
diary review as indicated in the study calendar.  
7.1.4 Clinical Procedures/Assessments 
7.1.4.1 Adverse event (AE) monitoring 
AEs will be collected from time of C1D1. The investigator or qualified designee will assess 
each subject to evaluate for potential new or worsening AEs as specified in the Trial Flow 
Chart and more frequently if clinically indicated.  Adverse experiences will be graded and 
recorded throughout the study and during the follow-up period according to NCI CTCAE 
Version 4.0 (see Section 11.2).  Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is possibly 
an event of clinical interest (ECI) of a potentially immunologic etiology (termed immune-
related adverse events, or irAEs); see the separate ECI guidance document in Appendix 4 
regarding the identification, evaluation and management of potential irAEs.   
Please refer to section 7.2 for detailed information regarding the assessment and recording 
of AEs.   
7.1.4.2 Full physical exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  

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7.1.4.3 Directed physical exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.4.4 Vital signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.4.5 Eastern Cooperative Oncology Group (ECOG) 
Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.   
7.1.4.6 Tumor imaging and assessment of disease 
Patients will undergo a CT Thorax and Abdomen at baseline, then every 2 cycles.  After 1 
year of follow-up, the interval of CT will be extended to once every 12 weeks. Radiographic 
assessments will be based on Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 
v1.1). Subjects with progressive disease by RECIST v1.1 but without rapid clinical 
deterioration may continue to be treated at the discretion of the investigator.   
Baseline Brain MRI or Brain CT will be required. 
7.1.4.7 Tumor tissue collection and correlative studies blood 
sampling 
 See section 4.2. 
7.1.5 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.  

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Table 9. Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
7.1.5.1.1 
Pplatelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  Any screening labs done within 7 days of 
C1D1 do not need to be repeated prior to first treatment. After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by 
the investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.5.2 Pharmacodynamic evaluations 
See section 4.3.3.1. 
Blood Collection for Anti-Pembrolizumab Antibodies  
7.1.6 Other Procedures 
7.1.6.1 Withdrawal/discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.7.3.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
7.1.7 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.7.1 Safety follow-up visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial drug administration or before the initiation of a new anti-cancer treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to 
Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-
cancer treatment should also be followed and recorded.  Subjects who are eligible for 
retreatment with pembrolizumab (as described in Section 7.1.7.3) may have up to two safety 
follow-up visits, one after the Treatment Period and one after the Second Course Phase. 
7.1.7.2 Follow-up visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 8 weeks (56 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 

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every 12 weeks (± 7 days). Every effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, end 
of the study or if the subject begins retreatment with pembrolizumab as detailed in Section 
7.1.7.3.  Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.7.3 will move from the follow-up phase to the Second Course Phase when 
they experience disease progression.   
7.1.7.2.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  
7.1.7.3 Second course phase (retreatment period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the 
study remains open and the subject meets the following conditions: 
• 
Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 
Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 
Received at least two treatments with pembrolizumab beyond the date 
when the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability 
AND 
• 
Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• 
Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• 
Has a performance status of 0 or 1 on the ECOG Performance Scale 
• 
Demonstrates adequate organ function as detailed in Section 5.1.2 

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• 
Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• 
Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference 
Section 5.7.2).  Subjects of child bearing potential are those who have not been 
surgically sterilized or have been free from menses for > 1 year.  
• 
Male subject should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.   
• 
Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
 
7.2 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject 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.  The start of AE collections will be 
C1D1. Abnormal Lab values, vital signs or test results that do not induce clinical 
signs/symptoms or require therapy, will not be considered clinically significant and will not be 
reported as Adverse Events. 
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 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. 

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Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or discontinuation 
of usual therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
All adverse events will be recorded from C1D1 through 30 days following cessation of 
treatment and at each examination on the Adverse Event case report forms/worksheets. 
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of 
Overdose to the Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available on 
the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to 
Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female 
partner that occurs during the trial or within 120 days of completing the trial completing the 
trial, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier.  All subjects and female partners of male subjects who 
become pregnant must be followed to the completion/termination of the pregnancy.  
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 

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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. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to 
Merck 
7.2.3.1 Serious adverse events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose; 
• 
Is an important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
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 to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
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.  

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Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of clinical interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported within 24 hours to the Sponsor and within 2 working days 
to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220).  Events of 
clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent). 
3.  Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-
Related Adverse Event Guidance Document”).  This document can be found in Appendix 
4 and provides guidance regarding identification, evaluation and management of ECIs 
and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 30 days following cessation of treatment, need to be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220), regardless of attribution to 
study treatment, consistent with standard SAE reporting guidelines. 
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should 
be evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event.  Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes.  If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes.  If no other cause is found, then it is 
assumed to be immune-related. 

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7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Any adverse 
event which changes CTCAE grade over the course of a given episode will have each 
change of grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
 
 
 

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Table 10. Evaluating Adverse Events 
An investigator who is a qualified physician or APP, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization 
indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not 
include an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, 
even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective 
procedure] for a preexisting condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious 
adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided 
by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the 
causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the 
required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with 
the components and their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance 
assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or 
environmental factors 
 
 

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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose 
drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. 
CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product 
relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the 
Merck product is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is 
not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 

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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRBs and investigators 
in accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 Statistical Analysis Plan Summary 
The phase I dose escalation will utilize the modified continuous reassessment method 
(mCRM) to identify the MTD.  A “pick-the-winner” design for the randomized phase II clinical 
trial is proposed by employing Simon minimax two-stage design and Bayesian posterior 
probability.  This design will have an 86% overall power to claim arm B as the winner when 
the true probabilities of response with arms A and B are 18% and 38%, respectively. The 
power slightly deceases to 75% when the response rate is 23% in arm A with 38% in arm B. 
The power is 57% when there is only 10% difference of response rate (arm A: 28%; arm B: 
38%). The type I error is controlled at 16%. 
8.2 
Statistical Analysis Plan 
8.2.1 Phase I dose escalation. 
The primary objective of this phase I dose escalation is to find a maximum tolerated dose 
(MTD) corresponding to a risk of DLT occurring in 30% of patients. Two dose levels have 
been identified for experimentation (200mg PO daily and 400mg PO daily) with a back-up 
dose at 100mg PO daily, and due to safety concerns the first cohort of patients will receive 
the lowest dose (200mg). The study uses the modified continuous reassessment method 
(mCRM) described later to design dose escalation (O'Quigley et al., 1990). The design will 
recruit patients in cohorts of three patients each and will not allow for dose-skipping during 
escalation. A total of 12 patients will be enrolled for the Phase I dose escalation. The initial 
guess of the risk of DLT at the lowest dose (200mg) is 10% whilst the best guess of the 
MTD is at dose level 2 (400mg) (i.e., a 30% risk of DLT at this dose level). The initial 
guesses of risk of DLT are established for each dose level as shown in Table 10.  
 
Table 10.  Initial estimates of the probability of DLT at each dose level. 
 
Dose cohort 
 
100mg PO Daily 
(back-up dose) 
200mg PO Daily 
(starting dose) 
400mg PO Daily 
initial 
guessed 
DLT probability 
1% 
10% 
30% 
 

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8.2.2 Definitions for Dose Limiting Toxicities. 
The period for evaluating DLTs is defined as the time period starting with the first dose of 
investigational products until the planned administration of the second dose of 
pembrolizumab. Subjects are considered evaluable for assessment of DLTs if they receive 
at least 75% of the protocol assigned doses of both pembrolizumab and vorinostat and 
complete the safety follow-up through the end of the DLT evaluation period, or experience a 
DLT during the  DLT evaluation period.  
Subjects who do not remain on the study up to this time for reasons other than DLT will be 
replaced with another subject at the same dose level. DLTs will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
v4.03).  A DLT will be defined as any Grade 3 or higher toxicity that occurs during the DLT 
evaluation period. Toxicity that is clearly and directly related to the primary disease or to 
another etiology is excluded from this definition.  
The following will be DLTs: 
• Any Grade 4 immune-related adverse event (irAE)  
• Any ≥ Grade 3 colitis  
• Any Grade 3 or 4 non-infectious pneumonitis irrespective of duration  
• Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the 
initiation of maximal supportive care  
• Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 
2 within 3 days after onset of the event despite optimal medical management 
including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline 
within 14 days  
• Liver transaminase elevation > 8 × upper limit of normal  (ULN) or total bilirubin  > 5 × 
ULN  
• Any ≥ Grade 3 non-irAE, except for the exclusions listed below    
 
The definition excludes the following conditions:   
• Grade 3 fatigue lasting ≤ 7 days  
• Grade 3 endocrine disorder  (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement  therapy and the subject is asymptomatic  
• Grade 3 inflammatory reaction attributed to a local antitumor response  (eg, 
inflammatory reaction at sites of metastatic disease/lymph nodes)  
• Concurrent vitiligo or alopecia of any AE grade  
• Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management  
• Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia 
will be a DLT regardless of duration or reversibility  
• Grade 3 or 4 lymphopenia  
• Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention, and improves by at least 1 grade within 3 days  

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• Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 
days  
• Grade 3 amylase or lipase abnormality that is not associated with symptoms or clinical 
manifestations of pancreatitis 
• Immune-related AEs are defined as AEs of an immune nature  (ie, inflammatory) in the 
absence of a clear alternative etiology. In the absence of a clinically significant 
abnormality, repeat laboratory testing will be conducted to confirm significant 
laboratory findings prior to designation as a DLT. Laboratory abnormalities that are 
not deemed to be clinical significant will not be considered a DLT.  
 
While the rules for adjudicating DLTs in the context of dose exploration are specified above, 
an AE not listed above may be defined as a DLT after a consultation with the sponsor and  
investigators, based on the emerging safety profile.  
 
8.2.3 Dose escalation. 
The maximum tolerated dose (MTD) is defined as the dose with the DLT rate of 30%.  
Starting at the first dose level of 200mg PO daily, if there are < 1 DLT then it is acceptable to 
escalate to the next dose level. If no DLT is observed at the first dose level (200mg PO 
daily) with 3 subjects, then dose escalation will continue with dosing groups of 3 subjects at 
a time. This will continue up to dose level 2 (400mg of vorinostat). The DLT assessment 
period is the first 21 days of treatment. 
 
If a DLT is observed at 200 mg PO daily, then the vorinostat dose will be de-escalated to 
100 mg PO daily with the intent of increasing the dose back to 200 mg PO daily if 100 mg 
PO daily is shown to be safe and well-tolerated. After the first DLT is observed or any 
proposed dose level is achieved without any DLTs, subsequent dose assignments are 
guided by the modified continuous reassessment method (mCRM) as described below.  
 
The mCRM works in the following way. If n subjects have been assigned and completed 21 
days of follow-up, let Yi=1 if the ith subject experienced DLT and let Yi=0 otherwise, for i = 
1,…, n. The mCRM model (O’Quigley et al. 1990) used here is 
 
Prob(Yi=1|dose level k)=F(θ, dose level k)= exp(3+ θ×dose(k)*)/(1+ exp(3+ θ×dose(k)*) 
 
where θ is the parameter to be estimated for the model, F is the probability of a subject i 
experiencing a DLT at dose level k, the dose(k)* is the standardized dose. The prior 
distribution on parameter θ is assumed to be a gamma distribution with shape=1 and 
scale=1. The Bayes’ theorem is used to update the prior distribution of θ. After each 
subject’s response is observed, the mean posterior density of the parameter, θ, is 
computed.  

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The dose to be administered to the next subject is the dose xn+1 such that |Prob(y=1| xn+1, 
θ(n)) – 0.3| is minimized (i.e., the dose with the estimated DLT rate closest to the target rate 
of 0.3). When a dose is escalated, skipping dose levels is not allowed so that any escalation 
would only be to the next higher dose level in the predefined sequence. When a dose is de-
escalated, a dose level can be skipped. 
 
The total sample size of the dose escalation followed by the mCRM to obtain the estimate of 
the MTD is 12 subjects. After each dosing group, the mCRM will provide a current estimate 
of the MTD, which will be recommended as the next dose. The DMC will determine when 
these estimates of the MTD become consistent to declare the MTD.  
 
Here is one hypothetical example (Table 11 and Figure 5) to illustrate how the mCRM 
works. Figure 6 summarizes the results of posterior probability of DLT in each dose and 
suggests the 400mg as the recommended dose (MTD).  
1. Assign the first 3 patients to the dose 200mg. 0 DLT is observed. The estimated 
toxicity rate is 1.1% in dose 100mg, 4.6% in dose 200mg, 10.9% in dose 400mg.  
The dose cohorts, 400mg, have a toxicity rate closer to 30% compared to the one in 
dose 200mg. Since dose-skipping during escalation is not allowed, the dose 400mg 
is chosen for the next 3 patients. 
2. Assign 4-6 patients to the dose 400mg. 1 DLT is observed. The estimated toxicity 
rate is 2% in dose 100mg, 10.3% in dose 200mg, 25.5% in dose 400mg.  Dose 
cohort, 400mg, has a toxicity rate closest to the target toxicity rate (30%), so the 
dose 400mg is chosen for the next 3 patients by the mCRM algorithm. 
3. Assign 7-9 patients to the dose 400mg. 1 DLT is observed. The estimated toxicity 
rate is 1.9% in dose 100mg, 11.4% in dose 200mg, 28.7% in dose 400mg.  Dose 
cohort, 400mg, has a toxicity rate closest to the target toxicity rate (30%), so the 
dose 400mg is chosen for the next 3 patients by the mCRM algorithm. 
4. Assign 10-12 patients to the dose 400mg. 1 DLT is observed. The estimated toxicity 
rate is 1.8% in dose 100mg, 11.7% in dose 200mg, 30.1% in dose 400mg.  Dose 
cohort 400mg has a toxicity rate closest to the target toxicity rate (30%). And it 
reaches the maximum of the sample size (n=12). The mCRM algorithm claims the 
dose 400mg as MTD. 
 
Table 11. Hypothetical example of the modified continuous reassessment method 
(mCRM). 
 
Patient ID 
Dose 
DLT (DLT=1) 
  
Level 
-1 
(100mg) 
Level 
1 
(200mg) 
Level 
2 
(400mg) 
1 
200mg 
0 
  
  
  
  
2 
200mg 
0 
  
  
  
  
3 
200mg 
0 
  
  
  
  
  
  
  
Estimated toxicity rate at end of this 
1.10% 
4.60% 
10.90% 

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dose 200mg 
  
  
  
  
Dose 400mg has the toxicity rate 
closest to the target toxicity rate 
(30%), so the dose 400mg is 
chosen for the next 3 patients. 
4 
400mg 
0 
  
  
  
  
5 
400mg 
0 
  
  
  
  
6 
400mg 
1 
  
  
  
  
  
  
  
Estimated toxicity rate at end of this 
dose 400mg 
2% 
10.30% 
25.50% 
  
  
  
  
Dose 400mg has the toxicity rate 
closest to the target toxicity rate 
(30%), so the dose 400mg is 
chosen for the next 3 patients. 
7 
400mg 
0 
  
  
  
  
8 
400mg 
1 
  
  
  
  
9 
400mg 
0 
  
  
  
  
  
  
  
Estimated toxicity rate at end of this 
dose 400mg 
1.90% 
11.40% 
28.70% 
  
  
  
  
Dose 400mg has the toxicity rate 
closest to the target toxicity rate 
(30%), so the dose 400mg is 
chosen for the next 3 patients. 
10 
400mg 
0 
  
  
  
  
11 
400mg 
0 
  
  
  
  
12 
400mg 
1 
  
  
  
  
  
  
  
Estimated toxicity rate at end of this 
dose 400mg 
1.80% 
11.70% 
30.10% 
  
  
  
  
The mCRM algorithm claims the 
dose 400mg as MTD.  
 
 
 
 

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Level 2: 
400mg 
 
 
 
 
 
Level 1: 
200mg 

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Figure 5. Hypothetical example of the modified continuous reassessment method 
(mCRM). 
 
 
 
Figure 6. A summary of the results of posterior probability of DLT at each dose level.  
The model suggests the 400mg as the recommended dose (MTD) depicted by the 
diamond.  
 
8.2.4 Operating characteristics. 
Table 12 shows a simulation study conducted to illustrate the performance of the design in 
various conditions.  Specifically, we explored different scenarios from toxicity as expected 
and greater than expected. Our initial guess of DLT probability is 1% for 100mg dose, 10% 

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for 200mg dose, and 30% for 400mg dose). Scenario 1 is the case that our initial guessed of 
DLT probability is same as the true DLT probability. Scenario 2 and 3 are the case that the 
true DLT probability is greater than our initial guessed of DLT probability with 100mg and 
200 mg as MTD, respectively. Scenario 4 is the same as Scenario 1 except a higher DLT 
probability in the back-up dose.   
 
Table 12.  A simulation study to depict the mCRM design for various conditions.  The 
MTD is highlighted in each scenario.  
 
100mg 
(back-up dose) 
200mg 
(starting dose) 
400mg 
Prior guess of DLT probability 
1% 
10% 
30% 
 
 
 
 
Scenario 1 
(Toxicity as expected) 
1% 
10% 
30% 
Scenario 2 
(greater than expected: 
100mg as MTD) 
30% 
40% 
60% 
Scenario 3 
(greater than expected: 
200mg as MTD) 
10% 
30% 
50% 
Scenario 4 
(greater than expected: 
400mg as MTD) 
5% 
10% 
30% 
 
Simulation results show that in each of these scenarios, the mCRM study design with 12 
subjects is superior to the 3+3 design in estimating the MTD correctly. Table 13 reports the 
probability of a dose to be selected as MTD (Percent Recommendation) and the probability 
of patients assigned to each dose level (Percent Experimentation). Ideally, if the mCRM 
design works well, we expect it will choose the true MTD dose with the highest probability 
(i.e., highest Percent Recommendation) and assign more patients in the true MTD dose (i.e., 
highest Percent Experimentation).  
In Scenario 1 with 400mg as true MTD, the mCRM design yields a high probability of 83.3% 
to claim 400mg as MTD. In contrast, the 3+3 design results in 44.8% to claim 400mg as 

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MTD and 44.8% for 200mg as MTD. Regarding probability of patients assigned to each 
dose level, ideally we would like to see more patients assigned in the MTD dose. There are 
56.7% patients assigned to the 400mg by the mCRM design compared to 42.7% by the 3+3 
design.  
In Scenario 2 with 100mg as true MTD, the probability to claim 100mg as MTD is 54.5% by 
the mCRM design and 20.4% by the 3+3 design. There are 34.3% patients assigned to the 
100mg by the mCRM design compared to 40.3% by the 3+3 design. 
In Scenario 3 with 200mg as true MTD, the probability of 200mg as MTD is 53.2% by mCRM 
design and 34.8% by 3+3 design. There are 58.2% patients assigned to the 200mg by the 
mCRM design compared to 49.4% by the 3+3 design. 
In Scenario 4 with 400mg as true MTD, the probability of 400mg as MTD is 83.5% by the 
mCRM design and 44.8% by the 3+3 design. Both designs have 42.7%-57.3% patients 
assigned to the 400mg dose level (mCRM: 57.3%; 3+3 design: 42.7%). 
These simulations show that the proposed mCRM design with 12 subjects is superior to the 
3+3 design in that it has a higher probability of estimating the MTD correctly. 
 
Table 13. The mCRM would allow more patients to be exposed to the MTD as 
compared to the 3+3 design.  The simulation scenarios are associated with a 
probability of a dose to be selected as the MTD (Percent Recommendation) and a 
proportion of patients assigned to each dose level (Percent Experimentation).  
 
 
 
Probability of a dose to be selected as MTD 
(Percent Recommendation) 
 
Probability of patients assigned to 
each dose level 
(Percent Experimentation) 
 
 
Dose Cohort 
 
Dose Cohort 
 
Method 
<100mg 
100mg 
200mg 
400mg 
 
100mg 
200mg 
400mg 
Scenario 1 
(Toxicity as expected:  
400mg as true MTD) 
CRM  
(n=12) 
0.0% 
0.4% 
16.3
% 
83.3
% 
 
1.6% 
41.7% 
56.7% 
 
3+3 
(n=9.38) 
0.3% 
10.1
% 
44.8
% 
44.8
% 
 
5.5% 
51.8% 
42.7% 
Scenario 2 
(greater than expected: 
100mg as true MTD) 
CRM 
(n=12) 
0.0% 
54.5
% 
36.6
% 
8.9% 
 
34.3% 
53.4% 
12.3% 

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3+3 
(n=10.16) 
55.7
% 
20.4
% 
21.4
% 
2.5% 
 
40.3% 
48.5% 
11.2% 
Scenario 3 
(greater than expected: 
200mg as true MTD) 
CRM 
(n=12) 
0.0% 
21.7
% 
53.2
% 
25.1
% 
 
18.6% 
58.2% 
23.3% 
 
3+3 
(n=10.57) 
16.5
% 
40.2
% 
34.8
% 
8.5% 
 
30.9% 
49.4% 
19.7% 
Scenario 4 
(greater than expected: 
400mg as true MTD) 
CRM 
(n=12) 
0.0% 
1.0% 
15.5
% 
83.5
% 
 
1.8% 
40.9% 
57.3% 
 
3+3 
(n=9.38) 
1.5% 
8.9% 
44.8
% 
44.8
% 
 
5.5% 
51.8% 
42.7% 
 
Randomized Phase II Statistical Design: Simon two-stage design + Bayesian posterior 
probability. 
A “pick-the-winner” design for the randomized phase II clinical trial is proposed by employing 
Simon minimax two-stage design and Bayesian posterior probability(Chen et al., 2017). 
Specifically, a Simon minimax two-stage design will be used for each experimental arm 
(Simon, 1989). If both arms fail at the first or second stage, the trial will stop. No winner will 
be claimed. If only one arm pass the second stage, the arm will be the winner. If both arms 
pass the second stage, we will use a Bayesian posterior probability, rB>A, (probability of the 
response rate in arm B higher than in arm A) to select the winner. Table 14 lists the rule to 
claim a winner. The operating characteristics of this design are detailed in the sample size 
calculation.  
 
Table 14.  Depiction of the Simon optimal two-stage or “pick-the-winner” design. 
 
 
 
Arm B 
 
 
fail in stage 1 
fail in stage 2 
pass 2nd stage 
Arm A 
fail in stage 1 
both losers 
both losers 
Arm B winner 
fail in stage 2 
both losers 
both losers 
Arm B winner 
pass 2nd stage 
Arm A winner 
Arm A winner 
Arm B winner if rB>A > 80% 
Arm A winner if rB>A < 20% 

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rB>A: posterior probability of the response rate in arm B higher than in arm A 
 
This design has several features: (1) Randomization reduces selection bias and allows a 
greater degree of comparability, (2) the Simon two-stage design will allow for termination of 
an ineffective regimen earlier when compared to historical control data, and (3) the Bayesian 
posterior probability provides additional power to detect a definitive differential treatment 
effect.  This trial design will allow us to more accurately determine if it is worthwhile to 
conduct a large phase III trial. We have used this trial design in a randomized three-arm 
phase II trial (p53 vaccine and ATRA) and were able to terminate two arms due to lack of 
efficacy and feasibility.  This allowed us to focus on the arm with p53 vaccine plus ATRA for 
efficacy evaluation (Creelan et al., 2013). 
 
8.2.5 Descriptive statistics 
For each arm, summaries of the primary endpoint (response rate) and important descriptors 
(e.g., age, gender) will be produced using descriptive statistics such as mean and standard 
deviation for measured continuous variables and marginal distributions for categorical 
variables. We will also use histograms and box-plots to understand aspects of data quality 
and overall characteristics of the data. All patients enrolled in the study will be included in 
the analysis (intention-to-treat analysis). No adjustments to the data are intended for dealing 
with missing values or patients who withdraw prior to completing the study.  
 
Objective tumor response rates will be calculated with a 2-sided 95% confidence interval 
(CI). Exploratory analysis with Chi-square tests to examine the relationship between clinical 
responses and treatment will be performed.  
 
8.2.6 Sample size calculation and Interim Analysis.  
From historical data(Edward B Garon, 2014) (Socinski, Checkmate 026, EMSO 2016; 
Hellman et al, Keynote 001, WCLC, 2015;  ), we will consider 25% response rate as not 
warranting further study. We will use 45% response rate as a promising result to pursue 
further study. In other words, we are interested in at least 20% (45% vs. 25%) improvement 
in treatment efficacy for arms B versus A. For each arm, using a Simon Mini-Max two-stage 
design with 10% type I error rate and 10% type II error rate, 23 patients will be enrolled in 
the first stage of the trial. If 5 or fewer patients respond, the treatment will be stopped. If 6 or 
more patients show a response, 16 additional patients (a total of 39 patients per group) will 
be enrolled. If the total number responding is 13 or less, we will conclude that the treatment 
is not effective. A total sample size will be 78 patinets if both arms finish the 2nd stage. If 
both arms fail at the first or second stage, the trial will stop. No winner will be claimed. The 
sample size will be 46 if both arms fail at the first stage and 62 if only one arm fails at the 
first stage. If only one arm pass the second stage, the arm will be the winner. If both arms 
pass the second stage, we will use the posterior probability, 𝑃𝑃𝑃𝑃(𝐵𝐵> 𝐴𝐴), (probability of the 
response rate in arm B higher than in arm A) to select the winner. A non-informative prior of 
beta distribution, beta(1,1) in both arms will be used to calculate the posterior probability. 
Arm B will be claimed as the winner if 𝑃𝑃𝑃𝑃(𝐵𝐵> 𝐴𝐴) > 𝛿𝛿= 0.8. 

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8.3 
Operating Characteristics 
The operating characteristics of the design is evaluated by simulation (10000 times) using R 
software (www.r-project.org) with "clinfun" package. In particular, we are interested in the 
probability of (correctly) selecting an arm as superior to the other arm if it is truly superior, 
and conversely, the probability of (incorrectly) selecting an arm that is no better than the 
other arm. 
8.4 
Power Analysis 
Power: Assuming that the true probabilities of response in arms B and A are 45% and 25%, 
respectively (scenario 1: 20% difference of response rate), the overall probability (power) of 
correctly choosing arm B as superior is 87% on the basis of superiority shown at the end of 
the trial. The probability of stopping arm A early and declaring arm B superior at the end of 
the trial is 83%. There are 7% of both arms passing the second stage with 3% claiming arm 
B as the winner by the Bayesian posterior probability. In a 15% difference of response rate, 
the overall power is 69% and 77% for the comparison of arms B and A with 40% versus 
25% (scenario 2) and 45% versus 30% (scenario 3), respectively. Proportion of both arms 
passing the 2nd stage is 6% in scenario 2 (scenario 3: 22%), with 2% (scenario 3: 9%) 
claiming arm B as the winner by the Bayesian posterior probability. 
8.5 
Type I error 
Type I error: In the null hypothesis of a 25% response rate in both arms, there are 8% 
misclassifying arm B as winner (i.e., 8% type I error). Among them, only 1% has both arms 
passing the 2nd stage, and less than 0.01% misclassify arm B as winner. 
8.6 
Summary 
Summary: With 𝛿𝛿=0.8, the design has a 87% power to detect a 20% difference of response 
rate. The power decreases to a range of 69-77% to differentiate a 15% difference of 
response rate. The type I error is controlled at 8% when both arms have a 25% response 
rate. 
8.7 
Table of Power Analysis 
 
Scenario 1: Arm B=0.45 versus Arm A=0.25 (Overall power of Arm B= 87%) 
 
B.fail.stage1 B.fail.stage2 B.pass 
A.fail.stage1 0.01 
0.04 
0.43 
A.fail.stage2 0.01 
0.03 
0.41 
A.pass 
0 
0.01 
0.07 
Both arms passing the 2nd stage: 7%. Among them, Arm B claims 3.05% as winner 
Overall power of Arm B= 87% 
 
Scenario 2: Arm B=0.4 versus Arm A=0.25 (Overall power of Arm B= 69%) 

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B.fail.stage1 B.fail.stage2 B.pass 
A.fail.stage1 0.03 
0.09 
0.35 
A.fail.stage2 0.03 
0.09 
0.33 
A.pass 
0 
0.02 
0.06 
Both arms passing the 2nd stage: 6%. Among them, Arm B claims 1.62% as winner 
Overall power of Arm B= 69% 
 
Scenario 3: Arm B=0.45 versus Arm A=0.3 (Overall power of Arm B= 77%) 
 
B.fail.stage1 B.fail.stage2 B.pass 
A.fail.stage1 0 
0.02 
0.24 
A.fail.stage2 0.01 
0.04 
0.43 
A.pass 
0 
0.02 
0.22 
Both arms passing the 2nd stage: 22%. Among them, Arm B claims 9.14% as winner 
Overall power of Arm B= 77% 
 
Scenario 4: Arm B=0.25 versus Arm A=0.25 (Type I error= 8.06%) 
 
B.fail.stage1 B.fail.stage2 B.pass 
A.fail.stage1 0.22 
0.21 
0.04 
A.fail.stage2 0.22 
0.19 
0.04 
A.pass 
0.04 
0.04 
0.01 
Both arms passing the 2nd stage: 1%. Among them, Arm B claims 0.01% as winner 
Type I error= 8.06% 
 
 
 
8.7.1 Statistical plan for immunogenicity profiles in phase Ib and phase II: 
 
Phase Ib expansion cohort (PD-1 pretreated: N=18). 
Two gene signatures (NF-kB, 12-chemokine genes) will be evaluated to test if they can 
predict the response to PD-1 blockade + HDACi treatment using the pre-treatment biopsy. 
For each gene signature, PCA will be used to calculate an index score based on the first 
principal component. The derived gene signature score will be then used to test if the 
response group has a higher score than the non-response group using the two-sample t 
test. A sample size of 18 patients will give an 80% power to detect an effect size of 1.6 with 
a two-sided 5% type error if the response rate is 30% (i.e., 5 responders and 13 non-

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responders) by the two-sample t test. If the response rate is 40% (i.e., 7 responders and 11 
non-responders), the power will increase to 87%. We will also test the difference of the 
score from pre to post-treatment between the responders and non-responders using two-
sample t-test. With this sample size (n=18) and 80% power, it will be able to detect an effect 
size of 1.57 and 1.45 for a response rate of 30% and 40%, respectively with a two-sided 5% 
type error by the two-sample t-test. In addition, we will also determine association of 
individual genes with response or resistance, including T cell co-stimulatory and inhibitory 
genes.  
 
Phase II cohort (PD-1 naïve). 
We would like to know if these gene signatures in pre-treatment biopsies could predict a 
differential treatment effect. That is, could patients with high gene signature score result in a 
higher response rate to anti-PD-1 but patients with either low or high respond to anti-PD-
1+HDACi? A logistic regression model will be used to evaluate this hypothesis by testing an 
interaction effect model, which includes two main effects, gene signature score and 
treatment status, and their interaction term. We will also test the difference of the score from 
pre to post-treatment between the two treatment groups using two-sample t-test. 
 
9.0 LABELING, 
PACKAGING, 
STORAGE 
AND 
RETURN 
OF 
CLINICAL SUPPLIES 
9.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 16. 
Table 16.  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 

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9.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, 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. 
9.4 Storage and Handling Requirements 
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. 
9.5 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 subjects 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. 
10.0 DATA SAFETY MONITORING PLAN 
10.1 Risk to Subjects 
10.1.1 Human subject involvement and characteristics 
Human subjects who have the diagnosis of advanced NSCLC are eligible to 
participate in the clinical trial described in this proposal. The risk to subjects will 
be outlined clearly and in detail in the informed consent. Women who are 
pregnant are not eligible. 
 
10.2 Recruitment and Informed Consent 
Patients who present to the Thoracic Oncology Program at the Moffitt Cancer Center or the 
OSU Thoracic Clinics who have advanced NSCLC are offered participation in the clinical 
trial described in this proposal. The trial is explained in detail to the patients by one of the 
investigators on the trial.  The patients are given the opportunity to read the informed 
consent document and are given a chance to ask questions.  If they wish to participate the 
patient will then sign the informed consent document in the presence of a witness. The 

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study team member who participates in the informed consent process also documents, in a 
clinic note, the nature of the consent process that occurred.  
 
10.3 Protection Against Risk 
To protect participants from excess risk, the above-mentioned study procedures and dose-
escalation scheme were instituted. Additional protection is provided through the data safety 
and monitoring plan described below. The complete care of each patient, including the 
clinical management of all toxicities, is provided to the patient by physicians at the Moffitt 
Cancer Center. The clinical data are kept in the patient's individual electronic hospital 
record. Research study documentation charts are kept in a locked secure room with limited 
access and through Oncore (a Web-based, password-protected database), with privacy 
protected to the full extent of the law. Authorized research investigators, the Department of 
Health and Human Services, and the Institutional Review Board may inspect the records. 
Final protocol and ICF approvals will be obtained from the IRB. 
Additional protection is provided through the data safety and monitoring plan described 
below.  
 
10.4 Importance of the Knowledge to be Gained 
The development of a well-tolerated and effective regimen in a disease could potentially at 
worst add to the armamentarium of available regimens and at best change standard of care. 
Specific strategies to improve the care of patients relapsing following chemotherapy for lung 
cancer are direly needed.  
 
10.5 Data Safety and Monitoring Plan 
The Data Safety & Monitoring Plan (DSMP) will ensure that this trial is well designed, 
responsibly managed, appropriately reported, and that it protects the rights and welfare of 
patients.  The following internal and external review and monitoring processes provide 
oversight and active monitoring of this trial: 
• 
The Principal Investigators (PI) 
• 
The Clinical Trials Office (CTO) 
• 
The Scientific Review Committee (SRC) 
• 
The Protocol Monitoring Committee (PMC); 
• 
Institutional Review Board (IRB). 
 
The protocol includes a section that specifies the following with respect to Adverse Event 
reporting: what constitutes an adverse event (versus what is a serious adverse event), the 
entities to which adverse events should be reported, the timing of this reporting, and the 
person or persons responsible for reporting.  This includes prompt (within one day of 

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knowledge of the event) reporting to the IRB for unanticipated risks to subjects and reporting 
in writing within five working days to the IRB and sponsor.  
 
10.6 Scientific Review Committee (SRC) 
The two Therapeutic boards of the SRC meet every other week one on the first Wednesday 
and the second one meets on the third Thursday of every month.  
Each SRC conducts a formal internal peer review of all clinical protocols and general 
scientific oversight of interventional clinical research. Protocols are reviewed for scientific 
merit, adequate study design, safety, availability of targeted study population, and feasibility 
of timely completion of all proposed research projects to be conducted by its assigned 
programs at each Cancer Center.  The SRC is responsible for evaluating the risk/benefit 
assessment and corresponding data and safety monitoring plan as part of the scientific 
review and approval process.   
 
10.7 PI Responsibility 
The PI of each study is ultimately responsible for every aspect of the design, conduct and 
actions of all members of the research team.  This includes the final analysis of the protocol.   
All protocols include a DSMP and procedures for its implementation commensurate with the 
risk and complexity of the study.  The DSMP must include a structured adverse event 
determination, monitoring and reporting system, including standardized forms and 
procedures for referring and/or treating subjects experiencing adverse events.  The plan 
must include data and safety-monitoring procedures for subjects enrolled who may be 
receiving a part of their protocol-required treatment at community sites. 
In all cases, the PI of the study will have primary responsibility for ensuring that the protocol 
is conducted as approved by the SRC and IRB.  The PI will ensure that the monitoring plan 
is followed, that all data required for oversight of monitoring are accurately reported to a 
DSMB and/or to the PMC and IRB as required, that all adverse events are reported 
according to protocol guidelines, and that any adverse actions reflecting patient safety 
concerns are appropriately reported. 
 
10.8 The Protocol Monitoring Committee (PMC) 
The PMC meets once a month.  The PMC reviews and evaluates safety and/or efficacy data 
for all physician authored clinical intervention trials. The PMC ensures the safety of patients 
and the validity and integrity of data. PMC reviews SAEs, deviations, Interim analysis, 
interim and final reports from the external Data Monitoring Committee (DMC) as well as 
audits both internally and externally. The PMC can make the following determinations, 
Accepted, Acceptable with Corrective Action and Tabled.    

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Investigators of studies, which are designated to be reviewed by the PMC for data and 
safety monitoring, shall provide an interim analysis report of the study’s progress and 
summary of adverse events and deviations based on the phase of the study and the 
associated risk of the study or more often if applicable.  The external DSMB (if applicable) 
shall forward its report for high-risk studies designated for external review at least annually 
or more often if applicable. 
 
10.9 Suspension/Termination 
The PMC and/or the IRB may vote to suspend or terminate approval of a research study not 
being conducted in accordance with the IRB, the Cancer Center and/or regulatory 
requirements or that has been associated with unexpected problems or serious harm to 
subjects.  The PMC/IRB will notify the PI in writing of such suspension or terminations.  It is 
the responsibility of the PMC/IRB Chairperson to ensure prompt written notification of any 
suspensions or terminations of PMC/IRB approval to the relevant Federal Agencies, 
including OHRP, FDA, the study sponsor/funding source and if applicable, the Affiliate 
Program. 
 
10.10 
Trial Discontinuation 
For reasonable cause the Investigator and/or sponsor may terminate this study prematurely. 
Conditions that may warrant termination include, but are not limited to: the discovery of an 
unexpected, significant, or unacceptable risk to the patients enrolled in the study or if the 
accrual goals are met. A written notification of termination will be issued. 
 
10.11 
Monitoring of the Study and Regulatory Compliance 
The Principal Investigator and the Clinical Research Coordinator assigned to the case will 
be primarily responsible for maintaining all study related documents including the clinical 
research forms.  Oncore is the database of record for all CRF entries and will be verified 
with source documentation. The review of medical records within PowerChart will be done in 
a manner to assure that patient confidentiality is maintained. 
 
10.12 
Internal Monitoring Plan 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database.  
Regulatory documents and case report forms will be reviewed routinely by the MCC Clinical 
Research Monitoring Core for accuracy, completeness and source verification of data entry, 
validation of appropriate informed consent process, adherence to study procedures, and 
reporting of SAEs and protocol deviations according to MCC Monitoring Policies.  

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10.13 
Protocol Modifications 
No modifications will be made to the protocol without the agreement of the investigators. 
Changes that significantly affect the safety of the patients, the scope of the investigation, or 
the scientific quality of the study will require Scientific Review Committee and Institutional 
Review Board approval prior to implementation, except where the modification is necessary 
to eliminate apparent immediate hazard to human subjects.  Any departures from the 
protocol must be fully documented in the case report form and the source documentation. 
10.14 
The Institutional Review Board (IRB) 
The trial will not be initiated without approval of the appropriate Institutional Review Board 
(IRB).  All administrative requirements of the governing body of the institution will be fully 
complied with.  This protocol, consent procedures, and any amendments must be approved 
by the IRB in compliance with current regulations of the Food and Drug Administration.  A 
letter of approval will be sent to the institution(s) funding the study prior to initiation of the 
study and when any subsequent modifications are made.  The IRB will be kept informed by 
the investigator as to the progress of the study as well as to any serious or unusual adverse 
events. 
10.15 
Patient Privacy 
In order to maintain patient confidentiality, all case report forms, study reports and 
communications relating to the study will identify patients by initials and assigned patient 
numbers.  The US Food and Drug Administration (FDA) may also request access to all 
study records, including source documentation for inspection. 
 
10.16 
Records Retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to 
the conduct of this study and the distribution of investigational drug, including CRFs, 
consent forms, laboratory test results, and medication inventory records, must be retained 
by the Principal Investigator for 2 years after marketing application approval.  If no 
application is filed, these records must be kept 2 years after the study is discontinued and 
the U.S. FDA and the applicable national and local health authorities are notified. 
10.17 
Compliance 
with 
Trial 
Registration 
and 
Results 
Posting 
Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
 

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11.0 APPENDICES 
11.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria 
for Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
11.4 See Events of Clinical Interest Guidance Document  
 
 

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