Clinical trial NCT02619253
Conditions: Renal Cell Carcinoma Urinary Bladder Neoplasms
Keywords: Immunotherapy Safety Pharmacodynamics Efficacy
Sponsor: Nabil Adra
Start date: 2016-02-23; Completion date: 2023-03-28
Enrollment: 52 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Primary objective: To assess the early signals for anti-tumor activity (i.e. objective response rate, progression-free survival) of pembrolizumab in combination with vorinostat in patients with advanced prostate, renal or urothelial cell carcinoma.

Secondary objectives: (1) To evaluate the overall safety profile of pembrolizumab in combination with vorinostat; (2) To assess the safety and tolerability of pembrolizumab in combination with vorinostat in patients with advanced prostate, renal or urothelial cell carcinoma in order to select the recommended Phase 2 Dose (RP2D)

Detailed description:
This is a Phase I/Ib, open-label, safety, and pharmacodynamics study of pembrolizumab in combination with vorinostat in patients with advanced prostrate, renal or urothelial cell carcinoma. This clinical study will be composed of a Dose Finding Phase and an Expansion Phase. The Dose Finding Phase will estimate the Recommended Phase II Dose (RP2D) in patients with advanced renal and urothelial cell carcinoma patients. The Dose Finding Phase will lead to the identification of an Expansion Test Dose for pembrolizumab in combination with vorinostat. The Expansion Test Dose will be the Recommended Phase II Dose (RP2D) (i.e. the highest tested dose that is declared safe and tolerable by the Investigators and Sponsor). Patients will be treated with oral vorinostat every day for 14 days, and with pembrolizumab at the fixed dose of 200 mg IV. Each cycle is every 21 days. Two dose levels of vorinostat will be tested in 2-patient cohorts according to the 3 + 3 standard design (100 mg and 200 mg). 200 mg dose represents 50% of the recommended vorinostat dose as single agent.

For the Dose Finding Phase (Combination Phase), the starting dose level of vorinostat will be 100 mg by mouth (PO) every day for 14 days, with 7 days break. The first dose level will have a minimum of 3 patients treated (unless the first 2 patients experience dose-limiting toxicities (DLTs) before the 3rd patient is enrolled).

Once the RP2D is identified, the Dose Expansion Phase will be opened. During the Dose Expansion Phase, the study will have a run-in phase with sequential single-agents and then the combination phase. The run-in phase may be waived at the investigator's discretion. The reason for the run-in phase during dose expansion is to obtain data on the immunomodulatory effects of vorinostat separately from pembrolizumab. Forty-five patients with prior treatments will be enrolled in three expansion cohorts: 15 anti-PD1 naive renal and urothelial patients 15 anti-PD1 resistant renal and urothelial patients (defined as patients with transient clinical response or without clinical response to prior immune-checkpoint inhibition), and 15 patients with androgen-sensitive or castration-resistant prostate cancer. The prostate cohort has been added in an amendment during the Dose Expansion Phase, and therefore, will not be part of the Dose Finding Phase.

Arms: arm 1: Estimate the Recommended Phase 2 Dose (RP2D) in patients with advanced renal and urothelial cell carcinoma patients. Patients will be treated with oral vorinostat every day for 14 days, and with pembrolizumab at the fixed dose of 200 mg IV. Each cycle is every 21 days. Two dose levels of vorinostat will be tested in 2 patient cohorts according to the 3 + 3 standard design (100 and 200 mg). arm 2: Once the Expansion Test Dose is identified, the Dose Expansion Phase will be opened and the combination will be tested in patients with advanced renal cell or urothelial cell carcinoma. Forty-five patients with prior treatments will be enrolled in three expansion cohorts: 15 anti-PD1 naive renal and urothelial patients, 15 anti-PD1 resistant renal and urothelial patients (defined as patients with transient clinical response or without clinical response to prior immune-checkpoint inhibition), and 15 patients with androgen-sensitive or castration-resistant prostate cancer.
Interventions: intervention 1: Pembrolizumab intervention 2: Vorinostat
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
1 
 
  
 
 
 
 
 
A Phase I/Ib, Open Label, Dose Finding Study to Evaluate Safety, Pharmacodynamics 
and Efficacy of Pembrolizumab (MK-3475) in Combination with Vorinostat in Patients 
with Advanced Prostate, Renal or Urothelial Cell Carcinoma 
 
Protocol Number: 
IUSCC-0551 
 
Coordinating Center: 
Indiana University Melvin and Bren Simon Comprehensive Cancer Center 
 
Principal Investigator: 
Nabil Adra, MD 
535 Barnhill Drive, RT 400 
Indianapolis, IN 46202  
317-944-5349 
nadra@iu.edu 
 
Co-Investigators: 
David Quinn, MBBS, PhD, FRACP, FACP (USC/Norris CCC) 
Noah Hahn, MD (Johns Hopkins University) 
Ted Logan, MD (Indiana University) 
Roberto Pili, MD 
 
Research Nurses: 
Sheila Dropcho, RN 
Marietta Moore, RN 
Christin Snow, RN, BSN 
 
 
Study Statistician: 
Hao Liu, PhD 
 
Support Provided By: 
Merck 
 
Protocol Version Date: 
April 07, 2021 
 
 
 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
2 
 
IND#s: 
128468  
Sponsor-Investigator – Nabil Adra, MD 
Investigational Agents - vorinostat and pembrolizumab 
 
138531 
Sponsor-Investigator - James W. Fletcher, MD 
Investigational Agent - 68Ga-PSMA-11 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
3 
 
PROTOCOL SIGNATURE PAGE 
 
A Phase I/Ib, Open Label, Dose Finding Study to Evaluate Safety, Pharmacodynamics and 
Efficacy of Pembrolizumab (MK-3475) in Combination with Vorinostat in Patients with 
Advanced Prostate, Renal or Urothelial Cell Carcinoma 
 
VERSION DATE:  07April2021 
 
I confirm I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable guidelines for good clinical practices, or the applicable laws and regulations of the 
country of the study site for which I am responsible, whichever provides the greater 
protection of the individual.  I will accept the monitor’s overseeing of the study.  I will 
promptly submit the protocol to applicable ethical review board(s). 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
  
 Date 
 
 
____________________________________ 
 Site Investigator Name (printed) 
 
 
____________________________________ 
 Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
 
PLASE COMPLETE AND EMAIL COPY TO INDIANA UNIVERSITY SIMON 
COMPREHENSIVE CANCER CENTER CLINICAL TRIALS OFFICE 
Instructions to the investigator: Please SIGN and DATE this signature 
page. PRINT your name and title, the name and location of the 
facility in which the study will be conducted, and the expected IRB 
approval date. Scan and email the completed form to Indiana 
University Simon Comprehensive Cancer Center and keep a record for 
your files. 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
4 
 
TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY ..................................................................................................... 7 
2.0 
TRIAL DESIGN ........................................................................................................... 7 
2.1 
Trial Design .............................................................................................................. 7 
2.2 
Trial Diagram ............................................................................................................ 9 
3.0 
OBJECTIVES ............................................................................................................... 9 
3.1 
Primary Objective ..................................................................................................... 9 
3.2 
Secondary Objectives ............................................................................................... 9 
3.3 
Correlative Objective ................................................................................................ 9 
4.0 
BACKGROUND & RATIONALE .............................................................................. 9 
4.1 
Background ............................................................................................................... 9 
4.2 
Rationale ................................................................................................................. 11 
5.0 
METHODOLOGY ..................................................................................................... 13 
5.1 
Entry Criteria .......................................................................................................... 13 
5.2 
Trial Treatments ...................................................................................................... 16 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ........................... 27 
5.4 
Rescue Medications & Supportive Care ................................................................. 28 
5.5 
Diet/Activity/Other Considerations ........................................................................ 29 
5.6 
Subject Withdrawal/Discontinuation Criteria ......................................................... 30 
5.7 
Discontinuation of Study Therapy after CR ........................................................... 31 
5.8 
Subject Replacement Strategy ................................................................................ 31 
5.9 
Pseudoprogression .................................................................................................. 31 
5.10 
Clinical Criteria for Early Trial Termination .......................................................... 31 
6.0 
SCHEDULE OF ASSESSMENTS ............................................................................. 33 
7.0 
TRIAL PROCEDURES .............................................................................................. 36 
7.1 
Trial Procedures ...................................................................................................... 36 
7.2 
Assessing and Recording of Adverse Events ......................................................... 45 
7.3 
Participating Site Reporting Responsibilities ......................................................... 51 
7.4 
Coordinating Center Reporting Responsibilities .................................................... 52 
8.0 
STATISTICAL METHODS ....................................................................................... 55 
8.1 
General Considerations ........................................................................................... 55 
8.2 
Study Design ........................................................................................................... 55 
8.3 
Analysis Populations ............................................................................................... 55 
8.4 
Sample Size, Accrual and Study Duration .............................................................. 55 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
5 
 
8.5 
Patient Characteristics ............................................................................................. 56 
8.6 
Significant Protocol Violations ............................................................................... 56 
8.7 
Concomitant Medications ....................................................................................... 56 
8.8 
Exposure and Compliance ...................................................................................... 56 
8.9 
Efficacy Analysis .................................................................................................... 56 
8.10 
Safety Analysis ....................................................................................................... 56 
8.11 
Interim Analysis ...................................................................................................... 57 
9.0 
DATA AND SAFETY Monitoring ............................................................................ 57 
9.1 
Data Safety Monitoring Committee ........................................................................ 57 
9.2 
DSMC DLT Review ............................................................................................... 58 
9.3 
IND Annual Reports ............................................................................................... 58 
9.4 
Study Auditing and Monitoring .............................................................................. 58 
9.5 
Data Management/ Oncore Reporting Requirements ............................................. 58 
9.6 
Study Accrual Oversight ......................................................................................... 58 
9.7 
Oncore Safety Reporting ........................................................................................ 58 
9.8 
Protocol Deviation Reporting ................................................................................. 59 
9.9 
Data Acquisition ..................................................................................................... 59 
10.0 
MULTICENTER GUIDELINES................................................................................ 59 
10.1 
Study Documents .................................................................................................... 59 
10.2 
Study Initiation ....................................................................................................... 59 
10.3 
Patient Enrollment .................................................................................................. 60 
10.4 
Data Monitoring ...................................................................................................... 60 
10.5 
Record Retention .................................................................................................... 60 
11.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES................................................................................................................... 60 
11.1 
Investigational Product ........................................................................................... 60 
11.2 
Packaging and Labeling Information ...................................................................... 62 
11.3 
Clinical Supplies Disclosure ................................................................................... 62 
11.4 
Storage and Handling Requirements ...................................................................... 62 
11.5 
Returns and Reconciliation ..................................................................................... 62 
12.0 
ADMINISTRATIVE AND REGULATORY DETAILS ........................................... 63 
12.1 
Compliance with Trial Registration and Results Posting Requirements ................ 63 
13.0 
REFERENCES ........................................................................................................... 64 
14.0 
APPENDICES ............................................................................................................ 65 
14.1 
ECOG Performance Status ..................................................................................... 65 
14.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ..................... 65 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
6 
 
14.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .................................................................... 65 
14.4 
Drug Diary .............................................................................................................. 69 
14.5 
Events of Clinical Interest Guidance Document ..................................................... 70 
14.6 
Woman of Childbearing Potential (WOCBP) definition ........................................ 70 
14.7 
Immune-Related Response Criteria ........................................................................ 71 
 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
7 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Vorinostat and pembrolizumab in prostate, urothelial and renal cell 
carcinoma 
Trial Phase 
I/Ib 
Clinical Indication 
Metastatic disease  
Trial Type 
Interventional 
Route of administration 
IV and oral 
Trial Blinding 
N/A 
Treatment Groups  
Anti-PD1/PD-L1 naïve and anti-PD1/PD-L1 resistant tumors 
Number of trial subjects 
51-57 
Estimated enrollment period 
18 months 
Estimated duration of trial 
24 months 
Duration of Participation 
24 months 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a Phase I/Ib, open-label, safety, and pharmacodynamics study of pembrolizumab in 
combination with vorinostat in patients with advanced prostate, renal or urothelial cell 
carcinoma. This clinical study will be composed of a Dose Finding Phase and an Expansion 
Phase. The Dose Finding Phase will estimate the Recommended Phase II Dose (RP2D) in 
patients with advanced renal and urothelial cell carcinoma patients. The Dose Finding Phase 
will lead to the identification of an Expansion Test Dose for pembrolizumab in combination 
with vorinostat. The Expansion Test Dose will be the Recommended Phase II Dose (RP2D) 
(i.e. the highest tested dose that is declared safe and tolerable by the Investigators and 
Sponsor). Patients will be treated with oral vorinostat every day for 14 days, and with 
pembrolizumab at the fixed dose of 200 mg 
IV. Each cycle is every 21 days. Two dose 
levels of vorinostat will be tested in 2-patient 
cohorts according to the 3 + 3 standard 
design (100 mg and 200 mg).  200 mg dose 
represents 50% of the recommended 
vorinostat dose as single agent.  
For the Dose Finding Phase (Combination 
Phase, Schema A), the starting dose level of 
vorinostat will be 100 mg by mouth (PO) 
every day for 14 days, with 7 days break. 
The first dose level will have a minimum of 
3 patients treated (unless the first 2 patients 
experience DLTs before the 3rd patient is 
enrolled).  
 
Schema A: Combination Phase 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
8 
 
DLTs are defined as Grade ≥ 3 hematological/non hematological toxicities attributable to 
vorinostat and/or pembrolizumab during the first 21 days of the combination treatment (days 
1-21). If DLTs occur in 1 patient treated at the starting dose level a minimum of another 
3 patients will be treated at this dose level. If a DLT occurs in more than 1 patient in the first 
6 patients the study will be terminated. If a DLT occurs in ≤ 1/6 patients, 3 additional 
patients will be treated at the next dose level (level 2) with 200 mg vorinostat PO. If no DLTs 
occur at dose level 2, this dose level will be recommended for the expansion cohorts of the 
study. Patients who experience Grade ≥ 3 toxicity and recover to ≤ Grade 1 (or to 
pretreatment baseline level toxicity) may continue treatment at the next vorinostat lower 
level. 
 
Once the RP2D is identified, the Dose 
Expansion Phase will be opened. During 
the Dose Expansion Phase, the study will 
have a run-in phase with sequential 
single-agents (Schema B) and then the 
combination phase (Schema A). The run-
in phase may be waived at the 
investigator’s discretion. The reason for 
the run-in phase during dose expansion is 
to obtain data on the immunomodulatory 
effects of vorinostat separately from 
pembrolizumab. Forty-five patients with 
prior treatments will be enrolled in three 
expansion cohorts: 15 anti-PD1 naive renal and urothelial patients, 15 anti-PD1 resistant 
renal and urothelial patients (defined as patients with transient clinical response or without 
clinical response to prior immune-checkpoint inhibition), and 15 patients with androgen-
sensitive or castration-resistant prostate cancer. The prostate cohort has been added in an 
amendment during the Dose Expansion Phase, and therefore, will not be part of the Dose 
Finding Phase. 
Anti-tumor activity will be assessed by radiological tumor assessments conducted at baseline, 
12 weeks and every 6 weeks thereafter, using RECIST version 1.1 (see Section 14.3). 
RECIST 1.1 will be used for treatment decisions until first radiologic evidence of progressive 
disease (PD). Following the first evidence of radiologic PD, treatment decisions may be  
made by the adaption of RECIST 1.1, termed the immune-related response criteria (irRC) 
(see Section 14.6) to account for the tumor response patterns seen with pembrolizumab 
treatment (e.g. tumor flare).  
1 Cycle = 3 weeks (21 days)  
Dose Level 
Pembrolizumab IV Q3W 
Vorinostat PO QD x 14 days 
        1 
               200 mg 
100 mg 
        2 
               200 mg 
200 mg 
Schema B: Run-In Phase 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
9 
 
The RP2D is the dose of pembrolizumab and vorinostat in combination chosen for further 
clinical development. Further experience in the Dose Expansion Cohort may result in a 
RP2D dose lower than the MTD. 
2.2 
Trial Diagram 
 
3.0 OBJECTIVES 
3.1 
Primary Objective  
To assess the early signals for anti-tumor activity (i.e. objective response rate, 
progression-free survival) of pembrolizumab in combination with vorinostat in patients 
with advanced prostate, renal or urothelial cell carcinoma. 
3.2 
Secondary Objectives  
• To evaluate the overall safety profile of pembrolizumab in combination with 
vorinostat. 
• To assess the safety and tolerability of pembrolizumab in combination with 
vorinostat in patients with advanced prostate, renal or urothelial cell carcinoma in 
order to select the recommended Phase 2 Dose (RP2D). 
3.3 
Correlative Objective 
• To characterize immune cell subsets, and miRs in tumor and/or blood  
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab and vorinostat (MK-3487). 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
10 
 
4.1.1 Pharmaceutical and Therapeutic Background 
Blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach for the treatment 
of solid tumors including renal cell carcinoma (RCC). PD-1 inhibition has shown single-agent 
activity in clear cell RCC patients whose disease has progressed following VEGF pathway 
inhibitor therapy 1. Recent data have also shown a significant activity of an anti PD-L1 
antibody in urothelial cell carcinoma patients 2. Though this new class of agents represents a 
very promising therapeutic strategy only a fraction of patients seems to achieve durable 
responses.  
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. 
Histone deacetylase (HDAC) inhibitors induce acetylation of several histone and non-histone 
proteins, which contributes to a wide spectrum of anti-tumor and immunomodulatory activities 
of this class of agents. Pan HDAC inhibitors have shown either immunosuppressive or 
immunopromoting properties through modulating cytokine expression, affecting macrophage 
and dendritic cells, or regulating costimulation molecules. HDAC inhibitors have been also 
shown to induce activation of major histocompatibility complex (MHC) class I and class II 
proteins, and co-stimulatory molecules CD40, CD80 and CD86. The results from the clinical 
trials with HDAC inhibitors in cutaneous T-cell lymphoma and large cell lymphoma patients 
that had lead the approval of vorinostat and romidepsin suggest that the antitumor activity these 
agents may be in part due to the modulation of the immune response. Our group has reported 
that the class I HDAC inhibitor entinostat suppresses regulatory T (Treg) cell function, 
enhances anti-tumor immune response and facilitates cytokine and vaccine immunotherapy in 
murine renal cell carcinoma and prostate cancer models, respectively 3,4. This Treg suppression 
action does not seem to be through a depletion mechanism. On further analysis, we observed 
that entinostat suppresses Foxp3 gene expression in Treg cells and inhibits suppressive 
function of Treg cells. Entinostat acetylates STAT 3 leading to down regulation of Foxp3. Our 
preclinical data have shown the synergistic effect of entinostat in combination with high dose 
interleukin 2 in the RENCA model 4. Based on these results, we have completed a CTEP-
Figure 1. Modulation of Treg function with class-
specific HDAC inhibitors. Class I HDAC inhibitors 
induce acetylation of STAT3 by inhibiting HDAC3 or 
HDAC1, downregulate Foxp3 gene expression and 
suppress Treg function. Class II HDAC inhibitor 
treatment induces Foxp3 hyperacetylation by targeting 
HDAC7 and HDAC 9, which leads to stabilization of 
Foxp3 protein and enhanced Treg function. SIRT 1 (Class 
III specific) inhibitor also induces hyperacetylation and 
stabilization of Foxp3 protein, and enhances the Treg 
function. A pan inhibitor may target Class I HDACs at a 
low dose and impair Treg function. At a higher dose, the 
pan inhibitor may target Class II HDAC and show a 
dominant Treg promoting effect6). 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
11 
 
sponsored phase I/II clinical trial with entinostat in combination with high dose interleukin 2 
in patients with RCC (NCT01038778). The phase I results have been recently reported and 
suggest a biological and clinical activity of this combination 5. Our preliminary data also 
suggest that inhibitors able to modify Class I HDACs (Class I specific and pan) decreased 
Foxp3 levels in Tregs in a dose-dependent manner, whereas class II specific HDAC inhibitors 
did not affect Foxp3 levels. This observation suggests that only class I HDAC inhibition results 
in Treg suppression. In addition, we observed that in vivo treatment with the pan HDAC 
inhibitor panobinostat showed opposite effects when applied at different doses: low dose 
inhibited Tregs suppressive function whereas high dose treatment promoted Treg function 6. 
Panoninostat has much higher affinity for class I HDACs than for class II HDACs 7. We 
hypothesize that pan HDAC inhibitors such as panobinostat and vorinostat primarily inhibit 
class I HDACs at low doses, which shows Treg suppressive effect similar to class I specific 
inhibitors. At a high dose, pan HDAC inhibitors saturate class I HDACs and targets class II, 
and the Treg-promoting effect resulting from class II HDACs inhibition becomes dominant.  
4.2 
Rationale 
Novel strategies to enhance the antitumor activity of immune-checkpoint inhibitors are under 
development. This study will assess the immunomodulatory activity of vorinostat in patients 
receiving the PD1 inhibitor pembrolizumab. We have chosen two diseases (renal and 
urothelial cell carcinoma) that have been reported to respond to PD1/PD-L1 inhibition. We 
have also include a cohort of patients with prostate cancer as a recent report have shown 
activity of pembrolizumab after enzalutamide. However, as a proof of principle, we will 
include both hormone sensitive and castration resistant metastatic prostate cancer 8. The 
schedule of vorinostat is based on our previous experience with this drug. We have 
completed a CTEP-sponsored phase I/II clinical trial with vorinostat in combination with 
bevacizumab in patients with pretreated RCC patients (NCT00324870). The dose of 200 mg 
PO (twice a day) BID 14 days on, 7 days off every 21 days was relatively well tolerated9. 
Based on the hypothesis that low dose pan HDAC inhibitors will have a suppressive function 
on Tregs but not on T effector cells, the starting dose of vorinostat will be 100 mg and will be 
escalated up to 200 mg only rather than the 400 mg dose approved for the treatment of 
cutaneous T cell lymphomas.   
Based on our preclinical data, this study will test the following hypotheses: 
1. Class I HDAC inhibition by either selective Class I HDAC or low dose pan HDAC 
inhibitors may decrease Tregs and MDSCs without affecting T effector cells 
2. Vorinostat may enhance the anti-tumor activity of immune-check point inhibitors by 
suppressing inhibitory cells and inducing PDL-1/2 expression. 
3. Vorinostat may re-sensitize patient previously treated with immune-check point 
inhibitors.  
4.2.1 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab. The dose escalation portion of this trial 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
12 
 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors.  All three dose levels were well tolerated and 
no dose-limiting toxicities were observed.  This first in human study of pembrolizumab 
showed evidence of target engagement and objective evidence of tumor size reduction at all 
dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  
Recent data from other clinical studies within the pembrolizumab program has shown that a 
lower dose of pembrolizumab and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
Pharmacokinetic (PK) data analysis of pembrolizumab administered Q2W and Q3W showed 
slow systemic clearance, limited volume of distribution, and a long half-life (refer to 
Investigator Brochure).  Pharmacodynamic (PD) data (IL-2 release assay) suggested that 
peripheral target engagement is durable (>21 days).  This early PK and PD 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 pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights. Pembrolizumab has been found to have a wide 
therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for  
pembrolizumab in the melanoma indication. The exposure margins are based on the notion of 
similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 
2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed 
that there was no significant impact of tumor burden on exposure. In addition, exposure was 
similar between the non-small-cell lung carcinoma (NSCLC) and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe. 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
13 
 
The choice of the starting dose of vorinostat (100 mg) is based on the preclinical data 
suggesting that low dose of pan HDAC inhibitors may have already positive 
immunomodulatory activity (see 4.1.1).   
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have one of the following diagnoses/conditions: 
a. Renal cell carcinoma - previously treated and progressive disease, locally 
advanced or metastatic 
b. Urothelial cell carcinoma - previously treated and progressive disease, locally 
advanced or metastatic 
c. Prostate cell carcinoma - progressive disease, locally advanced or metastatic 
disease (enrolling only at IUSCC and its affiliates). Patients with hormone-
sensitive disease where ADT in combination with either docetaxel or 
abiraterone is indicated will not be eligible (i.e. patients with high burden 
disease). 
2. Be willing and able to provide written informed consent for the trial. 
3. Be ≥ 18 years of age on day of signing informed consent. 
4. Have measurable disease based on RECIST 1.1 (Section 14.3) for patients with solid 
malignancies or evaluable disease as assessed by bone scan and/or PET scan.  
Patients with advanced or metastatic prostate cancer can have either androgen-
sensitive or castration-resistant disease. 
5. Have a performance status of 0-2 on the ECOG Performance Scale (Section 14.1). 
6. Demonstrate adequate organ function as defined in Table 1.   
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 
≤1.5 X upper limit of normal (ULN) OR 
 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
14 
 
(GFR can also be used in place of creatinine or 
CrCl) 
≥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. 
 
7. Female subject of childbearing potential (see appendix 14.6) should have a negative 
urine or serum pregnancy test within 72 hours prior to receiving the first dose of 
study medication.  If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.   
8. Subjects of childbearing potential should be willing to use 2 methods of contraception 
for the course of the study through 120 days after the last dose of study medication 
(reference Section 5.5.2).  Acceptable methods of birth control include: abstinence, 
partner with previous vasectomy, placement of an intrauterine device (IUD), condom 
with spermicidal foam/gel/film/cream/suppository, diaphragm or cervical vault cap, 
or hormonal birth control (pills or injections). NOTE: Females are considered of 
childbearing potential unless they are surgically sterile (they have undergone a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are 
postmenopausal (a woman who is ≥ 45 years of age and has not had menses for 
greater than 1 year). 
9.  Male subjects without a previous vasectomy should agree to use an adequate method 
of contraception (i.e. abstinence, condom with spermicidal foam/gel/film/cream) 
starting with the first dose of study therapy through 120 days after the last dose of 
study therapy. 
10. Subjects with urothelial carcinoma must have received a prior platinum-based 
regimen in the metastatic setting or have signed consent for this study within 12 
months of receiving a platinum-based regimen in the perioperative setting 
(neoadjuvant or adjuvant).  
11. Subjects with a history of diabetes mellitus must have HgbA1c level of < 8.5% upon 
study entry. 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
15 
 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. 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. 
2. 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. 
 
3. Has active TB (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to 
Cycle 1 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. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to Cycle 1 Day 1 or who has not recovered (i.e. ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
7. 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. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment.  This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability.   
9. 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 (e.g. thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
16 
 
10. Has known history of, or any evidence of active, non-infectious pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (only 
during Dose Expansion Phase for Cohort A). 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2: Trial Treatment 
Drug 
Dose/Potency Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg   
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Vorinostat  
100-200 mg  QD  
oral 
Day 1-14 of each 3 
week cycle 
Experimental 
 
Trial treatment should begin as close as possible to the date on which treatment is 
allocated/assigned. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background & Rationale.   


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
17 
 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
package insert.  
5.2.1.2 Dose Administration 
Treatment cycles consist of daily oral dosing of vorinostat (Days 1 through 14) and 
intravenous dosing of pembrolizumab (Day 1, Cycle 1).  The two-drug regimen will be given 
every 3 weeks.  The starting dose of vorinostat will be 100 mg orally QD per day for Days 1 
through 14.  The dose of pembrolizumab will be 200 mg IV on Day 1, every 21 days.  
5.2.1.3 Definition of Dose-Limiting Toxicity (DLT) 
DLTs include any Grade 3-5 toxicity related to vorinostat or pembrolizumab during the 
combination phase only (Cycle 1) (except for a ≥ Grade 3 decrease in lymphocytes). Grade 3 
nausea or vomiting should be considered a DLT only if unresponsive to therapy and ≥ 72 
hours in duration.  Patients must have taken at least 4 of the 14 doses of vorinostat to be 
considered evaluable for DLT determination. Patients who do not complete the first cycle of 
combination therapy during the dose finding phase will be replaced.  Patients who do not 
receive at least 75% of the expected dose of vorinostat due to toxicity are considered to have 
DLT. Delay in treatment due to a toxicity greater than 2 weeks is also considered a DLT. 
ALT>3xULN + Total bilirubin >2xULN will be a DLT which results in permanent drug 
discontinuation. 
3 patients will be enrolled at dose level 1: 
• If 1 DLT occurs in the first 3 patients, expand dose level 1 to 6 patients. 
• If 0-1 DLT occur in 6 patients, expand to dose level 2.  
• If 1 DLT occurs in the first 3 patients, expand dose level 2 to 6 patients. 
• If ≥ 2 DLTs occur in the 3-6 patient cohort at dose level 2, the lower dose level will 
be considered the MDT.  
• If ≥ 2 DLTs occur in the 3-6 patient cohort at dose level 1, the study will be 
terminated.  
 
5.2.1.4 Supportive Care Guidelines 
Note: there is an overlap in potential toxicity related to diarrhea.  
If the patient has diarrhea (loose stool) = Grade 2, follow the supportive care guidelines for 
Vorinostat below. If the patient has diarrhea (loose stool) ≥ Grade 3, follow the supportive 
care guidelines for Vorinostat below. 
If a patient has colitis (diarrhea with abdominal pain, mucus or blood in stool) ≥ Grade 2, 
follow the supportive care guidelines for Pembrolizumab below. 
Vorinostat: Because vorinostat’s dose limiting toxicities are anorexia, dehydration, diarrhea, 
and fatigue, patients should maintain adequate fluid and food intake.  Patients will be 
encouraged to seek a nutritional consult, if necessary.    


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
18 
 
Treat diarrhea promptly with appropriate supportive care, including loperamide.  Instruct 
patients to begin taking loperamide at the first signs of: 
• Poorly formed or loose stool 
• Occurrence of more bowel movements than usual in one day, or 
• Unusually high volume of stool.   
Loperamide should be taken in the following manner: 4 mg at first onset of diarrhea, then 2 
mg after each unformed stool.  Daily dose should not exceed 16 mg/day.  Loperamide should 
not be taken prophylactically.  Advise patients to drink plenty of clear fluids to help prevent 
dehydration caused by diarrhea.  Avoid loperamide if there is the presence of blood or mucus 
in the stool or if diarrhea is accompanied by fever.  If grade 3 or 4 diarrhea develops on 
loperamide, discontinue further treatment with vorinostat. 
Pembrolizumab: Supportive care guidelines for pembrolizumab can be found in Appendix 
14.5.  
5.2.1.5 Duration of Therapy  
Patients may continue on therapy until one of the following criteria applies: 
• Disease progression (with the exception of pseudoprogression as described in Section 
5.9), 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Patient decides to withdraw from the study, or 
• General or specific changes in the patient’s condition that renders the patient 
unacceptable for further treatment in the judgment of the investigator. 
5.2.1.6 Dose Modifications 
Vorinostat should be held when ≥ Grade 3 to 4 drug-related adverse experiences occur. After 
resolution of these adverse experiences to Grade 1 or less (or to pretreatment baseline level of 
toxicity) treatment with vorinostat may continue at the next lower dose (see 2.1). Once the 
dose has been reduced, patients must remain at the reduced dose for the remainder of the study.  
Patients may have their dose reduced once before being removed from the trial. Patients may 
only have their dose reduced to dose level 1. If grade 3 or 4 diarrhea develops despite 
supportive care, patients will discontinue further treatment with vorinostat. 
Vorinostat in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
Please see tables below for a list of adverse events experienced by patients who have been 
treated with vorinostat. 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
19 
 
 
 
 
 
 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
20 
 
Pembrolizumab: 
AEs associated with pembrolizumab exposure, including coadministration with additional compounds, may represent an immunologic 
aetiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination treatment and may affect more than one body system simultaneously. Therefore, early recognition and 
initiation of treatment is critical to reduce complications.  Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab/combination treatment, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Dose modification and toxicity management guidelines 
for irAEs associated with pembrolizumab/combination treatment are provided in Table 3. 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to a single component is likely to be 
difficult.  Therefore, while the investigator may attribute a toxicity event to the combination, to vorinostat or to pembrolizumab alone, 
for adverse events listed in Table 3, both interventions must be held according to the criteria in Table 3 Dose Modification and Toxicity 
Management Guidelines for Immune-Related Adverse Events Associated with Pembrolizumab. 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered immune-related, both interventions should be held 
according to recommended dose modifications. 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of pembrolizumab in this study, as described in Table 
3. 
1. If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant must be discontinued from all study 
interventions. 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
21 
 
2. If the toxicities do resolve and conditions are aligned with what is defined in Table 3, the combination of vorinostat and 
pembrolizumab may be restarted at the discretion of the investigator. In these cases where the toxicity is attributed to the combination 
or to vorinostat alone, re-initiation of pembrolizumab as a monotherapy may be considered at the principal investigator’s discretion. 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / surgical events and/or unforeseen 
circumstances not related to study intervention. However, intervention is to be restarted within 3 weeks of the originally scheduled dose 
and within 42 days of the previously administered dose, unless otherwise discussed with the Sponsor. The reason for study intervention 
interruption is to be documented in the patient's study record. 
 
Table 3: Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
monotherapy and IO Combinations  
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after 
corticosteroid taper. 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
•  Add prophylactic antibiotics for 
opportunistic infections 
•  Monitor participants for signs and 
symptoms of pneumonitis 
•  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
22 
 
 
Diarrhea/Colit
is  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
 
•  Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus) 
•  Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis 
•  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion 
Recurrent 
Grade 
3 
or 
Grade 4 
Permanently 
discontinue 
AST or ALT 
Elevation 
or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids (initial 
dose of 0.5 to 1 mg/kg prednisone or 
equivalent) followed by taper 
•  Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable) 
Grade 3 b or 4 c Permanently 
discontinue 
•  Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
T1DM 
or 
Hyperglycemi
a 
New 
onset 
T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated 
Withhold d 
•  Initiate insulin replacement therapy 
for participants with T1DM 
•  Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
23 
 
with evidence 
of 
β-cell 
failure 
•  Administer antihyperglycemic in 
participants with hyperglycemia 
 
Hypophysitis 
Grade 2 
Withhold 
•  Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated 
•  Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hyperthyroidis
m 
Grade 2 
Continue 
•  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
•  Monitor for signs and symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hypothyroidis
m 
Grade 2, 3 or 4 Continue 
•  Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care 
•  Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according 
to 
increased 
creatinine 
or 
acute 
kidney 
injury 
Grade 2 
Withhold 
•  Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
24 
 
Grade 2, 3 or 4 Permanently 
discontinue 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, or 
DRESS 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm 
etiology or exclude other causes 
Confirmed 
SJS, TEN, or 
DRESS 
Permanently 
discontinue 
All 
Other 
irAEs 
Persistent Grade
2 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm 
etiology or exclude other causes 
Grade 3 
Withhold 
or 
discontinue 
based 
on 
the 
event e  
Recurrent 
Grade 3 
or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for 
Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune 
related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; 
ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline 
normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
25 
 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control 
achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs. 
 
 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe hypersensitivity or anaphylaxis. 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 
hours of completion of infusion. Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4. 
Table 4 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g. 
from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until 
Participant may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of study intervention with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 


IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
26 
 
symptoms resolve and the participant should be premedicated for 
the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug intervention 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study 
drug intervention. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
27 
 
5.2.1.6 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Schedule of Assessments 
(Section 6.0).  Trial treatment may be administered up to 3 days before or after the scheduled 
Day 1 of each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e. infusion time is 30 minutes: -5 min/+10 min). 
The package insert contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
Patients should store vorinostat capsules at room temperature, 15 to 30 ºC (59 to 86 ºF).   Do not 
store above 300C. Avoid exposure to excessive moisture. Vorinostat capsules must be 
administered whole. Administer doses of vorinostat with food if possible. Vorinostat capsule 
should be administered according to the package insert. 
5.2.2 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Sponsor who will discuss this with the Merck Clinical team.  The final decision on 
any supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician.  
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before written informed consent and 30 
days after the treatment discontinuation should be recorded.  Concomitant medications 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
28 
 
administered after 30 days after treatment discontinuation should be recorded for SAEs and 
ECIs as defined in Section 7.2. 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab and vorinostat 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion with written Sponsor approval.   
• 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, Bacillus 
Calmette-Guérin, and typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 
Rescue Medications & Supportive Care 
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 for pembrolizumab are outlined in section 5.2.1.6 
of the protocol and in section 6.4.1 of the Investigator’s Brochure. 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 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
29 
 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the Investigator’s Brochure but does not need to follow the treatment 
guidance (as outlined in the Investigator’s Brochure). Refer to Section 5.2.1.6 for dose 
modifications.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the Investigator’s Brochure. 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.5.2 Contraception 
Pembrolizumab and vorinostat may have adverse effects on a fetus in utero.  Furthermore, it 
is not known if pembrolizumab or vorinostat have transient adverse effects on the 
composition of sperm.  Non-pregnant, non-breast-feeding women may be enrolled if they are 
willing to use 2 methods of birth control or are considered highly unlikely to conceive.  
Highly unlikely to conceive is defined as 1) surgically sterilized (they have undergone a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or 2) postmenopausal (a 
woman who is ≥45 years of age and has not had menses for greater than 1 year will be 
considered postmenopausal), or 3) not heterosexually active for the duration of the study. 
Acceptable methods of birth control include: abstinence, partner with previous vasectomy, 
placement of an intrauterine device (IUD), condom with spermicidal 
foam/gel/film/cream/suppository, diaphragm or cervical vault cap, or hormonal birth control 
(pills or injections). Subjects should start using birth control from written informed consent 
throughout the study period up to 120 days after the last dose of study therapy.  
Male subjects without a previous vasectomy should agree to use an adequate method of 
contraception (i.e. abstinence, condom with spermicidal foam/gel/film/cream) starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.3-Pregnancy and 
Lactation. If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
30 
 
5.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab and/or 
vorinostat, the subject will immediately be removed from the study.  The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor and 
to Merck without delay and within 24 hours to the Sponsor and within 2 working days to 
Merck if the outcome is a serious adverse experience (e.g. death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.3. 
5.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab or vorinostat 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. 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be removed from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons. If a subject withdraws 
from the study, they will no longer receive study intervention or be followed at scheduled 
protocol visits.  Specific details regarding discontinuation or withdrawal are provided in 
Section 7.1.4.1. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression (with the exception of pseudoprogression 
as described in Section 5.9) 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Unacceptable adverse experiences as described in Section 5.2.1.7 
• 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 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
31 
 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.6.4 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Schedule of 
Assessments) and Section 7.1.6 (Follow-up 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).  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. 
5.7 
Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with combination vorinostat and 
pembrolizumab and had at least two treatments with vorinostat and pembrolizumab beyond 
the date when the initial CR was declared.  Subjects who then experience radiographic 
disease progression may be eligible for up to one year of additional treatment with vorinostat 
and pembrolizumab via the Retreatment Phase at the discretion of the investigator if no 
cancer treatment was administered since the last dose of vorinostat and pembrolizumab, the 
subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is 
open.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  Additional details are provided in Section 7.1.6.4. 
5.8 
Subject Replacement Strategy 
Patients who do not complete the first cycle of combination therapy during the dose finding 
phase will be replaced. Patients who cannot complete Cycle 1 of the expansion phase for 
reasons unrelated to the study drug will also be replaced. 
5.9 
Pseudoprogression 
For a clinically stable subject with first radiologic evidence of progressive disease (PD), it is 
at the discretion of the site investigator to continue treating the subject with pembrolizumab 
until PD is confirmed at least 6 weeks from the date of the first tumor imaging suggesting 
PD. If radiologic PD is confirmed by the subsequent tumor imaging the subject should be 
discontinued from treatment unless, in the opinion of the investigator, the subject is 
achieving a clinically meaningful benefit. 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
32 
 
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. 
 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
33 
 
6.0 SCHEDULE OF ASSESSMENTS 
 
Trial Period: 
Screening 
Phase 
Run-in 
Phase13 
Combination Phase 
End of 
Treatment 
Post-Treatment 
Treatment Cycle 
Screening1 
(Visit 1) 
-2 
-1 
1 
1 
 
 
D 14 
2 
 
3 
 
4 
 
To be repeated beyond 8 
cycles 
Discontinua
tion 
Safety 
Follow-up2 
Follow-up 
Visits3 
Sur-
vival 
Follow-
up 
 
 
 
5 
6 
7 
8 
 
 
 
 
Scheduling Window (Days): 
-28 days to 
start of 
first cycle  
±  
3 
±  
3 
±  
3 
±  
3 
±  
3 
±  
3 
±  
3 
± 
3 
±  
3 
± 
3 
±  
3 
±  
3 
30 days post 
discon ± 3 
Per institu-
tional 
guidelines 
Every 6 
months 
± 30 
Administrative Procedures 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Treatment Administration 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Clinical Procedures/Assessments 
 
Review Adverse Events 
 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Full Physical Examination4 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Drug Compliance Review 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Vital Signs, Weight and Height (Screening 
Only) 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
ECOG Performance Status 
X 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Laboratory Procedures/Assessments9 
 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
34 
 
Trial Period: 
Screening 
Phase 
Run-in 
Phase13 
Combination Phase 
End of 
Treatment 
Post-Treatment 
Treatment Cycle 
Screening1 
(Visit 1) 
-2 
-1 
1 
1 
 
 
D 14 
2 
 
3 
 
4 
 
To be repeated beyond 8 
cycles 
Discontinua
tion 
Safety 
Follow-up2 
Follow-up 
Visits3 
Sur-
vival 
Follow-
up 
 
 
 
5 
6 
7 
8 
 
 
 
 
Scheduling Window (Days): 
-28 days to 
start of 
first cycle  
±  
3 
±  
3 
±  
3 
±  
3 
±  
3 
±  
3 
±  
3 
± 
3 
±  
3 
± 
3 
±  
3 
±  
3 
30 days post 
discon ± 3 
Per institu-
tional 
guidelines 
Every 6 
months 
± 30 
Pregnancy Test – Urine or Serum β-HCG 
x 5 
 
 
x 5 
x 5 
 
 
 
PT/INR and aPTT 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Comprehensive Serum Chemistry Panel 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Urinalysis 
x 
 
x 
 
 
x 
 
x 
 
x 
 
x 
x 
 
 
 
T3, FT4 and TSH 
x 
 
x 
 
 
x 
 
x 
 
x 
 
x 
x 
 
 
 
HgbA1c11 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Prostate Specific Antigen Test 
 
 
 
x 
 
 
x 
 
x 
 
x 
 
x  
 
 
 
Efficacy Measurements 
 
Tumor Imaging – CT16 
x 
 
 
 
 
 
x13 
 
 
x16 
 
 
x12 
 
x 6 
 
Tumor Imaging - Bone Scan 
x 
 
 
 
 
 
x12, 
13 
 
 
x12,16 
 
 
x12 
 
 
 
Tumor Imaging - 68Ga-PSMA-11 PET 
Scan17 
x 
 
 
 
 
 
 
x17 
 
 
 
 
 
 
 
 
Tumor Biopsies/Archival Tissue 
Collection/Correlative Studies Blood 
 
Archival (when available), Newly Obtained 
Tissue Collection (optional) 7 
x 
 
 
 
x15 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection 
x 
X8 
 
x 
 
x 
 
x 
 
x 
 
x 
x 10 
 
 
 
 
 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
35 
 
Footnotes:  
1 Procedures completed prior to consenting that are a part of a subject’s standard of care may be used if they fall within the 28 day window to start 
treatment. Screening procedures completed 7 days of C1D1 do not need to be repeated.  
2 If the subject discontinues treatment due to disease progression, a phone call to the patient can serve as the Safety Follow-up Visit if the End of 
Treatment Visit was done. If a subject initiates a new anti-cancer therapy within 30 days after the treatment discontinuation, the 30 day Safety 
Follow-up Visit must occur before the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move into 
Survival Follow-up. 
3 Applies to subjects who discontinue trial treatment for a reason other than disease progression. Subjects should be assessed per institutional 
guidelines by radiologic imaging to monitor disease status. Every effort should be made to collect information regarding disease status until the 
start of new anti-neoplastic therapy, disease progression, death, end of the study or if the subject begins retreatment with pembrolizumab. 
4 Full physical exams may also be done by the investigator or qualified designee throughout participation in the trial as clinically indicated. 
5 Only if clinically indicated and must be completed ≤ 7 days prior to the first dose of study medication 
6 It is recommended that after 1 year, imaging should be done every 6 months ± 2 weeks; however, institutional guidelines and investigator 
discretion may vary. 
7 Whenever possible, archival tissue from a tumor lesion will be obtained at screening. However, patients will be given the option to consent to a 
biopsy during the screening phase in case archival tissue cannot be retrieved and a second biopsy on Cycle 1 Day 14 (- 3 days). Missed tissue 
collection will not be considered a protocol deviation for the purposes of this study, as tissue collection is an exploratory objective for this study. 
8 Run-in Phase, Cycle -2 Days 1 and 14 
9 Laboratory tests for screening or entry into the Retreatment Phase should be performed within 10 days prior to the first dose of treatment.  After 
Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the investigator or 
qualified designee and found to be acceptable prior to each dose of trial treatment.  
10 When patients are taken off treatment and at the time of disease progression blood for correlative markers will be also obtained.   
11 HcbA1c only required for patients with diabetes mellitus at time of study entry. 
12 Only as clinically indicated (Cohort A and B).  Standard of care after initial 68Ga-PSMA-11 PET (Cohort C)  
13 Imaging will be done prior to dosing on C3D1. 
14 The run-in phase will only be done during the Dose Expansion Phase and may be waived at the investigator’s discretion. 
15 Window for second biopsy is -3 days not +/- 3 days as is the case for other procedures at this time point. Biopsy should occur approximately 2 
hours following the most recent dose of vorinostat on cycle 1 day 14. To ensure that these samples are obtained at the correct time, patients are 
urged to take their vorinostat dose in the clinic on the day of on-treatment sample collection. 
16 Imaging will be done every 3 cycles beginning cycle 6 throughout treatment. 
17 Applicable to a subset of patients in Cohort C (prostate cancer) only, as determined by the Principal Investigator. The Ga-PSMA-11 PET scan 
should be completed at 12 weeks (C4D1) 
 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
36 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Schedule of Assessments -Section 6.0 summarizes the trial procedures to be performed 
at each visit.  Individual trial procedures are described in detail below.  It may be necessary 
to perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g. HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
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’s approval 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 if the new information would affect the subject’s 
willingness to continue participation in the study as determined by the IRB. 
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 requirements, applicable laws and regulations and 
Sponsor requirements. 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
37 
 
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 during the 
screening period.  Medical history will include all active conditions, and any condition 
diagnosed within the prior 10 years that are considered to be clinically significant by the 
Investigator.  Details regarding the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
During the screening period, 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 written informed consent.  Treatment 
for the disease for which the subject has enrolled in this study will be recorded separately and 
not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and events of clinical interest 
(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 treatment discontinuation.  If a subject initiates a new anti-cancer therapy within 30 
days after treatment discontinuation, the 30 day Safety Follow-up Visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject 
will move into Survival Follow-up.  


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
38 
 
7.1.1.6 Assignment of Screening and Registration Number 
Subjects will be assigned a screening and registration number in sequential order by the 
Coordinating Center’s study coordinator, or for participating sites, the Multicenter Network 
Administrator, or designee. Additional details of this process can be found in the Study 
Procedures Manual. 
7.1.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
Subjects will be given a drug diary (Section 14.4) to record doses of vorinostat and any 
adverse events he or she may experience. Drug diaries will be collected at the start of the 
next cycle, or at the time of the next clinic visit, whichever is sooner. Any discrepancies in 
drug accountability will be clarified with the subject. 
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 Schedule of Assessments and more frequently if 
clinically indicated.  Adverse events will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE Version 4.0 (reference Section 14.2).  
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, 
and action taken with regard to trial treatment.  
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated 
to determine if it is possibly an Event of Clinical Interest (ECI) of a potentially immunologic 
etiology (termed immune-related adverse events, or irAEs); see the separate package insert 
regarding the identification, evaluation and management of potential irAEs. Detailed 
information regarding ECIs can be found in Section 14.5.   
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.  Full physical exams may also be done by the investigator or qualified designee 
throughout participation in the trial as clinically indicated and as specified in the Schedule 
of Assessments (section 6.0.)  After the first dose of study intervention, new clinically 
significant abnormal findings should be recorded as AEs.   
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
39 
 
7.1.2.3 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 Schedule of Assessments (Section 6.0).  Vital signs should include temperature, pulse, 
respiratory rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 14.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Schedule of Assessments.   
7.1.2.5 Tumor Imaging and Assessment of Disease 
Imaging studies (CT and bone scan) will be performed at baseline, before Cycle 3, every 3 
cycles thereafter and at treatment discontinuation as described in Section 7.1.4.1 below. CT 
modalities should be done according to standard of care for the patient’s disease. Bone scans 
should be done at baseline and then only as clinically indicated.  
Patients in Cohort C (prostate) will have two PET scans using 68Ga-PSMA-11: once at baseline 
and then at 12 weeks (Cycle 4) Not all patients in Cohort C will have the additional PET scans. 
This determination will be made by the Principal Investigator. 
Participant eligibility will be determined using local assessment (Investigator assessment) 
based on RECIST 1.1.  In addition, images (including via other modalities) that are obtained 
at an unscheduled time point to determine disease progression, as well as imaging obtained for 
other reasons, but which demonstrate radiologic progression, should also be used to determine 
progression. 
When the Investigator identifies radiographic progression per RECIST 1.1, efforts should be 
made to verify radiologic PD. Treatment should continue until PD has been verified.  
Regardless of whether PD is verified, if the Investigator considers the participant has 
progressed, but elects to implement irRC, the Investigator will assess for confirmation of 
progression by irRC at subsequent time points.   
7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling 
7.1.2.6.1 Pharmacodynamic Analysis  
All biopsies on this trial are optional for patients. Whenever possible, archival tissue from a 
tumor lesion will be obtained at screening. If archived tissue is not available, patients will be 
given the option to consent to a biopsy during the screening phase. Patients will also be given 
the option to consent to a biopsy on Day 14 of Cycle 1 (window -3 days). The treatment 
biopsy should occur approximately 2 hours following the most recent dose of vorinostat on 
cycle 1 day 14. To ensure that these samples are obtained at the correct time, patients are 
urged to take their vorinostat dose in the clinic on the day of on-treatment sample collection.  


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
40 
 
Biopsy for tumor tissue collection will only be done on patients who have accessible tumor 
per institutional guidelines. Missed tissue collection will not be considered a protocol 
deviation for the purposes of this study, as tissue collection is an exploratory objective for 
this study.  
Biomarker studies on tumor and blood biospecimens will be carried out to help understand 
the mechanism of action of the pembrolizumab and vorinostat combination. The run-in phase 
will help to assess the effect of single agents on the potential biomarkers. Results from these 
correlative studies will help in the identification of potential biomarkers of response to the 
pembrolizumab plus vorinostat combination, ultimately leading to the development of a 
patient selection strategy for further clinical investigation. As such, collection of tumor and 
blood biospecimens at baseline and on study will be of great importance.  
The pharmacodynamics of vorinostat and pembrolizumab will be evaluated. Correlative 
studies will include assessment of immune effects Tregs, MDSCs and other immune cells at 
defined time points per the study calendar (i.e., baseline, Run-in Phase Cycle -2 Days 1 and 
14 [Dose Expansion Phase only], Cycle 1 Day 1 before dosing, Cycle 2 Day 1 before dosing, 
every other cycle day 1 before dosing thereafter, and at treatment discontinuation).  
Imaging studies (CT and bone scan) will be performed at baseline, before Cycle 3, every 3 
cycles thereafter and at treatment discontinuation.  
Relationships between vorinostat exposure and pharmacodynamic effects (e.g. histone 
acetylation in peripheral blood mononuclear cells (PBMNCs) and changes in T cell subset 
population) will be characterized. Samples will be processed, PBMNCs isolated and histone 
acetylation status determined. Blood samples will be analyzed for immune cell sub 
populations. CD4+, CD4+/Foxp3, CD8+ cells, NK cells will be quantitated by FACS 
analysis. Foxp3 gene expression will be evaluated by quantitative RTPCR  
 
Correlative studies on blood samples: 
o CD45 cells 
o Effector CD4 T cells 
o Effector CD8 T cells 
o FoxP3+ CD4+ Regulatory T cells (Tregs) 
o CD11b+ CD14+ HLA-DR low/neg MDSCs 
o Circulating microRNAs 
o Chemokines profile (i.e. IL-8, HFG, ostepontin, etc.) 
 
Correlative studies on tumor samples 
o T effector cells 
o Tregs 
o MDSCs 
o M1/M2 macrophages 
Please refer to the Study Procedures Manual for Sample Collection and Processing and 
shipping instructions. 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
41 
 
7.1.2.6.2 Tumor Samples 
Formalin-Fixed Paraffin-Embedded Tissue: Archival tissue samples may be obtained from 
any time prior to drug dosing from either the original diagnosis or from any subsequent biopsy 
done prior to start of first drug treatment. Paraffin blocks are preferred, but if unavailable, five 
(5) 4 micron sections and two (2) to six (6) 10 micron sections from the same tumor block will 
be requested. 
Fresh tumor samples: Pretreatment and On Treatment tumor biopsy samples will be collected 
from patients who consent and who have accessible tumor per institutional procedures. The 
biopsy sample will be split into two portions:  one (1) portion will be placed in RNAlaterTM  
and one (1) portion will be placed in 10% formalin solution.   
 
The On Treatment samples will be collected ~2 hours following the most recent dose of 
vorinostat on cycle 1 day 14 (-3 days).  To ensure that these samples are obtained at the correct 
time, patients are urged to take their vorinostat dose in the clinic on the day of on-treatment 
sample collection. The time of the vorinostat dose and sample collection must be recorded. 
 
Please refer the Study Procedures Manual for additional processing and shipping instructions. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments for hematology, chemistry, 
urinalysis, and others are specified in Table 5. The Schedule of Assessments - Section 6.0 
summarizes the laboratory procedures to be performed at each visit. 
Laboratory tests for screening or entry into the Retreatment Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle -2, 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.  


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
42 
 
Table 5: 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 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
Blood for correlative studies  
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
43 
 
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 whenever 
possible.  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.  
Subjects who a) attain a CR or b) complete 24 months of treatment with pembrolizumab may 
discontinue treatment with the option of restarting treatment if they meet the criteria 
specified in Section 7.1.6.4.  After discontinuing treatment following assessment of CR, 
these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.1.6.1) and then proceed to the Follow-Up Period of the study (described in Section 7.1.6.2). 
7.1.4.2 Blinding/Unblinding 
This is an open-label trial. 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Schedule of Assessments. Specific procedure-
related details are provided above in Section 7.1 - Trial Procedures. 
7.1.6 Follow-up Requirements 
7.1.6.1 Safety Follow-up Visit 
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after 
treatment discontinuation or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  Subjects who are eligible for retreatment 
with pembrolizumab (as described in Section 7.1.6.4) may have up to two Safety Follow-up 
Visits, one after the Treatment Period and one after the Retreatment Phase. 
7.1.6.2 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-up Phase and should be assessed per institutional guidelines by 
radiologic imaging to monitor disease status. Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, end of the study or if the subject begins retreatment with pembrolizumab 
as detailed in Section 7.1.6.4.  Information regarding post-study anti-neoplastic treatment 
will be collected if new treatment is initiated. 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
44 
 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.6.4 will move from the Follow-Up Phase to the Retreatment Period when they 
experience disease progression.  
7.1.6.3 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 will be monitored every 6 
months (± 30 days) to assess for survival status until death, withdrawal of consent, or the end 
of the study, whichever occurs first.  
7.1.6.4 Retreatment Phase 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment phase is only available if the study remains open and the subject meets the 
following conditions: 
Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1 (Section 14.3), and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (reference Section 
5.5.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
45 
 
 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. Subjects should be re-consented prior to start of re-treatment. 
 
Visit requirements are outlined in Section 6.0 – Schedule of Assessments. 
 
7.2 
Assessing and Recording of Adverse Events 
7.2.1 Definitions of Adverse Events 
7.2.1.1 Adverse Event (AE) 
An adverse event is defined as untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. An adverse event can be ANY 
unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease 
temporarily associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, 
‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).  Adverse events will be graded according to 
the NCI Common Toxicity Criteria, Version 4.0. 
7.2.1.2 Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence resulting in one or more of the 
following: 
• Results in death or ANY death occurring within 90 days of last dose of study drug 
(even if it is not felt to be drug related)  
• Is life-threatening (defined as an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Hospitalizations that are not considered SAEs are:  
o Hospitalization planned prior to first administration of study drug 
o Hospitalization for elective treatment of a pre-existing condition unrelated to the 
study medication 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but,  based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above).  Examples of such events include, but are not 
limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; or the 
development of drug dependency or drug abuse. 
• Pregnancy 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
46 
 
o Pregnancy of a patient or of the female partner of a male patient during the 
study or within 120 days after the last dose of study drug should be reported 
via an SAE report.  Should pregnancy occur in a female participant during the 
treatment period, study drug should be discontinued and Merck notified 
immediately.  Should a pregnancy occur in a female companion of a male 
participant during the treatment period, the male participant can continue 
treatment and Merck notified immediately.  Any such pregnancy is to be 
followed until final outcome. Evaluating Adverse Events 
• In addition to the above criteria, AEs meeting either of the below criteria, although 
not serious per ICH definition, are reportable to Merck in the same time frame as 
SAEs to meet certain local requirements. Therefore, these events are considered 
serious by Merck for collection purposes. 
o Is a new cancer (that is not a condition of the study) 
o Is associated with an overdose of pembrolizumab 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
7.2.1.3 Unanticipated Problem 
Unanticipated Problem (UP): any incident, experience, or outcome that meets all of the 
following criteria: 
1) unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being study; 
2) related or possibly related to participation in the research; and  
3) suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) related to the research than was 
previously known or recognized. 
Only a small subset of adverse events occurring in human subjects participating in research 
will meet these three criteria for an unanticipated problem. Furthermore, there are other types 
of incidents, experiences, and outcomes that occur during the conduct of human subjects 
research that represent unanticipated problems but are not considered adverse events. For 
example, some unanticipated problems involve social or economic harm instead of the physical 
or psychological harm associated with adverse events. In other cases, unanticipated problems 
place subjects or others at increased risk of harm, but no harm occurs. 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
47 
 
7.2.1.4 Unexpected Adverse Event 
An adverse event not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the Investigator's brochure or package 
insert. 
Refer to Table 6 for additional details regarding each of the above criteria. 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
48 
 
Table 6: 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 pembrolizumab or vorinostat that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause pembrolizumab or vorinostat to be discontinued? 
Relationship to 
Pembrolizumab 
or Vorinostat 
Did pembrolizumab or vorinostat cause the adverse event? The determination of the likelihood that pembrolizumab or vorinostat 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 pembrolizumab or vorinostat and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely pembrolizumab or vorinostat caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to pembrolizumab or vorinostat 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 pembrolizumab or vorinostat?  
Is the time of onset of the AE compatible with a drug-induced effect? 
 
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 
 


 
 
 
 
 
 
IUSCC-0551  
Version 04/07/2021 
NCT#02619253 
49 
 
 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to 
Pembrolizumab 
or Vorinostat 
(continued)  
Dechallenge 
Was pembrolizumab or vorinostat 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 pembrolizumab or vorinostat; or (3) the trial is a single-dose drug trial); or (4) pembrolizumab or vorinostat are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to pembrolizumab or vorinostat 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) pembrolizumab or vorinostat 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 PEMBROLIZUMAB OR VORINOSTAT, OR IF REEXPOSURE TO PEMBROLIZUMAB OR VORINOSTAT 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 the pembrolizumab or vorinostat 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  pembrolizumab or vorinostat 
relationship). 
Yes, there is a reasonable 
possibility of pembrolizumab or 
vorinostat relationship. 
There is evidence of exposure to pembrolizumab or vorinostat.  The temporal sequence of the AE onset relative to the administration of 
pembrolizumab or vorinostat is reasonable.  The AE is more likely explained by pembrolizumab or vorinostat than by another cause. 
No, there is not a reasonable 
possibility pembrolizumab or 
vorinostat relationship 
Subject did not receive pembrolizumab or vorinostat OR temporal sequence of the AE onset relative to administration of the pembrolizumab or 
vorinostat is not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 


 
Version 04/07/2021 
NCT#02619253 
50 
 
7.2.2 Definition of an Overdose 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. An overdose of vorinostat will be defined as any dose of ≥5 
times the current dose being given (i.e. if 100 mg is indicated, 500 mg would be considered 
treatment overdose, and if 200 mg is indicated, 1000 mg would be considered treatment 
overdose). In the event of overdose, the subject should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of investigational 
product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
If a dose of investigational product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported as described in 
sections 7.2.5 and 10.5.  
7.2.3 Pregnancy and Lactation  
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial or within 120 days of completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  
All subjects and female partners of male subjects who become pregnant must be followed to 
the completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported as within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)  
7.2.4 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms and reported as 
described in sections 5.2.1.6 and 10.5. Events of Clinical Interest for this trial include: 
1.  An overdose of pembrolizumab, as defined in Section 7.2.2 - Definition of an Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results.  


 
Version 04/07/2021 
NCT#02619253 
51 
 
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  The trial site guidance for assessment and 
follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent). 
3. Additional adverse events: 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-Related 
Adverse Event Guidance Document”). This document can be found in Appendix 14.5 and 
provides guidance regarding identification, evaluation and management of ECIs and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days after 
the initiation of a new anticancer therapy, whichever is earlier, need to be reported as 
described in sections 5.2.1.6 and 10.5 regardless of attribution to study treatment, consistent 
with standard SAE reporting guidelines. 
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related. 
7.3 
Participating Site Reporting Responsibilities 
7.3.1 Reporting SAEs, ECIs and Pregnancy to the Coordinating Center (IU Simon 
Comprehensive Cancer Center) 
Any serious adverse event, unanticipated problem, event of clinical interest or pregnancy 
occurring from the first dose of vorinostat to within 90 days from the last dose of study drug 
must be reported to the IU Simon Comprehensive Cancer Center within 24 hours of 
notification or discovery of the incident, using the MedWatch Form 3500A (Mandatory 
Reporting). This form must be accompanied by a cover letter which:  identifies the event, is 
signed by the local principal investigator or treating physician, includes the applicable study 
number and title, and contains the following: 
• Site assessment of the event attribution to investigational treatment or study 
procedure 
• Site assessment of event expectedness (expected vs. unexpected) 


 
Version 04/07/2021 
NCT#02619253 
52 
 
• Assessment of whether or not the research places subjects at a greater risk of harm 
than was previously known or recognized 
• Assessment of the event’s affect on the risk to benefit ratio  
• Statement as to whether the informed consent statement should reflect changes in 
the potential risks involved 
• Statement as to whether the event has been reported previously, and if so, whether 
the frequency is considered unusually high 
 
Send to: 
 
IUSCC Clinical Trials Office 
ATTN: Multicenter coordinator/ IUSCC-0551 
  
 
Preferred E-mail: IUSCCSAE@iu.edu 
  
 
Backup Fax: 317-944-3601 
 
All SAEs must also be entered into OnCore for monthly review by the DSMC Coordinator. 
The Multicenter Network Administrator, or designee, will distribute all reports meeting 
expedited reporting criteria to all participating sites, the FDA and to Merck. Copies of all 
serious adverse event reports will be kept on file in the IU Simon Comprehensive Cancer 
Center Clinical Trials Office. 
7.3.2 Follow-up of AE, SAE, and Other Reportable Safety Event Information 
7.3.3 After the initial AE/SAE report, the investigator is required to proactively follow 
each participant at subsequent visits/contacts. All AEs, SAEs, and other 
reportable safety events including pregnancy and exposure during 
breastfeeding, events of clinical interest (ECIs), cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or 
the participant is lost to follow-up.. In addition, the investigator will make every 
attempt to follow all nonserious AEs that occur in allocated or randomized 
participants for outcome. Reporting to the IRB 
Each participating site will report SAEs, ECIs, pregnancies, and unanticipated problems to 
their IRB per local and institutional guidelines. 
 
7.4 
Coordinating Center Reporting Responsibilities 
7.4.1 Reporting to the IRB 
Unanticipated problems involving risks to subjects or others will be reported promptly to the 
IRB if they are:  
• unexpected; 
• related or possibly related to participation in the research; and 
• suggests that the research places subjects or others at a greater risk of harm than 
was previously known or recognized.   


 
Version 04/07/2021 
NCT#02619253 
53 
 
 
If the unanticipated problem does not meet all three (3) criteria listed above, the event does 
not have to be promptly reported to the Indiana University IRB.  However, it should be 
reported at the time of continuing review. 
 
Prompt reporting of unanticipated problems to the IRB is defined as within 5 business days 
from becoming aware of the event. 
 
7.4.2 Reporting to the FDA 
Per CFR 312.32 (c), the investigator-sponsor of the IND must notify the Food and Drug 
Administration (FDA) and all participating investigators in a written IND safety report of any 
adverse experience.  There are two types of reports to the FDA: 7-day and 15-day reports. 
7-Day Reports: 
The investigator-sponsor must notify the FDA and all participating investigators in a written 
IND safety report of any adverse experience: 
• fatal or life-threatening experience that is both 
• suspected to be associated with use of the drug and 
• unexpected (not in the investigator’s brochure) 
 
The FDA will be notified as soon as possible but no later than 7 calendar days after initial 
receipt of the information. 
 
15-Day IND Reports:  
Per CFR 312.32 (c), the investigator-sponsor of the IND must notify the Food and Drug 
Administration (FDA) and all participating investigators in a written IND safety report of any 
adverse experience: 
• suspected to be associated with use of the drug that is both  
• serious and  
• unexpected  (not in the investigator’s brochure) 
 
Each written notification shall be made as soon as possible, and no later than 15 calendar 
days after the investigator-sponsor’s initial receipt of the information.  
 
Report Content 
Each written notification may be submitted on FDA Form 3500A or in a narrative format and 
must bear prominent identification of its contents (i.e., “IND Safety Report”).  For purposes 
of this protocol, the MedWatch Report Form (FDA 3500A mandatory reporting), along 
with FDA Form 1571, and a cover letter submitted to the appropriate FDA division, will 
serve as the written IND safety report.  Follow-up information to a safety report should be 
submitted as soon as the relevant information is available. 
Submit: 
• MedWatch Report Form (FDA 3500A) 
• FDA Form 1571 
• Cover Letter 


 
Version 04/07/2021 
NCT#02619253 
54 
 
 
Notify the FDA via phone or fax using MedWatch 3500A (mandatory reporting form) 
• 
Phone: 1-888-463-6332, option #1  
• 
Fax: 1-800-FDA-0178 
 
The IUSCC Protocol Development Coordinator should be contacted to assist with all FDA 
submissions and will be provided with a copy of all events that are reported to the FDA.   
 
All IND submissions will be maintained in a master file in the IUSCC Clinical Trials Office. 
 
7.4.3 Reporting to Merck 
SAEs, ECIs and pregnancy reports and any other relevant safety information are to be 
forwarded to the Merck Global Safety facsimile number:  +1-215-993-1220 within 2 working 
days to Merck Global safety (Attn: Worldwide Product Safety; FAX 215 993-1220). 
A copy of all 15 Day Reports and FDA Annual Progress Reports as required by the FDA will 
be submitted to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at 
the time of submission to FDA. Investigators will cross reference this submission, according 
to local regulations, to the Merck Investigational Compound Number (IND) at the time of 
submission.   
All subjects with serious adverse events must be followed up for outcome. 
 
7.4.4 Reporting to Participating Sites 
For IND safety reports originating from this study, IUSCC will distribute reports which are 
serious, unexpected and suspected to be associated with the study intervention (possibly, 
probably or definitely related) to all participating sites in the form of an Expedited Safety 
Report (external safety/IND report) within 15 calendar days from determination that the 
suspected adverse reaction qualifies for reporting. Copies of these Expedited Safety Reports 
will be kept on file in the IU Simon Comprehensive Cancer Center Clinical Trials Office. 
When the sponsor(s) sends IND safety reports from external studies that involve the study 
drug(s), Multicenter Network Associate Administrator, or designee, will forward the reports 
to the sponsor-investigator.  The sponsor-investigator, or designee, will review these reports 
and determine if revisions are needed to the protocol or consent. IUSCC will forward these 
reports to participating sites every 2 weeks. 
If an adverse event or SAE requires modification of the informed consent, protocol or other 
study documents, participating sites will be informed by way of an amendment and during 
weekly teleconferences, or sooner, as deemed necessary by the Principal Investigator.   
 
7.4.5 Reporting to the IUSCC Data Safety Monitoring Committee (DSMC)  
Regardless of study sponsorship, the study team must enter all initial and follow-up SAEs, 
expedited, and noncompliance reports into OnCore® for review by the DSMC chair and/or 


 
Version 04/07/2021 
NCT#02619253 
55 
 
coordinator. Expedited reports may include IRB Prompt Report Forms, MedWatch, and 
additional SAE forms as required by the sponsor. When follow-up information is received, a 
follow-up report should also be created in OnCore®. This DSMC reporting requirement is in 
addition to any other regulatory bodies to be notified (i.e. IRB, FDA, pharmaceutical 
company, etc.). The DSMC chair and/or coordinator will review all SAE, expedited, and 
noncompliance reports monthly. 
 
8.0 STATISTICAL METHODS 
8.1 
General Considerations 
Statistical analysis of this study will be the responsibility of the Department of Biostatistics at 
Indiana University School of Medicine. Parameter estimates and relevant summary statistics 
will be reported for both efficacy and safety outcomes. Continuous variables will be 
summarized by means, medians, minima, maxima and standard deviations. Categorical 
variables will be summarized by frequencies and percentages. Missing data will not be 
imputed. Additional exploratory analysis will be conducted when appropriate. Changes from 
the analysis plan will not require an amendment to the protocol unless it changes a significant 
feature in the protocol. The statistical analysis methods are outline below. 
8.2 
Study Design 
This is an open-label phase I/Ib clinical trial. No randomization or blinding is involved. 
8.3 
Analysis Populations 
8.3.1 Efficacy Population 
The efficacy population comprises all patients who meet the eligibility criteria, are registered 
onto the study, get at least one dose of study drug, and have at least one follow-up evaluation. 
This set will be used for efficacy analysis. 
8.3.2 Safety Population 
The safety population comprises all patients who have received at least one dose of the study 
medication. This set will be used for safety analysis. 
8.4 
Sample Size, Accrual and Study Duration 
A minimum of 51 and maximum of 57 subjects (3-6 per 2 dose levels in the escalation phase 
+ 45 in three expansion cohorts) will be enrolled in this study. The primary sample size is 
dictated by the 3+3 design described earlier. Subjects not DLT evaluable in the finding phase 
will be replaced. Three expansion cohorts of up to n = 15 subjects each will be used to 
measure efficacy endpoints and is critical for the planning of the next phase of investigation. 
Having at least 12 patients per expansion cohort is adequate for the purposes of estimating 
effect sizes for larger trials for outcomes that are normally distributed or can be transformed 
to normality.10 Increasing to 15 per group will help account for the possibility that a few 
subjects may not be evaluable for efficacy.  Subjects not evaluable for efficacy in the 
expansion phase will be replaced.  A subject is not evaluable for efficacy if they do not have 
at least one follow-up assessment of disease status after completing 1 cycle of combination 


 
Version 04/07/2021 
NCT#02619253 
56 
 
therapy. This could be either a scan or an assessment of symptomatic deterioration.  Accrual 
is expected to take up to 12 months.  
 
8.5 
Patient Characteristics 
Baseline patient characteristics will be tabulated, such as demographics (age, race, gender), 
and disease characteristics. 
8.6 
Significant Protocol Violations 
Significant protocol violations such as with respect to eligibility criteria and treatment plan 
will be tabulated. 
8.7 
Concomitant Medications 
Drugs that might affect the study medication will be tabulated. 
8.8 
Exposure and Compliance 
Exposure to the study medication will be summarized by frequencies and rates of the doses 
given. Reasons of not completing all doses will be tabulated. 
8.9 
Efficacy Analysis 
Responses will be tabulated and objective response (CR+PR) via RECIST 1.1 will be 
summarized with the point estimate and corresponding exact 95% confidence interval. For 
patients with prostate cancer PSA response (≥50% decline from baseline), PSA progression 
(≥50% increase from baseline/nadir) and bone lesions progression on 68Ga-PSMA-11 PET or 
bone scans (≥2 lesions from baseline with confirmatory scans 6 weeks later showing ≥2 
additional lesions) will be reported. Progression free and overall survival will be estimated 
using standard Kaplan-Meier curves. The median time-to-event for each endpoint will be 
estimated along with the corresponding 95% confidence interval. Similar descriptive 
analyses will be performed using irRC criteria. Endpoints such as quantitative characteristics 
of humoral immune response will be characterized by their mean and corresponding 95% 
confidence interval. No statistical comparisons are planned. Analyses will be done separately 
by each expansion cohort. Patients enrolled in the Dose Finding Phase will be excluded when 
estimating efficacy for the design of a future trial. 
 
8.10 Safety Analysis 
Toxicities according to CTCAE 4.0 (see Section 14.2) will be summarized by frequencies 
and rates calculated as the proportion of patients in the safety population experiencing SAEs, 
discontinuations due to AEs, and AEs.  Two sets of tables will be generated: one for the 
overall toxicities and one for toxicities related to the study medication (possibly related, 
probably related and definitely related). Toxicities will be grouped by system using MedRA 
preferred terminology. Grade 1 to 4 will be reported individually and also as grade 3/4.  
Deaths will be reported individually. AEs will be reported by dose finding cohort.  In the 
Dose Finding Phase, DLT's will be evaluated in the first 21 days of therapy (see Section 


 
Version 04/07/2021 
NCT#02619253 
57 
 
5.2.1.3). The AEs during the expansion phase will also be reported separately by expansion 
cohort. 
Toxicity monitoring in the expansion phase will be continuous with each expansion arm 
monitored separately.  We will consider the treatment to be excessively toxic if the 
probability of dose limiting toxicities in the first 21 days of therapy is 33% or greater.  The 
following table is based on exact binomial probabilities dropping below 0.10, which we will 
define as an unlikely possibility: 
 
Stop if number of DLTs is: 
3 
4 
5 
6 
7 
8 
in N patients 
3 
4-6 
7-8 
9-10 
11-13 
14-15 
 
8.11 Interim Analysis 
No interim efficacy analysis will be performed 
9.0 DATA AND SAFETY MONITORING  
This study will be conducted in accordance with the IU Simon Comprehensive Cancer Center 
Institutional DSMP for High Risk Trials.   
Investigators will conduct continuous review of data and subject safety. Weekly review 
meetings for high risk trials are required and will include the principal investigator, clinical 
research specialist and/or research nurse (other members per principal investigator’s 
discretion). Weekly meeting summaries should include review of data and subject safety by 
including for each dose level: the number of subjects, significant toxicities as described in the 
protocol, dose adjustments and responses observed. Study teams should maintain meeting 
minutes and attendance for submission to the DSMC upon request.   
9.1 Data Safety Monitoring Committee  
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of 
subject safety, regulatory compliance, and data integrity for this trial.  The DSMC will 
review this study semi-annually to review overall trial progress, toxicity, compliance, data 
integrity, and accrual per the Institutional DSMP.   
 
Furthermore, the DSMC conducts an administrative review of serious adverse events (SAEs), 
deviations, reportable events, and any other outstanding business.  Major issues may require 
further DSMC review or action.   
 
For any increase in frequency of grade 3 or above adverse events (above the rate reported in 
the Investigator Brochure or package insert), the principal investigator will notify the DSMC 
Chair immediately.  The notification will include the incidence of study adverse events, 
grades, and attributions, as well as investigator statements regarding comparison with risks 
per the IB/ package insert.    
 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks 
(or benefits) to the subject warrant early closure of the study, the DSMC Chair and Compliance 


 
Version 04/07/2021 
NCT#02619253 
58 
 
Officer must be notified within 1 business day via email, and the IRB must be notified within 
5 business days. Alternatively, the DSMC may initiate suspension or early closure of the study 
based on its review. 
9.2 
DSMC DLT Review 
The principal investigator and study statistician will officially review all toxicity for each 
cohort of subjects prior to making dose escalation/expansion/de-escalation decisions.  Once a 
decision has been reached by the investigator, the official decision and toxicity data will be 
submitted to the DSMC via email (IUSCC-DLT-Review-L@list.iupui.edu).  Treating 
additional subjects may not proceed until official DSMC correspondence confirms approval 
of dosing decisions for the next stage.   
 
9.3 
IND Annual Reports 
For trials with an IND held locally by the IU principal investigator or university, the IND 
Annual Report will be prepared and submitted to the Compliance Team.  This report will be 
reviewed and approved by the DSMC prior to FDA submission. 
 
9.4 
Study Auditing and Monitoring  
All trials conducted at the IUSCC are subject to auditing and/or monitoring per the 
Institutional DSMP. Reports will be reviewed by the full DSMC at the time of study review.  
 
9.5 
Data Management/ Oncore Reporting Requirements 
The DSMC reviews data and study progress directly from Oncore; therefore, timely data 
entry and status updates are vital.  Study data must be entered within Oncore promptly, no 
later than one week from study visit occurrence.  Subject status in Oncore will be updated in 
real time, as this may affect overall trial enrollment status.  Global SAEs and deviations will 
be reviewed on a monthly basis by the DSMC Chair directly from Oncore.   
 
9.6 
Study Accrual Oversight  
Accrual data will be entered into the IU Simon Comprehensive Cancer Center OnCore 
system. The Protocol Progress Committee (PPC) reviews study accrual twice per year, while 
the PPC coordinator reviews accrual quarterly.  
 
9.7 
Oncore Safety Reporting 
In addition to protocol- and regulatory-required safety reporting, all serious adverse events 
(SAEs) will be captured in the Oncore system within 1 business day of notification.  Initial 
SAE reporting will include as much detail as available, with follow-up to provide complete 
information.  Attributions will be assessed to study drugs, procedures, study disease, and 
other alternate etiology.     
 


 
Version 04/07/2021 
NCT#02619253 
59 
 
9.8 
Protocol Deviation Reporting  
Protocol deviations will be entered into OnCore within 5 days of discovery and reviewed by 
the DSMC Chair on a monthly basis. Findings will be reported to the full DSMC at the time 
of study review.  For serious or repetitive protocol deviations, additional action may be 
required by the DSMC.  
 
9.9 Data Acquisition  
Case Report Forms and Data Submission: This study will utilize electronic Case Report 
Form completion in the OnCore® database. A calendar of events and required forms are 
available in OnCore® at https://cancer.iu.edu/oncore.  The OnCore® database is a 
comprehensive database used by the IUSCC CTO and supported by the Indiana University 
Cancer Center.   
Access to data through OnCore® is restricted by user accounts and assigned roles.  Once 
logged into the OnCore® system with a user ID and password, OnCore® defines roles for 
each user which limits access to appropriate data.   
All source documents are to remain in the patient’s clinic file.  All documents should be kept 
according to applicable federal guidelines.  Clinical trial data in OnCore® are periodically 
monitored by the IU Simon Comprehensive Cancer Center per the DSMC Charter.  
10.0 
 MULTICENTER GUIDELINES 
10.1 Study Documents 
Each participating site must submit regulatory documents (informed consents, 1572s, 
Financial Disclosures, IRB approval documents, Continuing Reviews, Amendments, patient 
brochures or recruitment material etc.) to the Coordinating Center. The Coordinating Center 
will provide each site with a comprehensive list of the required documents prior to study 
start-up, throughout the duration of the study and upon study close-out. It is the responsibility 
of the participating site to maintain copies of all documentation sent to the Coordinating 
Center. 
10.2 Study Initiation  
Before activating the clinical trial at each participating site, the IUSCC CTO Multicenter 
Network Administrator , or designee, will ensure that: 
• Full Institutional Review Board (IRB) approval has been obtained.  
• Research staff at the participating site has been trained in data entry into OnCore®  
• A start-up meeting with each institution has taken place via telephone 
conference. The start-up meeting will cover protocol details (including eligibility 


 
Version 04/07/2021 
NCT#02619253 
60 
 
criteria, treatment plan, etc.), responsibilities of the participating investigators, 
and reporting procedures.   
• A financial conflict of interest statement from each investigator has been 
obtained. 
10.3 Patient Enrollment 
After eligibility is confirmed by the participating site staff, a completed eligibility checklist, 
supporting source documentation, and signed consent will be sent to IUSCC for verification.  
The Multicenter Network Administrator, or designee, will confirm eligibilityand return the 
enrollment information to the site.  The site staff will then register the patient in OnCore®. 
Additional details of this process can be found in the Study Procedure Manual. 
10.4 Data Monitoring 
All multicenter investigator initiated trials conducted at the IUSCC are subject to data 
monitoring by the Multicenter Network Administrator, or designee. External sites will be 
notified of upcoming monitoring visits and will be expected to provide the Multicenter 
Network Administrator, or designee, with source documents for remote monitoring of 
patients.  Queries will be issued in OnCore® and a detailed monitoring report will be 
provided to the participating site.  The IUSCC will also forward any monitoring and/or 
auditing reports to the DSMC.  
When a patient enrolled on this trial, or the trial itself, is selected for local monitoring or 
auditing, the participating site will forward the results to the Multicenter Network 
Administrator, or designee. In addition, if a participating site patient is selected for local 
auditing by the IUSCC DSMC, the site will be responsible for sending IUSCC de-identified 
source documents.  
10.5 Record Retention 
All documentation of adverse events, records of study drug receipt, dispensation, destruction, 
and all IRB correspondence will be stored in accordance with all applicable federal 
guidelines. 
Following closure of the study, each participating site will maintain a copy of all site study 
records in a safe and secure location. The Coordinating Center will inform the investigator at 
each site at such time that the records may be destroyed. 
11.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
11.1 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 


 
Version 04/07/2021 
NCT#02619253 
61 
 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
 
 


 
Version 04/07/2021 
NCT#02619253 
62 
 
Table 7: Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
Vorinostat 100 mg 
Capsules 
 
11.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
11.3 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. 
11.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
11.5 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. 


 
Version 04/07/2021 
NCT#02619253 
63 
 
12.0 ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
 
 


 
Version 04/07/2021 
NCT#02619253 
64 
 
13.0 REFERENCES 
1. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P et al . Safety and 
activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 
2012, 28;366(26):2455-65. 
2. Powles T, Vogelzang NJ, Fine GD, Eder JP, Braiteh FS, Loriot Y, et al  Inhibition of 
PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder 
cancer (UBC). J Clin Oncol 32:5s, 2014 (suppl; abstr 5011). 
3. Kato Y, Yoshimura K, Shin T, Sanni T, Salumbides B, Schulick R, and Pili R. (2007) 
Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in 
combination with interleukin 2 in a murine model of renal cell carcinoma. Clin 
Cancer Res. 13(15 Pt 1):4538-46. 
4. Shen L, Ciesielski M, Ramakrishnan S, Miles K, Ellis L, Sotomayor Dr. Pili, Shrikant 
P, Fenstermaker R, Pili R. Class I histone deacetylase inhibitor entinostat suppresses 
regulatory T cells and enhances immunotherapies in renal and prostate cancer models. 
PLoS ONE.2012;7(1):e30815. 
5. Pili R, Shen L, George S, Hammers HJ, Sandecki A, Collins C, Carducci MA. Phase I 
study of high-dose interleukin 2, aldesleukin, in combination with the histone 
deacetylase inhibitor, entinostat, in patients with metastatic renal cell carcinoma: 
Safety and tolerability results. J Clin Oncol 31, 2013 (suppl 6; abstr 369). 
6. Shen L, Pili R. Class I histone deacetylase inhibition is a novel mechanism to target 
regulatory T cells in immunotherapy. Oncoimmunology. 2012 Sep 1;1(6):948-950. 
7. Atadja P Development of the pan-DAC inhibitor panobinostat (LBH589): successes 
and challenges. Cancer Lett. 2009 Aug 8;280(2):233-41.  
8. Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in 
patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II 
clinical trial.Pili R, Liu G, Chintala S, Verheul H, Rehman S, Attwood K, Lodge MA, 
Wahl R, Martin JI, Miles KM, Paesante S, Adelaiye R, Godoy A, King S, Zwiebel J, 
Carducci MA. Br J Cancer. 2017 Mar 28;116(7):874-883. 
9. Graff, J. N., Alumkal, J. J., Drake, C. G., Thomas, G. V., Redmond, W. L., Farhad, 
M., Cetnar, J. P., Ey, F. S., Bergan, R. C., Slottke, R., and Beer, T. M. (2016) Early 
evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget. 
2016 Aug 16;7(33):52810-52817.  
10. Julious S. Sample size of 12 per group rule of thumb for a pilot study. 
Pharmaceutical Statistics 2005, 4: 287-91. 
 
 
 


 
Version 04/07/2021 
NCT#02619253 
65 
 
14.0 APPENDICES 
14.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
14.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
Due to the size of the latest version of the Common Toxicity Criteria, copies of this appendix 
are not included with this protocol document. An electronic copy is available on the CTEP 
web site, http://ctep.cancer.gov/reporting/ctc.html. 
 
14.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study.  The same imaging technique regarding modality, ideally the same scanner, and 
the use of contrast should be used in a participant throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the 
accuracy of the assessment of response or progression based on imaging. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-
47. 


 
Version 04/07/2021 
NCT#02619253 
66 
 
In addition, volumetric analysis will be explored by central review for response assessment. 
14.3.1 Tumor Imaging and Assessment of Disease 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  For the 
abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used 
when CT with iodinated contrast is contraindicated, or when local practice mandates it.  MRI 
is the strongly preferred modality for imaging the brain.  The same imaging technique 
regarding modality, ideally the same scanner, and the use of contrast should be used in a 
participant throughout the study to optimize the reproducibility of the assessment of existing 
and new tumor burden and improve the accuracy of the assessment of response or 
progression based on imaging. 
Expedited confirmation of measurable disease based on RECIST 1.1 at Screening should be 
used to determine participant eligibility.  Confirmation that the participant’s imaging shows 
at least 1 lesion that is appropriate for selection as a target lesion per RECIST 1.1 is highly 
recommended prior to participation starting treatment.   
Participant eligibility will be determined using local assessment (Investigator assessment) 
based on RECIST 1.1.  In addition, images (including via other modalities) that are obtained 
at an unscheduled time point to determine disease progression, as well as imaging obtained 
for other reasons, but which demonstrate radiologic progression, should also be used to 
determine progression. 
When the Investigator identifies radiographic progression per RECIST 1.1, efforts should be 
made to verify radiologic PD. Treatment should continue until PD has been verified.     
14.3.2 Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of the 
first cycle.  The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1. 
The screening images must be submitted to the central imaging vendor for confirmation of 
measurable disease per RECIST 1.1 for eligibility prior to start of treatment. 
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if they are of diagnostic quality and performed within 28 days prior 
to the date of cycle 1 and can be assessed by the central imaging vendor.  
14.3.3 Tumor Imaging During the Study 
The first on-study imaging assessment should be performed at 4 weeks (28 days -7 days) 
from the date of screening.  Subsequent tumor imaging should be performed every 9 weeks 
(63 days ±3 days) or more frequently if clinically indicated.  After 18 weeks (126 days ±3 
days), participants who remain on treatment will have imaging performed every 9 weeks (63 
days ±3 days).  Imaging timing should follow calendar days and should not be adjusted for 


 
Version 04/07/2021 
NCT#02619253 
67 
 
delays in cycle starts.  Imaging should continue to be performed until disease progression is 
identified by the Investigator.  
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed.  Participants will then return to regular scheduled imaging every 9 
weeks, starting with the next scheduled imaging time point.  Participants who receive 
additional imaging for confirmation do not need to undergo the next scheduled tumor 
imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point.   
14.3.4 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window).  If previous imaging was obtained within 
4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory. In participants who discontinue study treatment due to documented disease 
progression and the investigator elects not to implement iRECIST, this is the final required 
tumor imaging. 
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging using 
the same imaging schedule used while on treatment (every 9 weeks in Year 1 or every 6 months 
after Year 1) to monitor disease status until the start of a new anticancer treatment, disease 
progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever 
occurs first. 
14.3.5 Second Course (Retreatment) Tumor Imaging 
Tumor imaging must be performed within 10 days prior to restarting treatment with 
pembrolizumab.  Local reading (Investigator assessment with site radiology reading) will be 
used to determine eligibility. 
The first on-study imaging assessment should be performed at 9 weeks (63 days ±3 days) 
after the restart of treatment.  Subsequent tumor imaging should be performed every 9 weeks 
(63 days ±3 days) or more frequently, if clinically indicated. 
Per RECIST 1.1, if tumor imaging shows initial PD, tumor assessment should be repeated 4 
to 8 weeks later in order to confirm PD with the option of continuing treatment while 
awaiting radiologic confirmation of progression with the option of continuing treatment 
while awaiting radiological confirmation of progression in clinically stable patients.  
Participants who obtain confirmatory imaging do not need to undergo scheduled tumor 
imaging if it is less than 4 weeks later and may wait until the next scheduled imaging time 
point, if clinically stable. 
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 


 
Version 04/07/2021 
NCT#02619253 
68 
 
occurs first.  Disease progression may be confirmed 4 to 8 weeks after the first tumor 
imaging indicating PD, in clinically stable participants. 
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window).  If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory.  For participants who discontinue study treatment due to documented 
disease progression, this is the final required tumor imaging. 
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by radiologic imaging 
every 6 months (180 days ±14 days) until either the start of a new anticancer treatment, 
disease progression, pregnancy, death, or the end of the study, whichever occurs first. 
 
 


 
Version 04/07/2021 
NCT#02619253 
69 
 
14.4 Drug Diary 
 
 
 
 
 
 
 
 


 
Version 04/07/2021 
NCT#02619253 
70 
 
14.5 Events of Clinical Interest Guidance Document 
Attached as PDF entitled, “Pembrolizumab ECI_Guidance 
Document_Version 5_FINAL_18-Dec-2014” 
 
 
 
14.6  Woman of Childbearing Potential (WOCBP) definition  
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
 
 


 
Version 04/07/2021 
NCT#02619253 
71 
 
14.7 Immune-Related Response Criteria 
INTRODUCTION 
Increasing clinical experience indicates that traditional response criteria (e.g., Response Evaluation 
Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health Organization [WHO]) may 
not be sufficient to characterize fully activity in the new era of target therapies and/or biologics.  In 
studies with cytokines, cancer vaccines, and monoclonal antibodies, complete response, partial 
response, or stable disease has been shown to occur after an increase in tumor burden as characterized 
by progressive disease by traditional response criteria.  Therefore, conventional response criteria may 
not adequately assess the activity of immunotherapeutic agents because progressive disease (by initial 
radiographic evaluation) does not necessarily reflect therapeutic failure.  Long-term effect on the 
target disease must also be captured.  The immune-related response criteria1 (irRC) are criteria that 
attempt to do that by enhancing characterization of new response patterns that have been observed 
with immunotherapeutic agents (i.e., ipilimumab).  (Note:  The irRC only index and measurable new 
lesions are taken into account.) 
GLOSSARY 
Term 
Definition 
SPD 
sum of the products of the two largest perpendicular diameters 
Tumor burden 
SPDindex lesions + SPDnew, measurable lesions 
Nadir 
minimally recorded tumor burden 
irCR 
immune-related complete response 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irSD 
immune-related stable disease 
irBOR 
immune-related best overall response 
 
BASELINE ASSESSMENT USING irRC 
Step 1. Identify the index lesions (five lesions per organ, up to ten visceral lesions and five cutaneous 
lesions).   
Step 2. Calculate the SPD of all of these index lesions: 
SPD = 
(Largest diameter of lesion i) × (Second largest diameter of lesion i). 
 
1  Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: 
immune-related response criteria. Clin Can Res 2009;15:7412−20. 
∑
i


 
Version 04/07/2021 
NCT#02619253 
72 
 
POST-BASELINE ASSESSMENTS USING irRC 
Step 1. Calculate the SPD of the index lesions.   
Step 2. Identify new, measurable lesions (≥ 5 × 5 mm; up to five new lesions per organ:  five new 
cutaneous lesions and ten visceral lesions).   
Step 3. Calculate the SPD of the new, measurable lesions. 
Step 4. Calculate the tumor burden: 
Tumor burden =  SPDindex lesions + SPDnew, measurable lesions 
Step 5. Calculate the change in tumor burden relative to baseline and the change in tumor burden 
relative to nadir. 
Step 6. Derive the overall response using the table below. 
Overall Response Criterion 
irCR 
Complete disappearance of all lesions (whether measurable or not, and no new 
lesions) confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date 
first documented 
irPR 
Decrease in tumor burden ≥ 50% relative to baseline confirmed by a 
consecutive assessment ≥ 4 weeks from the date first documented 
irSD 
Criteria for irCR, irPR, and irPD are not met; does not require confirmation 
irPD 
Increase in tumor burden ≥ 25% relative to nadir confirmed by a consecutive 
assessment ≥ 4 weeks from the date first documented 
irCR = immune-related complete response; irPD = immune-related progressive disease; 
irPR = immune-related partial response; irSD = immune-related stable disease. 
 
DETERMINATION OF irBOR 
Once a patient has completed all tumor assessments, his/her irBOR may be determined: 
Condition 
irBOR 
At least one irCR 
irCR 
At least one irPR and no irCR 
irPR 
At least one irSD and no irCR and no irPR 
irSD 
At least one irPD and no irCR, no irPR, and no irSD 
irPD 
irBOR = immune-related best overall response; irCR = immune-related complete response; 
irPD = immune-related progressive disease; irPR = immune-related partial response; 
irSD = immune-related stable disease.