A Phase I Trial of Pembrolizumab and Vorinostat Combined With Temozolomide and Radiation Therapy for Newly Diagnosed Glioblastoma
Phase: PHASE1
Conditions: Glioblastoma, Brain Tumor, GBM
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 
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SPONSOR:  Moffitt Cancer Center and Research Institute 
 
TITLE: A Phase I Trial of Pembrolizumab and Vorinostat Combined with Temozolomide    
              and Radiation Therapy for Newly Diagnosed Glioblastoma 
 
IND NUMBER: 137342 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: Solmaz Sahebjam MD 
                                                         Department of Neuro-Oncology, Moffitt Cancer Center 
 
 
 
 
         12902 Magnolia Drive 
 
 
 
 
         Tampa, FL 33612 
 
 
 
 
         Telephone: 1-813-745-4251 
 
 
 
 
         Fax: 1-813-745-3068 
 
 
 
 
         Email: Solmaz.Sahebjam@Moffitt.org  
 
 
                                
                                      
STATISTICIAN:   
Youngchul Kim PhD   
 
 
Original Protocol: 
 
Version 6.0, June 5, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 6 
2.0 
TRIAL DESIGN.......................................................................................................... 7 
2.1 
Trial Design ............................................................................................................. 7 
2.2 
Trial Diagram .......................................................................................................... 7 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 8 
3.1 
Primary Objective(s) & Hypothesis(es) ................................................................ 8 
3.2 
Secondary Objective(s) & Hypothesis(es)............................................................. 8 
3.3 
Exploratory Objective ............................................................................................ 8 
4.0 
BACKGROUND & RATIONALE ............................................................................ 8 
4.1 
Background ............................................................................................................. 8 
4.1.1 Pharmaceutical and Therapeutic Background ...................................................... 8 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 10 
4.2 
Rationale ................................................................................................................ 10 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 10 
4.2.2 Rationale for Dose Selection/Regimen/Modification of Pembrolizumab 
(MK-3475) .......................................................................................................... 12 
4.2.3 Biomarker Research ............................................................................................ 13 
5.0 
METHODOLOGY ................................................................................................... 13 
5.1 
Entry Criteria ........................................................................................................ 13 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 13 
5.1.2 Subject Inclusion Criteria.................................................................................... 13 
5.1.3 Subject Exclusion Criteria .................................................................................. 15 
5.2 
Radiation therapy ................................................................................................. 17 
5.2.1 Dose Specifications ............................................................................................. 17 

 
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5.2.2 Radiation Therapy Adverse Events..................................................................... 17 
5.3 
Trial Treatments ................................................................................................... 17 
5.3.2 Dose Selection/Modification .............................................................................. 23 
5.3.3 Timing of Dose Administration .......................................................................... 29 
5.3.4 Trial Blinding/Masking ....................................................................................... 29 
5.4 
Treatment Allocation ............................................................................................ 29 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 29 
5.5.1 Acceptable Concomitant Medications ................................................................ 30 
5.5.2 Prohibited Concomitant Medications.................................................................. 30 
5.6 
Rescue Medications & Supportive Care ............................................................. 31 
5.6.1 Supportive Care Guidelines ................................................................................ 31 
5.7 
Diet/Activity/Other Considerations ..................................................................... 35 
5.7.1 Diet ...................................................................................................................... 35 
5.7.2 Contraception ...................................................................................................... 35 
5.7.3 Use in Pregnancy ................................................................................................ 37 
5.7.4 Use in Nursing Women ....................................................................................... 37 
5.8 
Subject Withdrawal/Discontinuation Criteria ................................................... 37 
5.9 
Subject Replacement Strategy ............................................................................. 38 
5.10 
Clinical Criteria for Early Trial Termination ................................................... 39 
6.0 
TRIAL FLOW CHART ........................................................................................... 40 
6.1 
Study Flow Chart .................................................................................................. 40 
7.0 
TRIAL PROCEDURES ........................................................................................... 46 
7.1 
Trial Procedures ................................................................................................... 46 
7.1.1 Administrative Procedures .................................................................................. 46 
7.1.2 Clinical Procedures/Assessments ........................................................................ 48 

 
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7.1.3 Laboratory Procedures/Assessments .................................................................. 49 
7.1.4 Other Procedures ................................................................................................. 51 
7.1.5 Visit Requirements .............................................................................................. 51 
7.2 
Assessing and Recording Adverse Events .......................................................... 53 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor and to Merck ................................................................................... 53 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 54 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck.............. 55 
7.2.4 Evaluating Adverse Events ................................................................................. 56 
7.2.5 Sponsor Responsibility for Reporting Adverse Events ...................................... 62 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 62 
8.1 
Statistical Analysis Plan Summary ..................................................................... 62 
8.2 
Statistical Analysis Plan ....................................................................................... 62 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 62 
9.1 
Investigational Product ........................................................................................ 62 
9.2 
Packaging and Labeling Information ................................................................. 63 
9.3 
Clinical Supplies Disclosure ................................................................................. 63 
9.4 
Storage and Handling Requirements .................................................................. 63 
9.5 
Returns and Reconciliation .................................................................................. 63 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 63 
10.1 
Confidentiality ....................................................................................................... 63 
10.2 
Compliance with Financial Disclosure Requirements ....................................... 64 
10.3 
Compliance with Law, Audit and Debarment and Quality Management 
System .................................................................................................................... 64 
10.4 
Compliance with Trial Registration and Results Posting Requirements ........ 65 

 
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10.5 
Data Management ................................................................................................. 65 
11.0 
APPENDICES ........................................................................................................... 66 
11.1 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 66 
11.2 
Immune-Related Adverse Event Guidance ........................................................ 66 
12.0 
LIST OF REFERENCES ......................................................................................... 75 
 

 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Phase I trial of pembrolizumab with vorinostat and temozolomide 
for newly diagnosed glioblastoma 
Trial Phase 
Ib 
Clinical Indication 
Newly diagnosed glioblastoma 
Trial Type 
Open label 
Type of control 
Not applicable 
Route of administration 
Intravenous, Oral 
Trial Blinding 
Not applicable 
Treatment Groups  
1 Group 
Number of trial subjects 
32 
Estimated enrollment period 
24 months 
Estimated duration of trial 
36 months 
Duration of Participation 
24 months 
Estimated average length of 
treatment per patient 
15 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a standard 3+3 design and will include 2 cohorts: 1) dose escalation cohort, and 2) 
dose expansion cohort. Dose escalation will occur separately for concurrent radiotherapy part 
of treatment and maintenance part of treatment.  
2.2 
Trial Diagram 
 
 
 
 
Dose Escalation Phase 
Dose Escalation Schedule During Radiotherapy Phase 
Dose Level 
                                                           Dose 
Pembrolizumab  
Vorinostat  
Level -1 
200 mg IV every 3 weeks 
100 mg/day orally on days 1-5 every week during radiotherapy 
Level  1 
200 mg IV every 3 weeks 
200 mg/day orally on days 1-5 every week during radiotherapy 
Level 2 
200 mg IV every 3 weeks 
300 mg/day orally on days 1-5 every week during radiotherapy 
Dose Escalation Schedule During Maintenance Phase 
Dose Level 
                                                           Dose 
Pembrolizumab  
Vorinostat  
Level -1 
200 mg IV every 3 weeks 
200 mg/day orally 1 week on 1 week off  after radiotherapy 
Level  1 
200 mg IV every 3 weeks 
300 mg/day orally 1 week on 1 week off  after radiotherapy 
Level 2 
200 mg IV every 3 weeks 
400 mg/day orally 1 week on 1 week off after radiotherapy 
 
Dose Expansion Phase 
Twenty patients  will be treated with  vorinostat at MTD 
 (from dose escalation phase), pembrolizumab, temozolomide and radiation 
 
Patients with 
newly 
diagnosed 
glioblastoma 
Radiotherapy (60 Gy)  
Temozolomide (75 mg/m
2
/d) 
Pembrolizumab 200 IV q 3 wks 
Vorinostat on days 1-5 every wk 
 
TMZ (150-200 mg/m2/d) for 5 days q 28 
days for 6 months                        
Pembrolizumab 200 mg IV q 3 wks for 12 
months                                 
Vorinostat daily 1 week on 1 week off for 
12 months 

 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To evaluate the safety, tolerability, and to determine the maximum tolerated 
dose (MTD) of vorinostat given in combination with pembrolizumab, temozolomide, and 
radiotherapy in patients with newly diagnosed glioblastoma. 
Hypothesis:  Combination of pembrolizumab and vorinostat with radiotherapy and 
temozolomide will have acceptable safety and tolerability.  
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  To evaluate the 12 months and 24 months survival rate in patients with newly 
diagnosed glioblastoma who are treated with pembrolizumab in combination with 
vorinostat and standard treatment with radiotherapy and temozolomide. 
Hypothesis: Addition of pembrolizumab and vorinostat to standard treatment with 
radiotherapy and temozolomide will augment the survival. 
3.3 
Exploratory Objective 
(1) 
Objective: To explore tissue biomarkers that may predict tumor response to 
pembrolizumab in combination with vorinostat and standard treatment with 
radiotherapy and temozolomide in patients with newly diagnosed glioblastoma. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab and vorinostat. 
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 

 
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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.  
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. 
Temozolomide is an oral alkylating agent. Continuous daily temozolomide (75 mg per square 
meter of body-surface area per day, 7 days per week from the first to the last day of 
radiotherapy) plus radiotherapy (fractionated focal irradiation in daily fractions of 2 Gy given 
5 days per week for 6 weeks, for a total of 60 Gy), followed by six cycles of adjuvant 
temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle) is the 
United States Federal Drug Administration (FDA) approved treatment for patients with 
newly diagnosed glioblastoma [22]. This treatment increased the median survival from 12.1 
months with radiotherapy alone to 14.6 months [22]. The side effects of treatment included: 

 
Page 10 of 78 
 
grade 3 or 4 neutropenia in 4%, and grade 3 or 4 thrombocytopenia in 3%. The most 
common nonhematologic adverse event was moderate-to-severe fatigue [22]. 
Vorinostat is a small-molecule inhibitor of histone deacetylases (HDAC) that binds directly 
to the enzyme’s active site in the presence of a zinc ion and is approved by the FDA for use 
in patients with advanced cutaneous T-cell lymphoma. Vorinostat crosses blood-brain barrier 
and has shown activity against high-grade glioma in preclinical studies [23]. As per 
vorinostat Investigator Brochure, the most commonly reported adverse experiences are 
diarrhea, nausea, fatigue, thrombocytopenia, hyperglycaemia, vomiting, anorexia, anaemia, 
neutropenia, constipation, blood creatinine increased, leukopenia, dyspnea, weight decreased, 
decreased  appetite, alopecia, aspartate aminotransferase increased and cough are the most 
common adverse events. 
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 
Glioblastoma (GBM) remains one of the most fatal tumors with a median survival of about 
15 months, despite aggressive combination therapy with radiation and temozolomide (TMZ). 
Concurrent radiotherapy (60 Gy in 30 daily fractions) with TMZ (75 mg/m²/day) followed by 
6 cycles of TMZ (150–200 mg/m²/day for 5 days every 28 days) and NovoTTF are the only 
treatments which have shown survival benefit in newly diagnosed GBM patients [22; 24]. 
Thus, GBM remains a largely unmet medical need requiring novel and effective treatment 
strategies. 
Rational for combining pembrolizumab with radiotherapy and TMZ  
Part of the challenge in treating GBM is the naturally immunoprivileged environment of the 
brain. Pre-clinical studies have shown a significant increase in expression of PD-1 on 
peripheral blood CD4+ and CD8+ T cells in patients with high grade gliomas. In a study by 
Wei et al., PD-1+CD4+ T cells were clearly increased in peripheral blood of patients with 
GBM (16.3±0.6 %) compared to healthy cohort (2.5 ± 0.2 %) [25]. Expression of PD-1 and 
PD-L1 is found in the microenvironment of most high grade gliomas [26; 27]. PD-1 is 
expressed on tumor-infiltrating lymphocytes whereas PD-L1 is expressed on tumor cells and 
microglia in GBM specimens [28].  
Moreover, there is emerging evidence that radiotherapy synergizes with CTLA-4 and anti-PD 
1/PD-L1 blockade and produces tumor regression and long-term survival in a variety of 
cancer models [29; 30; 31; 32]. In a study by Zeng et al., combination of anti-PD-1 antibody 
with radiotherapy in a mouse orthotopic GBM model generated robust and durable responses 
and doubled the survival when compared with either modality alone [33]. In this study, 
analysis of the brain and spinal cord of animals treated with combination therapy showed an 

 
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increase in the cytotoxic to regulatory T cell ratio with increased tumor infiltration by 
cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+).  
Our investigator initiated trial sponsored by Merck (NCT02313272) has shown promising 
results in patients with recurrent GBM who are treated with hypofractionated stereotactic 
radiotherapy combined with pembrolizumab and bevacizumab. We have treated 32 patients 
so far and combination is very well tolerated and several patients have achieved objective 
response (complete response+ partial response). Durable responses as long as 16 months 
have been observed.   
This supports addition of pembrolizumab to standard concurrent chemoradiotherapy for 
newly diagnosed GBM. 
Rational for combining vorinostat and pembrolizumab with radiotherapy and TMZ 
Vorinostat, an orally bioavailable hydroxymate pan-histone deacetylase (HDAC) inhibitor, 
has shown anti-tumor activity against GBM cell lines in vitro and in vivo orthotopic 
xenografts models [33]. Combination of vorinostat with TMZ and radiotherapy has resulted 
on synergistic effect on growth inhibition of glioma cell lines. Moreover, vorinostat readily 
penetrates the blood-brain barrier and has radiosensitizing properties. Tumor samples of 
patients with GBM who have received vorinostat before surgery has shown that vorinostat 
can penetrate tumors and inhibit histone acetylation [34]. 
A growing body of evidence indicates that epigenetic silencing of genes involved in antigen 
processing and immune recognition results in immune escape and resistance to 
immunotherapy [35; 36]. Pre-clinical experiments have shown that use of HDAC inhibitors 
such as vorinostat can restore tumor immune recognition and synergize with anti-PD 1/PD-
L1 antibodies [36].  Studies on several murine models have shown that combination therapy 
significantly enhances the response to PD-1 blockade immunotherapy by robustly inducing 
expression of multiple chemokines in tumor cells, tumor infiltrating macrophages and T 
cells. In addition, this combination has resulted in augmented T cell infiltration and T-cell 
dependent tumor regression [37]. These results suggest that combination of HDAC inhibitors 
with PD-1 blockade represents a potential therapeutic strategy to maximize the immune 
response to checkpoint inhibitors. 
Furthermore, Galanis et al. have investigated the safety and efficacy of concurrent 
chemoradiotherapy with TMZ and vorinostat in patients with newly diagnosed GBM. The 
combination therapy was safe and well tolerated without any cases of radiation necrosis. 
Based on this study, maximum tolerated dose (MTD) for vorinostat in combination with 
TMZ and radiotherapy in patients with newly diagnosed GBM is 300 mg/day, days 1-5 
weekly during concurrent therapy and 400 mg/day on days 1-7 and 15-21 during 
maintenance therapy with TMZ [34; 38]. 
Collectively, we haves strong pre-clinical evidence that combining PD-1/PDL-1 blockade 
with HDAC inhibitors such as vorinostat and radiotherapy plus TMZ independently enhance 
anti-tumor immune responses and tumor regression. Hence, it is of great interest to study the 

 
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combination of all these treatment modalities in newly diagnosed GBM patients with very 
limited treatment options. 
4.2.2 Rationale for Dose Selection/Regimen/Modification of Pembrolizumab (MK-
3475)   
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 MK-3475 showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 
mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule utilized in 
Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent data from 
other clinical studies within the MK-3475 program has shown that a lower dose of MK-3475 
and a less frequent schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher 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 

 
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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. 
4.2.3 Biomarker Research 
Archival tissue will be collected and assessed for direct evaluation of the intratumoral 
immune compartment. If biopsy or surgical tumor specimens become available following 
study treatment, these tissues will be included in the analysis. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Newly diagnosed glioblastoma or gliosarcoma 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Histologically confirmed diagnosis of World Health Organization Grade IV 
malignant glioma. 
2. An interval of ≥ 21 days since surgical resection prior to treatment on the trial 
3. Be  18 years of age on day of signing informed consent. 
4. Karnofsky performance status of 70 or higher 
5. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 21 days of treatment initiation.   
 
 

 
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Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
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 
aCreatinine clearance should be calculated per institutional standard. 
 
6. Resting baseline O2 saturation by pulse oximetry of ≥ 92% at rest. 
7. Be willing and able to provide written informed consent/assent for the trial. 
8. Life expectancy ≥ 12 weeks 
9. Willingness to discontinue medications known to be associated with risk of Torsades 
de 
Pointes 
such 
as 
quinidine, 
procainamide, 
disopyramide, 
amiodarone, 
erythromycin, clarithromycin, chlorpromazine and haloperidol.  
10. Single lesion < 4 cm in longest diameter (diameter of enhancing lesion) 
11. Patient shouldn’t have received any anti-cancer therapy for glioblastoma in past. 
12. Female subject of childbearing potential should have a negative urine or serum 
pregnancy 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 (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception,  for 
the course of the study through 120 days after the last dose of study medication. 

 
Page 15 of 78 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
14. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate 
method of contraception as outlined in Section 5.7.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
15. Use of Optune device is allowed. 
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Had prior treatment of GBM with radiation and temozolomide. 
2. Has evidence of leptomeningeal disease. 
3. Had prior treatment with Gliadel. 
4. Is unable (due to existent medical condition) or unwilling to have a contrast enhanced 
MRI of brain. 
5. Is currently participating 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. 
6. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. Physiologic doses of steroid therapy (≤ 2 mg/day dexamethasone 
equivalents) by the time of first dose of treatment are allowed. 
 
7. Has a known history of active TB   (Bacillus Tuberculosis) 
 
8. Hypersensitivity to pembrolizumab or any of its excipients. 
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, 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. 

 
Page 16 of 78 
 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
11. 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. 
12. Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
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 with vitiligo or resolved 
childhood asthma/atopy would be an exception to this rule.  Subjects that require 
intermittent use of bronchodilators or local steroid injections would not be excluded 
from the study.  Subjects with hypothyroidism stable on hormone replacement or 
Sjorgen’s syndrome will not be excluded from the study. 
13. Has known history of, or any evidence of active, interstitial lung disease or non-
infectious pneumonitis requiring corticosteroid therapy. 
14. Has an active serious infection requiring systemic therapy. 
15. Had major surgical procedure, open biopsy, or significant traumatic injury within 21 
days prior to day 1 of treatment on study. 
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
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 received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
20. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
21. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 

 
Page 17 of 78 
 
22. 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. 
5.2 
Radiation therapy 
5.2.1 Dose Specifications 
Radiation therapy should begin after substantial recovery from surgical resection, not more 
than 42 (+/- 7) days after surgery. External-beam RT to a total dose of 60 Gy will be 
administered in daily doses of 2 Gy, typically on a 5 days on / 2 days off schedule as 
appropriate for scheduling, over 6-7 weeks. RT is administered to the pre-operative tumor 
volume plus a 2-3 cm margin, as directed by a radiation oncologist. Radiation therapy can be 
administered in a local facility. 
5.2.2  Radiation Therapy Adverse Events 
5.2.2.1 Acute 
Expected acute radiation-induced toxicities include hair loss, fatigue, and erythema or 
soreness of the scalp. Potential acute toxicities include nausea and vomiting as well as 
temporary aggravation of brain tumor symptoms such as headaches, seizures, and weakness. 
Reactions in the ear canals and on the ear should be observed and treated symptomatically; 
these reactions could result in short-term hearing impairment. Dry mouth or altered taste has 
been occasionally reported. 
5.2.2.2 Early Delayed 
Possible early delayed radiation effects include lethargy and transient worsening of existing 
neurological deficits occurring 1-3 months after radiotherapy treatment. 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
5.2.2.3 Late Delayed 
Possible late delayed effects of radiotherapy include risk of radiation necrosis, and endocrine 
dysfunction. In addition, neurocognitive deficits, which could lead to mental slowing and 
behavioral change, are possible. Permanent hearing impairment and visual damage are rare. 
Cataracts can be encountered. 
5.3 
Trial Treatments 
Treatment must begin within 21 days of registering to the trial. Treatment should also begin 
≥ 3 weeks and ≤ 6 (+/1) weeks following surgery.  Each cycle will consist of 12 weeks. 

 
Page 18 of 78 
 
 
Dose Escalation Cohort:  
 
Treatment will include two phases: 1) concurrent radiotherapy phase and 2) maintenance 
phase. Dose escalation will occur separately for concurrent radiotherapy part of treatment 
and maintenance part of treatment.  
The dose of pembrolizumab will be 200 mg dose IV every 3 weeks. The starting dose (i.e., 
dose level 1) of vorinostat was 200 mg/day orally on days 1-5 every week during 
radiotherapy and 300 mg/day orally 1 week on 1 week off during maintenance phase, starting 
after completion of concurrent therapy with radiation (+/- 3 days).  The dose of vorinostat 
during radiotherapy was reduced to 100 mg mg/day orally on days 1-5 every week due to 
DLT. This dose is well tolerated and is currently being expanded. 
The starting dose of vorinostat during maintenance phase, beginning after completion of 
concurrent therapy with radiation (+/- 3 days) was 300 mg/day orally 1 week on 1 week off. 
The dose is escalated to 400 mg/day orally 1 week on 1 week off, as per schema in a 3+3 
fashion.  
 
Concurrent Radiotherapy Phase: 
During concurrent radiotherapy phase of treatment, patients with newly diagnosed GBM will 
receive radiotherapy (60 Gy in 30 daily fractions) as mentioned above.  
Temozolomide (75 mg/m2/day orally) will be administered daily during the course of 
radiotherapy as per standard of care [22]. Temozolomide will be administered continuously 
from Day 1 of radiotherapy to the last day of radiation at a daily oral dose of 75 mg/m2. The 
dose will be determined using actual body surface area (BSA) as calculated in square meters 
at the beginning of the concomitant treatment. The BSA will be calculated from the height 
obtained at the screening visit and the weight obtained at the visit immediately before the 
first day of treatment. The dose of temozolomide does not have to be adjusted unless there 
has been at least a 10% change in body weight; recalculation of dose for < 10% weight 
changes is allowed at the discretion of the Investigator. The daily dose will be rounded to the 
nearest 5 mg.  
Vorinostat will be administered orally at 100, 200 or 300 mg/day dose on days 1-5 every 
week (based on dose level); starting on first day of radiotherapy. Safety and tolerability of 
vorinostat 300 mg/day dose on days 1-5 every week in combination with temozolomide (75 
mg/m2/day orally) has been proven in a phase I/II trial (N0874-ABTC 0902, Alliance) by 
Galanis et al. 2014 [38]. 
Pembrolizumab will be administered as an IV intravenous infusion and will be evaluated at 
200 mg. Pembrolizumab will be administered every 3 weeks (+/-3 days) starting on first day 
(+/- 3days) of radiotherapy. 

 
Page 19 of 78 
 
Table 2 summarizes the doses for pembrolizumab and vorinostat during radiotherapy 
part of treatment. 
Dose Escalation Schedule During Radiotherapy Phase 
Dose Level 
                                                           Dose 
Pembrolizumab  
Vorinostat  
Level -1 
200 mg IV every 3 weeks 
100 mg/day orally on days 1-5 every week during radiotherapy 
 
Level  1 
200 mg IV every 3 weeks 
200 mg/day orally on days 1-5 every week during radiotherapy 
 
Level 2 
200 mg IV every 3 weeks 
300 mg/day orally on days 1-5 every week during radiotherapy 
 
 
Maintenance Phase: 
During maintenance phase, temozolomide will start 4 weeks  (+/- 7 days) after last dose of 
radiotherapy and will continue for 6 cycles post radiotherapy (150-200 mg/m2/day, days 1-5 
every 4 +/- 1 weeks) as per standard of care [22]. As per standard of care, the starting dose 
for the first cycle will be 150 mg/m2/day, with a single dose escalation to 200 mg/m2/day in 
subsequent cycles if no temozolomide-related adverse events > Grade 2 are noted. The dose 
will be determined using the BSA calculated at the beginning of each treatment cycle. The 
BSA will be calculated from the height obtained at the screening visit and from the weight 
obtained at the visit immediately before each cycle. The dose of temozolomide does not have 
to be adjusted unless there has been at least a 10% change in body weight; recalculation of 
dose for < 10% weight changes is allowed at the discretion of the Investigator. The dose will 
also not be capped for those that are overweight. The daily dose will be rounded to the 
nearest 5 mg (where dosage strengths are available to accommodate rounding to 5 mg). 
Vorinostat will be administered orally at 200, 300 or 400 mg/day (based on dose level) on a 1 
week on 1 week off schedule for 12 months.  Vorinostat will start the day after completion 
of radiotherapy (+ 3 days). Safety of vorinostat 400 mg/day on a 1 week on 1 week off 
schedule in combination with maintenance temozolomide has been shown in a phase 1 study 
by Lee et al. 2012 [34]. 
Pembrolizumab 200 mg IV will continue every 3 weeks (+/-3 days) for 12 months or 18 
infusions whatever comes first.   
Table 3 summarizes the doses for pembrolizumab and vorinostat during maintenance part of 
treatment. 

 
Page 20 of 78 
 
Table 3  Dose Escalation Schedule for Pembrolizumab and Vorinostat maintenance 
part of treatment. 
Dose Escalation Schedule During Maintenance Phase 
Dose Level 
                                                           Dose 
Pembrolizumab  
Vorinostat  
Level -1 
200 mg IV every 3 weeks 
200 mg/day orally 1 week on 1 week off  after radiotherapy 
Level  1 
200 mg IV every 3 weeks 
300 mg/day orally 1 week on 1 week off  after radiotherapy 
Level 2 
200 mg IV every 3 weeks 
400 mg/day orally 1 week on 1 week off after radiotherapy 
 
In all patients, treatment with study drugs will continue until confirmed disease progression, 
patient refusal, patient lost to follow up, unacceptable toxicity, completion of scheduled 
dosing, whichever occurs first, or the study is terminated by the Sponsor (Moffitt Cancer 
Center). 
Dose Expansion Phase: 
 
The vorinostat doses used in the dose expansion cohort will be MTD determined from the 
dose escalation phase.  
Definition of Maximum Tolerated Dose: 
 
The maximum tolerated dose (MTD) is the highest dose of vorinostat in combination with 
pembrolizumab, temozolomide during and after radiation therapy that does not cause 
unacceptable toxicity in more than one of six patients at that dose level. The MTD is defined 
as one dose level below the highest toxic dose (i.e., the DLT dose).  
 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.3.1 5.3.1 Definition of Dose-Limiting Toxicity 
Toxicities will be graded in severity according to the guidelines outlined in the NCI-CTCAE 
version 4.0. Dose limiting CNS and non-CNS toxicities will be defined differently and will 
be based on events that occur during the study period. In order to be declared as dose-
limiting toxicity, an adverse event must be related to pembrolizumab and/or vorinostat. 
A dose-limiting toxicity (DLT) will be defined as any one of the following adverse events 
occurring within 6 weeks from last dose of radiation therapy for radiotherapy phase and 4 
weeks from the start day of maintenance dose of vorinostat [Cycle 1 Day 43 (+/-3)] for 
maintenance phase: 

 
Page 21 of 78 
 
     CNS toxicities: 
      Acute CNS toxicities (occurring ≤ 30 days after completing radiation therapy):  
 Any grade 3 or higher central nervous adverse events including but not limited 
to headache, dizziness, vertigo, new onset seizures, cerebral edema, cerebral 
hemorrhage, and new onset neurologic deficit. 
      Delayed onset CNS toxicities (occurring >30 days after completing radiation therapy): 
 Any grade 3 or 4 adverse event arising within the irradiated volume including 
but not limited to focal neurological deficits. 
      Non-CNS toxicities:       
 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)  
 Concurrent vitiligo or alopecia of any AE grade  

 
Page 22 of 78 
 
 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 14 days. Grade 3 or Grade 4 febrile 
neutropenia will be a DLT regardless of duration or reversibility  
 Grade 3 or 4 lymphopenia  
 Grade 3 or 4 thrombocytopenia that is not associated with clinically significant 
bleeding that requires medical intervention, and improves by at least 1 grade 
within 14 days  
 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  
 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.  
Dose escalation will be determined based on the occurrence of DLTs. For the purposes of 
determining whether to advance the dose levels, DLTs will be counted by patient. For all 
observed toxicities, subjects should be assessed for inter-current illness or other causes and 
treated as appropriate. 
 
In the event of the development of any grade 3 or 4 toxicity felt to be at least possibly related 
to pembrolizumab, pembrolizumab will be held until resolution to grade 1 or baseline 
assuming that occurs within 6 weeks window. Treatment with pembrolizumab can be 
resumed after resolution of DLT to grade 1 or baseline except for following adverse events: 
Grade 4 infusion reactions, ≥ Grade 3 pneumonitis, ≥ Grade 3 nephritis, ≥ Grade 3 colitis, 
increased  alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 
5 times upper limit of normal or total bilirubin greater than 3 times upper limit of normal.   
 
Dose escalation for vorinostat will follow the standard 3+3 design. The enrollment to 
expansion cohort for radiotherapy phase will be delayed for 6 weeks after the completion of 
radiation therapy by the last patient enrolled at the MTD dose level for radiation therapy 
phase. The enrollment to expansion cohort for maintenance phase will be delayed for 4 
weeks after the start day of maintenance dose of vorinostat [Cycle 1 Day 43 (+/-3)] by the 

 
Page 23 of 78 
 
last patient enrolled at the MTD dose level for maintenance phase. This period will allow 
monitoring potential delayed toxicities. Dose escalation/de-escalation will proceed according 
to the following scheme.   
 
Table 3 Dose Escalation Decision Rule 
 
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be declared the 
maximally administered dose (highest dose administered).  Three (3) 
additional patients will be entered at the next lowest dose level if only 
3 patients were treated previously at that dose. 
1 out of 3 
or 
≥ 2 grade 2 CNS toxicities 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, proceed to the expansion 
cohort. 
 If 1 or more of this group suffer DLT, then dose escalation is 
stopped, and this dose is declared the maximally administered dose.  
Three (3) additional patients will be entered at the next lowest dose 
level if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the dose to be used in the expanded cohort and will be 
considered recommended phase 2 dose.  
5.3.2 Dose Selection/Modification 
5.3.2.1 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 the dose calculation, preparation and administration 
are provided in the Pharmacy Manual. 
5.3.2.2 Dose Modification/Delay 
If the adverse event is related to only one drug, the dose modification/delay will be followed 
as per guidelines for that specific drug (outlined below) and other treatments will continue 
with no modification/delay. In cases that the AE can be related to more than one drug, all 
contributing drugs should be modified/delayed as per each drug’s specific guideline. 
5.3.2.2.1 Pembrolizumab 
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 

 
Page 24 of 78 
 
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 4 below.  
See Section 5.6.1 and Events of Clinical Interest Guidance Document for supportive care 
guidelines, including use of corticosteroids. 
Table 4 Dose Modification Guidelines for Pembrolizumab-Related Adverse Events 
Toxicity 
Hold 
Pembrolizumab 
For Grade 
Timing for Restarting 
Pembrolizumab 
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 
Hyperthyroidism  
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 
Permanently discontinue if 
recurrent pneumonitis.   
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. Discontinue 
pembrolizumab permanently for recurrent Grade 2 pneumonitis.  
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 Severe 
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 

 
Page 25 of 78 
 
Toxicity 
Hold 
Pembrolizumab 
For Grade 
Timing for Restarting 
Pembrolizumab 
Discontinue Subject 
12 weeks of the last dose.   
 
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. 
5.3.2.2.2 Vorinostat 
Dose interruption/hold/modification for vorinostat can occur at any time during treatment on 
study and are only performed if the event that caused the modification is possibly, probably or 
definitely related to vorinostat. 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). 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 26 of 78 
 
Toxicity 
Actions 
Grade 1 hematological 
ANC ≥1500 
Platelets < 100,000 but >75,000 
Grade 2 hematological 
Platelets < 75,000 but > 50,000 
Neutrophils (ANC) < 1500 but > 1000 
Grade 3-4 hematological 
Platelets and  ANC Only 
Platelets < 50.0 x 109 /L 
Neutrophils (ANC) < 1.0 x 109/L 
or Grade 3 non-hematological 
1. Continue with protocol therapy. 
1. Hold vorinostat until toxicity recovered 
to < grade 1 
2. Check CBC prior to next planned vorinostat dose 
3. If recovered resume treatment with no dose 
modification. If not recovered, continue to hold and 
re-check CBC at next planned vorinostat dose. 
1. Interrupt vorinostat, instituting symptomatic 
therapy as appropriate, until recovery to grade 1 
2. Reintroduce vorinostat as follows: 
reduce by one dose level. If vorinostat is already 
at the lowest dose level, discontinue further 
vorinostat. 
3. If toxicity remains at grade 1 after 4 weeks of 
treatment at reduced dosage, then at the 
discretion of the investigator a return to the 
initial vorinostat dosage may be made 
- If reappearance of above after actions 1 & 
2 
Discontinue treatment with vorinostat 
- If reappearance of above after actions 1-3 
Repeat 1 & 2 above but not 3. 
Grade 3 non–hematological (only) 
- If failure to return to grade  1 after 
     action 1 
Consider action 2 at the discretion of the 
investigator only if toxicity is grade 2, 
manageable, and patient was benefiting  from therapy 
Grade 4 non- hematological toxicity 
Discontinue vorinostat 
 
5.3.2.2.3 Temozolomide 
Temozolomide During Concomitant Radiation Therapy Phase 
Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) is required for all subjects 

 
Page 27 of 78 
 
receiving concomitant temozolomide and radiotherapy. 
No temozolomide dose reduction will be made, but delay or discontinuation of temozolomide 
administration will be decided weekly according to hematologic and non-hematologic 
adverse events (AEs), as specified below. 
If the administration of temozolomide has to be interrupted, the radiotherapy, pembrolizumab 
and vorinostat will proceed normally as long as the adverse event is solely related to 
temozolomide as per investigator’s assessment. Missed doses of temozolomide will not be 
made up at the end of radiotherapy. 
 
If one or more of the following are observed: 
ANC ≥ 0.5 and < 1.5 × 109/L 
Platelet count ≥ 10 and < 100 × 109/L 
Grade 2 non-hematologic AE considered possibly related to temozolomide (except 
alopecia, nausea and vomiting while on maximal antiemetic therapy, and fatigue) 
 
then treatment with concomitant temozolomide will be withheld until all of the following 
conditions are met: 
 
ANC ≥ 1.5 × 109/L 
Platelet count ≥ 100 × 109/L 
Grade ≤ 1 non-hematologic AE (except alopecia, nausea and vomiting, and fatigue) 
In case of hematologic AE as defined above, a complete blood count (CBC) should be 
performed at least twice weekly. In case of non-hematologic AE, the subject should be 
assessed at least weekly with relevant laboratory test(s). As soon as all of the above 
conditions are met, the administration of temozolomide will resume at the same dose as used 
initially. 
 
If one or more of the following are observed: 
ANC < 0.5 × 109/L (Grade 4) 
Platelet count < 10 × 109/L (Grade 4) 
Grade 3 or 4 non-hematologic AE considered possibly related to temozolomide (except 
alopecia, nausea and vomiting unless the subject has failed maximal antiemetic therapy, and 
fatigue) 
 
then treatment with concomitant temozolomide should be stopped. 
 
If the duration of radiotherapy exceeds 7 weeks, then concomitant treatment with 
temozolomide should be stopped after 42 days of temozolomide treatment. 
 
 
 
 
 
 

 
Page 28 of 78 
 
Summary of Temozolomide Delay or Discontinuation During Concomitant Radiation 
Therapy 
 
AE 
Value 
Grade 
Action 
ANC 
≥ 0.5 and < 1.5 × 109/L 
2, 3 
Delay temozolomide 
until: 
---ANC ≥ 1.5 × 109/L 
---Platelet ≥ 100 × 109/L 
---Non-hem AE ≤ Grade 1 
Platelet count 
≥ 10 and < 100 × 109/L 
2, 3 
Non-hematologic (except 
alopecia, nausea/vomiting unless 
on maximal antiemetic therapy) 
NA 
2 
ANC 
< 0.5 × 109/L 
4 
Stop concomitant 
temozolomide 
Platelet count 
< 10 × 109/L 
4 
Non-hematologic (except 
alopecia, nausea/vomiting) 
NA 
3 or 4 
 
Post-Radiation (maintenance) Temozolomide 
 
Continued dosing administration is based on adverse events (AEs) during the prior treatment 
cycle. If multiple AEs are seen, the dose administered should be based on the dose reduction 
required for the most severe grade of any single AE. 
 
On Day 1 of each cycle (within the prior 72 hours), ANC ≥ 1.5 × 109/L, platelet count 
≥ 100 × 109/L and all treatment-related grade 3 or 4 non-hematologic AEs (except alopecia, 
nausea, and vomiting) must have resolved (to grade ≤ 1). 
If temozolomide related AEs persist, treatment should be delayed by 2 weeks for up to 4 
consecutive weeks. If, after 4 weeks of delay, all temozolomide related AEs have still not 
resolved, then any further adjuvant treatment with temozolomide should be stopped. 
 
If, during the first cycle, all non-hematologic AEs observed were grade ≤ 2 (except alopecia, 
nausea and vomiting) and with platelets ≥ 100 × 109/L and ANC ≥ 1.5 × 109/L, then the 
temozolomide dose should be escalated to 200 mg/m2/day and this dose should be used as the 
starting dose for subsequent cycles. If treatment after cycle 1 has to be delayed because of 
ongoing non-hematologic AEs of grade ≥ 2, then no escalation is possible. If the dose was 
not escalated at cycle 2, then the dose should not be escalated in further cycles (Cycles 3 – 6). 
Treatment beyond cycle 6 can be allowed after discussion with Sponsor. In such cases 
treatment with temozolomide should stop after total of 12 cycles. 
 
If any non-hematologic AE observed was grade > 2 (except alopecia, nausea and vomiting) 
and/or if platelets < 50 × 109/L and/or ANC < 1 × 109/L, then the dose should be reduced to 
150 mg/m2/day if patient was receiving 200 mg/m2/day or 100 mg/m2/day if patient was on 
150 mg/m2/day when the AE occurred. 
 
For subjects who would require dose reductions to < 100 mg/m2/day, temozolomide will be 
stopped. Also, if any of the same non-hematologic grade 3 AE recurs (except alopecia, 
nausea and vomiting) after reduction for that AE, then temozolomide will be stopped. 
If any treatment-related non-hematologic AE observed was grade 4 (except alopecia, nausea 
and vomiting) then adjuvant temozolomide treatment should be stopped. 

 
Page 29 of 78 
 
 
Important: If the dose was reduced or delayed for adverse events, there will be no dose 
escalation in future cycles. 
 
5.3.3 Timing of Dose Administration 
Trial treatment should be administered after all procedures/assessments have been completed 
as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be administered up to 
3 days before or after the scheduled day due to administrative reasons.  
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered as a 30 minute IV infusion every 3 weeks (+/- 3 days).  
However, given the variability of infusion pumps, a window of -5 minutes and +10 minutes 
is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
Vorinostat should be taken with food, at regular intervals regardless of pembrolizumab 
infusion time.  On days the patient receives pembrolizumab, the vorinostat should be taken 
prior to the pembrolizumab infusion. 
Temozolomide should be given on empty stomach, at regular intervals regardless of 
pembrolizumab infusions or vorinostat. On days the patient receives pembrolizumab, the 
temozolomide can be taken prior to or after the pembrolizumab infusion. In patients who do 
not experience nausea, temozolomide can be taken after a small meal. 
5.3.4 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.4 
Treatment Allocation 
Dose level allocation will be performed by the Sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments. 
After review of patient’s eligibility and concomitant medications, the Sponsor (Moffitt 
Cancer Center) will approve patient’s enrollment, if appropriate, and assign a patient 
identification number, which will be used on all Case Report Form (CRF) pages and other 
trial-related documentation or correspondence referencing that patient. 
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 

 
Page 30 of 78 
 
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 principal investigator of study.  The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the subject's primary physician. However, the 
decision to continue the subject on trial therapy or vaccination schedule requires the mutual 
agreement of the Investigator, the Sponsor (Moffitt Cancer Center), and the subject. 
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. Only corticosteroids will be recorded on the case report form (CRF).  If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF. 
Although single doses of Vorinostat of up to 800 mg did not result in QTc prolongation, 
Vorinostat should be administered with particular caution in patients taking anti-arrhythmic 
medicines or other medicinal products that lead to QT prolongation. 
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 
other 
than 
temozolomide, pembrolizumab and vorinostat 
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab and vorinostat 
 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 required by patient’s 
symptoms.  The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor. 
 Any drug which is associated with risk of Torsades de Pointes 
 Vorinostat should not be administered concomitantly with other HDAC inhibitors 
(e.g., valproic acid) as class-specific adverse reactions may be additive. 

 
Page 31 of 78 
 
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. 
The major pathway(s) for metabolism of vorinostat involves glucuronidation and 
hydrolysis followed by β-oxidation. Therefore, it is anticipated that vorinostat will not be 
subject to drug-drug interactions when co-administered with drugs that are known to be 
CYP enzyme inhibitors. Formal drug-drug interaction studies have not been performed 
with vorinostat.  
- 
Prolongation of prothrombin time (PT) and International Normalized Ratio 
(INR) has been observed in patients receiving vorinostat concomitantly with 
coumarin- derivative anticoagulants. Physicians should carefully monitor PT 
and INR in patients concurrently administered vorinostat and coumarin 
derivatives. 
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. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). 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.  
 Pneumonitis:  

 
Page 32 of 78 
 
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 A second episode of grade  2 pneumonitis mandates discontinuation of study 
therapy. 
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. 
 
 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, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, 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: 

 
Page 33 of 78 
 
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 
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. 

 
Page 34 of 78 
 
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.  
Below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 5 Infusion Reaction (Pembrolizumab) 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. 
 
 

 
Page 35 of 78 
 
 Nausea and vomiting should be treated aggressively, and strong consideration 
should be given to the administration of prophylactic antiemetic therapy according to 
standard institutional practice. In particular, the use of antiemetics including 5HT3 
antagonists is encouraged. Patients should be strongly encouraged to maintain liberal 
oral fluid intake during therapy. 
 Hypokalemia or hypomagnesemia should be corrected prior to administration of 
vorinostat, and consideration should be given to monitoring potassium and 
magnesium in symptomatic patients (e.g. patients with nausea, vomiting, diarrhea, or 
fluid imbalance.) 
 
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, vorinostat, and temozolomide may have adverse effects on a fetus in utero.  
Furthermore, it is not known if pembrolizumab, temozolomide and vorinostat have transient 
adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 

 
Page 36 of 78 
 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 
 Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
 ‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 

 
Page 37 of 78 
 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with study regimen, 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 Sponsor (Moffitt 
Cancer Center) 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 
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 study drugs are 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 (Moffitt Cancer Center) 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. 

 
Page 38 of 78 
 
 Unacceptable adverse experiences as described in Section 5.3.2 
 Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 
7.1.2.6 
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 7.1.2.6 
 Unacceptable adverse experiences as described in Section 5.3.2 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 15 months of uninterrupted treatment with pembrolizumab or 20 
administrations of study medication, whichever is later. 
Note: 15 months of study medication is calculated from the date of first dose.  
 Administrative reasons 
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 end of treatment, 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. 
5.9 
Subject Replacement Strategy 
In dose escalation phase, subject will be replaced if they are considered inevaluable. A 
subjects will be considered DLT-evaluable if they have incurred a DLT within a DLT 
evaluation period or meet all of the following criteria: a) have received at least 85% of the 
prescribed doses of vorinostat, b) have received at least 85% of the prescribed doses of 
pembrolizumab, and c) have received the full dose (60 Gy) of radiation. 

 
Page 39 of 78 
 
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. 
 

 
 
 
Page 40 of 78 
 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
       Concurrent Radiotherapy Phase 
Trial Period: 
Screening Phase 
Treatment Cycles  
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) a 
Cycle 1 (Concurrent therapy with radiation, 12 weeks) 
Scheduling Window (Days): 
 
-21 to -1 
D1  
± 3 
D8  
± 3 
D15
± 3 
D22 
± 3 
D29  
± 3 
D36 
± 3 
D43
± 3 
D50
± 3 
D57
± 3 
D64 
± 3 
D71  ± 7 
D78 
± 3 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Radiation therapy 
 
 
X  
 (Total dose of 60 Gy; Monday-Friday) 
 
 
 
 
 
Temozolomide 
 
 
X 
Every day  
 
 
 
X (5 day regimen 
every 28 days) 
 
Pembrolizumab 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Vorinostat 
 
 
Days 1-5 of every week during radiation  
Daily one week on-one week off starting after radiation +/- 3 days 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Procedures/Assessments 
Review Adverse Events c 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Full Physical Examination 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 

 
 
 
Page 41 of 78 
 
 
Trial Period: 
Screening Phase 
Treatment Cycles  
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) a 
Cycle 1 (Concurrent therapy with radiation, 12 weeks) 
Scheduling Window (Days): 
 
-21 to -1 
D1  
± 3 
D8  
± 3 
D15
± 3 
D22 
± 3 
D29  
± 3 
D36 
± 3 
D43
± 3 
D50
± 3 
D57
± 3 
D64 
± 3 
D71  ± 7 
D78 
± 3 
Vital Signs and Weight 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
EORTC QLQ-C30 and  BNS20 
Questionnaire 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Karnofsky Performance Status 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Urinalysis 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
T3, FT4 and TSH 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Efficacy Measurements 
Brain MRI  with/without contrast 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection  
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
a Visit 1 assessment (physical examination and laboratories) can be used for main study screening (visit 2) if visit 2 occurs within 3 days from visit 1. 
b There will be two follow up visits which include full physical examination, laboratories, and brain MRI. 
c After the end of treatment, each subject will be followed for 30 days for adverse event monitoring. Serious adverse events will be collected for 90 days after the treatment. 

 
 
 
Page 42 of 78 
 
 
 
        Maintenance Phase 
Trial Period: 
Treatment Cycles  
Treatment Cycle/Title: 
Cycles 2 and 3 (12 weeks) 
Scheduling Window (Days): 
D1± 3 
D2-5± 3 
D22± 3 
D29 ± 3 
D30-33 ± 3 
D43± 3 
D57± 3 
D58-61± 3 
D64  ± 3 
Administrative Procedures 
Informed Consent 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
X 
 
 
X 
 
 
X 
Prior and Concomitant Medication Review 
X 
 
X 
 
 
X 
 
 
X 
Radiation therapy 
 
 
 
 
 
 
 
 
 
Temozolomide 
X (5 consecutive days every 28 days for total of 6 months)  
 
Pembrolizumab 
X 
 
X 
 
 
X 
 
 
X 
Vorinostat 
Daily one week on-one week off  +/- 3 days 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
Clinical Procedures/Assessments 
Review Adverse Events c 
X 
 
X 
 
 
X 
 
 
X 
Full Physical Examination 
X 
 
X 
 
 
X 
 
 
X 
Vital Signs and Weight 
X 
 
X 
 
 
X 
 
 
X 
EORTC QLQ-C30 and BNS20 Questionnaire 
X 
 
X 
 
 
X 
 
 
X 
Karnofsky Performance Status 
X 
 
X 
 
 
X 
 
 
X 
 
Pregnancy Test – Urine or Serum -HCG 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
 
X 
X 
 
X 
X 
 
X 
Comprehensive Serum Chemistry Panel 
X 
 
X 
 
 
X 
 
 
X 

 
 
 
Page 43 of 78 
 
 
Trial Period: 
Treatment Cycles  
Treatment Cycle/Title: 
Cycles 2 and 3 (12 weeks) 
Scheduling Window (Days): 
D1± 3 
D2-5± 3 
D22± 3 
D29 ± 3 
D30-33 ± 3 
D43± 3 
D57± 3 
D58-61± 3 
D64  ± 3 
Urinalysis 
X 
 
X 
 
 
 
 
 
X 
T3, FT4 and TSH 
X 
 
X 
 
 
X 
 
 
X 
 
Brain MRI  with/without contrast 
Every 6 +/- 4 weeks 
 
Archival or Newly Obtained Tissue Collection 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection  
X 
 
X 
 
 
X 
 
 
 
 
 

 
 
 
Page 44 of 78 
 
 
Trial Period: 
Treatment Cycles  
End of Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Cycles 4 and 5 (12 weeks) 
Discon 
Safety Follow-up 
Follow Up Visits b 
Survival Follow-Up 
Scheduling Window (Days): 
D1± 3 
D22± 3 
D43± 3 
D64  ± 3 
At time of Discon 
30 (+7 days post 
discon 
Every 8± 3 weeks post 
discon 
Every 12 (+/- 4) weeks  
Administrative Procedures 
Informed Consent 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
X 
X 
X 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
 
 
Radiation therapy 
 
 
 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
 
 
 
Pembrolizumab 
X 
X 
X 
X 
 
 
 
 
Vorinostat 
Daily one week on-one week off ± 3 days 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events c 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
 
EORTC QLQ-C30 and BNS20 Questionnaire 
X 
 
X 
X 
X 
 
X 
 
Karnofsky Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Test – Urine or Serum -HCG 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
X 
 
X 
X 
X 
 
T3, FT4 and TSH 
X 
X 
X 
X 
X 
X 
 
 

 
 
 
Page 45 of 78 
 
 
Trial Period: 
Treatment Cycles  
End of Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Cycles 4 and 5 (12 weeks) 
Discon 
Safety Follow-up 
Follow Up Visits b 
Survival Follow-Up 
Scheduling Window (Days): 
D1± 3 
D22± 3 
D43± 3 
D64  ± 3 
At time of Discon 
30 (+7 days post 
discon 
Every 8± 3 weeks post 
discon 
Every 12 (+/- 4) weeks  
 
Brain MRI  with/without contrast 
Every 8 +/- 2 weeks 
X 
 
X 
 
 
Archival or Newly Obtained Tissue Collection 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection  
 
 
 
 
 
 
 
 
 
a Visit 1 assessment (physical examination and laboratories) can be used for main study screening (visit 2) if visit 2 occurs within 3 days from visit 1. 
b There will be two follow up visits which include full physical examination, laboratories, and brain MRI. 
c After the end of treatment, each subject will be followed for 30 days for adverse event monitoring. Serious adverse events will be collected for 90 days after the treatment. 

 
 
 
 
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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 or qualified designee 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.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 

 
 
 
 
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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 brain tumor 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
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 brain cancer 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. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 
(+7) days after the last dose of trial treatment or discontinues active anti-tumor treatment 
(e.g. enrolling to hospice), the 30 day Safety Follow-up visit will not occur.  Once new anti-
cancer therapy has been initiated the subject will move into survival follow-up.  

 
 
 
 
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7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 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, and study visits as per 
the Trial Flow Chart. 
7.1.2.3 Directed Physical Exam 
For visits 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.   
7.1.2.4 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. 
7.1.2.5 Karnofsky Performance Scale (KPS) 
The investigator or qualified designee will assess KPS status at screening, prior to the 
administration of each dose of pembrolizumab and discontinuation of trial treatment as 
specified in the Trial Flow Chart.    
7.1.2.6 Tumor Imaging and Assessment of Disease 
All subjects will receive efficacy assessments with brain MRI at time points specified in Trial 
Flow Chart.  All MRIs (except the initial screening MRI) should occur at +/- 14 days per 
scheduled visits. Investigators may obtain more frequent follow-up MRI scans as medically 
indicated. Cases of suspected radiologic disease progression will be confirmed by an MRI 
performed approximately 8 weeks after the initial radiological assessment of progression. 

 
 
 
 
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Both Response Assessment Criteria for High-Grade Gliomas (RANO Criteria) and 
Immunotherapy Response Assessment in Neuro-Oncology (iRANO) will be used for 
assessing the response to study treatment. 
7.1.2.7 Tumor Tissue Collection and Correlative Studies  
Archival tumor tissue will be collected prior to therapy. If a biopsy or surgical resection is 
performed at the time of progression, tumor sample (block or slides) should be submitted for 
analysis. 
7.1.3 Laboratory Procedures/Assessments 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6.  
The total amount of blood to be drawn over the course of the trial (from pre-trial to post-trial 
visits), including approximate blood volumes drawn by visit and by sample type per subject 
can be found in the Procedures Manual.  
 

 
 
 
 
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Table 6 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Thyroid stimulating hormone (TSH) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Urine pregnancy test † 
Total thriiodothyronine (T3) 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Free tyroxine (T4) 
Absolute Neutrophil Count 
Uric Acid 
results are noted 
 
Absolute Lymphocyte Count 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphorus 
 
Blood for correlative studies 
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
† 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. 
 
 
 

 
 
 
 
Page 51 of 78 
 
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.  
7.1.3.1 Pharmacodynamic Evaluations 
7.1.3.1.1 Blood Collection for Serum Correlative Studies 
No serum correlative studies will be performed. 
7.1.4 Other Procedures 
7.1.4.1 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.  After discontinuing treatment, 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). 
7.1.5 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. 
7.1.5.1 Screening 
7.1.5.1.1 Screening Period 
Screening period begins by establishing the subject’s initial eligibility and signing of the 
informed consent form (ICF). Study treatment should be given within 21 days of signing 
ICF. 
7.1.5.2 Treatment Period 
Treatment period should start within 21 days of signing ICF unless discussed by Sponsor. 
Treatment period will start with concurrent chemoradiotherapy with temozolomide, 
pembrolizumab and vorinostat on C1 D1 (Radiotherapy Phase). 
All of the laboratories and vital signs will be collected prior to study drug dosing at the time 
points specified in Trial Flow Chart. 
Adverse event assessments will be documented at each visit throughout the study. 

 
 
 
 
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Quality of Life assessments using EORTC QLQ-C30 and BNS20 to be completed as 
described in Trial Flow Chart. 
Response to treatment will be assessed by the investigator and according to the RANO and 
iRANO criteria. Brain MRI will be performed according to the schedule in Trial Flow Chart 
until disease progression or treatment discontinuation, whichever occurs later. Brain MRIs 
can be obtained in shorter intervals as per physician discretion. 
7.1.5.3 Post-Treatment Visits 
Post-Treatment period begins when the decision to discontinue a subject from study therapy 
is made (no further study treatment). 
There will be two follow-up visits which include full physical examination, laboratories, and 
brain MRI. 
Quality of Life questionnaires will be completed in post-treatment visits. 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 (+7) days 
after the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment or discontinues active anti-tumor treatment (e.g. 
enrolling to hospice), the 30 day Safety Follow-up visit will not occur. 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. 
 
7.1.5.4 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 (± 3 week) by 
radiologic imaging to monitor disease status.  All radiologically determined disease 
progression must be confirmed by an additional confirmatory MRI scan approximately 8+/- 3 
weeks following the initial assessment of radiological progression. 
Every effort should be made to collect information regarding disease status until the start of 
new anti-neoplastic therapy, disease progression, death or end of the study. 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 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart for 
Retreatment.    

 
 
 
 
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7.1.5.4.1 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 (+/- 4) weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first.  
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 pembrolizumab, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
All adverse events will be recorded day 1 of study treatment (D1 C1) through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. Relation of adverse event to study treatment will be defined as definitely, 
probably, possibly, unlikely, or unrelated. The reporting timeframe for adverse events 
meeting any serious criteria is described in section 7.2.3.1. 
The investigator will make every attempt to follow all subjects with non-serious adverse 
events for outcome. 
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 

 
 
 
 
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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. 
For vorinostat, an overdose will be defined as any dose exceeding the prescribed dose by 
20%. 
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 study treatment 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) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation 
of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 

 
 
 
 
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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 study 
treatment 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 another important medical event  
 Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 7 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time of starting study treatment through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to study 
treatment, must be reported within 24 hours to the Sponsor (Moffitt Cancer Center) and 
within 2 working days to Merck Global Safety.  
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 following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 

 
 
 
 
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A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
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 reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the first dose of study treatment is administered, any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to 
the Sponsor and within 2 working days to Merck Global Safety if it is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at first study treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to 
Merck product, must be reported within 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety. 
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.  
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 

 
 
 
 
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All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

 
 
       Page 58 of 78 
 
Table 7 Evaluating Adverse Events 
An investigator who is a qualified physician, 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 for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); 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) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days.. 

 
 
       Page 59 of 78 
 
 
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 Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that 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 Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to 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 
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 

 
 
       Page 60 of 78 
 
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 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 Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to 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) Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is 
reasonable.  The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product  
Subject did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated 

 
 
       Page 61 of 78 
 
relationship 
AE.) 

 
 
       Page 62 of 78 
 
7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
The number of patients for the dose escalation cohort will depend on the safety of dose level 
1. There are two dose escalation levels and therefore the maximum sample size for the dose 
escalation cohorts will be 12 patients. In the dose expansion cohort, a total of 20 evaluable 
patients will be enrolled to confirm the safety at this dose and assess response to treatment. 
Therefore, the maximum sample size of the study is 32 patients. The sample size of 26 
patients in treated at the MTD dose (20+3 patients from dose expansion cohort and 6+/-3 
patients from the dose escalation) will give a two-sided 95% confidence interval (95%CI) of 
39% to 79% for a 12-month overall survival rate of 60% when there is no censored data. If 
the 12-months overall survival rate increases to 80%, the corresponding 95%CI will be 60% 
to 93%. A two-sided 95% confidence interval for the median overall survival time is from 10 
months to 23 months when the estimate of median overall survival time is 14.6 months and 
the percent censoring is anticipated to be 10%. These results assume Type-II Censoring and 
an exponential distribution of overall survival times with mean survival time of 21 months.  
  
8.2 
Statistical Analysis Plan 
Data will be summarized overall using descriptive statistics. Continuous data will be 
summarized with number of patients (n), mean, median, minimum, maximum, standard 
deviation, coefficient of variation, and geometric mean (where applicable). Categorical data 
will be summarized using frequency counts and percentages. Time-to-event outcome data 
will be summarized using Kaplan-Meier survival curve and median survival time.  
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 8. 
 
 

 
 
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Table 8  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. 
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 
Moffitt Cancer Center. 
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 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  Patient medical 
information obtained for the purposes of this study is confidential, and disclosure to third 
parties, other than those noted below, is prohibited.  Patients should be identified only by 
their initials and protocol-assigned patient ID number. For those patients whose surgical 

 
 
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specimen is processed and read by the central pathology laboratory, the patient’s billing 
information will be requested by this laboratory and will not be shared with the sponsor or 
any of its affiliates or representatives.  
Study personnel should follow the requirements of the Health Insurance Portability and 
Accountability Act (HIPAA). 
All clinical information is confidential, but data generated for this study must be available for 
inspection on request to representatives of the U.S. FDA, other national or local regulatory or 
health authorities, Endo Pharmaceuticals representatives, and the associated IRB. 
All records must be kept in a secured area. 
10.2 Compliance with Financial Disclosure Requirements 
Documentation of each Investigator’s proprietary or financial interest is required by the U.S. 
Code of Federal Regulations (21 CFR 54).  A financial disclosure form provided by Moffitt 
Cancer Center must be completed, signed, and dated by the Principal Investigator and each 
Sub-investigator listed on the Form FDA 1572.  This form must be executed prior to the 
personnel’s participation in the study.  The original form will be retained by Moffitt Cancer 
Center.  Each Investigator must inform Moffitt Cancer Center of any change in his/her 
financial interest for up to one year after the end of the study. 
10.3 Compliance with Law, Audit and Debarment and Quality Management System 
The Investigator must conduct the study according to this protocol. 
The study must be conducted by all Investigators in compliance with Good Clinical Practices 
(GCP) as defined as described in the U.S. FDA Code of Federal Regulations 21 CFR 312 
(Investigational New Drug Application), 21 CFR 50 (Protection of Human Subjects), 21 CFR 
54 (Financial Disclosure by Clinical Investigators), 21 CFR 56 (Institutional Review Boards) 
and ICH guidelines (Guideline to Good Clinical Practice). 
The PI of this 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 Data Safety Monitoring Plan (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. 
The PI of this 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 
DSMP and/or to the Protocol Monitoring Committee (PMC) and IRB as required, that all 

 
 
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adverse events are reported according to protocol guidelines, and that any adverse actions 
reflecting patient safety concerns are appropriately reported. 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. Regulatory documents 
and case report forms will be monitored internally according to Moffitt Cancer Center 
Monitoring Policies.  Monitoring will be performed regularly by the MCC clinical 
Monitoring Core to verify data is accurate, complete, and verifiable from source documents; 
and the conduct of the trial is in compliance with the currently approved 
protocol/amendments, 
Good 
Clinical 
Practice 
(GCP), 
and 
applicable 
regulatory 
requirements. 
The PMC monitors its assigned ongoing research protocols monthly for: adverse event 
reporting, data and safety monitoring, and internal audit findings. The PMC upon review of 
any agenda item may approve the study for continuation, require revisions, suspend or close 
a protocol. 
The PMC meets monthly and reviews accrual, patterns and frequencies of all adverse events, 
protocol violations and when applicable, internal audit results. 
Investigators of studies which are designed to be reviewed by the PMC for data and safety 
monitoring, shall provide a statistical 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 DSMP (if applicable) shall forward its report for high-
risk studies designated for external review at least annually or more often if applicable. 
10.4 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), Moffitt Cancer Center 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.     
10.5 Data Management 
Data will be maintained by the Moffitt Cancer Center. 
 

 
 
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11.0 APPENDICES 
11.1 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) 
11.2 Immune-Related Adverse Event Guidance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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RISK LANGUAGE (RL) FOR Pembrolizumab (MK-3475) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Implementation of Changes 
An implementation plan has been determined for the updated RL including notification of the subject group(s), the 
investigator and Institutional Review Board/Institutional Ethics Committee (IRB/IEC) as indicated below. 
Relevant Subject Groups to be Notified of Updated RL 
  New subjects to be enrolled in a new trial 
 New subjects to be enrolled in ongoing trial(s) 
 Subjects in an ongoing trial still receiving treatment 
 Subjects in an ongoing trial who have been off of study treatment but are still within the 
SAE Follow Up Period (≤90 days) 
 Subjects who completed participation in an ongoing trial 
Additional Comments: 
Note: The IRB/ERC, with input from the investigator (as needed), will make the final decision about the need to update 
consents and/or re-consent patients regardless of the Sponsor recommendations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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What is known about this study drug? 
Pembrolizumab, which is approved in the USA and some other countries, is available by 
prescription to treat several different cancers, but may not be approved to treat your 
type of cancer. 
Pembrolizumab works by helping your immune system to fight your cancer. 
However, pembrolizumab can also cause your immune system to attack normal organs 
and tissues in your body and can affect the way they work, which can result in side 
effects that may become serious or life-threatening, and in some cases, may lead to 
death. 
 
What side effects could the study drug(s) cause? 
 
VERY COMMON, SOME MAY BE SERIOUS (i.e. causing hospitalization, life- 
threatening or where noted, may cause death) 
Out of 100 people who receive pembrolizumab, 20 or more people may have the 
following: 
 Itching of the skin 
 Loose or watery stools 
 Cough 
 
COMMON, 
SOME 
MAY 
BE 
SERIOUS 
(i.e. 
causing 
hospitalization, 
life-threatening, or where noted, may cause death) 
Out of 100 people who receive pembrolizumab, at least 5 but less than 20 people 
may have the following: 
 Joint pain 
 Rash 
 Fever 
 Back pain 
 Pain in your belly 
 Loss of skin color 
 Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have 
infrequent or hard stools 
 Low levels of salt in the blood that may cause you to feel tired, confused, have a 
headache, muscle cramps and/or feel sick to your stomach 
 
 
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UNCOMMON, SOME MAY BE SERIOUS (i.e.causing hospitalization, 
life- threatening, or where noted, may cause death) 
Out of 100 people who receive pembrolizumab, at least 1 but less than 5 
people may have the following: 
 Inflammation of the lungs so you may feel short of breath and cough. 
Sometimes this might lead to death 
 Too much thyroid hormone so you may feel anxious, angry, have trouble 
sleeping, feel weak, tremble, sweat, feel tired, have loose and watery 
stools 
 Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, 
have a fever, feel short of breath at the time of receiving your infusion 
(IV) or just after, or pain at the site of infusion 
 Inflammation of the bowels/gut, which may cause severe pain in your 
belly with loose or watery stools, and black, tarry, sticky stools or stools 
with blood or mucus 
 Inflammation of the skin so you may have peeling of the skin, itchiness, 
and/or skin redness. The skin inflammation (i.e. peeling, itching and 
redness) could also be widespread throughout your body. More severe skin 
reactions may involve the inside of your mouth, the surface of your eye and 
genital areas, and/or may cause the top layer of your skin to peel from all 
over your body which can cause severe infection. These severe conditions 
can sometimes lead to death. 
RARE, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-
threatening, or where noted, may cause death) 
Out of 100 people who receive pembrolizumab, less than 1 person may 
have the following: 
 Inflammation of the nerves that may cause pain, weakness or tingling in 
your hands and feet, and may spread to your legs, arms and upper body 
leading to severe muscle weakness and possible temporary paralysis 
 Inflammation of the muscles so you may feel weak or have pain in your 
muscles 
 Inflammation of the pancreas (a gland in your abdomen that controls 
sugar levels) so you may have severe pain in the top part of your belly 
that may move to your back, feel sick to your stomach, and vomiting that 
gets worse when you eat 
 Inflammation of the eye so you may have eye redness, blurred vision, 
sensitivity to light, eye pain, see floaters or have headaches 
 
 
 
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 Inflammation of the liver that may make you feel sick to your stomach and 
vomit, feel like not eating,, feel tired, have a mild fever, have a pain in the 
right side of your belly, yellow eyes and skin, and dark urine 
 Inflammation of the pituitary gland (a gland in the head), which may cause  
you to feel sick to your stomach or have headaches, changes in your 
behavior, double vision, few to no menstrual cycles, weakness, vomiting and 
dizziness or fainting 
 Adrenal glands (glands on top of the kidneys) that may not make enough 
hormone, which could cause tiredness, weight loss, muscle weakness, 
feeling faint, joint, muscle and belly aches, nausea, vomiting, loose or watery 
stools, fever, salt craving, and sometimes darkening of the skin like a suntan 
 Type 1 Diabetes, a condition that can cause too much sugar in your blood, 
feeling thirstier than usual, frequent urination and weight loss. You are likely 
to need regular insulin shots. 
 Inflammation of the kidney so you may pass less urine or have cloudy or 
bloody urine, swelling and low back pain 
 Inflammation of the middle layer of your heart wall that may cause your heart 
to have difficulty pumping blood throughout your body, which can cause 
chest pain, shortness of breath and swelling of the legs. You may experience 
a fast or irregular heartbeat that may cause dizziness or fainting. Sometimes 
this condition can lead to death 
 Inflammation of the thyroid gland, an organ that makes and stores thyroid 
hormones. This condition may lead to change in your heart rate, blood 
pressure, body temperature, and the rate at which food is converted into 
energy. 
 A condition that may make you feel weak and tired and might have drooping 
of the eyelids, blurred or double vision, difficulty swallowing, slurred speech, 
weakness in your arms and legs, or difficulty breathing 
 The formation of small clusters of immune cells (called granulomas) in parts 
of your body such as your lymph nodes, eyes, skin,  or lungs 
 Inflammation of the brain with confusion and fever. This may also include: 
disorientation, memory problems, seizures (fits), changes in personality and 
behavior, difficulty speaking, weakness or loss of movement in some parts of 
your body, and loss of consciousness 
 
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<< NOTE: Only add the following language to all informed consents for 
hematologic malignancies trials. >> 
 
Patients treated with pembrolizumab who then go on to allogeneic stem cell 
transplant (a procedure in which a person receives blood-forming stem cells from a 
donor), should  inform their transplant physicians that they have received 
pembrolizumab in the past. 
In patients with any hematologic malignancy (cancers of the blood like Hodgkin 
lymphoma, multiple myeloma): there is a potential for an increased risk of severe 
complications following allogeneic stem cell transplant in patients who previously  
received pembrolizumab. 
Reports clotting of blood within the liver and severe graft versus host disease 
(which can include skin, liver and gastrointestinal symptoms), including death, 
have been received for patients who received allogeneic stem cell transplant 
after pembrolizumab therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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High Level Summary of Most Recent Changes 
1. General 
a. Wording of Rarely this condition can lead to death has been changed to 
Sometimes this condition can lead to death 
b. Changed the wording of some terms to align better with the other terms 
with regards to grammar and/or addition of symptoms upon Medical 
Director review 
c. Removed KEYTRUDA® from document 
2. Relevant Subject Groups to be Notified of Updated Risk Language 
a. Clarified the choice regarding subjects who are no longer receiving 
treatment 
b. Deleted Additional Comment 
3. What side effects could the study drug(s) cause? section 
a. Section streamlined to remove specific reference to the approved 
indications by name as well as specific clinical trial exposure numbers, 
etc. as information changes continually. 
b. Added pembrolizumab information from patient medication guides (USPI 
medication guide and/or SmPC patient leaflet) to explain how 
pembrolizumab works and how it may cause side effects. 
c. Used the format of 4 categories (Very Common, Common, Uncommon, 
and Rare) which simplifies and eliminates need for repetition of terms by 
overall and serious frequencies, etc. vs percentages. 
i. Removed duplicate terms, ie, that were in the previous version’s 
Common and Serious side effect percentage categories 
d. Removed reference to “immune-mediated” serious events <1%, as not 
helpful or informative for patient and has created numerous site/IRB/EC 
and Health Authority questions. 
e. Added simplified language for 4 new terms: thyroiditis, myasthenic 
syndrome, sarcoidosis, and encephalitis. 
4. Hematologic Malignancy trials language 
a. Changed paragraph order and text for readability 
 
 
 
 
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Events of Clinical Interest (ECI) – Reference Table 
 
 

 
 
 
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Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
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Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
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Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. 
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 Zheng H, Zhao W, Yan C, Watson CC, Massengill M, Xie M, et al: HDAC inhibitors 
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Galanis E, Anderson SK, Miller CR, Sarkaria JN, Jaeckle KA, Buckner JC, et al: 
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(RT) for newly diagnosed glioblastoma (GBM) (Alliance N0874/ABTC-0902). J Clin Oncol 
2014; 32:5s (suppl; abstr 2030).