A Phase 1 Study of Pembrolizumab Plus Vorinostat for Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Hodgkin Lymphoma
Phase: PHASE1
Conditions: Grade 3b Follicular Lymphoma, Recurrent B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between DLBCL and Classic HL, Recurrent Classic Hodgkin Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Follicular Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3a Follicular Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma, Recurrent Transformed Non-Hodgkin Lymphoma, Refractory B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between DLBCL and Classic HL, Refractory Classic Hodgkin Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory Follicular Lymphoma, Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma, Refractory Transformed Non-Hodgkin Lymphoma
Sponsor: City of Hope Medical Center

 
IRB #17080 
 
10/16/2020 
Version: 14 
CITY OF HOPE 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION 
 
 
TITLE:  A Phase 1 Study of Pembrolizumab Plus Vorinostat for Relapsed or Refractory Diffuse Large B-cell 
Lymphoma, Follicular Lymphoma, and Hodgkin Lymphoma 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 17080  
Protocol Date 10/16/20 
 
COH Initial Approval   
 
 
(Protocol v00 dated 04/21/2017)    
 
 
     Version: 00 
COH Amendment 01 
(Protocol v01 dated 07/13/2017)  
Version: 01 
COH Amendment 02 
(Title Page dated07/18/2017, Update Personnel) 
Version: 02 
COH Amendment 03 
(Protocol v02 dated 09/21/2017) 
Version: 03 
COH Amendment 04 
(Protocol v03 dated 11/22/2017) 
Version: 04 
COH Amendment 05 
(Protocol v04 dated 03/06/2018) 
Version: 05 
COH Amendment 06 
(Protocol v05 dated 05/18/2018) 
Version: 06 
COH Amendment 07 
(Title Page dated 06/21/2018, Update Personnel) 
Version: 07 
COH Amendment 08 
(Title Page dated 12/17/2018, Update Personnel) 
Version: 08 
COH Amendment 09 
(Protocol v06 dated 02/08/19) 
Version: 09 
COH Amendment 10 
(Protocol v07 dated 04/23/19) 
Version: 10 
COH Amendment 11 
(Title Page dated 05/31/2019, Update Personnel) 
Version: 11 
COH Amendment 12 
(Protocol v08 dated 09/11/19) 
Version: 12 
COH Amendment 13 
(Protocol v09 dated 06/04/20) 
Version: 13 
COH Amendment 14 
(Protocol v10 dated 10/16/20) 
Packet: 14 
 
DISEASE SITE: 
 
 
 
Diffuse Large B-cell Lymphoma, Follicular Lymphoma, and 
Hodgkin Lymphoma 
STAGE: 
 
 
 
 
Relapsed/Refractory 
MODALITY(IES): 
 
 
 
 
TYPE:  
 
 
 
 
Phase 1 
 
PRINCIPAL INVESTIGATOR: 
 
Alex Herrera, MD 
 
PARTICIPATING CLINICIANS: 
 
Saro Armenian, M.D., L. Elizabeth Budde, M.D., Thai Cao, M.D., 
Alexey Danilov, M.D., Justin Darrah, M.D.,  Stephen Forman, M.D., 
Myo Htut, M.D., Chatchada Karanes, M.D., Larry Kwak, M.D., 
Matthew Mei, M.D., Auayporn Nademanee, M.D., Liana Nikolaenko, 
M.D., Leslie Popplewell, M.D., Steven Rosen M.D., Geoffrey 
Shouse, D.O., Tanya Siddiqi, M.D., Jasmine Zain, M.D., Zheng 
Zhou, M.D., Ammar Chaudhry, M.D. 
 
 
NURSE PRACTITIONER:      
 
Yi-Ping Wen, NP (M.S.) 
 
 
 

 
This document is confidential and for research purposes only. Do not copy, redistribute, 
disclose or use except as authorized 
 
 
 
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
A Phase 1 Study of Pembrolizumab Plus Vorinostat for Relapsed or Refractory 
Diffuse Large B‐cell Lymphoma, Follicular Lymphoma, and Hodgkin Lymphoma 
 
Version Date:  10/16/20 
Protocol Version:  10 
 
City of Hope #:  17080 
Agents:  Pembrolizumab, Vorinostat 
IND Number:  135084 
Sponsor/ IND Holder:  City of Hope 
Industry Partner/ Funding Support:  Merck 
NCT Number:  NCT03150329 
 
 
 
 
 
 
Principal Investigator 
Alex F. Herrera, MD 
City of Hope National Medical Center 
Dept. of  Hematology 
T: 626‐256‐4673 x 62405 
F: 626‐301‐8256 
Email: aherrera@coh.org 
 
 
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
E‐mail: DCC@coh.org 
  

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PROTOCOL TEAM 
Biostatistician 
Lu Chen, PhD. 
Dept. of Information Sciences 
City of Hope National Medical 
Center 
T: 626‐256‐4673 x 86626 
F: 626‐471‐7106 
Email: lchen@coh.org 
 
Co‐Investigator 
Ammar Chaudhry, MD 
Department of Diagnostic 
Radiology 
City of Hope National Medical 
Center 
T : 626‐218‐6442 
Email : achaudhry@coh.org 
 
 
 
 
 
 
 
 
 
 

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Protocol Team ......................................................................................................................... 2 
1.0 
TRIAL SUMMARY.................................................................................................. 11 
2.0 
TRIAL DESIGN........................................................................................................ 21 
2.1 
Trial Design ........................................................................................................... 21 
2.2 
Trial Diagram ........................................................................................................ 22 
3.0 
OBJECTIVES ........................................................................................................... 22 
3.1 
Primary Objectives ............................................................................................... 22 
3.2 
Secondary Objectives ........................................................................................... 22 
3.3 
Exploratory Objectives ......................................................................................... 23 
4.0 
BACKGROUND & RATIONALE .......................................................................... 23 
4.1 
Study Diseases ....................................................................................................... 23 
4.1.1  Diffuse Large B-cell Lymphoma ........................................................................ 23 
4.1.2  Follicular Lymphoma .......................................................................................... 24 
4.1.3  Classical Hodgkin Lymphoma ............................................................................ 24 
4.2 
PD-1/PD-L1 Pathway and PD-1/PD-L1 Inhibition in Lymphoma ................... 24 
4.3 
Histone Deacetylase Inhibition and Vorinostat In Lymphoma ........................ 25 
4.4 
Study Agent: Pembrolizumab (MK-3475) .......................................................... 26 
4.4.1  Pharmaceutical and Therapeutic Background..................................................... 26 
4.4.2  Nonclinical Pharmacology .................................................................................. 27 
4.4.3  Nonclinical Pharmacokinetics............................................................................. 27 
4.4.4  Preclinical Safety ................................................................................................ 28 
4.4.5  Clinical Safety ..................................................................................................... 29 
4.4.6  Expected Adverse Events.................................................................................... 30 
4.4.7  Immune-Related Adverse Events ....................................................................... 31 

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4.5 
Study Agent: Vorinostat ....................................................................................... 32 
4.5.1  Pharmacology ..................................................................................................... 33 
4.5.2  Toxicology .......................................................................................................... 34 
4.5.3  Biological Activity of Vorinostat ........................................................................ 34 
4.5.4  Summary of Clinical Data .................................................................................. 35 
4.5.5  Safety .................................................................................................................. 36 
4.5.6  Expected Adverse Events.................................................................................... 36 
4.5.7  Drug Interactions ................................................................................................ 38 
4.6 
Rationale ................................................................................................................ 38 
4.6.1  Rationale for the Trial and Selected Subject Population .................................... 38 
4.6.2  Rationale for Pembrolizumab Dose Selection/Regimen/Modification ............... 39 
4.6.3  Rationale for Vorinostat Dose Selection/Regimen/Modification ....................... 40 
4.6.4  Rationale for Additional Patients in Expansion Cohort ...................................... 41 
4.6.5  Rationale for Endpoints ...................................................................................... 41 
4.6.6  Rationale for Biomarker Research/Correlative Studies ...................................... 42 
5.0 
METHODOLOGY ................................................................................................... 48 
5.1 
Entry Criteria ........................................................................................................ 48 
5.1.1  Diagnosis/Condition for Entry into the Trial ...................................................... 48 
5.1.2  Subject Inclusion Criteria ................................................................................... 49 
5.1.3  Subject Exclusion Criteria .................................................................................. 50 
5.2 
Inclusion of Women and Minorities .................................................................... 52 
6.0 
PARTICIPANT ENROLLMENT ........................................................................... 53 
6.1 
Pre-Enrollment Informed Consent and Screening Procedures ........................ 53 
6.2 
Participant Enrollment ......................................................................................... 53 

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6.2.1  COH DCC Availability and Contact Information............................................... 53 
6.2.2  Slot verification and reservation ......................................................................... 53 
6.3 
Screen Failures and Registered Participants Who Do Not begin Study 
Treatment .............................................................................................................. 53 
6.4 
Registration Process ............................................................................................. 53 
7.0 
TREATMENT PROGRAM ..................................................................................... 54 
7.1 
Treatment Allocation ............................................................................................ 54 
7.1.1  Treatment Duration ............................................................................................. 55 
7.1.2  Rules for Phase I Dose Escalation, De-Escalation and Expansion: Adapted 
Rolling 6 Design ................................................................................................. 55 
7.2 
Definition of Dose-Limiting Toxicity ................................................................... 56 
7.3 
Definition of the MTD and Recommended Phase II Dose ................................ 57 
7.4 
Replacement of Subjects ...................................................................................... 58 
7.5 
Expansion Cohort ................................................................................................. 58 
7.6 
Study Treatment: Pembrolizumab ...................................................................... 58 
7.6.1  Dose Selection/Modification .............................................................................. 58 
7.6.2  Pembrolizumab Administration and Storage ...................................................... 61 
7.7 
Study Treatment: Vorinostat ............................................................................... 63 
7.7.1  Vorinostat Dose/Delay Modification Guidelines ................................................ 65 
7.8 
Trial Blinding/Masking ........................................................................................ 66 
7.9 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 66 
7.9.1  Acceptable Concomitant Medications ................................................................ 66 
7.9.2  Prohibited Concomitant Medications ................................................................. 67 
7.10 
Rescue Medications & Supportive Care ............................................................. 68 
7.10.1  Supportive Care Guidelines ................................................................................ 68 

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7.11 
Diet/Activity/Other Considerations ..................................................................... 72 
7.11.1  Diet ...................................................................................................................... 72 
7.11.2  Contraception ...................................................................................................... 72 
7.11.3  Use in Pregnancy ................................................................................................ 74 
7.11.4  Use in Nursing Women ....................................................................................... 74 
7.12 
Subject Withdrawal/Discontinuation Criteria ................................................... 74 
7.12.1  Discontinuation of Study Therapy after CR ....................................................... 75 
7.13 
Clinical Criteria for Early Trial Termination ................................................... 75 
8.0 
TRIAL FLOW CHART (STUDY CALENDAR) .................................................. 77 
8.1 
Study Flow Chart .................................................................................................. 77 
9.0 TRIAL PROCEDURES ................................................................................................. 81 
9.1 
Administrative Procedures .................................................................................. 81 
9.1.1  Informed Consent ................................................................................................ 81 
9.1.2  Inclusion/Exclusion Criteria ............................................................................... 81 
9.1.3  Medical History .................................................................................................. 82 
9.1.4  Prior and Concomitant Medications Review ...................................................... 82 
9.1.5  Disease Details and Treatments .......................................................................... 82 
9.1.6  Assignment of Screening Number ...................................................................... 83 
9.1.7  Trial Compliance (Medication/Diet/Activity/Other) .......................................... 83 
9.2 
Clinical Procedures/Assessments ......................................................................... 83 
9.2.1  Adverse Event (AE) Monitoring ......................................................................... 83 
9.2.2  Adverse Event (AE) collection guidelines .......................................................... 83 
9.2.3  Full Physical Exam ............................................................................................. 83 
9.2.4  Vital Signs ........................................................................................................... 83 

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9.2.5  Eastern Cooperative Oncology Group (ECOG) Performance Scale .................. 84 
9.2.6  Tumor Imaging and Assessment of Disease ....................................................... 84 
9.3 
Tumor Tissue Collection ...................................................................................... 86 
9.3.1  Tumor tissue handling guidelines ....................................................................... 86 
9.4 
Correlative Studies Blood Sampling ................................................................... 88 
9.4.1  Overview and Timepoints ................................................................................... 88 
9.4.2  Labeling of blood samples .................................................................................. 88 
9.4.3  Blood collection .................................................................................................. 88 
9.4.4  Sample Processing by APCF (COH) .................................................................. 90 
9.5 
Laboratory Procedures/Assessments .................................................................. 91 
9.5.1  Correlative Studies .............................................................................................. 93 
9.5.2  Other Procedures ................................................................................................. 93 
9.5.3  Visit Requirements .............................................................................................. 93 
10.0 
Endpoint Evaluation Criteria/Measurement of Effect .......................................... 96 
10.1 
Response Criteria .................................................................................................. 96 
10.2 
Endpoint Definitions ............................................................................................. 97 
11.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 99 
11.1 
Statistical Analysis Plan ....................................................................................... 99 
11.1.1  Demographic and Baseline Characteristics......................................................... 99 
11.1.2  Toxicity Analysis ................................................................................................ 99 
11.1.3  Analysis of Anti-tumor Activity ......................................................................... 99 
11.2 
Safety Analysis and Stopping Rules for Excessive Toxicity in the Expansion 
Cohort .................................................................................................................... 99 
11.3 
Sample Size Accrual Rate .................................................................................. 100 

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11.4 
Correlative Studies ............................................................................................. 100 
12.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 101 
12.1 
Investigational Product ...................................................................................... 101 
12.2 
Packaging and Labeling Information ............................................................... 101 
12.3 
Clinical Supplies Disclosure ............................................................................... 102 
12.4 
Storage and Handling Requirements ................................................................ 102 
12.5 
Returns and Reconciliation ................................................................................ 102 
13.0 
STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY 
MONITORING ....................................................................................................... 102 
13.1 
Site Lead Investigator Responsibilities ............................................................. 102 
13.2 
All Investigator Responsibilities ........................................................................ 103 
13.3 
Study PI Responsibilities .................................................................................... 103 
13.4 
Protocol Management Team (PMT) ................................................................. 103 
13.5 
Monitoring/ Auditing .......................................................................................... 104 
13.6 
Quality Assurance ............................................................................................... 104 
13.7 
City of Hope Data and Safety Monitoring Committee (DSMC) .................... 104 
14.0 
ADVERSE EVENT AND UNANTICIPATED PROBLEM REPORTING ...... 105 
14.1 
Definitions ............................................................................................................ 105 
14.2 
Events of Special Interest Requiring Expedited Reporting ............................ 107 
14.2.1  Overdose ........................................................................................................... 107 
14.2.2  Pregnancies ....................................................................................................... 108 
14.2.3  Abnormal Liver Function Tests ........................................................................ 108 
14.3 
Routine AE Reporting Guidelines ..................................................................... 108 
14.4 
Expedited AE Reporting Guidelines ................................................................. 108 

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14.5 
Additional reporting requirements ................................................................... 109 
15.0 
DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING ............. 111 
15.1 
Source Documents ............................................................................................... 111 
15.2 
Data Capture Methods and Management ........................................................ 111 
15.3 
Case Report Forms/ Data Submission Schedule .............................................. 111 
15.4 
Regulatory Records ............................................................................................ 112 
16.0 
ADHERENCE TO THE PROTOCOL ................................................................. 112 
16.1 
Definitions ............................................................................................................ 112 
16.1.1  Unplanned deviations ........................................................................................ 112 
▪ 
Emergency Modifications ................................................................................... 112 
16.1.2  Planned Non-Emergency Deviations (Single Subject Exception) .................... 112 
16.2 
Reporting of Deviations ...................................................................................... 113 
16.2.1  Reporting Unplanned Deviations ...................................................................... 113 
16.2.2  Reporting Planned Non-Emergency Deviations/ Single Subject Exceptions ... 113 
17.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................... 113 
17.1 
Ethical Standard ................................................................................................. 113 
17.2 
Regulatory Compliance ...................................................................................... 113 
17.3 
Institutional Review Board ................................................................................ 114 
17.4 
Informed Consent ............................................................................................... 114 
17.5 
Participant Withdrawal ..................................................................................... 115 
17.6 
Special and Vulnerable Populations ................................................................. 115 
17.6.1  Inclusion of Women and Minorities ................................................................. 115 
17.6.2  Exclusion of Children ....................................................................................... 115 
17.6.3  Inclusion of HIV Positive Individuals .............................................................. 115 

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17.6.4  Vulnerable Populations ..................................................................................... 115 
17.7 
Participant Confidentiality ................................................................................ 116 
17.8 
Use of Unused (Leftover) Specimens Collected for this Trial ......................... 117 
17.9 
Conflict of Interest .............................................................................................. 117 
17.10  Financial Obligations, Compensation, and Reimbursement of Participants 117 
17.11  Publication/Data Sharing ................................................................................... 118 
Appendix A: ECOG Performance Status ......................................................................... 119 
Appendix B: Registration Coversheet ............................................................................... 120 
Appendix C: The 2014 Lugano Classification .................................................................. 121 
Appendix D: Tissue Shipping Guidelines to City of Hope Pathology Core .................. 125 
Appendix E: Tissue Shipping Guidelines to the Jackson laboratory (FL patients only)
................................................................................................................................... 125 
Appendix F: Correlative Blood Collection Form for Non-COH Sites Only .................. 127 
Appendix G: Correlative Blood Collection Form for all Sites (for FL patients only) .. 128 
Appendix H: Blood shipping Guidelines to City of Hope APCF .................................... 129 
Appendix I: Blood shipping Guidelines to the Jackson Laboratory (FL patients only)
................................................................................................................................... 130 
Appendix J: Correlative Tissue Form for Shipping to COH Pathology Core .............. 131 
Appendix K: Expedited Reporting CoverSheet ............................................................... 132 
Appendix L: Lyric Criteria ................................................................................................ 133 
References ........................................................................................................................ 134 
 

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1.0 TRIAL SUMMARY 
 
 
Protocol Title: 
A Phase I Study of Pembrolizumab Plus Vorinostat for Relapsed or Refractory 
Diffuse Large B-cell Lymphoma, Follicular Lymphoma, and Hodgkin Lymphoma 
Brief Protocol Title for the Lay Public (if applicable): 
Pembrolizumab Plus Vorinostat for Treatment of Relapsed or Refractory 
Lymphomas 
Study Phase: 
I, with an expansion cohort 
Participating Sites: 
- City of Hope 
Rationale for this Study: 
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most 
common B-cell non-Hodgkin lymphomas (NHL), which together comprise the majority of 
NHLs.1 Classical Hodgkin lymphoma (HL) is also a lymphoma of B-cell origin that 
accounts for about 10% of all lymphomas.1 While upfront therapy for DLBCL and HL 
cures the majority of patients, about 20-40% of patients will have relapsed or refractory 
(rel/ref) disease.2 Standard of care treatment for rel/ref DLBCL and HL is salvage 
chemotherapy followed by autologous stem cell transplantation (ASCT). However, this 
approach only cures about a third to half of eligible patients.3 DLBCL and HL patients who 
are refractory to second-line therapy or relapse after ASCT have dismal outcomes.4 Unlike 
DLBCL and HL, the great majority of FL patients are incurable with standard therapy. 
Agents used to treat FL in the second-line and beyond typically lead to shorter remissions.5 
Improved therapies for patients with rel/ref HL, DLBCL, and FL are urgently needed. 
The programmed death receptor-1 (PD-1) pathway is an immune checkpoint that normally 
serves to dampen immune responses in tissues. PD-1 is expressed on activated T-cells and 
binds its ligands, PD-L1 and PD-L2, on tissue cells or antigen presenting cells to decrease 
T-cell activation, proliferation, and survival.6 Tumor cells can co-opt this pathway to evade 
attack by the host immune system.6 A wide range of hematologic malignancies express 
PD-1 or PD-L1, including HL,7 DLBCL,8 and FL.9 In addition, molecular analyses have 
demonstrated that genetic alterations involving PD-L1 and PD-L2 are critical in the 
pathogenesis of HL and subtypes of DLBCL.7, 10 
Monoclonal antibody inhibitors of PD-1 have produced clinical responses in early-phase 
studies in patients with a range of lymphomas, including HL, DLBCL, and FL. A PD-1 
inhibitor, pidilizumab, produced responses as a single-agent in patients with rel/ref FL and 
HL,11 and yielded a 66% overall response rate (ORR) when used in combination with 
rituximab in patients with rel/ref FL.12 In a phase Ib study of another PD-1 inhibitor, 
pembrolizumab, in hematologic malignancies, a 66% ORR was observed in patients with 

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HL who had failed prior brentuximab vedotin.13 Similarly, in a phase I study of the PD-1 
inhibitor, nivolumab, an 87% ORR and 100% clinical benefit rate was observed in patients 
with relapsed or refractory HL,14 along with a 36% ORR in relapsed or refractory DLBCL, 
and a 40% ORR in relapsed or refractory FL.15  
Although responses to PD-1 inhibitors have been observed in patients with HL, DLBCL, 
and FL, there is room for improvement. Despite the high response rate observed to single-
agent PD-1 inhibition, the complete response (CR) rate in patients with HL appears to be 
only 10-20%14 and is only 5-10% in patients with DLBCL or FL.15 The addition of a 
synergistic agent with PD-1 inhibition may enhance anti-tumor activity and result in deeper 
and more durable responses. An attractive combination partner is vorinostat, a histone 
deacetylase inhibitor (HDACi), which has demonstrated activity in a range of lymphomas, 
including HL, DLBCL, and FL.16, 17 18-21  
HDACi therapy has many immunologic effects on tumor cells and immune effector cells 
that may enhance the effect of PD-1 blockade when given in combination. HDACis 
immunomodulate tumor cells, by increasing expression of tumor-associated antigens, 
upregulating genes that control antigen presentation machinery, and promoting release of 
mediators of immunogenic cell death.22 HDACis also have important effects on immune 
cells, including enhancing CD8+ cytotoxic T-lymphocyte (CTL) function, decreasing 
regulatory T-cell numbers and function, and modulating myeloid-derived suppressor cell 
(MDSC) differentiation.22 Most notably, there is evidence that HDAC inhibition 
combined with PD-1/PD-L1 pathway blockade results in enhanced anti-tumor 
activity in preclinical models. HDACis directly upregulate PD-L1 expression in 
melanoma cell lines, murine models, and patient tumor samples.23 Indeed, combined 
HDAC and PD-1 inhibition results in synergistic killing of tumor cells and HDACis reverse 
tumor resistance to checkpoint blockade in pre-clinical murine breast and colorectal cancer 
models.24 Zheng et al. found that HDAC inhibition with romidepsin increases in vitro PD-
L1 expression in lung cancer cell lines, promotes T-cell infiltration into lung cancers, and 
enhances function of recruited T-cells in a mouse model. In mice inoculated with lung 
cancer tumor cells, combined romidepsin and anti-PD-1 therapy significantly reduced 
tumor growth compared to HDAC or PD-1 inhibition alone.25 The authors chose to study 
romidepsin based on a screen of drugs that could induce T-cell chemokine expression, but 
the authors also demonstrated in the study that vorinostat had similar effects. In a separate 
study using a murine model of lung cancer, vorinostat increased CD8+ T-cell infiltration 
into tumors.26 In light of the observation that non-responders to anti-PD-1 therapy have a 
deficiency of tumor infiltrating T-cells in pre-treatment tumor biopsies,27 the ability of 
vorinostat and HDACis to increase T-cell recruitment into tumors and to induce PD-L1 
expression on tumor cells, as well as the ability of HDACis to synergize with anti-PD-1 
therapy suggests that vorinostat may be an ideal agent to combine with a PD-1 inhibitor to 
increase the frequency and depth of responses in lymphoma patients. We will conduct a 
phase I study with an expansion cohort to evaluate the safety and obtain a preliminary 
estimate of the efficacy of combining pembrolizumab with vorinostat for the treatment of 
rel/ref HL, DLBCL, and FL. 

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Objectives: 
Primary Objectives: 
In adults with relapsed or refractory DLBCL, FL, or HL: 
- To assess the safety and tolerability of vorinostat plus pembrolizumab therapy by 
evaluation of toxicities including: type, frequency, severity, attribution, time course and 
duration.  
- To determine the maximum tolerated dose (MTD) and the recommended phase II dose 
(RP2D) of vorinostat when given in combination with pembrolizumab. 
Secondary Objectives: 
- To obtain preliminary estimates of the anti-tumor activity of pembrolizumab plus 
vorinostat therapy by assessing the overall response rate (ORR), complete response (CR) 
rate, duration of response (DOR), overall survival (OS) and progression-free survival 
(PFS).  
Exploratory Objectives:  
- To evaluate responses according to the Lymphoma Response to Immunomodulatory 
therapy Criteria (LYRIC).28 
- To explore genomic biomarkers of response and resistance to pembrolizumab plus 
vorinostat therapy in patients with DLBCL, FL, or HL. 
- To explore immunologic biomarkers of response and resistance to pembrolizumab plus 
vorinostat therapy in patients with DLBCL, FL, or HL. 
- To explore the value of circulating DNA (ctDNA) as a biomarker of response to 
pembrolizumab plus vorinostat therapy. 
- To explore the association between baseline total metabolic tumor volume, complete 
response, and PFS after pembrolizumab plus vorinostat therapy in patients with HL or 
DLBCL. 
- To explore the association between change in total metabolic tumor volume between 
baseline and 12 weeks, complete response, and PFS after pembrolizumab plus vorinostat 
therapy in patients with HL or DLBCL. 
- To explore the association between outcomes (overall response, complete response, PFS) 
and other baseline quantitative PET (qPET) parameters including total lesion glycolysis 
and SUVmax in patients with HL or DLBCL. 

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Study Design: 
This is a prospective, single-arm, open-label phase I study of pembrolizumab (MK-3475) 
plus vorinostat in subjects with relapsed or refractory diffuse large B-cell lymphoma 
(DLBCL), follicular lymphoma (FL), or classical Hodgkin lymphoma (HL) that have failed 
at least one prior line of therapy. Eligible subjects must have: 1. Recurrence of disease after 
a documented complete response (CR); 2. Progression of disease after a partial response 
(PR) to the prior regimen; 3. Partial response, stable disease (SD) or progressive disease 
(PD) with evidence of measurable residual disease at the completion of the prior treatment 
regimen. 
This phase I trial will implement a modified rolling six dose escalation design, a more 
conservative version of the rolling six design of Skolnik, et al. for enrollment with dose 
escalation, de-escalation, or expansion of a cohort on the basis of the occurrence of dose 
limiting toxicities (DLTs).29 An estimated 52 subjects will be enrolled on this study to 
evaluate the safety and tolerability of combined pembrolizumab and vorinostat therapy. 
The study will consist of a dose-escalation portion and an expansion cohort of 40 patients 
to obtain additional safety data regarding the study combination. In the dose-escalation 
portion of the study, vorinostat will be dosed according to the assigned dose level. In the 
expansion cohort, subjects will receive vorinostat at the RP2D. In both the dose-escalation 
and expansion cohort portions of the study, subjects will receive pembrolizumab 200mg 
intravenously every 3 weeks. Cycle length will be 21 days. Study treatment will continue 
for a maximum of 24 months, or until progressive disease (PD), unacceptable toxicity, 
withdrawal of consent, pregnancy of the subject, non-compliance, or administrative 
reasons. Subjects will have disease re-assessment after every 4 cycles. Subjects who 
achieve documented CR with study therapy may consider study treatment discontinuation 
after receiving 2 additional cycles of study therapy beyond documentation of CR and at 
least 24 weeks total of therapy.  
At the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (90 days for severe adverse events and events of clinical interest). Subjects who 
discontinue treatment for reasons other than disease progression will have post-treatment 
follow-up for disease status until disease progression, initiation of a new anti-cancer 
therapy, withdrawal of consent, or becoming lost to follow-up.  
The primary objective of the trial is to evaluate the safety and tolerability of combined 
pembrolizumab and vorinostat therapy in subjects with relapsed or refractory DLBCL, FL, 
or HL. The dose escalation portion of the study will evaluate the safety and tolerability of 
the study regimen, establish the maximum tolerated dose (MTD), and determine the 
recommended Phase II dose (RP2D). Through the expansion cohort, we will obtain 
additional safety information, including information about any delayed toxicities, and we 
will obtain a preliminary estimate of the efficacy of the combination in subjects with 
relapsed or refractory DLBCL, FL, or HL, as assessed by the overall response rate (ORR). 
The complete response (CR) rate, duration of response (DOR), overall survival (OS) and 
progression-free survival (PFS) will also be studied. Response assessments will be 

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performed by investigators using the 2014 Lugano Classification and as a secondary 
endpoint we will evaluate the responses according to the LYRIC criteria. Immunologic and 
genomic biomarkers of response and resistance to study therapy will be explored. 
Endpoints: 
- Primary Endpoint: Toxicity 
- Secondary Endpoints: Overall response rate (ORR), complete response (CR) rate, time to 
response (TTR), duration of response (DOR), overall survival (OS) and progression free 
survival (PFS). 
Sample Size/Number of Trial Subjects: 
Expected sample size will be 52 evaluable patients (12 in the dose-escalation portion of the 
study, and 40 in the expansion cohort). The minimum sample size is 6 evaluable patients. 
Considering replacement of inevaluable patients, the maximum study accrual is set at 60 
patients. 
Estimated Duration of the Study 
Estimated Enrollment Period: 48 months 
Estimated Duration of Trial: 72 months 
Duration of Participation: Subjects will participate in the trial from the time the subject 
signs informed consent through the final protocol-specified study activity. Following the 
screening phase (28 days or less), eligible subjects will be enrolled and will receive both 
study agents in 21-day cycles. Study treatment will continue for a maximum of 24 months. 
Subjects who achieve a complete response (CR) may consider stopping study therapy early 
if they meet criteria for holding therapy. 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). Subjects who discontinue for reasons other than 
disease progression will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study new anti-cancer therapy, withdrawing consent, or 
becoming lost to follow-up. 
Summary of Subject Eligibility Criteria: 
Inclusion Criteria: 
 
Eligible patients must: 
 Have a histologically confirmed diagnosis of follicular lymphoma, diffuse large B-cell 
lymphoma, or classical Hodgkin lymphoma according to the WHO classification, with 
hematopathology review at the participating institution. 
o FL: grade 1, 2, 3A, or 3B are eligible. 
o DLBCL: subtypes of DLBCL including transformed indolent 
lymphomas (TIL), primary mediastinal large B-cell lymphoma 

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(PMBCL), and aggressive B-cell lymphoma unclassified (BCL-U) are 
eligible. 
o HL: all classical HL subtypes are eligible except for nodular lymphocyte 
predominant Hodgkin lymphoma, which is excluded. 
NOTE: Per Amendment (Protocol V9 dated 06-04-20), this study will only enroll HL 
patients who have had prior exposure to PD-1/PD-L1 immunotherapy. FL, DLBCL, 
and HL patients without prior exposure to PD-1/PD-L1 immunotherapy are no 
longer eligible. 
 Patients with HL or DLBCL must refuse or not be candidates for curative autologous 
stem cell transplantation. 
 Have relapsed or refractory disease after at least 1 prior regimen, including: 
o Recurrence of disease after a documented complete response (CR). 
o Progression of disease after a partial response (PR) to the prior regimen. 
o Partial response (PR), stable disease (SD) or progressive disease (PD) at the 
completion of the prior treatment regimen. If a patient has PR to prior regimen 
without PD, there must be biopsy-proven residual disease that is measurable. 
NOTE: Per Amendment (Protocol V10 dated 10-16-20), this study will only enroll HL 
patients who are refractory to PD-1/PD-L1 immunotherapy. 
Refractory to PD-1/PD-L1 immunotherapy is defined as patients who had prior exposure 
to PD-1/PD-L1 immunotherapy and either - achieved a best response of SD or PD or - 
achieved a best response of CR/PR but developed PD while on active PD-1/PD-L1 
treatment. 
1. Documented informed consent of the participant or legally authorized 
representative. 
2. Be  18 years of age on day of signing informed consent. 
3. Have measurable disease by CT or PET scan, with one or more sites of disease ≥ 
1.5cm in longest dimension.   
4. Be willing to provide tissue from a fresh core or excisional biopsy of a tumor lesion 
prior to starting study therapy or from archival tissue of a biopsy that was performed 
after the most recent systemic therapy. 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 

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6. Demonstrate adequate organ function as defined in Table 1, all screening labs 
should be performed within 14 days of treatment initiation. 
7. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.   
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 3 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 received prior allogeneic hematopoietic stem cell transplant within the past 5 
years, requires immunosuppression, or has evidence of active graft-versus-host-
disease. 
4. Has received prior autologous hematopoietic stem cell transplant within the last 60 
days. 
5. Has a known history of active TB infection (Bacillus Tuberculosis). 
6. Hypersensitivity to pembrolizumab or any of its excipients. 
7. Has had a prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 3 weeks earlier. If a patient has 
progressive or stable disease to prior regimen, rituximab is allowed up to 2 weeks 
prior to the initiation of study therapy. 
8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
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. 
9. Has taken valproic acid, or another histone deacetylase inhibitor, within 2 weeks prior 
to study Day 1. 

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10. 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. 
11. Has known active central nervous system (CNS) involvement by lymphoma, 
including parenchymal and/or lymphomatous meningitis. Subjects with prior CNS 
involvement by lymphoma must have a baseline MRI and lumbar puncture at 
screening that demonstrate no active lymphoma in the CNS. 
12. Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. Hemolytic 
anemia associated with the lymphoma does not exclude a patient from the study. 
13. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
14. Has an active infection requiring systemic therapy. 
15. Has a mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3 
electrocardiograms (ECGs) using Fridericia formula. 
16. Is unable to swallow capsules, has a partial or small bowel obstruction, or has a 
gastrointestinal condition resulting in a malabsorptive syndrome (e.g. small bowel 
resection with malabsorption). 
17. 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. 
18. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
19. 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. 
20. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
21. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
22. Has received a live vaccine within 30 days of planned start of study therapy. 
 
Investigational Product Dosage and Administration: 
Pembrolizumab 200mg IV Q3weeks. 
Vorinostat 100mg capsules PO according to dose level. 
Clinical Observations and Tests to be Performed: 
 Full medical history and demographics  
 Complete physical exam  

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 ECOG Performance Status  
 Vital signs, weight and height, and oxygen saturation 
 12-lead ECG 
 Buccal swab 
 Bone marrow aspirate and biopsy (not for all patients: specific requirements are 
provided in study calendar and footnote j). 
 Tumor biopsy 
 Review of prior and concomitant medications  
 PET-CT or IV contrast-enhanced CT scan of neck, chest, abdomen, pelvis of 
diagnostic quality (and/or MRI for lesions not well-visualized by CT). Clinical 
laboratory tests for:  
o Hematology 
o Serum chemistry 
o Thyroid function panel 
o Coagulation (PT, PTT, INR) 
o Serum or urine pregnancy test (for women of childbearing potential who 
have not been free from menses for > 1 year) 
o Urinalysis 
 
Refer to the Study Flow Chart (section 8.1) for a detailed schedule of these activities. 
 
Statistical Considerations: 
This is a phase I study, including dose-escalation and expansion portions of the study. The 
dose-escalation will have 2 dose levels and 2 possible de-escalation dose levels, for a total 
of 4 possible dose levels. Patients will be treated according to dose level assignment. In the 
expansion portion of the study, subjects will receive therapy at the RP2D. 
 
The dose-escalation portion of the trial will employ a modified Rolling 6 design, a more 
conservative version of the Rolling 6 design of Skolnik, et al 29. In this design, at most, 3 
patients will be under observation for DLT on the current test dose level at any time. 
Patients who are not evaluable for DLT will be replaced. Once each patient is evaluable 
for toxicity and passes without a DLT, an additional patient may be accrued on that dose 
level -up to 6 patients. Once 3 patients are evaluable with no patient at that dose level 
experiencing a DLT, the dose can be escalated, or up to 3 additional patients may be treated 
at the current dose level. Although this design does not require that 6 patients be treated, 
no more than 6 evaluable patients will be accrued to any dose level during the dose finding 
portion of this study. If at any time, the dose level has 1 documented DLT with fewer than 
6 evaluable patients, accrual will continue until 6 patients are evaluable.  Escalation will 
terminate as soon as two or more patients experience any DLT attributable to the study 
treatment, at a given dose level. MTD will be declared at the highest dose level at which 6 

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patients have been treated and at most 1/6 patients experiences DLT. If more than 1/6 
patients experiences DLT, then the next lower dose will be expanded. There will be no 
intrapatient dose escalation. 
 
Patient demographic and baseline characteristics, including age, gender, medical history, 
and prior therapy, will be summarized using descriptive statistics. For continuous variables, 
descriptive statistics (number [n], mean, standard deviation, standard error, median 
(range)) will be provided. For categorical variables, patient counts and percentages will be 
provided. 
 
Observed toxicities will be summarized by type (organ affected or laboratory determination 
such as absolute neutrophil count), severity (by NCI CTCAE v4.03 and nadir or maximum 
values for lab measures), date of onset, duration, reversibility, and attribution. Tables will 
be constructed to summarize the observed incidence by severity and type of toxicity. 
 
ORR will be calculated as the proportion of evaluable patients that have confirmed CR or 
PR, as defined according to the 2014 Lugano Classification, exact 95% confidence 
intervals will be calculated for these estimates. CR rate will be similarly estimated. 
Response rates will also be evaluated based on number and type of prior therapy(ies). 
Duration and time to response (DOR and TTR), as well as overall survival (OS) and 
progression-free survival (PFS) will be estimated using the product-limit method of Kaplan 
and Meier. 
Because of the unique immune-related adverse events (IrAEs) observed with checkpoint 
inhibitors, we will monitor for “unacceptable toxicity” with this new combination of drugs 
(defined in Section 10.2). The expected rate of “unacceptable toxicity” should not be 
≥33%. The early stopping rule for unacceptable toxicity will be assessed after enrollment 
of 12 patients (total, across cohorts) treated at the RP2D and will be assessed once the 12th 
patient has completed at least 4 cycles of therapy. If >3 “unacceptable toxicity” events 
occur in the first 12 patients (≥33%) treated (across disease subtypes) at RP2D, or at a rate 
≥33% thereafter at the quarterly review, accrual will be halted and a full review of these 
events will be performed by the City of Hope Data Safety Monitoring Committee (DSMC). 
Patient accrual will not resume until approved by the DSMC to do so. These rules are in 
addition to the quarterly review of all toxicities submitted to the City of Hope Data Safety 
Monitoring Committee (DSMC). Patients with ongoing toxicity will be followed until 
resolution or stability. 
Sponsor/Licensee: 
Investigator-initiated trial at City of Hope 
Supported by Merck, Inc. 
Case Report Forms 
Medidata Rave EDC® 
 

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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a prospective, single-arm, open-label phase I study of pembrolizumab (MK-3475) plus 
vorinostat in subjects with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), 
follicular lymphoma (FL), or classical Hodgkin lymphoma (HL) that have failed at least one 
prior line of therapy. Eligible subjects must have: 1. Recurrence of disease after a documented 
complete response (CR); 2. Progression of disease after a partial response (PR) to the prior 
regimen; 3. Partial response, stable disease (SD) or progressive disease (PD) with evidence of 
measurable residual disease at the completion of the prior treatment regimen. If a patient has 
PR to prior regimen without PD, there must be biopsy-proven residual disease that is 
measurable. 
An estimated 52 subjects will be enrolled on this study to evaluate the safety and tolerability 
of combined pembrolizumab and vorinostat therapy. The study will consist of a dose-escalation 
portion and an expansion cohort of 40 patients to obtain additional safety data regarding the 
study combination. In the dose-escalation portion of the study, vorinostat will be dosed 
according to the assigned dose level. In the expansion cohort, subjects will receive vorinostat 
at the recommended Phase II dose (RP2D). In both the dose-escalation and expansion cohort 
portions of the study, subjects will receive pembrolizumab 200mg intravenously every 3 
weeks. Cycle length will be 21 days. Study treatment will continue for a maximum of 24 
months, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, 
pregnancy of the subject, non-compliance, or administrative reasons. Subjects will have 
disease re-assessment after every 4 cycles. Subjects who achieve documented CR with study 
therapy may consider study treatment discontinuation after receiving 2 additional cycles of 
study therapy beyond documentation of CR and at least 24 weeks total of therapy.  
At the end of treatment, each subject will be followed for 30 days for adverse event monitoring 
(90 days for severe adverse events and events of clinical interest). Subjects who discontinue 
treatment for reasons other than disease progression will have post-treatment follow-up for 
disease status until disease progression, initiation of a new anti-cancer therapy, withdrawal of 
consent, or becoming lost to follow-up.  
The primary objective of the trial is to evaluate the safety and tolerability of combined 
pembrolizumab and vorinostat therapy in subjects with relapsed or refractory DLBCL, FL, or 
HL. The dose escalation portion of the study will evaluate the safety and tolerability of the 
study regimen, establish the maximum tolerated dose (MTD), and determine the recommended 
Phase II dose (RP2D). Through the expansion cohort, we will obtain additional safety 
information, including information about any delayed toxicities, and we will obtain 
preliminary estimates of the anti-tumor activity of the combination in subjects with relapsed 
or refractory DLBCL, FL, or HL, as assessed by the overall response rate (ORR). The complete 
response (CR) rate, duration of response (DOR), overall survival (OS) and progression-free 
survival (PFS) will also be studied. Response assessments will be performed by investigators 
using the 2014 Lugano Classification. As an exploratory objective, we will also assess response 

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and disease progression according to the new Lymphoma Response to Immunomodulatory 
therapy Criteria (LYRIC) criteria (Appendix L).28 Immunologic and genomic biomarkers of 
response and resistance to study therapy will be explored. 
2.2 
Trial Diagram 
 
* Disease Staging will be by either PET/CT (preferred) or CT scan, and will be performed every 4 cycles until disease 
progression or off study therapy (See Sections 9.2.6 and 10.1 for details). A bone marrow biopsy will be performed at 
screening only in FL patients and some DLBCL and HL patients according to study calendar (footnote j). Following 
initial screening, and unless clinically indicated, bone marrow specimens will be collected only to confirm CR, and only 
on patients who had bone marrow involvement at baseline.  
** End of Treatment visit. 
*** Follow up Phase for patients who have completed treatment without disease progression will include staging every 
12 weeks for the first year and every 18 weeks thereafter, until disease progression or off study. 
3.0 OBJECTIVES 
In adults with relapsed or refractory DLBCL, FL, or HL: 
3.1 
Primary Objectives 
- To assess the safety and tolerability of vorinostat plus pembrolizumab therapy by 
evaluation of toxicities including: type, frequency, severity, attribution, time course and 
duration. 
- To determine the maximum tolerated dose (MTD) and the recommended phase II dose 
(RP2D) of vorinostat when given in combination with pembrolizumab. 
3.2 
Secondary Objectives 
- To obtain preliminary estimates of the anti-tumor activity of pembrolizumab plus vorinostat 
therapy by assessing the overall response rate (ORR), complete response (CR) rate, duration 
of response (DOR), overall survival (OS) and progression-free survival (PFS).  

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3.3 
Exploratory Objectives 
(1) Evaluate responses and disease progression according to the Lymphoma Response to 
Immunomodulatory therapy Criteria (LYRIC).28 
(2) Explore genomic biomarkers of response and resistance to pembrolizumab plus vorinostat 
therapy in patients with DLBCL, FL, or HL. 
(3) Explore immunologic biomarkers of response and resistance to pembrolizumab plus 
vorinostat therapy in patients with DLBCL, FL, or HL. 
(4) Explore the value of circulating DNA (ctDNA) as a biomarker of response to 
pembrolizumab plus vorinostat therapy. 
(5) Explore the association between baseline total metabolic tumor volume, complete 
response, and PFS after pembrolizumab plus vorinostat therapy in patients with HL or 
DLBCL. 
(6) Explore the association between change in total metabolic tumor volume between baseline 
and 12 weeks, complete response, and PFS after pembrolizumab plus vorinostat therapy in 
patients with HL or DLBCL. 
(7) Explore the association between outcomes (overall response, complete response, PFS) and 
other baseline quantitative PET (qPET) parameters including total lesion glycolysis and 
SUVmax in patients with HL or DLBCL. 
4.0 BACKGROUND & RATIONALE 
4.1 
Study Diseases 
4.1.1 Diffuse Large B-cell Lymphoma 
DLBCL is an aggressive B-cell non-Hodgkin lymphoma (NHL) and is the most common 
subtype of NHL in the United States. DLBCL accounts for about a quarter to one-third of cases 
of NHL,1, 30 with approximately 22,000 estimated new cases and 10,000 deaths in 2013. Initial 
chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone (R-CHOP) cures about two-thirds of DLBCL patients. While the addition of 
rituximab to standard induction chemotherapy for DLBCL has improved cure rates after 
upfront treatment, it has led to inferior outcomes in the one-third of patients with relapsed or 
refractory (rel/ref) DLBCL.3 Standard therapy for rel/ref DLBCL is salvage chemo-
immunotherapy followed by autologous stem cell transplantation (ASCT) in chemosensitive 
patients. The overall response rate (ORR) after salvage chemo-immunotherapy is lower (51%) 
when patients have received prior rituximab, and the overall 3-year event free survival for 
patients with rel/ref DLBCL eligible to receive aggressive therapy (salvage chemo-
immunotherapy and ASCT) who have received prior rituximab is only 21%.3 Even among 

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patients who respond to salvage therapy and undergo ASCT, about half will relapse after 
ASCT. Outcomes in patients with DLBCL who relapse after ASCT are dismal and treatment 
options are limited.4 Improved therapy for rel/ref DLBCL is urgently needed. 
4.1.2 Follicular Lymphoma 
Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL), and 
second most common subtype of NHL overall, accounting for approximately 20% of all 
NHLs.1, 31 The median age at diagnosis in patients with FL is 60 to 65 years old. Aside from a 
proportion of limited stage patients (a minority of FL patients, 15-30%), FL is not curable with 
standard therapy. The great majority of FL patients will either have relapse after an initial 
response/remission to upfront chemo-immunotherapy or a minority of patients will have 
refractory disease. Although FL is often responsive to subsequent treatments, agents used in 
the second-line and beyond typically lead to shorter remissions.23 Although hematopoietic 
stem cell transplantation (HSCT) can be utilized in patients with rel/ref FL to prolong 
remission duration and potentially provide durable responses and cures, there are significant 
toxicities associated with transplantation and many FL patients are not eligible for HSCT due 
to co-morbidities or age.32-36 Effective novel, targeted therapies that have favorable toxicity 
profiles are urgently needed for patients with FL. 
4.1.3 Classical Hodgkin Lymphoma 
Classical HL is a lymphoma of B-cell origin that is defined by the presence of Hodgkin-Reed-
Sternberg cells in a background of inflammatory cells. HL accounts for about 10% of all 
lymphomas, with approximately 9,000 new cases in the United States in 2013 and 1,200 
deaths.1 Although the majority of patients with HL are cured with upfront therapy, as many as 
20-40% of patients will have relapsed or refractory disease.37, 38 Similar to DLBCL, standard 
of care treatment for patients with rel/ref HL is salvage chemotherapy followed by ASCT in 
chemosensitive patients, and about half of HL patients who undergo ASCT will relapse.39, 40 
HL patients who are refractory to second-line therapy or relapse after ASCT have poor 
outcomes.41 Therefore, improved therapies for patients with rel/ref HL are urgently needed. 
4.2 
PD-1/PD-L1 Pathway and PD-1/PD-L1 Inhibition in Lymphoma 
The programmed death receptor-1 (PD-1) pathway is an immune checkpoint that normally 
serves to dampen immune responses in tissues. PD-1 is expressed on activated T-cells and 
binds its ligands, PD-L1 and PD-L2, on tissue cells or antigen presenting cells to decrease T-
cell activation, proliferation, and survival.6 Tumor cells can co-opt this pathway to evade attack 
by the host immune system.6 A wide range of hematologic malignancies express PD-1 or PD-
L1, including Hodgkin’s lymphoma (HL),7 diffuse large B-cell lymphoma (DLBCL),8 primary 
mediastinal B-cell lymphoma (PMBCL),7, 42 follicular lymphoma (FL),9 chronic lymphocytic 
leukemia/small lymphocytic lymphoma (CLL/SLL),43 peripheral T-cell lymphomas 
(PTCL),44-48 multiple myeloma (MM),49 acute myelogenous leukemia (AML),50, 51 and 
myelodysplastic syndrome (MDS).52, 53 In addition, molecular analyses have demonstrated that 
genetic alterations involving PD-L1 and its overexpression are critical in the pathogenesis of 

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HL, PMBCL, and Epstein-Barr virus-associated post-transplant lymphoproliferative 
disorders.7, 10 
Inhibitors of PD-1 and PD-L1 have produced clinical responses in early-phase studies in 
patients with a range of lymphomas, including HL, DLBCL, and FL. Pidilizumab (CureTech, 
Yavne, Israel) produced responses as a single-agent in patients with rel/ref FL, CLL, and HL, 
in a phase I study,11 and yielded a 66% ORR when used in combination with rituximab in 
patients with relapsed or refractory FL in a phase II study.12 A phase Ib study of nivolumab 
demonstrated an 87% overall response rate (ORR) and 100% clinical benefit rate in 23 patients 
with relapsed or refractory HL.14 A subsequent phase II study of nivolumab in 80 patients who 
failed ASCT as well as prior brentuximab vedotin confirmed a high ORR of 66%, with 9% of 
patients having a complete response per independent review. Notably, the majority of 
responders remained in remission at the time of censoring, thus a significant proportion of 
responses appear to be durable.54 A phase Ib study of pembrolizumab in 31 patients with rel/ref 
HL who failed prior brentuximab vedotin demonstrated a 65% ORR with 16% of patients 
achieving CR.55 A phase II study of pembrolizumab in patients with rel/ref HL is ongoing, but 
interim reports have demonstrated an ORR of 70%.56 Similarly, in a phase Ib study of 
nivolumab, a 36% ORR was observed in patients with rel/ref DLBCL, and a 40% ORR was 
observed in patients with rel/ref FL.57 In an early interim analysis, the PD-L1 inhibitor, 
atezolizumab, in combination with obinutuzumab produced a 15% ORR in patients with rel/ref 
DLBCL or FL. 
4.3 
Histone Deacetylase Inhibition and Vorinostat In Lymphoma 
Histone deacetylases (HDAC) are important epigenetic regulators of gene expression, 
modulating many cellular functions including cell proliferation and survival. They induce 
deacetylation of histones, the core proteins around which the nucleic acids are wound, keeping 
them in tight coils, thus silencing gene expression, including genes involved with cell 
differentiation, survival, and apoptosis. HDAC inhibitors (HDACi) render the DNA more open 
for transcription, resulting in increased expression of several genes that are often silenced in 
cancer, such as tumor suppressor genes.  
HDACis, including vorinostat, have been evaluated in a range of malignancies, including 
lymphoma and other hematologic malignancies. In a phase I study of vorinostat in hematologic 
malignancies, several patients with rel/ref lymphomas exhibited anti-tumor responses, 
including 4 patients with HL and 3 patients with DLBCL (including 2 with transformed 
DLBCL).16 Phase II studies of vorinostat in DLBCL and HL only produced ORR of 5.6% and 
4% respectively, however, a significant proportion of patients in the HL study (48%) had stable 
disease (SD) and 7 HL patients remained progression-free for over a year.17, 58 Panobinostat is 
another HDACi that has been evaluated in the treatment of HL, producing a 27% ORR in a 
phase II study of rel/ref patients with relapse after ASCT.59 The ORR to single agent vorinostat 
in patients with rel/ref FL is 47-49%, with a long median DOR of 27 months in responders. 
Vorinostat has also been evaluated in combination with rituximab for the treatment of FL, 
resulting in an ORR of 46%, including 67% for previously untreated patients and 41% for 
rel/ref patients.18  

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Vorinostat and other HDACis have been studied extensively in the treatment of cutaneous T-
cell lymphomas (CTCL) and peripheral T-cell lymphomas (PTCL). Romidepsin is an HDACi 
that has been approved for the treatment of PTCL and CTCL. Of the 131 patients enrolled in 
the pivotal phase II trial, 130 had histologically confirmed PTCL by central review. The 
objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. The 
median duration of response was 17 months, with the longest response ongoing at 34+ months. 
Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression 
at a median follow-up of 13.4 months.60 Belinostat is a pan-HDAC inhibitor that was evaluated 
in an open-label phase II study. A total of 129 relapsed/refractory PTCL patients received 1000 
mg/m2 belinostat infusion on days 1–5 of every 3-week cycle. Among 120 evaluable patients, 
the ORR was 26%, including 10% CR, and median response duration was 8.3 months.61 
4.4 
Study Agent: Pembrolizumab (MK-3475) 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475. 
4.4.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved. PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins. PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 

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of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors .  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas 
PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid 
tissue or chronic inflammatory environments.  PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function 
in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers 
were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested 
to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL). This suggests 
that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype. It is designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune 
response, including the anti-tumor immune response. KeytrudaTM (pembrolizumab) has 
recently been approved in the United Stated for the treatment of patients with unresectable or 
metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 
mutation positive, a BRAF inhibitor. 
4.4.2 Nonclinical Pharmacology 
Pembrolizumab strongly enhances T lymphocyte immune responses in cultured blood cells 
from healthy human donors, cancer subjects, and primates.  In T-cell activation assays using 
human donor blood cells, the EC50 has been 0.1 to 0.3 nM. In addition to interleukin-2 (IL-2), 
tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and levels of other cytokines 
were found to be modulated by pembrolizumab. The antibody potentiates existing immune 
responses only in the presence of antigen and does not non-specifically activate T cells. Using 
an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to significantly inhibit 
tumor growth in a variety of syngeneic murine tumor models.    
4.4.3 Nonclinical Pharmacokinetics 
After intravenous (IV) administration of pembrolizumab to cynomolgus monkeys, systemic 
exposure to pembrolizumab independent of sex, increased with increasing dose. Systemic 
exposure for the 7-day dosing interval increased after repeated dosing from 40 to 200 mg/kg. 
Area under the concentration-time curve (AUC) for the 7-day dosing interval (AUC[0-7 days]) 
after one dose appeared to be dose-proportional from 0.3 to 200 mg/kg, suggesting dose-
independent pharmacokinetics (PK). Terminal half-life (t½) values from individual animals 
after repeated IV dosing ranged from 11.8 to 23.7 days (mean values ranged from 15.7 to 22.3 
days) across the doses tested. 

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

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had a minimal effect on the mean group systemic exposure to pembrolizumab during the study 
and did not impact the evaluation of potential toxicity of pembrolizumab for the duration of 
the 6-month study as there were no test article-related effects on any of the parameters 
examined and as no monkey in the mid- and high-dose groups developed ADA during the 
dosing phase. In conclusion, pembrolizumab administered once every other week over a 6-
month duration to cynomolgus monkeys was well tolerated and the no observed effect level 
(NOEL) was ≥200 mg/kg/dose (the highest dose tested). 
In addition, tissue cross-reactivity studies using monkey and human specimens were conducted 
to evaluate the potential cross reactivity of pembrolizumab with cryosections of cynomolgus 
monkey tissues and normal human tissues.  Results demonstrated the expected on-target 
staining of the membranes of mononuclear leukocytes in both species. The off-target staining 
(cytoplasmic and stromal) that occurred in many tissues of both species was considered 
spurious binding inherent to the experimental conditions of the in vitro tissue cross reactivity 
studies with no in vivo toxicological significance. 
4.4.5 Clinical Safety 
Several ongoing studies are testing the anti-tumor activity of pembrolizumab. Protocol 001 
(PN001), an open-label Phase I study is being conducted to evaluate the safety and clinical 
activity of pembrolizumab when administered as monotherapy.  The dose escalation portion 
of this study evaluated three dose levels of single agent pembrolizumab (1 mg/kg, 3 mg/kg, 
and 10 mg/kg), in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities (DLTs) were observed, therefore the maximum 
tolerated dose (MTD) has not been determined.  The ongoing expansion part of this study is 
evaluating pembrolizumab in subjects with melanoma and non-small cell lung cancer 
(NSCLC).  Protocol 002 (PN002), a Phase II study, is also being conducted to evaluate the 
safety and clinical activity of pembrolizumab in melanoma.  This study is examining two dose 
levels of pembrolizumab (2 mg/kg and 10 mg/kg) in subjects with metastatic melanoma.   Due 
to the limited amount of safety data for this compound a well-defined safety profile has not 
been established, however immune-related adverse events (irAEs) are expected based on the 
nature of the compound, its mechanism of action and reported experience with 
immunotherapies that have a similar mechanism of action. Protocol 013 is a Phase 1b study 
testing pembrolizumab at a fixed dose of 10 mg/kg every 2 weeks in patients with 
myelodysplastic syndromes, cHL, PD-L1-positive non-Hodgkin lymphoma, and multiple 
myeloma. This study is ongoing. 
In the pembrolizumab monotherapy trials (P001/P002, P012, P013, and P028, plus the P011 
monotherapy arm), the overall incidence of AEs ranged from 83.0% (73 of 88 subjects in P012) 
to 100% (10 of 10 subjects in P011). The most commonly reported AEs included fatigue, 
diarrhea, decreased appetite, nausea, and anemia. The incidence of drug-related AEs (DRAEs) 
ranged from 39.8% (35 of 88 subjects in P013) to 80.0% (8 of 10 subjects in P011). The most 
commonly reported DRAEs across all studies were nausea, fatigue, and diarrhea. The 
incidence of Grade 3-5 DRAEs across studies ranged from 6.8% (6 of 88 in P013) to 12.0% 
(187 of 1562 subjects) in P001/P002. The most commonly reported Grade 3-5 DRAEs were 

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anemia, alanine aminotransferase increased, and aspartate aminotransferase increased. Most 
subjects who experienced an AE continued in the study, with the incidence of AEs leading to 
discontinuation ranging from 1.9% (8 of 430 subjects in P028) to 12.3% (192 of 1562 subjects 
in P001/P002). The majority of AEs leading to discontinuation were not considered drug-
related. Discontinuations due to a DRAE were infrequent and ranged from 0% (no subjects in 
P011) to 4.5% (4 of 88 subjects in P013). The most commonly reported DRAEs leading to 
discontinuation were pneumonitis, alanine aminotransferase increased, and aspartate 
aminotransferase increased. 
 
The overall pattern of AEs observed in melanoma subjects enrolled in P002 demonstrates 
favorable safety profile when this immune therapy is compared to chemotherapy. Consistent 
with prior observations from randomized comparisons of the 2 mg/kg and 10 mg/kg dose levels 
when given every 3 weeks, there are no important differences in the safety profile of 
pembrolizumab at these 2 dose levels, and both doses appear to have a favorable safety profile 
compared to chemotherapy. 
 
In the pembrolizumab monotherapy trials, the most commonly reported drug-related serious 
adverse events (DRSAEs) (those that occurred in 3 or more subjects overall in at least 1 study) 
were pneumonitis (range of 0.7% to 1.3% of subjects); colitis (range of 0.3% to 0.9% of 
subjects), pyrexia (range of 0.3% to 0.5% of subjects); diarrhea (range of 0.2% to 0.4%); 
hepatitis (0.7% of subjects); nausea, adrenal insufficiency, hyponatraemia, hyperthyroidism, 
hypophysitis, vomiting, and dyspnea (0.3% of subjects each); and dehydration, generalised 
edema, hypothyroidism, renal failure acute, and pericardial effusion (0.2% of subjects each). 
The remaining DRSAEs occurred in 1 or 2 subjects each per study. 
 
Among P001 and P002 studies, the incidence of adverse events of special interest (AEOSI) 
was 16.1%. Overall, the most commonly reported AEOSI included hypothyroidism (7.2% of 
subjects), pneumonitis (2.9% of subjects), infusion reaction (2.5% of subjects), and 
hyperthyroidism (2.2% of subjects). The incidences of the remaining AEOSI were low (range 
of 0.1 to 1.3% of subjects). The overall incidence of drug-related AEOSI was 14.3%. Overall, 
2.6% of subjects discontinued treatment due to an AEOSI and the most commonly reported 
drug-related AEOSI leading to discontinuation was pneumonitis (1.3% of subjects). Only one 
subject died of AEOSI (pneumonitis, 0.1% of subjects). No corticosteroids were used to 
manage myositis, pericarditis, thyroiditis, type 1 diabetes mellitus, uveitis and vasculitis. 
 
For additional information on the study agent, please refer to the Investigator’s Brochure. 
 
4.4.6 Expected Adverse Events 
Per the IB, the expected toxicities for pembrolizumab are as follows (asterisk signifies ≥ 10%; 
no asterisk signifies 1-10%, † signifies < 1%, and ^ signifies unknown frequency): 

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Blood and lymphatic system 
disorders (includes 
investigations) 
Anemia, neutropenia†, thrombocytopenia†, leukopenia†, 
lymphopenia†, eosinophilia†, hemolyƟc anemia†,immune 
thrombocytopenic purpura† 
Cardiac 
Myocarditis† 
Endocrine 
Hyperthyroidism, hypothyroidism, hypophysiƟs †, adrenal 
insuﬃciency †, thyroidiƟs† 
Eye 
UveiƟs †, dry eye †, Vogt‐Koyanagi‐Harada disease ^ 
Gastrointestinal  
Diarrhea*, nausea *, abdominal pain, vomiting, colitis, 
constipation, dry mouth, pancreaƟƟs †, small intestine perforation 
† 
General Disorders and 
Administration Site 
Fatigue *, asthenia, edema, pyrexia, influenza‐like illness, chills 
Hepatobiliary 
HepaƟƟs† 
Immune system 
Infusion related reactions, severe infusion reactions †, sarcoidosis 
†, solid organ transplant rejection ^, GvHD (potential risk), 
haemophagocytic lymphohistiocytosis † 
Investigations (excluding 
hematologic) 
AST/ALT increased, blood alkaline phosphatase increased, blood 
creaƟnine increased, low sodium levels†, low potassium levels†, 
low calcium levels†, blood bilirubin increased†, amylase 
increased†, increased calcium† 
Metabolism and Nutrition 
Decreased appetite, type 1 diabetes mellitus † 
Musculoskeletal and Connective 
Tissue  
Arthralgia, back pain, myositis, musculoskeletal pain, arthritis, pain 
in extremity, tenosynovitis † 
Nervous system 
Headache, dizziness, dysgeusia, epilepsy†, lethargy†, Guillian‐Barré 
syndrome†, peripheral neuropathy†, myasthenic syndrome†, 
encephalitis†, myelitis† 
Psychiatric disorders 
Insomnia † 
Renal and urinary  
NephriƟs † 
Respiratory, Thoracic and 
Mediastinal 
Cough, pneumonitis, dyspnoea 
Skin and Subcutaneous Tissue  
Pruritus*, rash*, vitiligo, dry skin, erythema, hair color change †, 
eczema †, alopecia †, severe skin reacƟons†, Steven‐Johnson 
Syndrome†, toxic epidermal necrolysis† 
Vascular Disorders 
Hypertension † 
 
4.4.7 Immune-Related Adverse Events 
An irAE is defined as a clinically significant AE of any organ that is associated with study 
drug exposure, is of unknown etiology, and is consistent with an immune-related mechanism. 
AEOSI data for melanoma and lung subjects demonstrates that irAEs were reported in 16.1% 
of subjects (251 of 1562) overall; AEOSI were considered by the Investigators to be drug 
related in 14.3% of subjects (223 of 1562). The majority of AEOSI were Grade 1 or 2 in 

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severity. Overall, serious AEOSI occurred in 4.2% of subjects at 2 mg/kg Q3W, 3.7% of 
subjects at 10 mg/kg Q3W, and 3.9% of subjects at 10 mg/kg Q2W. There was one AEOSI 
(pneumonitis) related to death in 10 mg/kg Q3W arm, in a subject with NSCLC. The rate of 
discontinuation due to AEOSI was low (2.6%). 
 
The most commonly reported immune-related adverse events across the dose schedules are 
hypothyroidism (7.2%), pneumonitis (2.9%), hyperthyroidism (2.2%), colitis (1.3%) and skin 
AEOSI (1.3% including all terms). Based on the mechanism of action of MK-3475 and similar 
immunomodulatory agents, Merck is interested in potential irAEs, and encourages appropriate 
investigation of signs and symptoms suggestive of these. Consultation with the appropriate 
medical specialist should be considered when investigating a possible irAE. These events can 
occur after the first dose to several months after the last dose of treatment. Mild irAEs are 
usually treated symptomatically and do not require dosing delays or discontinuation. Higher 
grade and persistent lower grade irAEs typically necessitate withholding or discontinuing 
treatment and administration of systemic steroids or other immunosuppressive agents (such as 
tumor necrosis factor blockers), when systemic steroids are not effective. Early recognition of 
irAEs and initiation of treatment are critical to reduce the risk of complications, since the 
majority of irAEs are reversible with the use of steroids and other immune suppressants. 
 
4.5 
Study Agent: Vorinostat 
Histone deacetylase (HDAC) inhibitors are a novel class of anti-cancer agents that act by 
regulating chromatin structure and function24. HDACis induce acetylation of histones, the core 
proteins around which the nucleic acids are wound. The HDACis exert their targeted action 
during post-translational acetylation of core nucleosomal histones, which affects chromatin 
structure, thereby regulating gene expression. DNA that is wrapped around condensed, non-
acetylated histones is transcriptionally inactive, whereas acetylation of N-terminal histone 
lysine residue exposes DNA to important transcription factors that promote transcriptional 
activity.62, 63 The dynamic equilibrium between histone acetylation and deacetylation is 
regulated by histone acetyltransferases (HATs) and HDACs. The action of HDACs on 
nucleosomal histones leads to tight coiling of chromatin and silencing of expression of various 
genes, including those implicated in the regulation of cell survival, proliferation, differentiation 
and apoptosis. 64 The effects of HDACs are not limited to histone deacetylation. HDACs also 
act as members of a protein complex to recruit transcription factors to the promoter region of 
genes, including those of tumor suppressors, and they affect the acetylation status of specific 
cell cycle regulatory proteins.65 
Acetylation of regulatory proteins such as heat shock protein 90, hypoxia-inducing factor alpha 
and alpha tubulin, may also contribute to the anti-cancer effects of HDAC inhibitors.66-69 These 
molecular events ultimately result in induction of apoptosis, cell cycle arrest, modulation of 
anti-cancer immunity and inhibition of angiogenesis.67, 70-73 
Vorinostat is described chemically as N-hydroxy-N'-phenyloctanediamide. The empirical 
formula is C14H20N2O3. The molecular weight is 264.32 and the structural formula is:  

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Vorinostat is a hydroxamic acid derivative that inhibits class I and II HDACs.  It has been 
approved by the United States Food and Drug Administration (FDA) for the treatment of 
patients with cutaneous T-cell lymphoma at a dose of 400mg by mouth once daily.74 It is 
administered orally on either a continuous daily or intermittent schedule. The common adverse 
effects of vorinostat include nausea, emesis, fatigue and thrombocytopenia.65 
4.5.1 Pharmacology 
Vorinostat, the drug form of the compound suberoylanilide hydroxamic acid (SAHA, or MK-
0683), is a novel agent that inhibits the enzymatic activity of histone deacetylases (HDACs). 
Vorinostat is a potent inhibitor of HDAC activity and binds directly to the catalytic pocket of 
Class I and II HDAC enzymes. Vorinostat inhibits the enzymatic activity of both Class I 
(HDAC1, 2 and 3) and Class II (HDAC6) HDACs at low nanomolar concentrations (IC50<86 
nM). The anti-neoplastic effect of vorinostat is attributed to the inhibition of HDAC activity 
and subsequent accumulation of acetylated proteins, including the core nucleosomal histones. 
This accumulation influences the regulation of gene expression. Exposure to vorinostat led to 
G1 or G2 phase cell-cycle arrest, apoptosis, or differentiation in cultured transformed cells. 
The growth inhibitory activity of vorinostat was demonstrated on the 60 cell line screen at 
National Cancer Institute (NCI), with IC50s ranging from approximately 38.6 nM to 6.2 μM. 
Additionally, vorinostat demonstrated synergistic and additive activity in combination with 
other cancer therapies (including radiation, kinase inhibitors, cytotoxic agents, and 
differentiating agents) in a variety of cultured human transformed cell lines. 
 
The pharmacokinetics and toxicokinetics of vorinostat have been evaluated in mice, rats, dogs 
and humans. Rapid oral absorption has been noted in all species studied. Vorinostat (0.5 to 50 
μg/mL) exhibited moderate reversible binding to plasma proteins. In human plasma, vorinostat 
appears to bind primarily to human serum albumin; however, some binding of vorinostat was 
also observed in solutions of human α1-acid glycoprotein. 
 
Vorinostat is excreted exclusively as metabolites, the majority of metabolites are derived from 
glucuronidation and hydrolysis with β-oxidation pathway metabolites accounting for the rest. 
As vorinostat is not eliminated via cytochrome P450 pathways, it is anticipated that vorinostat 
will not be subject to drug-drug interactions when co-administered with drugs that are known 
to be CYP inhibitors. Although vorinostat was not a potent reversible inhibitor of the 
cytochrome P450 isozymes (IC50 >75 μM), gene expression studies detected some potential 
for suppression of CYP2C9 and CYP3A4 activities at ≥10 μM vorinostat however, 
these changes were observed at concentrations higher than the pharmacologically relevant 
serum concentration of 2 μM (Cmax). 
 

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4.5.2 Toxicology 
The main toxicities observed in in vivo animal models were weight loss and inappetence, 
anemia (rats only at 3.6 times the equivalent 400 mg human dose), leukopenia (rats only at 1.3 
times the equivalent 400 mg human dose), thrombocytopenia (male rats only, statistically 
significant change at 0.5 times the equivalent 400 mg human dose but within normal range at 
all doses), and gastrointestinal tract irritation (dogs only, at 8.5 times the equivalent 400 mg 
human dose). Although statistically significant and dose-dependent, many of the clinical 
pathology findings were within normal historical ranges indicating that they should not have 
major toxicological consequences. The toxicities appeared to be rapidly reversible within 12 
to 14 days. There has been no evidence of cardiac toxicity based on electrocardiogram (ECG, 
dogs only), blood pressure (dogs only), heart rate (dogs only), creatinine kinase, organ weight, 
gross pathology, or histopathology assessments in studies up to one month duration. No 
serious, irreversible damage to any vital organ has been observed. Importantly, toxicities in 
rats and dogs were predictive of adverse effects in humans (thrombocytopenia, anaemia, 
nausea, diarrhea, fatigue). Toxicities present in animals would be manageable in the clinic, and 
the onset of serious toxicity is readily forecast by prodromal symptoms. The nonclinical 
toxicity profile of vorinostat is acceptable for an oncology drug. 
 
Vorinostat was evaluated in a panel of genetic toxicity assays; in vivo and in vitro assays were 
found to be positive. Therefore, vorinostat should not be taken by pregnant women. Pregnancy 
should be avoided both in female subjects taking vorinostat, and in female partners of male 
subjects taking vorinostat for at least 30 days after last dose of vorinostat, as data are not yet 
available to establish the safety of vorinostat ingestion in male patients who impregnate their 
partners. 
 
4.5.3 Biological Activity of Vorinostat 
Vorinostat was identified originally by its ability to induce differentiation of murine 
erythroleukemia cells at micromolar concentrations.75, 76 Subsequently, it was found to induce 
differentiation or arrest growth of a wide variety of human carcinoma cells.  To date, vorinostat 
activity has been reported in transformed hematopoietic cells, such as a multiple myeloma 
(MM),77 acute promyelocytic leukemia (APL),78 acute lymphocytic leukemia (ALL), chronic 
myelogenous leukemia (CML),79 Waldenstrom’s macroglobulinemia,80 and cutaneous T-cell 
lymphoma (CTCL).81  Activity has also been reported in cell lines representing other tumor 
types including bladder transitional cell carcinoma,82 breast cancer,83 prostate cancer,84 head 
and neck squamous cell carcinoma, and colon carcinoma.85 
Vorinostat has demonstrated biological and anti-neoplastic activity in xenograft models of 
human carcinomas. Intraperitoneal administration of vorinostat (up to 100 mg/kg/day) caused 
significant inhibition of tumor growth in human cutaneous T-cell lymphoma (CTCL), prostate 
cancer, human breast cancer, and human colon cancer xenografts in mice without toxic side 
effects.  Some tumor regression was even noted. Oral vorinostat also inhibited growth of 
established rat mammary tumors. Additionally, oral vorinostat administered to carcinogen-
treated rats increased tumor latency and reduced mammary tumor incidence, multiplicity, and 

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volume. Oral vorinostat administered to carcinogen-treated mice reduced lung tumor 
multiplicity. In addition, the intraperitoneal administration of vorinostat in combination with 
retinoic acid induced leukemic remission and prolonged survival in a therapy-resistant 
transgenic mouse model of acute promyelocytic leukemia (APL).86 Furthermore, 
administration of vorinostat in combination with bortezomib significantly inhibited tumor 
growth compared to either agent alone using the orthotopic model of human pancreatic cancer. 
The combination of vorinostat with bortezomib was well tolerated. These data show that 
significant anti-tumor activity can be achieved in these nonclinical models at easily-tolerated 
vorinostat doses. 
4.5.4 Summary of Clinical Data 
As of 02-Jul-2012 the clinical safety of vorinostat is supported by data from 1,740 patients 
(1,744 patient-exposures) who have been treated in Merck-sponsored Phase I, II, and III studies 
(PN001, PN002, PN003, PN004, PN005, PN006, PN008, PN011, PN012, PN013, PN014, 
PN015, PN016, PN025, PN029, PN030, PN042, PN048, PN055, PN056, PN058, PN064, 
PN066, PN070, PN074, PN088, PN089, PN095, PN098, and PN103) conducted in patients 
with both hematologic malignancies and solid tumors. (The additional four (4) patient-
exposures occurred in PN005, the initial supportive study, where patients enrolled in 1 cohort 
were permitted to enroll in a subsequent cohort at a later time point). Merck, including MSD 
KK (Japan), has sponsored 30 vorinostat studies that are completed (24), closed (3), or ongoing 
(3). Three (3) Merck-sponsored studies (PN016, PN056, and PN064) were terminated. 
 
The NCI is working in collaboration with Merck to further evaluate vorinostat. The NCI-
sponsored studies of vorinostat are in progress or are planned in a variety of different 
indications both in hematologic malignancies as well as solid tumors. As of 02-Jul-2012, 1,718 
patients have received vorinostat as either monotherapy or combination chemotherapy in 61 
studies sponsored by the NCI. A separate U.S. Investigational New Drug application (IND) is 
held by NCI for these studies. 
 
In addition, vorinostat is also being evaluated in studies initiated and sponsored by independent 
Investigators (MISP studies), both as monotherapy and as combination chemotherapy. As of 
02-Jul-2012, 85 of these MISP studies have enrolled 1,607 patients. These active studies are 
enrolling and additional studies are planned. Merck has outsourced the management, including 
data collection, of 4 clinical trials involving vorinostat and radiation to the NCCN. As of 02-
Jul-2012, all 4 of these studies were opened and had enrolled a total of 31 patients. Data from 
these 31 patients are reported separately. A separate U.S. Investigational New Drug application 
(IND) is held by the NCCN investigators for these studies. Therefore, over 5,000 patients have 
received at least one dose of vorinostat in studies sponsored by either Merck, the NCI, NCCN, 
or independent Investigators. ZOLINZA™ (vorinostat) was approved by the U.S. Food and 
Drug Administration (FDA) on 6-Oct-2006 for the treatment of cutaneous manifestations in 
patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or 
recurrent disease on or following two systemic therapies. ZOLINZA™ (vorinostat) has been 
approved in several other markets around the world for this indication as well. 
 

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4.5.5 Safety 
The total daily doses studied ranges from 200 mg to 900 mg. The tolerability of oral vorinostat 
appears to be determined by total daily dose and the length of consecutive days of dosing. The 
maximum tolerated dose (MTD) for continuous daily dosing without a rest period is 400 mg 
daily or 200 mg BID. The MTD for intermittent dosing is 300 mg BID x 3 consecutive days 
per week, or 250 mg TID x 14 consecutive days followed by a 7-day rest. Dose-limiting 
toxicities (DLTs) of single agent vorinostat were mainly non-hematologic (anorexia, 
dehydration, diarrhea, and fatigue); hematologic toxicities are primarily anemia and 
thrombocytopenia, most of which were mild to moderate. The majority of these DLTs occurred 
within the first month on oral vorinostat. The DLTs were manageable because these toxicities 
resolved quickly after drug administration was interrupted. The optimal dose, dose frequency, 
and dose duration remain under active investigation. 
 
4.5.6 Expected Adverse Events 
The types of adverse experiences observed in clinical trials of vorinostat were those usually 
associated with chemotherapy, such as nausea, fatigue, diarrhea, anorexia, vomiting, 
constipation and cytopenias. The three major clinical categories of adverse experiences 
attributable to vorinostat include a constellation of gastrointestinal symptoms, constitutional 
complaints, and cytopenias. However, most of the adverse experiences were manageable. In 
fact, most of the very common adverse experiences were reversible and could be managed 
using conventional supportive care for chemotherapy. On the whole, treatment with oral 
vorinostat was well tolerated for use in the outpatient setting. Please see below for specific 
information regarding vorinostat-related adverse experiences observed when vorinostat was 
administered either as monotherapy or in combination with other agents, in Merck-sponsored 
clinical trials. 
 
Nausea and Vomiting 
Drug-related nausea and vomiting are commonly observed with vorinostat therapy: 51.3% all 
grades nausea, 4.9% grades 3-5 nausea; 32.5% all grades vomiting, 3.2% grades 3-5 nausea. 
Nausea and vomiting should be managed according to standard practice as outlined in the 
published American Society of Clinical Oncology (ASCO) antiemetic guidelines. Briefly, 
antiemetic agents including, but not limited to, 5HT-3 antagonists, aprepitant, lorazepam, 
diphenhydramine or phenothiazines may be considered. The use of empiric anti-emetic 
coverage is strongly encouraged, as is early and aggressive management of nausea, decreased 
oral intake and/or vomiting in patients treated with vorinostat. 
 
Diarrhea 
Drug-related diarrhea is commonly with vorinostat therapy: 43.5% all grades diarrhea, 6.7% 
grades 3-5 diarrhea. Diarrhea should be treated promptly with appropriate supportive care. 
Patients should be instructed to begin taking loperamide at the first sign of: 1) poorly formed 
or loose stool, 2) occurrence of more bowel movements than usual in one day or 3) unusually 
high volume of stool. Diarrhea should be managed with loperamide or according to 
institutional guidelines. However, loperamide should be deferred if blood or mucus is present 

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in the stool or if diarrhea is accompanied by fever. In this setting, appropriate diagnostic 
microbiologic specimens should be obtained to exclude an infectious etiology. Patients should 
also be advised to drink liberal quantities (at least 2 liters/day) of clear fluids to help prevent 
dehydration. 
 
Dehydration 
Altered taste and decreased food and liquid intake are associated with vorinostat 
administration. These toxicities can be actively managed with fluid management and 
nutritional consultation, as appropriate. To prevent dehydration, patients should consume at 
least 2 liters of fluid orally, on a daily basis, in particular during the days that patients are being 
treated with vorinostat. If patients are experiencing dysgeusia, popsicles or oral electrolyte 
fluid replacement may be recommended. 
 
Anemia 
Treatment with vorinostat can cause dose-related anemia which may result in fatigue, lethargy 
or shortness of breath. If hemoglobin is reduced during treatment with vorinostat, the dose 
should be modified or therapy discontinued, as outlined in the respective protocol.  
 
Neutropenia 
Drug-related neutropenia is observed with vorinostat therapy, 17.8% all grades neutropenia, 
13.3% grades 3-5 neutropenia. Growth factors should only be utilized according to protocol 
guidelines. 
 
Thrombocytopenia 
Treatment with vorinostat can cause dose-related thrombocytopenia. Transfusion of platelets 
may be used if clinically indicated in a manner consistent with the guidelines for dose 
modification as outlined in the respective protocol. 
 
Hyperglycemia 
Hyperglycemia has been observed in patients receiving vorinostat. Serum glucose should be 
monitored, especially in diabetic or potentially diabetic patients. Adjustment of diet and/or 
therapy for increased glucose may be necessary. 
 
Hypokalemia or Hypomagnesemia 
Hypokalemia and hypomagnesemia should be corrected prior to administration of vorinostat, 
and consideration should be given to monitoring potassium and magnesium in symptomatic 
patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms.) 
 
Pulmonary Embolism 
Among the 1,740 patients enrolled in Merck-sponsored studies, pulmonary embolism and deep 
vein thrombosis have been reported in 30 (1.7%) and 32 (1.8%) patients, respectively. 
Investigators should be alert to the signs and symptoms of PE and DVT, particularly in patients 
with a prior history of thromboembolic experiences. 
 

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QTc Prolongation 
QTc prolongation has been observed in patients receiving vorinostat although no statistical 
correlation has been established between the use of vorinostat and QTc prolongation. If 
clinically indicated or outlined in the respective study, baseline and periodic ECGs should be 
performed during treatment. Vorinostat should be administered with particular caution in 
patients with congenital long QT-syndrome and patients taking anti-arrhythmic medicines or 
other medicinal products that lead to QT prolongation. 
 
4.5.7 Drug Interactions 
The major pathways of metabolism of vorinostat involve glucuronidation and β-oxidation. As 
vorinostat is not eliminated via CYP450 pathways, it is anticipated that vorinostat will not to 
be subject to drug-drug interactions when co-administered with drugs that are known to be 
CYP450 inhibitors. Although vorinostat was not a potent reversible inhibitor of the CYP450 
isozymes, studies performed to monitor gene expression changes indicated some potential for 
suppression of CYP2C9 and CYP3A4 activities at ≥10 µM vorinostat; however, these changes 
were observed at concentrations higher than the pharmacologically relevant concentration of 
2 µM (Cmax). 
Prolongation of prothrombin time (PT) and International Normalized Ration (INR) have been 
observed in patients receiving vorinostat concomitantly with coumarin-derivative 
anticoagulants.  Physicians should carefully monitor PT and INR in patients concurrently 
administered vorinostat and coumarin derivatives.  Vorinostat should not be administrated with 
other HDAC inhibitors (e.g., valproic acid) as class-specific adverse reactions may be additive. 
Severe (grade 4) thrombocytopenia with associated gastrointestinal bleeding and anemia has 
been reported with the concomitant use of vorinostat and valproic acid. 
4.6 
Rationale 
4.6.1 Rationale for the Trial and Selected Subject Population 
Although responses to PD-1 inhibitors have been observed in patients with HL, DLBCL, and 
FL, there is room for improvement. Despite the high response rate observed to single-agent 
PD-1 inhibition, the complete response (CR) rate in patients with HL appears to be only 10-
20%.14 Meanwhile, the ORR and CR rate are only 35-40% and 5-10% in patients with DLBCL 
or FL, respectively.15 The addition of a synergistic agent with PD-1 inhibition may enhance 
anti-tumor activity and result in deeper and more durable responses. An attractive combination 
partner is vorinostat, a histone deacetylase inhibitor (HDACi), which has demonstrated activity 
in a range of lymphomas, including HL, DLBCL, and FL.16, 17 18-21  
HDACi therapy has many immunologic effects on tumor cells and immune effector cells that 
may enhance the effect of PD-1 blockade when given in combination. HDACis 
immunomodulate tumor cells, by increasing expression of tumor-associated antigens, 
upregulating genes that control antigen presentation machinery, and promoting release of 
mediators of immunogenic cell death.22 HDACis also have important effects on immune cells, 

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including enhancing CD8+ cytotoxic T-lymphocyte (CTL) function, decreasing regulatory T-
cell numbers and function, and modulating myeloid-derived suppressor cell (MDSC) 
differentiation.22 Most notably, there is evidence that HDAC inhibition combined with PD-
1/PD-L1 pathway blockade results in enhanced anti-tumor activity in preclinical models. 
HDACis directly upregulate PD-L1 expression in melanoma cell lines, murine models, and 
patient tumor samples.23 Indeed, combined HDAC and PD-1 inhibition results in synergistic 
killing of tumor cells and HDACis reverse tumor resistance to checkpoint blockade in pre-
clinical murine breast and colorectal cancer models.24 Zheng et al. found that HDAC inhibition 
with romidepsin increases in vitro PD-L1 expression in lung cancer cell lines, promotes T-cell 
infiltration into lung cancers, and enhances function of recruited T-cells in a mouse model. In 
mice inoculated with lung cancer tumor cells, combined romidepsin and anti-PD-1 therapy 
significantly reduced tumor growth compared to HDAC or PD-1 inhibition alone.25 The 
authors chose to study romidepsin based on a screen of drugs that could induce T-cell 
chemokine expression, but the authors also demonstrated in the study that vorinostat had 
similar effects. In a separate study using a murine model of lung cancer, vorinostat increased 
CD8+ T-cell infiltration into tumors.26 In light of the observation that non-responders to anti-
PD-1 therapy have a deficiency of tumor infiltrating T-cells in pre-treatment tumor biopsies,27 
the ability of vorinostat and HDACis to increase T-cell recruitment into tumors and to induce 
PD-L1 expression on tumor cells, as well as the ability of HDACis to synergize with anti-PD-
1 therapy suggests that vorinostat may be an ideal agent to combine with a PD-1 inhibitor to 
increase the frequency and depth of responses in lymphoma patients. We will conduct a phase 
I study with an expansion cohort to evaluate the safety and obtain a preliminary estimate of the 
efficacy of combining pembrolizumab with vorinostat for the treatment of rel/ref HL, DLBCL, 
and FL. 
4.6.2 Rationale for Pembrolizumab Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab (MK-3475). The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated and 
no dose-limiting toxicities were observed. This first in human study of MK-3475 showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. Recent data 
from other clinical studies within the MK-3475 program has shown that a lower dose of MK-
3475 and a less frequent schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic (PD) data 
(IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provided 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 

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parameters of MK-3475 were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed 
for other antibodies and would support both body weight normalized dosing or a fixed dose 
across all body weights. MK-3475 has been found to have a wide therapeutic range based on 
the melanoma indication. The differences in exposure for a 200 mg fixed dose regimen relative 
to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the 
established exposure margins of 0.5-5.0 for MK-3475 in the melanoma indication. The 
exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 
mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and 
exposure). The population PK evaluation revealed that there was no significant impact of 
tumor burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
2 mg/kg and comparable doses of pembrolizumab in solid tumors were further explored 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 for this study of the 200 mg Q3W, representing a switch to fixed dosing, is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
4.6.3 Rationale for Vorinostat Dose Selection/Regimen/Modification  
Several doses and dosing schedules of vorinostat have been utilized in the treatment of solid 
tumors and hematologic malignancies. The FDA approved dose is 400mg once a day for the 
treatment of cutaneous T-cell lymphoma. The MTD of vorinostat is 400mg daily or 200mg 
twice a day (BID) for continuous dosing without a resting period, or 300mg BID for 3 
consecutive days per week for intermittent dosing. In phase I and II studies of vorinostat for 
the treatment of lymphomas, a range of doses and schedules have been used, including 400mg 
daily, 600mg daily, or 400mg BID continuously;16 200mg BID for 14 days followed by a 7-
day break in 21-day cycles;17, 19 300mg BID followed by a 7-day break, which was 
subsequently modified to 300mg BID for 3 days followed by 4 days of rest;58 and 100mg in 

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the morning/200mg in the evening for days 1-5 and 8-12 of a 21-day cycle.87, 88 Anti-lymphoma 
activity was seen at all the above dose levels. While it is expected that vorinostat will have 
anti-lymphoma activity in this setting, as described above, the rationale for its use in this trial 
is its immunomodulatory effects. Therefore, we will employ an intermittent dosing schedule 
of days 1-5 and 8-12 of a 21-day cycle, which was well-tolerated in a phase I study of vorinostat 
combined with alisertib, an agent with overlapping toxicities with vorinostat.87, 88 Because of 
the potential for overlapping toxicity and/or potentiation of the immune-related effects of 
pembrolizumab, we will pursue a dose-escalation, starting at a lower dose of vorinostat than 
the MTD - 100mg BID dosed per the above schedule. 
4.6.4 Rationale for Additional Patients in Expansion Cohort 
Monotherapy with PD-1 blockade does not produce durable remissions in the great majority 
of patients with R/R HL. Therefore, effective therapies for patients with R/R HL who have 
prior exposure to PD-1 blockade is a major unmet need. Among the initial 42 patients enrolled 
onto the study, there were 15 patients with prior exposure to PD-1 blockade and the results 
were extremely promising with 13 out of 15 patients achieving an objective response. 
Therefore, we will enroll an additional 10 patients with R/R HL who have prior anti-PD-1/PD-
L1 exposure to more adequately explore the safety and anti-tumor activity of pembrolizumab 
plus vorinostat in this unique population. In addition, to minimize heterogeneity among PD-
1/PD-L1 exposed patients (some could be PD1/PD-L1-exposed but still sensitive) we narrowed 
the eligibility to PD-1/PD-L1 refractory to focus on this particular group of patients where 
there is a high unmet need. 
4.6.5 Rationale for Endpoints 
4.6.5.1 Safety Endpoints 
The primary endpoint is toxicity. Toxicity will be described by type, severity (according to 
NCI CTCAE v4.03), duration, reversibility, and attribution. Because of the unique immune-
related adverse events (IrAEs) observed with checkpoint inhibitors, we will monitor for 
“unacceptable toxicity” with this new combination of drugs (defined in Section10.2). In this 
phase I study, safety, tolerability, and the determination of the MTD/RP2D are the primary 
endpoints. While pembrolizumab and vorinostat have been well-tolerated in clinical trials 
administered alone or in combination with other agents, we will assess the safety of this 
particular combination. 
4.6.5.2 Efficacy Endpoints 
In this phase I study, we aim to obtain a preliminary estimate of the anti-tumor activity of 
pembrolizumab plus vorinostat in patients with relapsed or refractory DLBCL, FL, or HL, as 
determined by the ORR. ORR is defined as the proportion of patients who achieve complete 
or partial response (CR+PR). Additional secondary endpoints for the study will be CR rate, 
time to response (TTR), duration of response (DOR), overall survival (OS) and progression-
free survival (PFS). Each study agent, pembrolizumab and vorinostat, has demonstrated 

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activity in non-Hodgkin lymphoma (NHL) and HL. In FL and DLBCL, the ORR to either 
agent does not exceed 40-50%, and thus can be improved on. In early studies thus far, the ORR 
to PD-1 inhibition in HL appears to be high, ranging from 66-87%. However, the CR rate is 
low (< 20%) with either agent in DLBCL, FL, and HL. Therefore, an improvement in the ORR 
with combined vorinostat plus pembrolizumab therapy would be an exciting development in 
the field, particularly in DLBCL and FL, and would merit further study of the combination. 
Likewise, an improvement in CR rate would be a critically important development in 
optimizing PD-1 inhibitor therapy. 
4.6.6 Rationale for Biomarker Research/Correlative Studies 
Immunologic and genomic biomarkers have been associated with tumor response to 
immunotherapy, including checkpoint inhibitors like pembrolizumab. We propose to evaluate 
a series of exploratory immunologic and genomic correlatives to explore the association 
between each biomarker and response or resistance to combined pembrolizumab and vorinostat 
therapy. The correlative studies described below are exploratory in nature, and meant to be 
hypothesis-generating -they will not be powered for statistical significance. The below 
description is an anticipated rather than an exact list of studies that will be performed, as the 
investigators reserve the right to adjust the studies to be performed as techniques evolve and 
new data may become available that is relevant to the study agent and/or study population. 
 Immunologic Biomarkers: 
PD-L1 expression in tumor cells is a biomarker for response to anti-PD1 therapy in solid 
tumors.89 PD-L1 expression has also been demonstrated in all HL patients tested who 
responded to PD-1 inhibition with pembrolizumab or nivolumab.13, 14 Furthermore, the pattern 
and spatial relationship between PD-1 and PD-L1-expressing cells are associated with response 
in patients with melanoma treated with pembrolizumab.27  
The presence, abundance, and composition of tumor infiltrating lymphocyte (TIL) populations 
in various tumor types are associated with clinical outcome.90-92 In addition, the presence of 
certain TIL populations, particularly CD8+ T-cells, and their spatial orientation in tumors is 
associated 
with 
outcome 
after 
immunotherapy, 
including 
PD-1 
blockade 
with 
pembrolizumab.27, 93 Using high-resolution spectral analysis and automated scanning of tissue 
sections, the Lee laboratory at City of Hope has developed a technique for quantitative, spatial 
IHC analysis of TIL and other immune cell subsets in a tumor. The Lee lab has demonstrated 
that spatial grouping patterns of TILs and dendritic cells differ between tumor-draining lymph 
nodes and normal lymph nodes and are associated with outcome in patients with breast 
cancer.94, 95 
We will evaluate the relationship between response to study therapy and PD-L1 expression 
and potentially other checkpoint receptors/ligands by immunohistochemistry (IHC) in pre-
treatment tumor samples. We will perform quantitative, spatial immunofluorescence analysis 
using the Vectra system in the Lee laboratory, including PD-L1 and potentially other 
checkpoint receptors/ligands, dendritic cells, tumor associated macrophages,96 TILs including 

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CD8+ cells and regulatory T-cells, and possibly other immune cell subsets and explore the 
association with response to study therapy. We will also analyze changes in immune cell 
subsets by flow cytometry on peripheral blood mononuclear cells (PBMCs) at baseline and 
during treatment and explore the association with response to study therapy. Cytokine analyses 
may be performed on the plasma portion of these samples. 
 Genomic Biomarkers: 
Genomic signatures define distinct subsets of DLBCL and are associated with outcome after 
standard therapy in patients with DLBCL, FL, HL.97-101 Genomic studies have elucidated 
tumor target-specific and microenvironmental characteristics that predict response to novel 
immunotherapies, including checkpoint inhibitors. One key target-specific genomic biomarker 
of response to immunotherapy is a tumor’s mutational burden. In clinical trials of melanoma 
patients treated with the anti-CTLA-4 antibody, ipilimumab, and non-small cell lung cancer 
(NSCLC) patients treated with pembrolizumab, patients with a higher mutational load in pre-
treatment tumor samples have a higher rate of durable clinical benefit, objective response rate, 
and improved survival compared to patients with fewer mutations.102, 103 Nonsynonymous 
genetic mutations result in the formation of neoantigens that improve recognition of the tumor 
by the host immune system, which appears to drive anti-tumor responses in the enhanced 
effector cell milieu created by checkpoint blockade. Similarly, in melanoma patients who have 
durable, complete responses after adoptive TIL therapy, specific neoantigens resulting from 
nonsynonymous mutations can be identified that are responsible for the robust anti-tumor 
responses observed.104, 105 
In addition to a tumor’s mutational profile, tumor gene expression patterns impact response to 
novel immunotherapies. Increased expression of genes that encode for immune-related targets, 
such as T-cell surface markers, immune receptors, and cytokines/chemokines, in pre-treatment 
melanoma tumor samples are associated with response to ipilimumab.106 Similarly, 
overexpression of immune-related genes in pretreatment tumors of patients with melanoma 
and NSCLC is associated with outcome after treatment with an antigen-specific tumor vaccine 
and immunostimulant.107 
We will explore whether total mutational burden or genomic signatures as determined, for 
example, by mutational or gene expression profiles in pre- (and post-treatment, if available) 
tumor samples are associated with response and outcome after vorinostat plus pembrolizumab 
therapy. 
 Circulating DNA as biomarker: 
The detection of circulating tumor DNA (ctDNA) has been studied in lymphoma. Next-
generation sequencing (NGS)-based ctDNA detection performed by NGS of the 
immunoglobulin (Ig) or T-cell receptor genes can identify ctDNA in the peripheral blood 
mononuclear cells (PBMC) and plasma (cell-free DNA) at diagnosis in a range of lymphomas, 
including classical Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL).108-111 In 
addition, ctDNA levels correlate with treatment response in DLBCL, and the persistence or 

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recurrence of ctDNA during and after upfront therapy is associated with subsequent DLBCL 
relapse.110, 111 In a small study using Ig-NGS in patients with FL, 85% of patients had a tumor 
clone identified from the diagnostic biopsy, and 83% had ctDNA in the peripheral blood at 
diagnosis. In patients who underwent observation without treatment and also patients treated 
with chemoimmunotherapy, higher ctDNA levels at diagnosis were associated with shorter 
progression-free survival (PFS).112 While the Ig-NGS method is powerful, the investigation of 
only Ig genes limits its sensitivity, resulting in a sizable minority of patients in whom the assay 
is not applicable (ctDNA only detected in 73% of FL starting cohort). Meanwhile, ctDNA 
assessment using capture-based NGS for recurrent mutations and rearrangements has been 
explored in DLBCL, and the method appears feasible and highly sensitive.113, 114 Like IgNGS, 
capture-based NGS MRD detection exploits the genetic features of a lymphoma to identify 
tumor-specific DNA in the peripheral blood of patients with lymphoma. Utilizing 
bioinformatics pipelines optimized for low input DNA, hybridization capture-based NGS is 
performed on a patient sample (i.e. peripheral blood, tumor tissue) that evaluates a panel of 
single-nucleotide variants (SNVs), insertions/deletions (indels), and chromosomal 
translocations known to be recurrently mutated in a specific lymphoma subtype (to date, 
primarily DLBCL). CtDNA can be quantitated by calculating the proportion of tumor-specific 
cfDNA molecules within a sample (the variant allele fraction). Thus far, studies have 
demonstrated that genetic alterations detected in ctDNA using capture-based NGS analysis of 
the peripheral blood are highly concordant with genetic alterations determined by NGS of a 
primary DLBCL tumor sample.115-117 Similar to IgNGS, capture-based NGS based MRD 
detection can identify ctDNA in patients with DLBCL prior to treatment, can quantify ctDNA 
levels that track with treatment response and resistance, and can detect relapse prior to and at 
the time of clinically apparent relapse.114-116, 118 
NGS-based ctDNA assessment methods have demonstrated initial promise in detecting ctDNA 
in HL. In early studies, IgNGS could identify a tumor clone for tracking using tumor tissue in 
56-71% of HL patients and ctDNA was detected in the PBMC and/or plasma of 73% of those 
patients.109, 119 In one study of ctDNA assessment in patients with lymphoma who had 
undergone allogeneic stem cell transplantation, out of two HL patients who relapsed, ctDNA 
was detected prior to and at the time of relapse in one patient and at the time of relapse in the 
other patient.119 Using a separate NGS method, Vandenberghe et al. identified tumor-specific 
genomic imbalances in cfDNA from the plasma of HL patients with early or advanced stage 
disease at diagnosis that became undetectable after treatment response.120 Finally, XPO1 
mutations could be detected at diagnosis in the plasma of patients with cHL and tracked after 
treatment using a digital PCR technology.  The persistence of this mutation showed a possible 
association with relapse in patients a negative PET scan at end of treatment.121 
We will explore the value of circulating DNA (ctDNA) as a biomarker of response to study 
therapy by next-generation sequencing (NGS) using blood samples collected during treatment. 
 
 

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 Quantitative PET assessment in HL and DLBCL: 
 In Hodgkin Lymphoma 
For better characterization of therapeutic response and prediction of outcome in patients with 
lymphoma, significant progress has been made in standardizing qualitative methods and 
integration of FDG PET in the international working group criteria (IWG) for lymphoma 
assessment.122 However, there is a growing need for the development of quantitative imaging 
metrics as operator-independent surrogate measures to predict treatment response and 
survival. In this regard, standardized uptake values (SUV) have been the most widely used 
quantitative measure for assessing tumor metabolic activity and treatment response. In 
Hodgkin lymphoma (HL), SUVmax cut-off was investigated as a predictor of progression after 
two cycles of chemotherapy,123 however, without validation studies to define a widely accepted 
cut off value, these criteria have not yet been adopted for HL. 
The PET-derived whole body metabolic metrics, metabolically active tumor volume (MTV*) 
and total lesion glycolysis (TLG**) measure metabolic activity in an entire tumor mass to 
reflect tumor biology. With the recent development of software based automated assessments, 
volume-based metabolic parameters have become increasingly available quantitative PET 
(qPET) indices. Although these metrics have the potential to become a useful index for 
assessing treatment response and survival they are yet to be standardized and validated to 
translate to a clinical practice platform. Recent studies have reported that a high total MTV 
predicted a lower survival in various retrospective studies in HL showing variation in the 
strength of outcome prediction but promising data in early stage HL.124-128 Based on these 
encouraging results, there is interest in utilizing qPET parameters, including MTV, to tailor 
treatment in HL, but these metrics require validated in larger, prospective studies. In addition, 
there is controversy with respect to the methodologies used among various investigators,124, 
125, 129 though studies that have evaluated different methodologies have shown similar utility 
to the various methods.130 Preliminary results suggest that qPET metrics may not be applicable 
across treatment regimens. As part of the HD18 trial by the German Hodgkin Lymphoma Study 
Group Mettler et al found that baseline MTV was a predictive factor for early response to 
BEACOPP after two cycles. However, no prognostic value for end of treatment response and 
ultimate outcome was observed with an interim PET-adapted treatment strategy.129 However, 
in the LYSA AHL2011 trial, which utilized a similar PET-adapted BEACOPP-based approach 
in advanced stage HL, MTV was prognostic for PFS. When combined with interim PET status, 
MTV and interim PET results together identified a subset of patients at high risk for treatment 
failure.131  
In patients with relapsed or refractory HL treated with sequential BV followed by ICE 
chemotherapy (in patients not in complete response after BV), baseline MTV and TLG were 
found to be strong prognostic factors for outcome. In multivariate analyses, baseline MTV 
remained the main independently prognostic factor associated with treatment outcome along 
with end of treatment PET status, and baseline MTV enhanced the prognostic value of end of 
treatment PET status for outcome.132 Thus, there are data to support the use of qPET parameters 
as a prognostic factor in HL, both alone and in combination with the dynamic response data 
gained with interim or end of treatment PET. 

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*MTV refers to the total volume, measured in cm3 or ml, of the metabolically active tumor 
volume encompassed by a volume of interest (VOI), either for a single lesion or for multiple 
lesions. 
**TLG is the product of SUVmean in the defined VOI and the MTV; the rationale is to combine 
tumor burden and its metabolic activity, having an index that is correlated to both the volume 
and the uptake of the volume. 
 
 In DLBCL 
Several working groups have recognized quantitative measures as an important tool in staging 
and response assessment in DLBCL, for instance SUVmax or ΔSUVmax. Studies 
investigating the role of ΔSUVmax demonstrated its usefulness for response stratification in 
DLBCL.133 Additionally, FDG-PET provides biomarkers such as the metabolic tumor volume 
(MTV) or total lesion glycolysis (TLG), which incorporate information concerning tumor 
burden and disease activity. Metabolic measures were reported to have a prognostic value in 
non-Hodgkin lymphoma. Mikhaeel et al. demonstrated that MTV at staging is an important 
prognostic factor for DLBCL and that combining MTV with results of early PET response 
assessment improves the predictive power.134 Similar findings emerged from a recently 
published analysis including 510 DLBCL patients treated within the PET-guided therapy 
optimization trial PETAL.135 Interestingly, it has been also shown that MTV is a valid 
prognosticator in elderly individuals with DLBCL receiving R-CHOP. A study by Vercellino 
and colleagues found high pretreatment MTV to be significantly associated with inferior PFS 
and OS in this group.136 Including patients from the LNH073B study, a French working group 
additionally examined the role of radiomic features characterizing lesion dissemination and 
reported that combining them with baseline MTV further improves risk stratification in 
DLBCL patients.137 Furthermore, several retrospective studies have shown in DLBCL that 
high baseline TMTV measured by fluorodeoxyglucose PET/CT was associated with worse 
progression-free survival (PFS) and/or OS. 
 
The intention of this work is to validate the prognostic value of qPET metrics, in particular 
MTV, in a prospective trial incorporating novel immunotherapy into the treatment of 
relapsed/refractory HL and DLBCL. 
Methods for Quantitative PET Assessment Studies 
 
PET/CT scans are performed after 6–8 hours of fasting and after the intravenous administration 
of ~10–15 mCi (370–555 Mbq) of 18F-FDG. After 50–70 minutes of radiotracer uptake, PET 
images are acquired on a non-contrast 16-slice PET/CT system (GE Medical Systems). Three-
dimensional (3D) iterative reconstruction using a 168 × 168 matrix with a zoom of 1.0, FWHM 
filter of either 5.0 or 6.0 mm, and 2 iterations with 8 subsets is used generate PET images. The 
non-contrast whole body CT data is utilized for lesion anatomic localization and attenuation 
correction. 18F-FDG PET/CT images region-of-interest (ROI) will be performed using the 
commercially available, FDA-approved “Mirada Medical PET/CT XD Oncology Review” 

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software (Mirada Medical) and SECTRATM. The ROI measurement - Standard uptake value 
(SUV; g/mL) – attempts to measure the normalized amount of radioactive concentration found 
on qualitative (visual) PET inspection in selected part of the body at a certain time. Some 
variation of the normalization factor for the SUV exist, including: body weight (SUVbw), lean 
body weight (SUVlbw), and body surface area (SUVbsa). Calculations reported in this study 
will rely on the general standard of care: SUVbw and it is calculated using the formula 
recommended by the QIBA SUV Subcommittee: 
 SUVbw(pixel) in g/mL= activity (pixel) in (Bql/ml)/injected dose in Bql/patient weight 
in grams).  
 
Image DICOM tags are used to perform the calculation, including: patient’s weight, acquisition 
date time, radionuclide half-life and radiopharmaceutical start date/time.  
  
The background red marrow of each patient is defined by using a 1 cm3 diameter region of 
interest in the most inferior vertebral body which does not demonstrate focally increased FDG 
uptake or vertebroplasty material. Focal lesions for each patient are defined as focal areas, 
measuring at least 1 cm in diameter, not otherwise demonstrated to be artifacts by comparison 
with coregistered CT, recognizable as discrete foci of increased 18F-FDG uptake on maximum 
intensity projection images (MIP), and exhibiting a max SUV (SUVmax) greater than the 
SUVmax for the patient's background red marrow. 
 
The volume of each lesion and its 3D margins are determined by incorporating all contiguous 
pixels with activity greater than 0.1 g/mL above that of the background marrow. Because of 
the considerable statistical variability inherent in the acquisition, reconstruction, and display 
of accumulations of radiopharmaceuticals in the clinical imaging setting, SUVs obtained from 
larger regions of interest (ROI) are more reproducible than single pixel determinations such as 
SUVmax. For this reason, we have chosen to quantify activity by calculating the SUVmax defined 
as the average SUVs, corrected for lean body mass, of the pixels in a sphere 1.2 cm in diameter 
(1 cc) centered to include the most intense pixel. 
 
The total MTV for disease in each patient is defined as the sum of MTVs of all the individual 
focal lesions identified in the analysis. The TLG of each focal lesion is calculated by 
multiplying the MTV of that lesion with its corresponding mean SUV (TLG = SUVmean × 
MTV). The global TLG of each patient is defined as the sum of the TLGs for all the focal 
lesions in the analysis. 
 
All volumes of interest that are drawn by the automated computer system will be evaluated by 
the reader to delete those regions that are not deemed to be associated with tumor. The review 
computer system will automatically calculate all quantitative assessments (SUVmax, MTV, 
TLG) for each lesion at baseline, mid therapy (when available) and end of therapy (EOT). In 
addition, at EOT, we will calculate the percentage of change from baseline for each qPET 
parameter. 
 

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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Eligible patients must: 
 Have a histologically confirmed diagnosis of follicular lymphoma, diffuse large B-cell 
lymphoma, or classical Hodgkin lymphoma according to the WHO classification, with 
hematopathology review at the participating institution. 
o FL: grade 1, 2, 3A, or 3B are eligible. 
o DLBCL: transformed indolent lymphomas (TIL), primary mediastinal large 
B-cell lymphoma (PMBCL), and aggressive B-cell lymphoma unclassified 
(BCL-U) are eligible. 
o HL: all classical HL subtypes are eligible except for nodular lymphocyte 
predominant Hodgkin lymphoma, which is excluded. 
NOTE: Per Amendment (Protocol V9 dated 06-04-20), this study will only enroll HL 
patients who have had prior exposure to PD-1/PD-L1 immunotherapy. FL, DLBCL, and 
HL patients without prior exposure to PD-1/PD-L1 immunotherapy are no longer 
eligible. 
 Patients with HL or DLBCL must refuse or not be candidates for curative autologous stem 
cell transplantation. 
 Have relapsed or refractory disease after at least 1 prior regimen, including: 
o Recurrence of disease after a documented complete response (CR) 
o Progression of disease after a partial response (PR) to the prior regimen 
o Partial response (PR), stable disease (SD) or progressive disease (PD) at the completion 
of the prior treatment regimen. If a patient has PR to prior regimen without PD, there 
must be biopsy-proven residual disease that is measurable. 
NOTE: Per Amendment (Protocol V10 dated 10-16-20), this study will only enroll HL 
patients who are refractory to PD-1/PD-L1 immunotherapy. 
Refractory to PD-1/PD-L1 immunotherapy is defined as patients who had prior exposure to 
PD-1/PD-L1 immunotherapy and either - achieved a best response of SD or PD or - achieved 
a best response of CR/PR but developed PD while on active PD-1/PD-L1 treatment. 

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5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Documented informed consent of the participant or legally authorized representative. 
2. Be  18 years of age on day of signing informed consent. 
3. Have measurable disease by CT or PET scan, with one or more sites of disease ≥ 1.5cm 
in longest dimension.  
4. Be willing to provide tissue from a fresh core or excisional biopsy of a tumor lesion 
prior to starting study therapy or from archival tissue of a biopsy that was performed 
after the most recent systemic therapy. 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
6. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 14 days of treatment initiation.   
Table 1. Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000 /mcL 
Exception: Unless documented bone marrow involvement by 
lymphoma. 
Platelets 
≥75,000 / mcL 
Exception: Unless documented bone marrow involvement by 
lymphoma. 
Hemoglobin 
≥8 g/dL without transfusion or EPO dependency (within 7 days 
of assessment) 
Exception: Unless documented bone marrow involvement by 
lymphoma. 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN or ≤ 3X ULN if patient has Gilbert’s disease 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 involvement by lymphoma  as 
the etiology of transaminase elevation 
Albumin 
>2.5 mg/dL 
Coagulation 

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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 by the Cockcroft-Gault equation 
 
7. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
8. Female subjects of childbearing potential (Section 7.11.2) must be willing to use an 
adequate method of contraception as outlined in Section 7.11.2 – Contraception,  for 
the course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
9. Male subjects of childbearing potential (Section 7.11.2) must agree to use an adequate 
method of contraception as outlined in Section 7.11.2- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
5.1.3 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 3 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 received a prior allogeneic hematopoietic stem cell transplant within the past 5 
years, requires immunosuppression, or has evidence of active graft-versus-host-
disease. 
4. Has received prior autologous hematopoietic stem cell transplant within the last 60 
days. 

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5. Has a known history of active TB   (Bacillus Tuberculosis) 
 
6. Severe hypersensitivity to pembrolizumab or any of its excipients. 
7. Has had a prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 3 weeks earlier. If a patient has progressive or stable 
disease to prior regimen, rituximab is allowed up to 2 weeks prior to the initiation of 
study therapy. 
8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
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.   
9. Has taken valproic acid, or another histone deacetylase inhibitor, within 2 weeks prior to 
study Day 1. 
10. 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. 
11. Has known active central nervous system (CNS) involvement by lymphoma, including 
leptomeningeal involvement. Subjects with prior CNS involvement by lymphoma must 
have remission of the CNS component of the lymphoma. These subjects must have a 
baseline MRI during screening without evidence of new or enlarging brain lesions and 
must not have any new or progressive neurologic symptoms. 
12. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. A history of hemolytic anemia associated with the lymphoma 
does not exclude a patient from the study. 
13. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis 
14. Has an active infection requiring systemic therapy. 

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15. Has a QT interval corrected for heart rate (QTc) > 470 ms using the Fridericia formula. 
If the screening electrocardiogram (ECG) has a QTc > 470ms, the mean QTc of 3 ECGs 
can be utilized, but must be < 470 ms. 
16. Is unable to swallow capsules, has a partial or small bowel obstruction, or has a 
gastrointestinal condition resulting in a malabsorptive syndrome (e.g. small bowel 
resection with malabsorption). 
17. 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.   
18. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
19. 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. 
20. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
21. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
22. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
5.2 Inclusion of Women and Minorities 
The study is open to anyone regardless of gender or ethnicity.  Efforts will be made to extend 
the accrual to a representative population, but in a trial which will accrue approximately 52 
subjects, a balance must be struck between subject safety considerations and limitations on the 
number of individuals exposed to potentially toxic or ineffective treatments on the one hand 
and the need to explore gender, racial, and ethnic aspects of clinical research on the other.  If 
differences in outcome that correlate to gender, racial, or ethnic identity are noted, accrual may 
be expanded or additional studies may be performed to investigate those differences more 
fully. 

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6.0 PARTICIPANT ENROLLMENT 
6.1 
Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done 
only after obtaining written informed consent.  As long as they were performed within the 
appropriate time frame, studies or procedures that are performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values and/or to determine 
pre-eligibility, even if the studies were done before informed consent was obtained. Reference 
is made to Section 8.0 - Study Calendar. The informed consent process is to be fully 
documented, and the prospective participant must receive a copy of the signed informed 
consent document.    
6.2 
Participant Enrollment 
6.2.1 COH DCC Availability and Contact Information 
Eligible participants will be registered on the study centrally by the DCC at City of Hope.  
DCC staff are available between the hours of 8:00 a.m. and 5:00 p.m. PST, Monday 
through Friday (except holidays).   DCC contact information is as follows: 
 
e-mail: DCC@coh.org 
6.2.2 Slot verification and reservation 
During the dose escalation stage, eligible Phase 1 participants will be assigned a dose level 
(Section 7.0). Once the recommended phase 2 dose (RP2D) is defined, participants will enroll 
at the RP2D dose (expansion cohort). 
Issues that would cause treatment delays should be discussed with the Principal Investigator. 
Designated study staff should call the DCC to verify current slot availability, and to reserve a 
slot for a specific prospective subject. 
The DCC should be notified of cancellations of prospective participants holding slots as soon 
as possible. 
6.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
The DCC is to be notified of all participants who sign consent but do not meet eligibility criteria 
or do not initiate protocol therapy.   
6.4 
Registration Process 
To register a participant, the subsequent procedure is to be followed. 
1. The participating site’s data manager/coordinator/research nurse should contact the 
DCC via telephone or email to provide notification regarding the pending registration 
and communicate desired timeline of the registration, especially if it must be completed 
promptly to meet the registration window. 

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2. The data manager/coordinator/research nurse should then e-mail copies to 
DCC@coh.org  of the following documents to the DCC:  
 
Completed Eligibility Criteria List (printed from Section 5.1 of the protocol) 
 
Source documentation to support eligibility criteria**  
 
Signed informed consent document 
 
Signed HIPAA authorization form (if separate from the informed consent 
document) 
 
Signed subject’s Bill of Rights  
3. After having received all transferred documentation, the DCC will complete the review 
the documents to verify eligibility, working with the study team as needed to resolve 
any missing required source elements. A participant failing to meet all protocol 
eligibility requirements will not be registered.  
4. Once eligibility has been confirmed, DCC staff will send a Confirmation of 
Registration Form and signed eligibility checklist, including the participant study 
number to:  
 
the COH Study PI and COH study team designees (including but not limited to 
study monitor(s) and statistician(s)). 
5. Upon receipt of the Confirmation of Registration Form, COH study team will register 
the patient in OnCore. 
 
7.0 TREATMENT PROGRAM 
The agents to be used in this trial are outlined below in Table 2: 
Table 2. Study Agents 
Study Agents 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 21-day 
cycle 
Experimental 
Vorinostat 
100mg 
capsules, dose 
will vary by 
dose level 
BID 
Oral 
Per Dose Escalation 
rules 
Experimental 
 
7.1 
Treatment Allocation 
There will be no randomization or stratification as part of this study. All patients who consent 
to the study, meet eligibility criteria, and are registered on the trial will receive study treatment. 
This is a phase I study, including a dose-escalation portion of the study with 2 dose levels and 
2 possible de-escalation dose levels, for a total of 4 possible dose levels. The starting dose will 

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be 100mg of vorinostat twice a day (BID), and 200mg IV pembrolizumab.  Subjects will 
receive oral vorinostat according to dose level schedule and dose. Pembrolizumab will be 
administered on day 1 of each cycle thereafter. Study therapy will be administered in 21-day 
cycles. The planned dose levels in the dose-escalation portion of the study are outlined in Table 
3 below. 
Once the RP2D has been determined, an expansion cohort of 40 patients will be enrolled and 
treated at the RP2D, to acquire additional safety and tolerability data about the combination. 
Table 3. Phase I Dose Levels 
Dose Level 
Vorinostat 
Pembrolizumab (day 1) 
-2 
100mg PO BID, d1-3, 8-10 
200mg IV 
-1 
100mg PO BID, d1-3, 8-10, 15-17 
200mg IV 
1 (starting) 
100mg PO BID, d1-5, 8-12 
200mg IV 
2 
200mg PO BID, d1-5, 8-12 
200mg IV 
 
7.1.1 
Treatment Duration 
Study treatment will continue until the subject completes 24 months of treatment with the study 
regimen, or experiences radiographically-confirmed PD (Section 9.2.6 and Section 9.2.6.1), 
unacceptable adverse experiences, either DLT (Section 7.2) or other unacceptable toxicity 
(section 10.2), or meets other criteria for study withdrawal or treatment discontinuation  
7.1.2 
Rules for Phase I Dose Escalation, De-Escalation and Expansion: Adapted 
Rolling 6 Design 
This phase I trial will employ a modified Rolling 6 design, a more conservative version of the 
Rolling 6 design of Skolnik, et al 29. In this design, at most, 3 patients will be under observation 
for DLT on the current test dose level at any time. Patients who are not evaluable for DLT will 
be replaced. Once each patient is evaluable for toxicity and passes without a DLT, an additional 
patient may be accrued on that dose level – up to 6 patients. Once 3 patients are evaluable with 
no patient at that dose level experiencing a DLT, the dose can be escalated, or up to 3 additional 
patients may be treated at the current dose level. Although this design does not require that 6 
patients be treated, no more than 6 evaluable patients will be accrued to any dose level during 
the dose finding portion of this study. If at any time, the dose level has 1 documented DLT 
with fewer than 6 evaluable patients, accrual will continue until 6 patients are evaluable.  
Escalation will terminate as soon as two or more patients experience any DLT attributable to 
the study treatment, at a given dose level. MTD will be declared at the highest dose level at 
which 6 patients have been treated and at most 1/6 patients experiences DLT. If more than 1/6 
patients experiences DLT, then the next lower dose will be expanded. There will be no 
intrapatient dose escalation. These rules are outlined in Table 4: 
Table 4. Dose Escalation Rules 
 

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7.2 
Definition of Dose-Limiting Toxicity 
The dose-limiting toxicity (DLT) observation period will be 42 days (2 cycles). DLT 
assessment will occur on cycle 3, day 1 prior to receipt of cycle 3, day 1 of study therapy. 
Toxicities will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE, Version 4.03) accessible at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
DLT will be defined as one of the following AEs that is at least possibly related to study 
treatment. 
Hematologic 
 Grade 4 neutropenia lasting > 7 days (despite the use of growth factor support). 
 Grade 4 thrombocytopenia lasting > 7 days or requiring platelet transfusion. 
 Grade 3 or 4 thrombocytopenia associated with grade 2 or higher bleeding. 
 Grade 4 anemia not associated with lymphoma. 
# Patients on Current Level 
Action 
With DLT^ 
Evaluable  
Evaluable + At Risk^ 
 
0 
0 
1-2 
Accrue next patient at this level* 
0 
0 
3 
Hold accrual 
0 
1 
1-3 
Accrue next patient at this level 
0 
1 
4 
Hold accrual 
0 
2 
2-4 
Accrue next patient at this level 
0 
2 
5 
Hold accrual 
0 
3-6 
3-6 
Accrue next patient at the next higher level*,+ 
1 
1 
1-2 
Accrue next patient at this level 
1 
1 
3 
Hold Accrual 
1 
2 
2 
Accrue next patient at this level 
1  
2 
3-4 
Hold accrual 
1 
3-5 
3-5 
Accrue next patient at this level 
1 
3-5  
6 
Hold accrual 
1 
6 
6 
Accrue next patient at the next higher level* 
2** 
any 
any 
Accrue next patient at next lower level (max 6) 
^: 
DLT: a patient with a documented DLT 
 
Evaluable: a patient who is either fully evaluable for toxicity for the purpose of dose escalations or has a DLT 
 
At Risk: a patient who is on treatment and has not yet passed the evaluation period nor had a DLT 
*:  During the dose-escalation portion, if higher dose level is already closed, the next lower dose will accrue to a total of 6 patients, 
with 2 or higher DLTs requiring further dose de-escalation. 
+: 
Although under this scenario escalating to the next higher dose level is suggested, additional patients can be accrued to the 
current level -up to n=6 patients. 
**:  Patients treated on a higher dose will have their treatment modified to the dose below the dose level with 2 DLTs, if pending 
patients have DLT. 

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 Any Grade 5 AE. 
Non-hematologic 
 Grade ≥ 3 pneumonitis that does not resolve to grade ≤ 1 within 3 days after initiation of 
supportive care measures. 
 Any clinically relevant grade 3 or grade 4 AE with the exception of: 
o Grade 3 asymptomatic laboratory abnormalities, including lipase or amylase, that are 
not clinically relevant, not requiring hospitalization or delay of treatment. 
o Grade 4 laboratory abnormalities including, but not limited to, hypo- or hyperglycemia, 
hypo- or hypernatremia, hypo- or hyperkalemia, hypo- or hypermagnesemia, hypo- or 
hyperphosphatemia, or hyperuricemia that resolve within 48 hours to Grade ≤ 2 with 
supportive measures. 
o Grade 3 nausea, or fatigue controlled with supportive measures. 
o Grade 3 vomiting if the subject does not require total parenteral nutrition (TPN), tube 
feeding, or hospitalization, and the toxicity improves to < grade 3 within 72 hours. 
o Grade 3 asymptomatic endocrinopathy. 
o Grade 3 fatigue related to endocrinopathy that resolves within 7 days of hormone-
replacement or corticosteroid therapy. 
o Grade 3 local inflammatory response attributed to local antitumor response. 
o Vitiligo or alopecia of any grade. 
 Any Grade 5 AE. 
 
7.3 
Definition of the MTD and Recommended Phase II Dose 
Dose escalation will proceed according to the schema outlined in Table 4. The maximum 
tolerated dose (MTD) is defined as the highest dose level at which < 33% of evaluable subjects 
experienced DLT, when at least 6 patients were treated at that dose level. The MTD will be 
considered the recommended phase II dose (RP2D), however the principal investigator may 
ultimately choose a lower dose level as the RP2D, depending on toxicity considerations, dose 
reduction on subsequent cycles, and other considerations. 

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7.4 
Replacement of Subjects 
During the Phase I dose escalation portion of the study, subjects will be replaced for any of the 
following: 
 Missed 30% or more doses of vorinostat during the DLT period (not due to DLT). 
 Did not receive the dose of pembrolizumab during the DLT period. 
 Study drug discontinuation for any reason other than DLT during the DLT period. 
Subjects who are replaced for missed doses may continue to receive study treatment if there is 
clear clinical benefit, but will not be included in DLT analysis. 
During the expansion cohort portion of the study, subjects who discontinue study therapy prior 
to the first tumor response assessment for a reason other than progressive disease will be 
replaced. 
7.5 
Expansion Cohort 
Once the RP2D has been determined, an expansion cohort of 40 patients will be enrolled and 
treated at the RP2D, to acquire additional safety and tolerability data about the combination. 
Toxicity monitoring will continue during the expansion segment. In addition, because of the 
unique immune-related adverse events (IrAEs) observed with checkpoint inhibitors, we will 
monitor for “unacceptable toxicity” with this new combination of drugs (defined in 
Section10.2). If >3 “unacceptable toxicity” events occur in the first 12 patients (≥33%) treated 
(across disease subtypes) at RP2D, or at a rate ≥33% thereafter at the quarterly review, we will 
halt accrual to fully evaluate these events and assess whether the regimen should be modified. 
7.6 
Study Treatment: Pembrolizumab 
7.6.1 Dose Selection/Modification 
7.6.1.1 Pembrolizumab Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 -
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual and Section 7.6.2.   
7.6.1.2 Pembrolizumab Dose Modification (Escalation/Titration/Other) 
Note: If pembrolizumab administration is held for toxicity, and the toxicity is most likely 
attributed to pembrolizumab and not attributed to vorinostat, administration of vorinostat can 
continue. 

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During the Phase I portion of the study, no intrapatient dose de-escalation will be allowed 
during the DLT period. After the DLT period, the following dose modifications are permitted 
for pembrolizumab-related adverse events according the guidelines outlined below in Table 5 
for pembrolizumab. If, according to Table 5, pembrolizumab is discontinued permanently, the 
patient should continue to receive vorinostat. 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These immune-related adverse events may occur shortly 
after the first dose or several months after the last dose of pembrolizumab treatment and may 
affect more than on 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, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation 
to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated 
with pembrolizumab are provided in Table 5.See Section 7.10.1 for supportive care guidelines, 
including use of corticosteroids. 
Table 5. Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 
0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks 
of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity 
grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs and 
symptoms of pneumonitis 
 
Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment 
 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 

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Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 Administer corticosteroids 
(initial dose of 1-2 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. 
Grade 4 
Permanently 
discontinue 
AST / ALT elevation 
or Increased bilirubin 
Grade 2 
Withhold 
 Administer corticosteroids 
(initial dose of 0.5- 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 or 4  
Permanently 
discontinue 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure 
Withhold 
 Initiate insulin 
replacement therapy for 
participants with T1DM  
 Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
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 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
 Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per 
standard of care 
 
Monitor for signs and symptoms of 
thyroid disorders.  
 

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Nephritis and Renal 
dysfunction 
Grade 2 
Withhold  
 Administer 
corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 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 
All other immune-
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
 Based on type and 
severity of AE administer 
corticosteroids  
 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the type 
of event.  Events 
that require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab 
may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control 
(in case of T1DM).   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the overall study PI. The reason for 
interruption should be documented in the patient's study record. 
7.6.2 Pembrolizumab Administration and Storage 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 8.0). 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 is supplied free of charge by Merck and Co. 

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Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution.  
 
Pembrolizumab Solution for Infusion is a sterile, non-pyrogenic aqueous solution supplied in 
single-use Type I glass vial containing 100 mg/4 mL of pembrolizumab. The product is 
preservative-free, latex free solution which is essentially free of extraneous particulates.  
 
Pembrolizumab (MK-3475) Solution for Infusion vials are filled to a target of 4.25mL 
(106.25mg) to ensure recovery of 4.0mL (100mg).  
 
Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial: pembrolizumab 
Solution for Infusion vials should be stored at refrigerated conditions 2 - 8 °C (36 - 46 °F) and 
protected from light. Do not shake and do not freeze. Vials should be stored in the original box 
to ensure the drug product is protected from light.  
 
Pembrolizumab (MK-3475) infusion solutions should be prepared in 0.9% Sodium Chloride 
Injection, USP (normal saline) or regional equivalent or 5% Dextrose Injection, USP (5% 
dextrose) or regional equivalent and the final concentration of pembrolizumab in the infusion 
solutions should be between 1 mg/mL and 10 mg/ml.  
 
The infusion solution should be administered through an intravenous line containing a sterile, 
non-pyrogenic, low-protein binding, 0.2 micron to 5 micron in-line or add-on filter. 
 
Pembrolizumab should not be mixed with other diluents. 
From a microbiological point of view, diluted solution should be used as soon as possible after 
preparation. 
 
Pembrolizumab solutions (which contain no preservative) may be stored at room temperature 
for a cumulative time of up to 6 hours. The 6-hour countdown begins when the vial is pierced 
and includes room temperature storage of  admixture solutions in the IV bags and the duration 
of infusion. (Please note this 6-hour timeframe is to provide a microbial control strategy. The 
microbial clock only starts when the product stopper is pierced and not when the vial is 
removed from the refrigerator.)  
In addition, IV bags may be stored under refrigeration at 2°C to 8°C (36 °F to 46 °F), total 
cumulative storage time at room temperature and refrigeration should not exceed 24 hours.  
 
Temperature monitoring records are required when pembrolizumab admixture solution is 
refrigerated during storage or transfer. Only a period with recorded 2-8 °C can be accounted 

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for refrigerated time. Time when temperature is above 8 °C and below 25°C should be 
deducted from a 6-hour room temperature storage time bucket.  
 
If refrigerated, allow the IV bags to come to room temperature prior to use. 
 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Discard the drug product vial if visible particles are observed. In 
addition, the following precautions should be observed: 
•   Do not use pembrolizumab if discoloration is observed. 
•   Do not shake or freeze the vial(s). 
•   Do not administer the product as an intravenous (iv) push or bolus. 
•   Do not combine, dilute or administer it as an infusion with other medicinal products. 
7.7 
Study Treatment: Vorinostat 
Chemical Name:  N-hydroxy-N’-phenyl-octane-1,8-diotic acid diamide; N-hydroxyl-N’-phenyl 
(9CI) octanediamide; suberoylanilide hydroxamic acid 
 
Other Names: SAHA, L-001079038, WIN 64652, MSK390, AP390 
 
Classification: Antineoplastic 
CAS Registry Number:  149647-78-9 
 
Molecular Formula: C14H20N203 
 
M.W.: 264.32 
 
Approximate Solubility: Water ≤ 5 mg/mL 
 
Description:  Histone deacetylase (HDAC) inhibitor  
 
Mode of Action: Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin 
remodeling and gene transcription via the dynamic process of acetylation and deacetylation of 
core histones. 
 
Vorinostat, a potent inhibitor of HDAC activity, binds directly to the catalytic pocket of HDAC 
enzymes. It causes G1 or G2 phase cell-cycle arrest, apoptosis, or differentiation in cultured 
transformed cells. 
 
How Supplied: Vorinostat is supplied free of charge by Merck and Co., Inc. Vorinostat is 
supplied as a white, opaque gelatin, size 3 capsule, containing 100 mg of vorinostat. 
 

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The inactive ingredients contained in each capsule are microcrystalline cellulose, sodium 
croscarmellose, and magnesium stearate.  
 
Vorinostat 100 mg capsules are supplied in bottles containing 120 capsules. 
 
Storage: Store vorinostat capsules at 20-25⁰C. Excursions permitted between 15 and 30 ºC (59 
to 86 ºF).  
 
Stability:  Shelf life stability studies of the intact bottles are on-going. 
 
Route of Administration: Orally 
 
Method of Administration: Unless otherwise stated in the protocol, vorinostat capsules must be 
administered whole. It is recommended that vorinostat be taken with food. 
 
Patients should not make up missed doses. If a patient has an episode of emesis after taking 
vorinostat, patient should be instructed not to take an additional dose. 
 
Potential Drug Interactions: The major pathways of vorinostat metabolism involve 
glucuronidation and β-oxidation. As vorinostat is not eliminated via CYP450 pathways, no drug-
drug interactions are expected with known CYP450 inhibitors or inducers. Although vorinostat 
was not a potent reversible CYP450 inhibitor, studies performed to monitor gene expression 
changes indicated some potential for CYP2C9 and CYP3A4 activity suppression. However, these 
changes were observed at concentrations higher than the pharmacologically relevant 
concentration of 2 µM (Cmax). 
 
Prothrombin time and INR prolongations have been reported in patients taking vorinostat 
concomitantly with coumarin derivative anticoagulants. Monitor these patients more frequently 
for alterations in their coagulation parameters.  
 
Special Handling: 
Vorinostat is an anticancer drug. Clean powder spills from broken or 
damaged vorinostat capsules carefully minimizing inhalation. Wash spill area at least 3 times with 
ethyl alcohol, followed by water. 
 
Patient Care Implications: Because vorinostat’s dose limiting toxicities are anorexia, 
dehydration, diarrhea, and fatigue, patients should maintain adequate fluid and food intake. 
Encourage patients to seek a nutritional consult. Patients should be instructed to drink at least 2 
liters of fluids daily to prevent dehydration. 
 
Treat diarrhea promptly with appropriate supportive care, including loperamide. Instruct patients 
to begin taking loperamide at the first signs of: 1) poorly formed or loose stool, 2) occurrence of 
more bowel movements than usual in one day, or 3) unusually high volume of stool. Loperamide 
should be taken in the following manner: 4 mg at first onset of diarrhea, then 2 mg after each 
unformed stool. Daily dose should not exceed 16 mg/day. Loperamide should not be taken 

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prophylactically. Advise patients to drink plenty of clear fluids to help prevent dehydration caused 
by diarrhea. Avoid loperamide if there is the presence of blood or mucus in the stool or if diarrhea 
is accompanied by fever. If grade 3 or 4 diarrhea develops, discontinue further treatment with 
vorinostat. 
 
Patients should not have taken valproic acid, another histone deacetylase inhibitor, for at least 2 
weeks prior to study enrollment. 
 
7.7.1 Vorinostat Dose/Delay Modification Guidelines 
Note: If vorinostat is dose-reduced or held for toxicity, and the toxicity is most likely attributed 
to vorinostat and not attributed to pembrolizumab, administration of pembrolizumab can 
continue. 
Vorinostat dose reductions are NOT permitted during the DLT period. Following the 
completion of the DLT period, the vorinostat doses may be modified for toxicity according to 
the below guidelines in Tables 6 and 7. Vorinostat dose delays are permitted during the DLT 
period due to study treatment-related toxicity, however, if a patient misses > 30% of the 
vorinostat doses due to toxicity, this will be considered a DLT. 
Table 6. Vorinostat Dose Reduction Guidelines 
Vorinostat Dose Reductions 
Starting dose 
1st dose reduction 
2nd dose reduction 
3rd dose reduction 
4th dose reduction 
Dose Level 1 
Dose Level -1 
Dose Level -2 
Dose Level -2 
schedule but 100mg 
daily 
N/A** 
Dose Level 2 
Dose Level 1 
Dose Level -1 
Dose Level -2 
Dose Level -2 
schedule but 100mg 
daily 
mg = milligrams; po = orally; BID = twice daily 
**Patients requiring a dose reduction to below 100 mg daily of vorinostat at dose level -2 
schedule will discontinue vorinostat permanently. 
Table 7. Vorinostat Dose Delay Guidelines 
Grade of Event 
Management/Next Dose for Vorinostat 
≤ Grade 1 
No change in dose. 

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Grade 2 
If tolerable to patient, no change needed but monitor patient 
more frequently. If intolerable to patient, hold* drug until 
toxicity ≤ Grade 1 then resume drug at same dose. 
Grade 3 (1st occurrence) 
Hold* until ≤ Grade 1. Resume at same dose.  
Grade 3 (after 1st dose 
reduction) 
Hold* until ≤ Grade 1: if toxicity related to drug, resume at 1 
dose lower; if toxicity not related to drug, resume at same dose 
or 1 dose lower.** 
Grade 
3 
(subsequent 
occurrences) 
 Hold* until ≤ Grade 1: if toxicity related to drug, resume at 1 
dose lower; if toxicity not related to drug, resume at same dose 
or 1 dose lower**. 
Grade 4 
Discontinue vorinostat. However, if patient is clearly benefiting 
from treatment, may continue after recovery to ≤ Grade 1 at PI’s 
discretion. 
*If optimally managed, patients requiring a delay of >2 consecutive weeks will discontinue 
vorinostat 
 **Patients requiring a dose reduction to below 100 mg daily of vorinostat at dose level -2 
schedule will discontinue vorinostat permanently. 
7.8 
Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
7.9 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the Merck Clinical team. The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician.  
7.9.1 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. 

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All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs. 
Use of growth factors, including filgrastim or pegfilgrastim and erythropoietin, is permitted 
per institutional policy and in accordance with American Society of Clinical Oncology 
(ASCO) guidelines.138 Red blood cell transfusions are permitted per institutional guidelines. 
Platelet transfusions are permitted, but will be considered a DLT if required during the DLT 
period. 
7.9.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase 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 those specified in this protocol 
 Radiation therapy  
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
 Other histone deacetylase inhibitors (e.g. valproic acid). 
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 that are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 

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7.10 Rescue Medications & Supportive Care 
7.10.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Use of growth factors, including filgrastim or pegfilgrastim and 
erythropoietin, is permitted per institutional policy and in accordance with American Society 
of Clinical Oncology (ASCO) guidelines.138 Red blood cell transfusions are permitted per 
institutional guidelines. Platelet transfusions are permitted, but will be considered a DLT if 
required during the DLT period. 
Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below and in the ECI guidance document. Where 
appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 7.6.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Please review the ECI document in detail for management of IrAEs and corticosteroid dosing, 
the below is meant to be a quick reference. 
 Myocarditis 
o For suspected immune-mediated myocarditis, ensure adequate evaluation to 
exclude other etiologies. 
o Administer corticosteroids as appropriate. 
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 

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o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  Supportive care with 
loperamide or other standard anti-diarrheal medication is acceptable. For Grade 
2 or higher diarrhea, consider GI consultation and endoscopy to confirm or rule 
out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 Hyperthyroidism or Hypothyroidism:  

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Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 Management of Infusion Reactions: 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.  
Table 8 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 8. Pembrolizumab Infusion Reaction Treatment Guidelines 

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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g. 
from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the participant should be premedicated for 
the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment 
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further study 
drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 
 

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7.11 Diet/Activity/Other Considerations 
7.11.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
7.11.2 Contraception 
Study treatment may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
study treatment has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 

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 Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
 †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 

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7.11.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on study treatment, 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 14.2.2. 
7.11.4 Use in Nursing Women 
It is unknown whether study treatment (pembrolizumab or vorinostat) is excreted in human 
milk. Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment. 
7.12 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons. Specific details 
regarding discontinuation or withdrawal are provided in Section 9.5.2 - Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 9.5.3.5 
o Unacceptable adverse experiences, either DLT (Section 7.2) or other unacceptable 
toxicity (Section 10.2). 
o Intercurrent illness that prevents further administration of treatment 

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o Investigator’s decision to withdraw the subject 
o The subject has a confirmed positive serum pregnancy test 
o Noncompliance with trial treatment or procedure requirements 
o The subject is lost to follow-up 
o Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study pembrolizumab, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose.  
o Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 8 (Protocol Flow 
Chart) and Section 9.5.3 (Visit Requirements). After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected for 
90 days after the end of treatment). 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 for overall survival until 
death, withdrawal of consent, or the end of the study (last patient off therapy), whichever 
occurs first. 
7.12.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with study treatment and had at least two cycles 
of study treatment beyond the date when the initial CR was declared.  
7.13 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 

 
This document is confidential and for research purposes only. Do not copy, redistribute, 
disclose or use except as authorized 
 

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8.0 TRIAL FLOW CHART (STUDY CALENDAR) 
8.1 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
 
1 
2 3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visitsg 
Survival 
Follow-Up 
5 
6 
7 
8 
D
1 
D
8 
D
15 
D
1 
D
1 
D
1 
D 
15 
D
1 
D
1 
D
1 
D
1 
D 
15 
Scheduling Window (Days): 
-28 to D1 
 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
See 
b 
± 
3 
± 
3 
± 
3 
± 
3 
See 
b 
At time of 
Disconl 
30 days post 
disconm 
Every 12 
weeks post 
discon† 
 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival Status 
 
X 
 
 
X X X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Clinical Procedures/Assessments 
Vorinostat administration 
 
X 
 
 
X X X 
 
X 
X 
X 
X 
 
 
 
 
 
Pembrolizumab administration 
 
X 
 
 
X X X 
 
X 
X 
X 
X 
 
 
 
 
 
Review Adverse Events 
 
X X 
 
X X X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Physical Examination 
X 
X X 
 
X X X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Vital Signs, Weight, and oxygen saturation 
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 
 
 
Buccal swab 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 

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Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
 
1 
2 3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visitsg 
Survival 
Follow-Up 
5 
6 
7 
8 
D
1 
D
8 
D
15 
D
1 
D
1 
D
1 
D 
15 
D
1 
D
1 
D
1 
D
1 
D 
15 
Scheduling Window (Days): 
-28 to D1 
 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
See 
b 
± 
3 
± 
3 
± 
3 
± 
3 
See 
b 
At time of 
Disconl 
30 days post 
disconm 
Every 12 
weeks post 
discon† 
 
Pregnancy Test - Urine or Serum -HCGn 
X** 
X 
 
 
X X X 
 
X 
X 
X 
X 
 
X 
X 
 
 
PT/INR and aPTT* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential* 
X 
X X X X X X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Comprehensive Serum Chemistry Panelc* 
X 
X X X X X X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Urinalysis* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH (thyroid panel) 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
12-lead ECG 
X 
X 
 
 
X X X 
 
X 
 
 
 
 
X 
 
 
 
Efficacy Measurements 
PET-CT or CT N/C/A/Pe 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Xk 
 
Xd 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tumor Tissue 
Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
 
 
 
Bone Marrow Aspirate and Biopsyj  
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection 
 
X 
 
 
X 
 
 
 
Xi 
 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 

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* Should be performed within 14 days of treatment initiation. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 
hours prior to dosing. 
** Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first 
dose of study medication. 
† Imaging time point will be every 12 weeks (± 7 days) during the first year, and every 18 weeks thereafter (± 7 days). 
a Vorinostat and pembrolizumab will be administered according to dose level in the Phase I dose-escalation portion of study and at 
RP2D in the expansion cohort portion of study. Vorinostat will be administered according to dose level, pembrolizumab will be 
administered on day 1 of each cycle. Cycle length will be 21 days. 
b Should be performed between Day 15 and Day 21 (-3 days). 
c Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH (only for DLBCL and 
FL patients), potassium, total protein, SGOT [AST], SGPT [ALT], sodium, uric acid, phosphorus, magnesium and direct bilirubin (if 
total bilirubin is elevated above the upper limit of normal). 
d After 1 year, the imaging time point will occur every 18 weeks (+/- 7 days). 
e PET-CT or CT N/C/A/P will be performed on cycle 4 day 15-21 (-3 days), cycle 8 day 15-21 (- 3 days), and every 4 cycles thereafter 
on day 15-21 (-3 days). Note: if there is no evidence of neck involvement by lymphoma at baseline, CT of chest, abdomen and pelvis 
(C/A/P) can be performed instead of N/C/A/P at subsequent re-staging. See sections 9.2.6 and 10.1 for additional imaging details. 
f Collection of tumor tissue (fresh or archival) from standard of care tumor biopsy performed at the time of lymphoma 
relapse/progression, unless the tumor is inaccessible or there is a safety concern. 
g Study follow-up period for subjects who remain on study but discontinue study treatment for a reason other than PD will remain on 
study and continue onto the Study Follow-up Period, and scans should be performed every 12 weeks (and then every 18 weeks after the 
first year, see †) starting from last on-treatment scan. 

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h For participants who progress during this study: Efforts should be made to collect a blood sample (if not collected within the last 30 
days) at a planned SOC visit or a protocol  visit. It will not be a deviation if the SOC visit/protocol visit falls outside of the ± 30 day 
window. 
i For FL participants who end treatment for reasons other than progression: Collect at ~3 months (± 7 day) and ~6  months (± 7 day) at 
a planned SOC visit or a protocol visit.  It will not be a deviation if the planned SOC visit/COH protocol visit falls outside of the ± 7 
day window. 
j A screening bone marrow biopsy is not required for HL patients, but can be performed for staging purposes at investigator discretion. 
For FL and DLBCL patients: - if a bone marrow biopsy was performed within 3 months prior to Day 1 and was negative, patients do 
not need to have a bone marrow biopsy performed at screening (unless clinically indicated), - if a bone marrow biopsy was previously 
performed and was positive, then the patient will have a bone marrow biopsy at screening, unless this previous bone marrow biopsy was 
performed within 3 months prior to Day 1 and patient did not have any systemic therapy in the meantime. Following initial screening, 
unless clinically indicated, bone marrow specimens will be collected only to confirm CR, and only on patients who had bone marrow 
involvement at baseline. 
k PET-CT (or CT) at time of discontinuation will only be performed in patients who discontinue treatment for progression. Note: if a 
previous scan was obtained within 4 weeks prior to the date of discontinuation, then repeating the scan at treatment discontinuation is 
not mandatory. 
l Assessments to be performed within 10 days of treatment discontinuation (except tumor imaging, see footnote k). Assessments 
performed after last dose of study agent and within 7 days of the decision to end treatment may serve as EOT assessments. 
m Safety visit to occur 30 (-2/+7) days post-last dose of protocol therapy. Safety follow up may be extended until resolution/stabilization 
of reportable AEs. 
n Pregnancy testing will also be performed whenever an expected menstrual cycle is missed or when pregnancy is otherwise suspected. 
 

 
 
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9.0 TRIAL PROCEDURES 
The Trial Flow Chart - Section 8.0 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. 
9.1 
Administrative Procedures 
9.1.1 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/ERC’s 
approval/favorable opinion in advance of use. The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
9.1.2 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.  

 
 
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9.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
9.1.4 Prior and Concomitant Medications Review 
9.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
9.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded. 
9.1.5 Disease Details and Treatments 
9.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
9.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
9.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, 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.  

 
 
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9.1.6 Assignment of Screening Number 
After signing consent, each subject will be assigned a screening number that will then serve 
as the study ID for the duration of the study, if the patient is deemed eligible and enrolled 
to the study. 
9.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
The investigator or qualified designee will review the subject’s compliance with vorinostat 
dosing and administration and collect the subject’s vorinostat diary on day 1 of each cycle. 
9.2 
Clinical Procedures/Assessments 
9.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated. 
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.03. Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
9.2.2 Adverse Event (AE) collection guidelines  
 During Cycles 1-2, all grade toxicities with start and stop dates will be reported in the 
eCRFs.  
 After Cycle 2 until the end of the safety follow-up period (30-days post-last dose for 
AE or 90 days post-last dose for SAE), the highest grade toxicity per cycle and the 
highest grade toxicity and all SAEs during the safety follow-up period with start/stop 
dates will be reported in the eCRFs. 
9.2.3 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. A full physical exam should be performed during screening.  
9.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 8.0). Vital signs should include temperature, pulse, respiratory 
rate, weight, blood pressure, and oxygen saturation. Height will be measured at screening only. 

 
 
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9.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified 
in the Trial Flow Chart.   
9.2.6 Tumor Imaging and Assessment of Disease 
Disease response/progression will be evaluated using the 2014 Lugano Classification (see 
Appendix C) 122, 139. Participants who meet the definition of progressive disease per Lugano 
Classification should be evaluated using the LYRIC criteria (see Appendix L).   
For all patients: 
‐ 
Disease staging will be performed every 4 cycles until disease progression or off study 
therapy. 
‐ 
Disease assessment will be performed either by PET-CT (FDG-avid histologies) or 
diagnostic quality CT of the neck, chest, abdomen and pelvis (N/C/A/P) with IV 
contrast (see restrictions below).  
‐ 
MRI may be performed at the investigator’s discretion for lesions not well-visualized 
by CT, or if CT with intravenous contrast is contraindicated. 
‐ 
Whenever a PET-CT is not performed, a diagnostic quality (N/C/A/P) CT with IV 
contrast must be performed instead. 
Note: if there is no evidence of neck involvement by lymphoma at baseline, CT of 
chest, abdomen and pelvis (C/A/P) can be performed instead of N/C/A/P at subsequent 
re-staging. 
For DLBCL and HL patients only: 
‐ 
Disease assessment requires a PET-CT be performed at baseline (within the screening 
window) and at cycle 4 (Day 15-21 [-3 days]). 
‐ 
Although not required, it is recommended that DLBCL and HL patients who are not in 
CR get a PET-CT at least every 8 cycles thereafter, and every 24 weeks for patients 
who discontinued for other reasons than CR. 
‐ 
Assessment with PET-CT is required to confirm CR. Once CR has been confirmed, 
diagnostic quality (N/C/A/P) CT with IV contrast can be used instead of PET-CT until 
progression, unless otherwise specified below. 
Note: if there is no evidence of neck involvement by lymphoma at baseline, CT of 
chest, abdomen and pelvis (C/A/P) can be performed instead of N/C/A/P at subsequent 
re-staging. 

 
 
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For FL patients only: 
‐ 
Disease assessment by diagnostic quality (N/C/A/P) CT with IV contrast or PET-CT is 
allowed at any time point. 
Note: if there is no evidence of neck involvement by lymphoma at baseline, CT of 
chest, abdomen and pelvis (C/A/P) can be performed instead of N/C/A/P at subsequent 
re-staging. 
PET-CT and CT results will be read by radiology at each study site and investigator response 
based on radiology reading will be performed. Lymphoma response assessment based on PET-
CT/CT will be based on the 2014 Lugano Classification (Appendix C).139 
Unless clinically indicated, bone marrow aspirate and biopsy need only to be performed to 
confirm CR in patients with bone marrow involvement at study enrollment. 
For patients with progression of disease on imaging, it is strongly recommended that a 
confirmatory biopsy be obtained whenever possible. Note that an FDG-negative PET scan 
will only be considered complete remission in patients whose tumor was FDG-avid at baseline. 
9.2.6.1 Disease Progression Assessments 
Response patterns observed with immunotherapeutic agents such as pembrolizumab may 
extend beyond the typical time course of responses seen with cytotoxic agents, and can 
manifest a clinical response after an initial increase in tumor burden or even the appearance of 
new lesions. Standard response criteria may not provide a complete response assessment of 
immunotherapeutic agents like pembrolizumab. Therefore, at a scheduled disease assessment, 
if the assessment demonstrates PD, the study regimen may be continued, at the discretion of 
the principal investigator, until the next disease response assessment provided that the subject’s 
clinical condition is stable and the conditions below are met. However, imaging should occur 
at any time where there is clinical suspicion of progression. 
Subjects may continue to receive treatment in the event of progressive disease if the following 
criteria are met: 
o Absence of signs or symptoms (including worsening of laboratory values) indicating 
disease progression. 
o No decline in ECOG performance status. 
o Absence of rapid progression of disease 
o Absence of progressive tumor at critical anatomical sites (e.g. spinal cord compression) 
requiring urgent alternative medical intervention.  

 
 
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At disease response assessments beyond the initial assessment, the Investigator, in consultation 
with the Principal Investigator, may keep a clinically stable subject on study treatment as long 
as the subject meets the above criteria and is deriving clinical benefit. 
9.3 
Tumor Tissue Collection  
Each subject will have tumor tissue collected from either a standard of care fresh core or 
excisional biopsy of a tumor lesion prior to starting study therapy or will have available 
archival tissue from a biopsy that was performed after the most recent systemic therapy. All 
participants will have bone marrow (BM) aspirate performed at baseline (unless performed -
within window specified and -meeting requirements specified in study calendar (footnote j) 
prior to consent as standard of care) except HL patients for who a screening bone marrow 
biopsy is not required (but can be performed for staging purposes at investigator discretion). 
Subjects with bone marrow involvement at baseline will have a bone marrow biopsy to confirm 
CR. It is recommended that progression of disease be confirmed by biopsy, if feasible, and 
fresh or archival tissue should be collected from that tumor biopsy for research purposes. 
9.3.1 Tumor tissue handling guidelines 
9.3.1.1 Guidelines for paraffin-embedded specimens  
Using the formalin-fixed paraffin embedded (FFPE) tissue block, the following samples will 
be processed for correlative studies:  
o If tissue block is available submit: 
 6 paraffin scrolls measuring 10 μm thick placed into a Nunc tube and 
frozen at -80° C AND 
 10 x 5 micron unstained slides 
o If tissue block is unavailable submit 20 x 5 μm unstained slides 
 5 of these unstained slides will be processed according to the QualTek 
Sample Handling Manual. 
 
Note: For FL patients only (both escalation and expansion cohort): COH will submit a 
subset of tumor tissue (scrolls or slides) to the Jackson Laboratory for ctDNA analysis (upon 
sample receipt for non-COH sites). Refer to COH clinical study protocol #17072 for details 
and to Appendix E for tissue shipping guidelines. 
 
9.3.1.2 Guidelines for fresh tumor tissue processing  
Three core biopsies OR excisional biopsies should be submitted. If fewer than 3 core biopsies 
are available because of safety, then 1 or 2 cores may be submitted. 

 
 
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Core biopsies:  
Three core biopsies will be obtained for diagnostic purposes and 3 similar additional cores will 
be obtained for research.  
The research portion of the specimen (banking): 
o One core biopsy will be snap frozen in OCT fixative, and an additional half of a 
core will be snap frozen without OCT fixative.  
o Half of a core will be finely minced in a 10cm petri dish and frozen at -80° C in a 
Nunc tube in 1 ml of RPMI-1640 medium containing 20% fetal calf serum and 10% 
DMSO, then will be transferred to liquid nitrogen.  
o Half of a core will be processed for DNA and RNA extraction according to the 
manufacturer’s recommendation.  
o The final half of a core biopsy will be processed to dissociate the cells, with the cell 
suspension cryopreserved in liquid nitrogen. 
Excisional biopsies:   
o An approximately 1cm x 1cm tumor sample will be divided into 5 equal portions 
and processed as described for core biopsies. 
The diagnostic portion of the specimen:  
o Process in a routine fashion by hematopathology. Using the formalin-fixed paraffin 
embedded (FFPE) tissue block, 15 x 5 micron unstained slides will be obtained 
 5 of these unstained slides will be processed according to the QualTek Sample 
Handling Manual. 
Bone marrow specimens: 
 
5 cc of bone marrow aspirate will be sent to the City of Hope CICSL for 
processing and storage according to instructions in the laboratory manual. 
 
10 x 5 micron unstained slides 
 
5 of these unstained slides will be processed according to the QualTek Sample 
Handling Manual. 
 
9.3.1.3 Labeling of samples 
Samples will be labeled with the study number, subject ID (issued by DCC), date, time point 
of collection (i.e. baseline or progression) and if applicable patient initials.  
9.3.1.4 Sample shipment and receiving lab 
Tissue specimens collected at the above indicated time points will be taken to COH Pathology 
Core. Please include the Correlative Tissue form (Appendix J). 

 
 
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9.4 
Correlative Studies Blood Sampling 
9.4.1 Overview and Timepoints 
Peripheral blood (PB) will be collected for additional correlative studies prior to study 
treatment on day 1 of cycles 1 and 2, and 5, and every 4 cycles thereafter. Refer to Table 9 for 
details. 
Table 9. Overview of correlative blood studies 
Time points of 
collection 
Total 
volume 
collected 
Tube type 
Receiving laboratory 
Type of 
analysis (non‐
exhaustive) 
HL and 
DLBCL 
patients 
FL 
patients 
C1D1, C2D1, C5D1 
20 ml 
Green‐top (sodium or lithium 
heparin) 
APCF 
APCF 
FACS 
C1D1, C2D1, C5D1, 
and every 4 cycles 
thereafter and at 
discontinuation 
20 ml 
Purple‐top (K+EDTA) 
(For all COH patients except FL) 
OR 
Cell‐free DNA BCT® (Streck) 
(For all COH FL patients) 
APCF 
JAX 
ctDNA/MRD 
Sites should request Cell‐free DNA BCT® (Streck) for FL patients from Dr. Honey Reddi or designee 
(Honey.Reddi@jax.org). For DLBCL and HL patients, sites should request tubes from the COH Data 
Coordinating Center (DCC). Contact information: E‐mail: DCC@coh.org. 
APCF = Analytical Pharmacology Core Facility (COH). 
JAX = The Jackson Laboratory. 
 
9.4.2 Labeling of blood samples 
Label tubes with COH protocol #, subject ID (issued by DCC), date and timepoint of collection 
(e.g. C1D1 for Day1 of Cycle 1), and if applicable patient initials. 
9.4.3 Blood collection 
Before scheduled blood collection (at least one day in advance) e-mail Leslie Smith-Powell 
(LSmith-Powell@coh.org) or Stephanie Lee (stlee@coh.org) at the Analytical Pharmacology 
Core Facility (APCF) to inform them of a pending collection. 
Refer to Table 10 for collection and post-collection instructions. 

 
 
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Note: Collection of blood in Cell-free DNA BCT® (Streck) or purple tubes has priority 
over the collection of blood in green-top tubes. Also, any heparin in the collection tube of 
the line used to draw the blood in purple tube will make it unusable. 
Table 10. Blood sample collection and post-collection instructions. 
Tube 
Type 
Collection details 
Site of 
collection 
Post‐collection instructions 
HL and DLCBL patients 
FL patients 
Green‐
top 
1‐ Blood samples will be collected 
from an indwelling venous catheter or 
by venipuncture. 
2‐ Invert tubes eight times after 
collection. 
3‐ Immediately place the tubes on ice. 
COH 
 
Promptly deliver the blood 
samples on ice to the APCF, 
Shapiro room 1042 for processing 
within 4 hours. 
 
Same as for 
HL and DLBCL 
patients 
 
Purple‐
top 
Same as for green‐top. 
COH 
Only 
Promptly 
deliver 
the 
blood 
samples  on  ice  to  the  APCF, 
Shapiro room 1042 for processing 
within 4 hours. 
N/A 
Cell‐free 
DNA 
BCT® 
(Streck)* 
1‐ If applicable, follow 
recommendations for order of draw 
outlined in CLSI GP41‐A6**. 
2‐ Blood samples will be collected 
from an indwelling venous catheter or 
by venipuncture. 
Prevention of backflow: 
(Since cell‐free DNA BCT® contain chemical 
additives)  
a.  Keep  patient’s  arm  in  the  downward 
position during the collection procedure. 
b. Hold the tube with the stopper in the 
uppermost  position  so  that  the  tube 
contents do not touch the stopper or the 
end 
of 
the 
needle 
during 
sample 
collection.  
c. Release tourniquet once blood starts to 
flow in the tube, or within 2 minutes of 
application. 
3‐ Fill tube completely. 
4‐ Remove tube from adapter and 
immediately mix by gentle inversion 8 
to 10 times. 
5‐ Do not freeze samples. Store 
samples at 18‐25oC until shipment. 
COH 
 
N/A 
 
Ship samples 
to JAX (see 
Appendix I). 
Refer to COH 
clinical study 
protocol 
#17072 for 
details. 
 

 
 
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* Tubes are stable when stored at 2‐300C through expiration date. Do not use expired tubes. If there 
is any indication of cloudiness or visible precipitate immediately contact: (1) For FL patients, Dr. Honey 
Reddi  or  designee  (Honey.Reddi@jax.org),  any  unused/expired  blood  collection  kits  should  be 
returned to the Jackson Laboratory Laboratory. (2) For DLBCL and HL patients, contact the COH Data 
Coordinating Center. Contact information: E‐mail: DCC@coh.org.  
** Additional guidelines: Cell‐Free DNA BCT should be drawn after the EDTA tube and before the 
fluoride oxalate (glycolytic inhibitor) tube. If a Cell‐Free DNA BCT tube immediately follows a heparin 
tube in the draw order, Streck recommends collecting a non‐additive or EDTA tube as a waste tube 
prior to collection in the Cell‐Free DNA BCT tube. 
9.4.4 Sample Processing by APCF (COH) 
COH samples only: Blood samples will be kept on a rocker set at low speed to mimic 
circulation and avoid clot formation until processing.  
Green-top tubes (PBMCs AND plasma), for FACS/Cytokine assays: 
(Process within 4h of collection for COH samples OR upon receipt of non-COH samples). 
 Centrifuge for 10 min at 1800g at 4oC. Both supernatant and pellet will be used. 
 Plasma: 
- 
The resulting upper plasma layer from each tube will be drawn up sequentially 
into a sterile 5 mL syringe and pushed through a sterile 0.2/0.8 micron 
disposable filter.  
- 
The filtered plasma will then be transferred in 500 µL aliquots into multiple 
appropriately-labeled Starstedt microfuge tubes.  
- 
To one aliquot, add 0.5 mL glycerol/0.02% sodium azide solution to dilute the 
plasma 50/50 v/v. Keep the diluted plasma sample at -20˚C and do not freeze.  
- 
All the remaining plasma aliquots will be stored frozen at -80˚C until ready for 
testing. 
 PBMCs: 
- 
Dilute the blood remaining in the green-top tubes used to prepare plasma above 
1:1 with Hank’s Balanced Salt Solution (or equivalent) in a sterile conical 
centrifuge tube. 
- 
Isolate PBMCs by Ficoll-gradient separation per COH APCF procedures. 
- 
PBMCs samples will be stored in liquid nitrogen until use. 

 
 
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9.5 
Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial, 
including laboratory tests for hematology, chemistry, urinalysis, and others are specified in 
Table 11. 

 
 
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Table 11. 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) 
(only for DLBCL and FL patients) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
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 
 
 
 
Creatinine 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 

 
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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.  
9.5.1 Correlative Studies 
A non-exhaustive list of correlative studies is provided in Section 4.6.5 “Rationale for 
Biomarker Research”. 
Correlative studies will mainly be performed in the laboratories of Peter Lee, MD, Chair of the 
City of Hope Beckman Research Institute Division of Cancer Immunotherapeutics and Tumor 
Immunology, and John Chan, MD, Professor of Pathology at City of Hope Medical Center. 
For FL patients only, some tumor and blood samples will be analyzed at the Jackson 
Laboratory (ctDNA studies) (see COH clinical study protocol #17072). 
9.5.2 Other Procedures 
9.5.2.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events that are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 9.2. Subjects who a) attain a 
CR or b) complete 24 months of treatment with pembrolizumab may discontinue treatment. 
After discontinuing treatment following assessment of CR or completing 24 months of 
treatment, these subjects should return to the site for a Safety Follow-up Visit and then proceed 
to the Follow-Up Period of the study. 
9.5.3 Visit Requirements 
Visit requirements are outlined in Section 8.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 9.0 - Trial Procedures. 
9.5.3.1 Screening Period 
The following procedures will be performed during Screening: 
 Informed Consent  
 Review of eligibility criteria (Inclusion/Exclusion criteria)  
 Medical history and demographics  
 Review of prior and concomitant medications  

 
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 Complete physical exam  
 Vital signs, weight and height, and oxygen saturation 
 ECOG Performance Status  
 12-lead ECG 
 Bone marrow aspirate and biopsy (Not for all patients: refer to study calendar and 
footnote j). 
 Collection of tumor tissue from fresh tumor biopsy or archival specimen 
 PET-CT (DLBCL, HL, FL) or IV contrast-enhanced CT scan of neck, chest, abdomen, 
pelvis of diagnostic quality (only FL). MRI can be used for lesions not well-visualized 
by CT, or if CT with IV contrast is contraindicated. See sections 9.2.6 and 10.1 for 
additional details.  
 Clinical laboratory tests for:  
o Hematology 
o Serum chemistry 
o Coagulation (PT, PTT, INR) 
o Serum or urine pregnancy test (for women of childbearing potential who have 
not been free from menses for > 1 year). Should be performed within 72 hours 
prior to first dose of therapy. 
o Urinalysis 
9.5.3.2 Treatment Period 
The following procedures will be performed during the treatment period: 
NOTE: This is a list of procedures. Not all procedures will necessarily be performed at 
each cycle. 
• 
Complete physical exam  
• 
ECOG Performance Status  
• 
Vital signs and weight  

 
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• 
Buccal swab 
• 
12-lead ECG  
• 
Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o Thyroid function panel 
o Serum or urine pregnancy test (for women of childbearing potential who have 
not been free from menses for > 1 year). 
• 
Review of AEs 
• 
Research laboratory blood samples collected pre-dose for correlative studies (See 
section 9.4 for additional details). 
• 
PET-CT or IV contrast-enhanced CT scan of neck, chest, abdomen, pelvis of diagnostic 
quality. See sections 9.2.6 and 10.1 for additional details.  
• 
To be completed to confirm CR: 
o PET scan (if only CT scan was used for response assessment) 
o Bone marrow aspirate and biopsy (if bone marrow was involved at baseline) 
• 
Dosing  
o Dispense vorinostat and diary card  
o In-clinic administration of vorinostat 
o In-clinic administration of pembrolizumab (after vorinostat administration) 
9.5.3.3 Post-Treatment Visits 
9.5.3.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted 30 days after the last dose of trial 
treatment or before the initiation of a new anti-cancer treatment, whichever comes first. 
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 

 
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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.  
9.5.3.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 12 weeks (84 ± 7 days) by radiologic 
imaging to monitor disease status.  After 1 year, the imaging time point will occur every 18 
weeks (± 7 days). Every effort should be made to collect information regarding disease status 
until the start of new anti-neoplastic therapy, disease progression, death, and end of the study.  
Information regarding post-study anti-neoplastic treatment will be collected if new treatment 
is initiated. 
9.5.3.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and will be followed for survival status 
until death, withdrawal of consent, or the end of the study, whichever occurs first. Survival 
assessment to occur bi-annually or as requested by the Study PI via medical record review, 
review of social security registry, or telephone call. 
10.0 ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF EFFECT 
10.1 Response Criteria 
Disease response/progression will be evaluated using 2014 Lugano Classification (see 
Appendix C)122, 139. Participants who meet the definition of progressive disease per Lugano 
Classification should be evaluated using the LYRIC criteria (see Appendix L).   
For all patients: 
‐ 
Disease staging will be performed every 4 cycles until disease progression or off study 
therapy. 
‐ 
Disease assessment will be performed either by PET-CT (FDG-avid histologies) or 
diagnostic quality CT of the neck, chest, abdomen and pelvis (N/C/A/P) with IV 
contrast (see restrictions below). 
‐ 
MRI may be performed at the investigator’s discretion for lesions not well-visualized 
by CT, or if CT with intravenous contrast is contraindicated. 
‐ 
Whenever a PET-CT is not performed, a diagnostic quality (N/C/A/P) CT with IV 
contrast must be performed instead. 
Note: if there is no evidence of neck involvement by lymphoma at baseline, CT of 
chest, abdomen and pelvis (C/A/P) can be performed instead of N/C/A/P at subsequent 
re-staging. 

 
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For DLBCL and HL patients only: 
‐ 
Disease assessment requires a PET-CT be performed at baseline (within the screening 
window) and at cycle 4 (Day 15-21 [-3 days]). 
‐ 
Although not required, it is recommended that DLBCL and HL patients who are not in 
CR get a PET-CT at least every 8 cycles thereafter, and every 24 weeks for patients 
who discontinued for other reasons than CR. 
‐ 
Assessment with PET-CT is required to confirm CR. Once CR has been confirmed, 
diagnostic quality (N/C/A/P) CT with IV contrast can be used instead of PET-CT until 
progression, unless otherwise specified below. 
Note: if there is no evidence of neck involvement by lymphoma at baseline, CT of 
chest, abdomen and pelvis (C/A/P) can be performed instead of N/C/A/P at subsequent 
re-staging. 
For FL patients only: 
‐ 
Disease assessment by diagnostic quality (N/C/A/P) CT with IV contrast or PET-CT is 
allowed at any time point. 
Note: if there is no evidence of neck involvement by lymphoma at baseline, CT of 
chest, abdomen and pelvis (C/A/P) can be performed instead of N/C/A/P at subsequent 
re-staging. 
PET-CT and CT results will be read by radiology at each study site and investigator response 
based on radiology reading will be performed. Lymphoma response assessment based on PET-
CT/CT will be based on the 2014 Lugano Classification (Appendix C).139 
Unless clinically indicated, bone marrow aspirate and biopsy will be performed only to confirm 
CR and only in patients with bone marrow involvement at study enrollment. 
For patients with progression of disease on imaging, it is strongly recommended that a 
confirmatory biopsy be obtained whenever possible. Note that an FDG-negative PET scan 
will only be considered complete remission in patients whose tumor was FDG-avid at baseline. 
As a secondary endpoint, we will evaluate the LYRIC refinement of the Lugano classification 
(Appendix L), which is specifically aimed at improving response evaluation in lymphoma 
immunotherapy clinical trials.28 
10.2 Endpoint Definitions 
Overall Response Rate (ORR): Defined as the proportion of patients that have a documented 
CR or PR at any time during study treatment. 
Complete Response (CR) rate: Defined as the proportion of patients that have a documented 
CR at any time during study treatment. 

 
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Duration of Response (DOR): Defined as the time from the first achievement of PR or CR to 
time of PD. Patients who never achieve PR or CR are excluded. Patient who has not had disease 
progression/relapse at last follow-up is censored at the time of last follow-up. If a patient 
receives non-protocol anti-lymphoma treatment prior to disease progression, the patient is 
censored at the time of non-protocol anti-lymphoma treatment. 
   
Overall Survival: Defined as time from initiation of study therapy to death from any cause.  
If a patient is alive at the last evaluation time period, survival time is censored at the time of 
last follow-up. 
Progression-Free Survival (PFS): Defined as the time from initiation of study therapy to the 
first observation of disease relapse/progression or death from any cause, whichever occurs 
first. If the patient has not progressed relapsed or died, the patient is censored at the time of 
last follow-up. If a patient receives non-protocol anti-lymphoma treatment prior to disease 
progression, the patient is censored at the time of non-protocol anti-lymphoma treatment. 
Toxicity: Toxicity and adverse events will be recorded using the NCI CTCAE 4.03 scale. 
Observed toxicities will be summarized by type (organ affected or laboratory determination 
such as absolute neutrophil count), severity (by NCI CTCAE v4.03 and nadir or maximum 
values for lab measures), date of onset, duration, reversibility, and attribution.  
Unacceptable Toxicity: defined as one of the following AEs that is at least possibly related to 
study treatment, at any point on study therapy: 
 Any Gr 3 or higher IrAE that does not resolve to Gr ≤1 within 7 days with the exception 
of: 
▫ Grade 3 immune-related hepatitis if ALT or AST < 8 x ULN or total bilirubin < 5 
x ULN. 
▫ Grade 3 asymptomatic endocrinopathy. 
▫ Local inflammatory response to study therapy. 
 Any other Gr ≥4 AE with the exception of: 
▫ Non-clinically significant laboratory abnormalities 
▫ Local inflammatory response to study therapy. 
 Any Gr 5 AE. 

 
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11.0 STATISTICAL ANALYSIS PLAN 
11.1 Statistical Analysis Plan 
11.1.1 
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including age, gender, medical history, and 
prior therapy, will be summarized using descriptive statistics. For continuous variables, 
descriptive statistics (number [n], mean, standard deviation, standard error, median (range) will 
be provided. For categorical variables, patient counts and percentages will be provided. 
11.1.2 
Toxicity Analysis 
Observed toxicities will be summarized by type (organ affected or laboratory determination 
such as absolute neutrophil count), severity (by NCI CTCAE v4.03 and nadir or maximum 
values for lab measures), date of onset, duration, reversibility, and attribution.  
11.1.3 
Analysis of Anti-tumor Activity 
This study will aim to obtain preliminary estimates of the anti-tumor activity of the study 
combination. ORR will be calculated as the proportion of evaluable patients that have 
confirmed CR or PR, as defined according to the 2014 Lugano Classification, exact 95% 
confidence intervals will be calculated for these estimates. Response rates will also be 
evaluated based on number and type of prior therapy(ies). Time to response, duration of 
response, as well as progression-free survival and overall survival will be estimated using the 
product-limit method of Kaplan and Meier. 
These efficacy analyses will be performed separately for DLBCL, FL, and HL patients. Any 
patient treated at the RP2D, including those from the dose-escalation cohort, will be included 
in efficacy analyses. Patients will be evaluable for efficacy assessment if they received at least 
one dose of vorinostat and one dose of pembrolizumab and underwent at least one response 
assessment. Patients will be evaluable for efficacy if they discontinued study therapy prior to 
the first response assessment because of progression of disease rather than solely because of 
unacceptable toxicity, withdrawal of consent, or investigator decision. If a patient discontinues 
study treatment prior to the first response assessment due to progressive disease, the treating 
physician is encouraged to obtain imaging to confirm progression.  
11.2 Safety Analysis and Stopping Rules for Excessive Toxicity in the Expansion Cohort 
During enrollment into the expansion cohort, toxicity information recorded will include the 
type, severity, and the probable association with the study regimen. Tables will be constructed 
to summarize the observed incidence by severity and type of toxicity. 
Because of the unique immune-related adverse events (IrAEs) observed with checkpoint 
inhibitors, we will monitor for “unacceptable toxicity” with this new combination of drugs 

 
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(defined in Section10.2). The expected rate of “unacceptable toxicity” should not be ≥33%. 
The early stopping rule for unacceptable toxicity will be assessed after enrollment of 12 
patients (total, across cohorts) treated at the RP2D and will be assessed once the 12th patient 
has completed at least 4 cycles of therapy. If >3 “unacceptable toxicity” events occur in the 
first 12 patients (≥33%) treated (across disease subtypes) at RP2D, or at a rate ≥33% anytime 
thereafter at the quarterly review, accrual will be halted and a full review of these events will 
be performed by the City of Hope Data Safety Monitoring Committee (DSMC). Patient accrual 
will not resume until approved by the DSMC to do so. These rules are in addition to the 
quarterly review of all toxicities submitted to the City of Hope Data Safety Monitoring 
Committee (DSMC). Patients with ongoing toxicity will be followed until resolution or 
stability.    
11.3 Sample Size Accrual Rate 
The expected sample size is 52 evaluable patients: 12 during the dose-escalation portion, and 
40 patients in the expansion cohort. The minimum sample size is 6 evaluable patients. Patients 
evaluable/inevaluable for dose-escalation portion and for dose expansion cohort are defined in 
Section 7.4 and 11.1.3 respectively. Considering replacement of inevaluable patients, the 
maximum study accrual is set at 60 patients.   
11.4 Correlative Studies 
A non-exhaustive list of correlative studies is provided in Section 4.6.4.3 “Biomarker 
Research”. These studies are exploratory in nature and meant to be hypothesis-generating. 
Genomic Correlative Analyses: Comprehensive genomic analyses (i.e., WES and GEP) will 
be performed on pre-treatment tumor samples. We will: 1) quantify and compare total exonic 
mutational load between responders and non-responders; 2) assess association between 
mutational load and PFS; 3) assess individual genetic alterations for association with response 
and PFS; 4) compare GEP between responders and non-responders and assess association with 
PFS. 
Statistical Considerations: Total exonic mutational load (TEML) will be quantified for each 
subject using the pre-treatment samples; these measures will be summarized within and across 
histology-based cohorts. Wilcoxon rank sum tests will be used to compare TEML levels 
between two groups, and Fisher exact tests to compare incidence of specific mutations between 
groups. In addition, logistic regression models will be used to evaluate the influence of TEML 
on whether or not patients responded to therapy. For HL patients, we will evaluate influence 
of TEML on achievement of CR, assuming that approximately 30% will achieve CR. We will 
also evaluate the TEML on achievement of CR or PR for at least 6 months. For the DLBCL 
and FL cohorts, we will evaluate each for the influence of TEML on achievement of response 
(~40-50%) using logistic regression analyses. For each of these cohorts, we will also assess 
the influence of TEML on PFS using Cox regression models and log-rank tests. Multivariable 
versions of these models will also be used to adjust for other clinical characteristics. Similar 
analyses will be used for evaluating the influence of specific mutations (dichotomized 

 
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measures) as well as GEP. We will use a log2 transformation of the GEP measures in our 
analyses, following standard practice for these types of expression measures. We will also 
evaluate the influence of immunologic markers on response and PFS for these different 
histology groups in a similar manner. Spatial markers will be assessed via a density measure 
of the different immune cell subsets and checkpoint molecules. Finally, we will also assess if 
there are meaningful cut-points for the TEML and other continuous measures that correspond 
with response or PFS using recursive partitioning algorithms. The influence of these resulting 
dichotomized markers will then be assessed in relation to the corresponding clinical outcomes. 
Quantitative PET analyses: Quantitative PET parameters and their change over time will be 
summarized by various descriptive statistics. We will explore their association with clinical 
endpoints (complete response, overall response and PFS) using appropriate statistical tests 
(such as two-sample t-test and Wilcoxon rank sum test for analyses on response and log rank 
test for analyses on PFS) and regression analyses (logistic regression for response and Cox 
proportional hazards model for PFS).  
12.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
12.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 12. 
Table 12.  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
Vorinostat 100mg 
Oral Capsule 
 
12.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 

 
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12.3 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. 
12.4 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. 
12.5 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. 
13.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY 
MONITORING  
13.1 Site Lead Investigator Responsibilities 
The Site Lead Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations (CFR). The Site Lead Investigator 
must assure that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines 
regarding clinical trials both during and after study completion. 
It is the responsibility of the Site Lead Investigator to oversee the safety of the study at his/her 
site. This safety monitoring will include careful assessment and appropriate reporting of 
adverse events, deviations, and unanticipated problems.  
The Site Lead Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms at his/her site. For remote or onsite 
monitoring and auditing, the Site Lead Investigator will provide access to his/her original 

 
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records to permit verification of proper entry of data. At the completion of the study, all case 
report forms will be reviewed by the Site Lead Investigator and will require his/her final 
signature to verify the accuracy of the data. 
An investigator is responsible for ensuring that an investigation is conducted according to the 
signed investigator statement, the investigational plan, and applicable regulations; for 
protecting the rights, safety, and welfare of participants under the investigator's care; and for 
the control of drugs under investigation.  
13.2 All Investigator Responsibilities 
All investigators agree to: 
o Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when necessary to protect the safety, 
rights or welfare of subjects.  
o Personally conduct or supervise the study (or investigation).  
o Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.  
o Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64.  
o Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments.  
o Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee).  
o Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.  
o Promptly report to the IRB and the Sponsor all changes in the research activity and 
all unanticipated problems involving risks to subjects or others (to include 
amendments and IND safety reports).  
o Seek IRB and Sponsor approval before any changes are made in the research study, 
except when necessary to eliminate hazards to the patients/subjects.  
o Comply with all other requirements regarding the obligations of clinical 
investigators and all other pertinent requirements listed in § 21 CFR part 312. 
13.3 Study PI Responsibilities 
The Study PI is responsible for the conduct of the clinical trial, including overseeing that 
sponsor responsibilities as defined in § 21 CFR 312. 
13.4 Protocol Management Team (PMT) 
The PMT minimally consisting of the Study Principal Investigator, collaborating investigators, 
the research nurse, the clinical research associate/coordinator, and the study biostatistician is 
responsible for ongoing monitoring of the data and safety of this study. 

 
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The PMT will meet (in person or via teleconference) at least monthly, and will meet at least 
quarterly with the study biostatistician, to review study status. This review will include, but 
not be limited to, reportable AEs and UPs, and an update of the ongoing study summary that 
describes study progress in terms of the study schema. The meeting will be a forum to discuss 
study 
related 
issues 
including 
accrual, SAE/AEs 
experienced, 
study 
response, 
deviations/violations and study management issues. The appropriateness of further subject 
enrollment and the specific intervention for subsequent subject enrollment are addressed, 
including the implementation of stopping rules. 
13.5 Monitoring/ Auditing 
Clinical site auditing/ monitoring is conducted to ensure that the rights of human subjects are 
protected, that the study is implemented in accordance with the protocol and regulatory 
requirements, and that the quality and integrity of study data and data collection methods are 
maintained. Monitoring for this study will be performed by the City of Hope Office of Clinical 
Trials Auditing and Monitoring (OCTAM). 
  
The site Investigator/Institution will permit the study monitors and appropriate regulatory 
authorities direct access to the study data and to the corresponding source data and documents 
to verify the accuracy of this data. The Investigator will allocate adequate time for such 
monitoring activities.  The Investigator will also ensure that the monitor or other compliance 
or quality assurance reviewer is given access to all the above noted study-related documents 
and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space 
to conduct the monitoring visit. 
  
Details of clinical site monitoring are documented in the OCTAM SOP that is provided as a 
supplement to this document. This document specifies the frequency of monitoring, monitoring 
procedures, the level of clinical site monitoring activities (e.g., the percentage of subject data 
to be reviewed), and the distribution of monitoring reports.  Staff from OCTAM will conduct 
monitoring activities and provide reports of the findings and associated action items in 
accordance with the details described in the SOP.  Documentation of monitoring activities and 
findings will be provided to the study team, study PI, and the COH DSMC. 
13.6 Quality Assurance 
The City of Hope Clinical Research Information Support will provide quality assurance.  
An additional level of quality assurance of the study-required images will be performed by the 
Study PI. 
13.7 City of Hope Data and Safety Monitoring Committee (DSMC) 
This is a Risk Level 4 study, as defined in the City of Hope Data and Safety Monitoring Plan 
because the trial involves a COH IND. 
The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety 
of participants in clinical trials, and the conduct, progress, validity, and integrity of the data for 

 
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all clinical trials that are sponsored by City of Hope. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the study. 
The committee reviews the progress and safety of all active research protocols that are not 
monitored by another safety and data monitoring committee or board. 
The COH DSMC will review and monitor toxicity and accrual data from this trial. Information 
that raises any questions about participant safety will be addressed with the Principal 
Investigator, statistician and study team. 
This study will utilize the Phase 1 Tracking Log to monitor data and safety for dose escalation. 
The Tracking Log will contain dose levels administered, dose limiting toxicities (DLT), DLT-
defining adverse events, and any details regarding dose level escalation. The record of doses 
administered and resultant adverse events will be included in the PMT Report. 
The DSMC will review the study’s status per COH policies and/or more frequently if 
necessary. The DSMC will review up-to-date participant accrual; summary of all adverse 
events captured via routine and expedited reporting; a summary of deviations; any response 
information; monitoring reports, and summary comments provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request. A review of outcome 
results (response, toxicity and adverse events) and factors external to the study (such as 
scientific or therapeutic developments) is discussed, and the Committee votes on the status of 
each study.  
Data and safety will be reported from the date of activation to the COH DSMC using the PMT 
report per COH policies. 
14.0 ADVERSE EVENT AND UNANTICIPATED PROBLEM REPORTING 
The authorized investigator will be responsible for determining the event name, assessing the 
severity (i.e., grade), expectedness, and attribution of all adverse events. 
14.1 Definitions 
o Adverse Event (AE) [Modified from the definition of adverse event in 21 CFR 312.32] 
- An adverse event is any untoward medical experience or change of an existing 
condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  
o Serious Adverse Event (SAE) [Modified from the definition of unexpected adverse 
drug experience in 21 CFR 312.32] - defined as any expected or unexpected adverse 
events that result in any of the following outcomes: 
 
Death 
 
Is life-threatening experience (places the subject at immediate risk of death from 
the event as it occurred) 
 
Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
existing hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 

 
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 
Secondary malignancy 
 
Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the outcomes listed above (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, 
blood dyscrasias of convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse). 
o Adverse Event Description and Grade 
 
The description and grading scales found in the most recent version of CTCAE will 
be utilized to characterize AEs. AEs not covered by specific terminology listed 
should be reported with common medical terminology, and documented according 
to the grading scales provided in the CTCAE v 4.0. The NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v. 4.0 will be utilized for AE grading.  All 
appropriate treatment areas should have access to a copy of the CTCAE v. 4.0.  A 
copy can be downloaded from the NCI/ CTEP web site.  
 
o Unexpected Adverse Event – An adverse event is unexpected if it is not listed in the 
investigator’s brochure and/or package insert; is not listed at the specificity or severity 
that has been observed; is not consistent with the risk information described in the 
protocol and/or consent; is not an expected natural progression of any underlying 
disease, disorder, condition, or predisposed risk factor of the research participant 
experiencing the adverse event. Modified from 21 CFR 312.32 (a). 
o Expected Adverse Event - An adverse event is expected if it does not meet the criteria 
for an unexpected event, OR is an expected natural progression of any underlying 
disease, disorder, condition, or predisposed risk factor of the research participant 
experiencing the adverse event. 
o Adverse Event Attribution 
The following definitions will be used to determine the causality (attribution) of the 
event to the study agent or study procedure. 
 
Unrelated – The event is clearly related to other factors such as the 
participant’s clinical state, other therapeutic interventions, or concomitant 
medications administered to the participant. 
 
Unlikely – The event is doubtfully related to the investigational agent(s). The 
event was most likely related to other factors such as the participant’s clinical 
state, other therapeutic interventions, or concomitant drugs. 
 
Possible – The event follows a reasonable temporal sequence from the time of 
drug administration, but could have been produced by other factors such as the 
participant’s clinical state, other therapeutic interventions, or concomitant 
drugs. 
 
Probable – The event follows a reasonable temporal sequence from the time of 
drug administration, and follows a known response pattern to the study drug. 

 
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The event cannot be reasonably explained by other factors such as the 
participant’s clinical state, therapeutic interventions, or concomitant drugs. 
 
Definite – The event follows a reasonable temporal sequence from the time of 
drug administration, follows a known response pattern to the study drug, cannot 
be reasonably explained by other factors such as the participant’s condition, 
therapeutic interventions, or concomitant drugs, AND occurs immediately 
following study drug administration, improves upon stopping the drug, or 
reappears on re-exposure. 
o Unanticipated Problem (UP) – Any incident, experience, or outcome that meets all 
three of the following criteria: 
 
Unexpected (in terms of nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
 
Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may have 
been caused by the drugs, devices or procedures involved in the research); AND 
 
Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
14.2 Events of Special Interest Requiring Expedited Reporting 
14.2.1 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. In the event of overdose, the subject should be observed closely for signs 
of toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
For purposes of this trial, an overdose of vorinostat is considered to be any dose more than the 
prescribed dose. No specific information is available on the treatment of overdose of 
vorinostat. There is no specific antidote for vorinostat overdose. In clinical studies, the highest 
total daily doses tested were 600 mg (once daily), 800 mg (400 mg twice daily) and 900 mg 
(300 mg three times daily). In four patients who took more than the recommended study dose 
(without exceeding the highest doses tested), no adverse experiences were reported. Patients 
should be advised not to make up missed doses. If a patient has an episode of emesis after 
taking vorinostat, patient should be instructed not to take an additional dose. 
 

 
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14.2.2 Pregnancies 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Efforts must be made by the investigator to follow the outcome of pregnancy outcome per 
institutional policies.  
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. If the new-born is healthy additional follow-up is not 
necessary. 
Any pregnancy related event described above must be reported to the Study PI/ DCC 
immediately within 24 hours of awareness (see Section 14.4). 
14.2.3 Abnormal Liver Function Tests 
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. 
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. 
14.3 Routine AE Reporting Guidelines 
AEs will be collected from the signing of informed consent until ending study participation.  
Routine AE reporting will occur via data entry into the study eCRF.  AEs reported through 
expedited processes (e.g., reported to the IRB, FDA, etc.) must also be reported in routine 
study data submissions. 
 
AEs recorded in the CRF include: 
o All events considered unrelated, unlikely, possibly, probably or definitely 
related to protocol therapy 
o Any Grade 1-5 during the DLT period (cycles 1 and 2), highest grade after 
cycle 2 during each cycle and during the safety follow-up period. 
o All SAEs. 
14.4 Expedited AE Reporting Guidelines 
Each adverse event will be assessed to determine if it meets the criteria for expedited reporting. 
Adverse event reporting is to occur according to the site’s specific IRB guidelines, and as 
outlined in this Section. 

 
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Table 14.4 indicates what events must be reported expeditiously. 
Serious Adverse Events that require expedited reporting and unanticipated problems will be 
reported according to the approved City of Hope’s Institutional policy via electronic 
submission in iRIS.  
Table 14.4 Expedited Reporting Guidelines 
Time point 
What to report expeditiously 
From the signing of the consent to study 
completion 
All unanticipated problems 
 
Screening up to Day 1 of protocol therapy 
 
Pregnancy and lactation 
 
Any reason for not starting Day 1 of protocol 
therapy  
For the time period beginning at treatment 
through 90 days following cessation of 
treatment, or 30 days following cessation of 
treatment if the subject initiates new anticancer 
therapy, whichever is earlier 
 
All SAEs regardless of relationship to protocol 
therapy, study procedure, underlying disease 
or concomitant treatment. 
 
Death due to any cause other than progression 
of the cancer under study 
 
All AEs that meet the definition of a UP 
 
Overdose (Section 14.2.1) of either agent 
 
Pregnancies and lactation (Section 14.2.2) 
 
Abnormal liver function tests (Section 14.2.3). 
For participants yet to initiate anti-cancer 
therapy: From Day 1 of therapy up to 120 days 
post-last pembrolizumab dose 
Pregnancies and lactation (Section 14.2.2). 
Post Safety follow-up to removal from study 
All SAEs that are considered possibly, probably, or 
definitely related to pembrolizumab 
Note: follow-up reports must be submitted for all events that require expedited reporting when the 
status of the event changes and until the resolution or stabilization of the event. 
 
o Reportable adverse events must be followed until the event is resolved, stabilized, or 
determined to be irreversible by the investigator; for ongoing reportable adverse events 
that are unrelated to protocol therapy, the follow-up period may end 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier.  
14.5 Additional reporting requirements 
The Study PI (or designee) will: 
o For IND Sponsor reporting purposes only: Report to the FDA, (via COH Office of IND 
Development and Regulatory Affairs (OIDRA)) regardless of the site of occurrence, 
any SAE that meets the FDA’s criteria for expedited reporting following the reporting 
requirements and timelines set by the FDA: 

 
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Serious Adverse Events meeting the requirements for expedited reporting to the Food 
and Drug Administration (FDA), as defined in 21 CFR 312.32, will be reported as an 
IND safety report using the MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the MedWatch 3500A are: 
‐ Any unexpected fatal or life threatening adverse experience associated with use 
of the drug must be reported to the FDA no later than 7 calendar days after initial 
receipt of the information [21 CFR 312.32(c)(2)] 
‐ Any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt 
of the information [21 CFR 312.32(c)(1)] 
‐ Any follow-up information to a study report shall be reported as soon as the 
relevant information becomes available. [21 CFR 312.32(d)(3)] 
The PI or designee will be responsible for contacting the Office of IND Development 
and Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports 
to the FDA.  OIDRA will assist the PI with the preparation of the report and submit the 
report to the FDA in accordance with the approved City of Hope’s Institutional policy. 
  
o Report to Merck using a MedWatch form, (via COH OIDRA) regardless of the site of 
occurrence, any expedited AEs within 2 working days of being aware of the event. 
The initial report will be as complete as possible and include an assessment of the causal 
relationship between the event and the study agent(s).  Information not available at the 
time of the initial report will be documented on a follow-up report and submitted to 
Merck.  
 
The Merck protocol number will be included on expedited reports (or on the fax cover 
letter).  A copy of the fax transmission confirmation of the expedited report to Merck 
will be retained with the patient records. 
 
Merck Global Safety  
Attn: Worldwide Product Safety 
Fax: (215) 993-1220 
 
o Submit annually within 60 days (via COH OIDRA) of the anniversary date of when 
the IND went into effect, an annual report to the FDA which is to include a narrative 
summary and analysis of the information of all FDA reports within the reporting 
interval, a summary report adverse drug experiences, history of actions taken since the 
last report because of adverse drug experiences. 
o Forward to Merck (via COH OIDRA) a copy of the FDA Annual Progress Report at 
the time of submission to the FDA. 

 
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o Report to the COH DSMC a Protocol Management Team (PMT) report per frequency 
stated in COH policies, to include aggregate analysis of safety information and accrual 
and participant status. 
o Report to Merck aggregate safety information at the time of COH DSMC PMT report. 
 
15.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
15.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy 
dispensing records, recorded data from automated instruments, laboratory data) that are 
relevant to the clinical trial.  The Site Investigator or their designee will prepare and maintain 
adequate and accurate source documents.  These documents are designed to record all 
observations and other pertinent data for each patient enrolled in this clinical trial.  Source 
documents must be adequate to reconstruct all data transcribed onto the case report forms. 
15.2 Data Capture Methods and Management 
Data for this trial will be collected using Medidata RAVE, City of Hope’s electronic capture 
system. Medidata RAVE is a web based, password protected system that is fully compliant 
with global regulatory requirements, including 21CRF Part 11 compliant.  
15.3 Case Report Forms/ Data Submission Schedule 
Study personnel at each site will enter data from source documents corresponding to a 
participant’s visit into the protocol-specific electronic Case Report Form (eCRF) when the 
information corresponding to that visit is available.  
The investigator is responsible for all information collected on participants enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the investigator. All case report forms must be completed by 
designated study personnel.  The completed case report forms must be reviewed, signed and 
dated by the Site Investigator or designee in a timely fashion. 
All data will be collected using electronic data collection system described in Section 15.2, 
and will be submitted according to the timelines indicated in Table 14. 
Table 14. Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 14 calendar days of treatment administration 
Adverse Event Report Forms 
Cycle 1 and 2: Within 7 calendar days of the assessment/notification 
Cycle 3+: Within 10 calendar days of the assessment/notification  
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms  
Within 10 calendar days of the assessment 

 
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Form 
Submission Timeline 
Off 
Treatment/Off 
Study 
Forms 
Within 10 calendar days of completing treatment or being taken off study for 
any reason 
Follow up/ Survival Forms 
Within 14 calendar days of the protocol defined follow up visit date or call 
15.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance 
with Good Clinical Practice guidelines and FDA regulations. 
16.0 ADHERENCE TO THE PROTOCOL 
A deviation is a divergence from a specific element of a protocol that occurred without prior 
IRB approval. 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. Protocol deviations may be on the part 
of the participant, the investigator, or study staff.   
All deviations from the protocol must be documented in study participant source documents 
and promptly reported to the Study PI and to the local IRB according to its policies 
requirements.  The Study PI will report the deviation according to City of Hope’s deviation 
policy for reporting deviations. 
16.1 Definitions  
16.1.1 Unplanned deviations 
▪ 
Emergency Modifications 
Investigators may implement a deviation from the protocol to eliminate an immediate hazard(s) 
for the protection, safety, and well-being of the study patient to trial participants without prior 
IRB or Sponsor approval. 
▪ 
Deviations Discovered After They Have Occurred 
Unplanned deviations from the protocol must be documented in study subject source 
documents. 
 
16.1.2 Planned Non-Emergency Deviations (Single Subject Exception) 
A planned deviation involves circumstances in which the specific procedures called for in a 
protocol are not in the best interests of a specific patient. It is a deviation that is anticipated and 
receives prior approval by the PI and the IRB.  

 
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16.2 Reporting of Deviations 
16.2.1 Reporting Unplanned Deviations 
For any such deviation, the Study PI will notify the COH DSMC and IRB within 5 calendar 
days of its occurrence via iRIS in accordance with the Clinical Research Protocol Deviation 
policy. 
A list of these deviations will be submitted along with the Protocol Management Team (PMT) 
reports to the COH DSMC. 
16.2.2 Reporting Planned Non-Emergency Deviations/ Single Subject Exceptions 
Any planned deviation must be submitted as a “planned protocol deviation” via iRIS in 
accordance with IRB guidelines and the Clinical Research Protocol Deviation policy. An IRB 
approved planned deviation does not need to be submitted as a deviation to the DSMC. 
 
17.0 ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research 
(US National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research, April 18, 1979) and the Declaration of Helsinki. 
17.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to 
the following considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 
Title 21 Part 312 – Investigational New Drug Application  
 
Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  
 
Section 801 of the Food and Drug Administration Amendments Act   

 
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o Applicable state and local laws. For research occurring in California, this includes 
but is not limited to State of California Health and Safety Code, Title 17 
o Applicable institutional research policies and procedures 
17.3 Institutional Review Board 
An Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 
and 21 CFR 50, 56 and State of California Health and Safety code, Title 17, must review and 
approve this protocol, informed consent form and any additional documents that the IRB may 
need to fulfill its responsibilities (Investigator’s Brochure, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) prior to 
initiation of the study. Revisions to approved documents will require review and approval by 
the IRB before the changes are implemented in the study. All institutional, NCI, Federal, and 
State of California regulations must be fulfilled. 
The IRB’s written unconditional approval of the study protocol and the informed consent 
document must be in the possession of the investigator before the study is initiated. 
The IRB will be informed of serious unexpected, unanticipated adverse experiences, and 
unanticipated problems occurring during the study, and any additional adverse experiences in 
accordance with the standard operating procedures and policies of the IRB; new information 
that may affect adversely the safety of the patients of the conduct of the study; an annual update 
and/or request for re-approval; and when the study has been completed. 
17.4 Informed Consent  
The Principal Investigator or IRB approved named designee will explain the nature, duration, 
purpose of the study, potential risks, alternatives and potential benefits, and all other 
information contained in the informed consent document. In addition, they will review the 
experimental subject’s bill of rights if applicable, and the HIPAA research authorization form. 
Prospective participants will be informed that they may withdraw from the study at any time 
and for any reason without prejudice, including as applicable, their current or future care or 
employment at City of Hope or any relationship they have with City of Hope. Prospective 
participants will be afforded sufficient time to consider whether or not to participate in the 
research. 
After the study has been fully explained, written informed consent will be obtained from either 
the prospective participant or his/her guardian or legal representative before study 
participation. The method of obtaining and documenting the informed consent and the contents 
of the consent must comply with the ICH-GCP and all applicable regulatory requirements. 
A copy of the signed informed consent will be given to the participant or his/her legally 
authorized representative. The original signed consent must be maintained by the investigator 
and available for inspection by sponsor designated representatives, or regulatory authority at 
any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in 
the study and continues throughout study participation. 

 
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17.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. 
The withdrawal must be documented per institutional policies.   
Participant withdrawal may consist of any of the following with regard to study procedures 
and data collection: 
o Withdrawal from study treatment, but agreement to continue with active study 
procedures and chart review and follow-up procedures. 
o Withdrawal from study treatment and all active procedures, but agreement for chart 
review and follow-up procedures. 
o Withdrawal from study treatment, all active procedures, and any future data 
collection. 
Participants who agreed to the collection of research blood samples may withdraw consent to 
use their specimens, if they are not yet processed as detailed in the consent form.  Once the PI 
and site PI is notified of this withdrawal of informed consent, the research specimens will not 
be used in any research. At that time, any of the existing specimens will be destroyed. 
17.6 Special and Vulnerable Populations  
17.6.1 Inclusion of Women and Minorities 
The study is open anyone regardless of gender or ethnicity. If differences in outcome that 
correlate to gender, racial, or ethnic identity are noted, accrual may be expanded or additional 
studies may be performed to investigate those differences more fully. 
Pregnant women are excluded from the study. Animal reproduction studies have not been 
conducted, and there are no controlled data in human pregnancy. 
Therefore, vorinostat and pembrolizumab should not be taken by pregnant women. 
17.6.2 Exclusion of Children 
Children/ adolescents (< 18 years old of age) are excluded from this study because the 
historical comparator trials were conducted in adults. Future studies may be planned to include 
children/ adolescents. 
17.6.3 Inclusion of HIV Positive Individuals 
Participants with a history of HIV are excluded due to concerns about inadvertent 
augmentation of infectious and/or inflammatory activity. 
17.6.4 Vulnerable Populations 
45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant 
women, mentally incapacitated persons, or economically or educationally disadvantaged 
persons as vulnerable populations.  

 
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Adults lacking capacity to consent are not excluded from participation. This study does not 
pose additional risks for adults lacking capacity than for the general population.  In such 
instances, informed consent will be sought and documented from the prospective participant’s 
legally authorized representative in agreement with institutional policies and COH IRB 
approval. 
17.7 Participant Confidentiality  
Participant confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to any study information relating to participants. 
This research will be conducted in compliance with federal and state requirements relating to 
protected health information (PHI), including the requirements of the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed 
participant authorization informing the participant of the nature of the PHI to be collected, who 
will have access to that information and why, who will use or disclose that information, ant the 
rights of a research participant to revoke their authorization for use of their PHI. In the event 
that a participant revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of participant 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the participant is 
alive) at the end of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for 
Privacy of Individually Identifiable Health Information, 45 CFR 164.508. When results of this 
study are reported in medical journals or at meetings, identification of those taking part will 
not be disclosed and no identifiers will be used. 
Medical records of participants will be securely maintained in the strictest confidence, 
according to current legal requirements.  Data will be entered, analyzed and stored in 
encrypted, password protected, secure computers that meet all HIPAA requirements.   All data 
capture records, drug accountability records, study reports and communications will identify 
the patient by initials and the assigned patient number. Source documents provided to 
coordinating center for the purpose of auditing or monitoring will be de-identified and labeled 
with the study number, subject ID, and if applicable patient initials. 
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist 
of trial-related monitoring/ auditing, IRB reviews, and FDA/regulatory authority inspections. 
The participant’s confidentiality will be maintained and will not be made publicly available to 
the extent permitted by the applicable laws and regulations. 
Participant specimens will be de-identified (coded) prior to submission to research 
laboratories. The specimens will be labeled with the study number, subject ID, institution and 

 
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timepoint of collection. The key to the code will be maintained in the COH clinical trials 
management system which is a secure environment. 
17.8 Use of Unused (Leftover) Specimens Collected for this Trial 
Unused samples in existence at study completion (i.e. completion of all research activities 
under this study) will be either: (a) discarded or (b) placed in a COH IRB approved 
biorepository with clinical information and potentially PHI attached. 
With regard to which option will apply, each site IRB may choose to either: (a) leave the 
determination to the participant via a question in the informed consent document, which would 
communicated to the study registrar (DCC) at the time of participant registration, OR b) may 
choose to make a single determination on behalf of their respective participants, and 
communicate that determination to their respective participants via the informed consent. 
17.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study 
Sponsor (City of Hope) prior to participation in this study.  All City of Hope investigators will 
follow the City of Hope conflict of interest policy. 
All study personnel are required to disclose financial interests in the company involved with 
this study, Merck. 
17.10 Financial Obligations, Compensation, and Reimbursement of Participants 
The investigational drugs, pembrolizumab and vorinostat, will be provided free of charge by 
Merck. Should pembrolizumab become commercially available during the course of study 
treatment, the research participant and/or the insurance carrier may be asked to pay for the 
costs of the drug.  
Neither the research participant nor the insurance carrier will be responsible for the research 
procedures related to this study.  
The standard of care drugs and procedures provided will be the responsibility of the research 
participant and/or the insurance carrier. The research participant will be responsible for all 
copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth 
by the insurance carrier.  The research participant and/or the insurance carrier will be billed for 
the costs of treatment and diagnostic procedures in the same way as if the research participant 
were not in a research study.   
In the event of physical injury to a research participant, resulting from research procedures, 
appropriate medical treatment will be available at the City of Hope or at the non-COH site to 
the injured research participant, however, financial compensation will not be available. There 
are no plans for City of Hope to provide financial compensation in the event of physical injury 
to a participant. 

 
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The research participant will not receive reimbursement or payment for taking part in this 
study. 
17.11 Publication/Data Sharing  
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by City of Hope for the purposes of performing the study, will 
be published or passed on to any third party without the written approval of the Study PI. Any 
investigator involved with this study is obligated to provide City of Hope with complete test 
results and all data derived from the study. 
The preparation and submittal for publication of manuscripts containing the study results shall 
be in accordance with a process determined by mutual written agreement among City of Hope 
and Merck. The publication or presentation of any study results shall comply with all 
applicable privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments 
Act of 2007 or FDAAA), Title VIII, Section 801, this trial will be registered onto 
ClinicalTrials.gov and results will be reported on ClinicalTrials.gov within 12 months of the 
estimated or actual completion date of the trial, whichever date is earlier. 
 
 

 
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APPENDIX A: ECOG PERFORMANCE STATUS  
ECOG Performance Status Scale 140 
Grade 
Descriptions 
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. 
 

 
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APPENDIX B: REGISTRATION COVERSHEET  
COH IRB#: A Phase I Study of Pembrolizumab Plus Vorinostat for Relapsed or Refractory Diffuse Large B‐cell 
Lymphoma, Follicular Lymphoma, and Hodgkin Lymphoma 
Data Coordinating Center:   
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Email:  DCC@coh.org (use #secure# in subject line) 
Site Principal Investigator  
Name: 
Address: 
 
 
Phone:  
Fax:  
e‐mail: 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
Medical Record No: 
Investigator/Treating Physician: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
  Hispanic 
Codes: 
 
Caucasian 
  Non‐Hispanic 
01 Private 
06  Military  or  Veterans 
Adm. sponsored 
 
Asian 
  Other_________________ 
02 Medicare 
07 Self‐pay (no 
insurance) 
 
American Indian 
 
03 Medicare & 
private ins. 
08 No means of 
payment  (no insurance) 
 
Native Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other_______________
____________________ 
05 Medicaid & Medicare 
Reason for Screen Failure:  
 
Reason for Failing to Initiate Protocol Therapy: 
 
 
 
 
 

 
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APPENDIX C: THE 2014 LUGANO CLASSIFICATION 
The 2014 Lugano Classification will be used in this study for assessment of tumor response. PET/CT will be used 
study for HL and DLBCL, and is acceptable for FL, while CT with IV contrast (or MRI) can be used for FL. 
Response 
Site 
CT‐Based Response 
PET‐CT Based Response 
Complete 
Response 
 
Complete radiologic response (all 
of the following) 
Complete metabolic response (even 
with a persistent mass) 
Lymph nodes and 
extralymphatic sites 
 Target nodes/nodal masses 
must regress to ≤1.5 cm in 
longest diameter.  
 
 No extralymphatic sites of 
disease. 
 Score ≤ 3* with or without a 
residual mass on 5‐point scale†. 
 
 It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or 
marrow (e.g., with chemotherapy 
or myeloid colony‐stimulating 
factors), uptake may be greater 
than normal mediastinum and/or 
liver. In this circumstance, 
complete metabolic response may 
be inferred if uptake at sites of 
initial involvement is no greater 
than surrounding normal tissue 
even if the tissue has high 
physiologic uptake. 
Nonmeasured 
lesion 
Absent 
Not applicable 
Organ enlargement 
Regress to normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Normal by morphology; if 
determinate, IHC negative 
No evidence of FDG‐avid disease in 
marrow 
Partial 
Response 
 
Partial remission (all of the 
following) 
Partial metabolic response 
Lymph nodes and 
extralymphatic sites 
 ≥ 50% decrease in SPD of up 
to 6 target measurable nodes 
and extranodal sites 
 When a lesion is too small to 
measure on CT, assign 5 mm 
X 5 mm as the default value 
 When no longer visible, 0 X 0 
mm 
 For a node > 5 mm X 5 mm, 
but smaller than normal, use 
actual measurement for 
calculation 
 Score 4 or 5† with reduced uptake 
compared with baseline and 
residual mass(es) of any size 
 At interim, these findings suggest 
responding disease 
 At end of treatment, these 
findings indicate residual disease 

 
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Response 
Site 
CT‐Based Response 
PET‐CT Based Response 
Nonmeasured 
lesion 
Absent/normal, regressed, but 
no increase 
Not applicable 
Organ enlargement 
Spleen must have regressed by 
> 50% in length beyond normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context 
of a nodal response, consideration 
should be given to further evaluation 
with MRI or biopsy or an interval 
scan 
No response 
or stable 
disease 
 
Stable disease 
No metabolic response 
Target nodes/nodal 
masses, extranodal 
lesions 
< 50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Score 4 or 5† with no signiﬁcant 
change in FDG uptake from baseline 
at interim or end of treatment 
Nonmeasured 
lesion 
No increase consistent with 
progression 
Not applicable 
Organ enlargement 
No increase consistent with 
progression 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
No change from baseline 
Progressive 
disease 
 
Progressive disease requires at 
least 1 of the following 
Progressive metabolic disease 
Individual target 
nodes/nodal masses 
PPD progression: 
Score 4 or 5 with an increase in 
intensity of uptake from baseline and/or 
Extranodal lesions 
An individual node/lesion must 
be abnormal with: 
 Longest diameter (LDi) > 1.5 
cm and 
 Increase by ≥ 50% from PPD 
nadir and 
 An increase in LDi or smallest 
diameter (SDi) from nadir 
 0.5 cm for lesions ≤ 2 cm 
 1.0 cm for lesions > 2 cm 
 New FDG‐avid foci consistent with 
lymphoma at interim OR 
 end‐of‐treatment assessment 

 
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Response 
Site 
CT‐Based Response 
PET‐CT Based Response 
 In the setting of 
splenomegaly, the splenic 
length must increase by > 
50% of the extent of its prior 
increase beyond baseline 
(e.g., a 15‐cm spleen must 
increase to 16 cm). If no prior 
splenomegaly, must increase 
by at least 2 cm from 
baseline 
 New or recurrent 
splenomegaly 
Nonmeasured 
lesion 
New or clear progression of 
preexisting nonmeasured 
lesions 
None 
New lesions 
 Regrowth of previously 
resolved lesions 
 A new node > 1.5 cm in any 
axis 
 A new extranodal site < 1.0 
cm in any axis; if > 1.0 cm in 
any axis, its presence must 
be unequivocal and must be 
attributable to lymphoma 
 Assessable disease of any 
size unequivocally 
attributable to lymphoma 
 New FDG‐avid foci consistent with 
lymphoma rather than another 
etiology (eg, infection, 
inflammation).  
 If uncertain regarding etiology of 
new lesions, biopsy or interval 
scan may be considered. 
Bone marrow 
New or recurrent involvement 
New or recurrent FDG‐avid foci 
 
Measured dominant lesions:  
Up  to  six  of  the  largest  dominant  nodes,  nodal  masses,  and  extranodal  lesions  selected  to  be  clearly 
measurable in two diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas.  
 
Non‐nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous 
lesions, or those noted on palpation.  
 
Nonmeasured lesions:  
Any disease not selected as measured, dominant disease and truly assessable disease should be considered 
not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant 
or measurable or that do not meet the requirements for measurability but are still considered abnormal, 
as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively  with  measurement,  including  pleural  effusions,  ascites,  bone  lesions,  leptomeningeal 
disease,  abdominal  masses,  and  other  lesions  that  cannot  be  confirmed  and  followed  by  imaging.  In 
Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than 
in the mediastinum with complete metabolic response, but should be no higher than surrounding normal 
physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors). 

 
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*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time 
of an interim scan. However, in trials involving PET where de‐escalation is investigated, it may be preferable 
to consider a score of 3 as inadequate response (to avoid undertreatment).  
 
†PET 5‐point score:  
1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely 
to be related to lymphoma. 
 
Abbreviations:   
CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse 
diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross 
product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the 
product of the perpendicular diameters for multiple lesions. 
 
 
 
 
 

 
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APPENDIX D: TISSUE SHIPPING GUIDELINES TO CITY OF HOPE PATHOLOGY CORE  
These guidelines apply to non‐COH sites only. 
All biological material must be shipped according to applicable  government  and International Air 
Transport Association (IATA) regulations.  
Shipping guidelines can also be found on the FedEx website. 
1. Aim  to  ship  samples  on  a  Monday  through  Wednesday.  If  this  is  not  feasible,  advance 
arrangements  should  be  made  with  City  of  Hope  Pathology  Core  (DL‐PATHCORE‐
BiospecimenSupport@COH.org).   
2. Notify  City  of  Hope  Pathology  Core  (DL‐PATHCORE‐BiospecimenSupport@COH.org)  of 
impending shipment. To request a FedEx shipping label, email DCC@coh.org and indicate the 
planned shipment date. 
3. Slides/  Blocks:  Batch  ship  at  room  temperature  via  FedEx.  During  extreme  heat,  include 
refrigerated (not frozen) gel packs or gel insulators. 
It is recommended to ship samples via FedEx overnight (for a delivery by 3 pm or earlier the 
next  day)  or  FedEx  2‐day  (with  a  morning  delivery).  During  extreme  heat,  ship  via  FedEx 
overnight (for a delivery ideally by 10.30 am, or 3 pm the next day). 
4. Frozen samples should be batch shipped on dry ice via FedEx overnight (for a delivery by 
10.30 am the next day). The shipment should contain enough dry ice to last at least 72 hours. 
5. On the day of shipment, email the sample shipment information to City of Hope Pathology 
Core (DL‐PATHCORE‐BiospecimenSupport@COH.org). 
6. Ship  samples  with  a  copy  of  the  correlative  tissue  form  (Appendix  J)  and  a  copy  of  the 
pathology report to: 
 
Karen Miller 
COH Pathology Core 
City of Hope National Medical Center 
1500 E. Duarte Road 
Familian Science (Building 084), Room 1207 
Duarte, CA 91010 
Telephone: 626‐218‐8408 
Email: DL‐PATHCORE‐BiospecimenSupport@COH.org 
APPENDIX E: TISSUE SHIPPING GUIDELINES TO THE JACKSON LABORATORY (FL PATIENTS ONLY) 
PER COH PROTOCOL # 17072 

 
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These guidelines apply to COH only, for the shipping of tissue from FL patients only. 
Follow the requirements for the proper packaging and shipping of biomedical material found 
in 42 CFR Part 72 - Interstate Shipment of Etiologic Agents Centers for Disease Control and 
Prevention, Office of Health and Safety Biosafety Branch. 
 
Laboratory receiving samples: 
Dr. Reddi’s laboratory 
When to ship: 
Batch ship slides/ paraffin scrolls via overnight courier 
Temperature conditions of shipment: 
Room temperature  
Days to ship: 
Monday‐Wednesday for receipt Tuesday‐Friday by the 
laboratory. If this is not feasible, advance arrangements 
should be made with Dr. Honey Reddi or designee. 
 
1. Request shipment billing details from the COH Study Coordinator. 
2. On the day of shipment, notify via email the tracking number to: 
a. Dr. Honey Reddi or designee and  
b. the COH Data Coordinating Center (DCC@coh.org) 
3. Ship samples to with the sample manifest: 
Dr. Honey Reddi 
Clinical Lab Director 
10 Discovery Drive 
The Jackson Laboratory for Genomic Medicine 
Farmington, CT   
Phone: 860.837.2062 
Email: Honey.Reddi@jax.org 
 
 
 

 
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APPENDIX F: CORRELATIVE BLOOD COLLECTION FORM FOR NON‐COH SITES ONLY 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
 
To be used by non‐COH sites for the following blood samples being sent to COH APCF: 
- 
Green‐top tubes from all patients. 
- 
BCT tubes from HL and DLBCL patients only. 
 
Sample # 
Timepoint of 
Collection * 
Expected 
Volume 
Tube Type Used 
(Select One) 
Collected 
Volume 
Time of Collection 
Date of 
Collection 
Indicate 
which sample 
was collected 
1. 
 
Cycle 1, Day 1 
20 mL 
Green‐top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
2. 
 
Cycle 2, Day 1 
20 mL 
Green‐top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
3. 
 
Cycle 5, Day 1 
20 mL 
Green‐top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
4. 
 
Cycle 9, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
5. 
 
Cycle 13, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
6. 
 
Cycle 17, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
7. 
 
Cycle 21, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
8. 
 
Cycle 25, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
9. 
 
Cycle 29, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
10. 
 
At Discontinuation 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
* Peripheral blood is collected prior to study treatment on Day 1 of each indicated cycle. 
A  copy  of  this  form  should  accompany  the  sample  shipments  to  COH  APCF.  Refer  to  the  blood  shipping 
guidelines for shipping instructions to COH APCF (Appendix H). 
CRA/Study Coordinator/ Nurse:   
Contact Number: 
CRA/Study Coordinator/ Nurse Signature:   
Date: 
 

 
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APPENDIX G: CORRELATIVE BLOOD COLLECTION FORM FOR ALL SITES (FOR FL PATIENTS ONLY) 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
 
To be used by all sites for the following blood samples being sent to the Jackson Laboratory: 
- 
BCT tubes from FL patients only. 
 
Sample # 
Timepoint of 
Collection * 
Expected 
Volume 
Tube Type Used 
(Select One) 
Collected 
Volume 
Time of Collection 
Date of 
Collection 
Indicate 
which sample 
was collected 
1. 
 
Cycle 1, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
2. 
 
Cycle 2, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
3. 
 
Cycle 5, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
4. 
 
Cycle 9, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
5. 
 
Cycle 13, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
6. 
 
Cycle 17, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
7. 
 
Cycle 21, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
8. 
 
Cycle 25, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
9. 
 
Cycle 29, Day 1 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
10. 
 
At Discontinuation 
20 mL 
Cell‐free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
* Peripheral blood is collected prior to study treatment on Day 1 of each indicated cycle. 
A copy of this form should accompany the sample shipments to Dr. Reddi’s laboratory. Refer to Appendix I for 
shipping instructions to Dr. Reddi’s laboratory. 
CRA/Study Coordinator/ Nurse:   
Contact Number: 
CRA/Study Coordinator/ Nurse Signature:   
Date: 

 
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APPENDIX H: BLOOD SHIPPING GUIDELINES TO CITY OF HOPE APCF 
These guidelines apply to non‐COH sites only, for the shipping of all green‐top tubes and cell‐free DNA 
BCT® (Streck) tubes from HL and DLBCL (and not FL) patients. 
Follow the requirements for the proper packaging and shipping of biomedical material found in 42 CFR 
Part 72 ‐ Interstate Shipment of Etiologic Agents Centers for Disease Control and Prevention, Office of 
Health and Safety Biosafety Branch. 
 
1. Aim  to  ship  samples  on  a  Monday  through  Wednesday.  If  this  is  not  feasible,  advance 
arrangements  should  be  made  with  Leslie  Smith‐Powell  (LSmith‐Powell@coh.org)  or 
Stephanie Lee (stlee@coh.org) or their representative. 
1. Blood samples in green‐top tubes will be sent overnight at around +4oC with a refrigerated 
cool pack in an appropriate container via FedEx. Cell‐free BCT tubes will be shipped together 
with green tubes for the first 3 time points. Starting from C9, cell‐free BCT tubes should be 
shipped as as soon as possible but no more than 3 days after being drawn via overnight courier 
at ambient temperature. 
2. On the day of shipment, email Leslie Smith‐Powell (LSmith‐Powell@coh.org) or Stephanie Lee 
(stlee@coh.org) or their representative the FedEx shipment #. 
3. Ship samples with a copy of the correlative blood collection form and a copy of the latest 
CBC results (with differential) and the date of the test to: 
 
Dr. Tim Synold 
Analytical Pharmacology Core Facility  
Shapiro 1042 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 

 
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APPENDIX I: BLOOD SHIPPING GUIDELINES TO THE JACKSON LABORATORY (FL PATIENTS ONLY) 
PER COH PROTOCOL # 17072 
These guidelines apply to all sites, for the shipping of cell‐free DNA BCT® (Streck) tubes from FL 
patients only. 
Follow the requirements for the proper packaging and shipping of biomedical material found in 42 CFR 
Part 72 ‐ Interstate Shipment of Etiologic Agents Centers for Disease Control and Prevention, Office of 
Health and Safety Biosafety Branch. 
Laboratory receiving samples: 
Dr. Reddi’s laboratory 
When to ship: 
As soon as possible but no more than 3 days after being 
drawn, should be shipped via overnight courier 
Temperature conditions of shipment: 
Ambient temperature  
Days to ship: 
Monday‐Wednesday for receipt Tuesday‐Friday by the 
laboratory. If this is not feasible, advance arrangements 
should be made with Dr. Honey Reddi or designee. 
 
1. Request shipment billing details from the COH Study Coordinator. 
2. On the day of shipment, notify via email the tracking number and a copy of Blood Collection 
Form to: 
a. Dr. Honey Reddi or designee and  
b. The COH Data Coordinating Center (DCC@coh.org) 
3. Ship samples with a copy of the Blood Collection Form to: 
Dr. Honey Reddi 
Clinical Lab Director 
10 Discovery Drive 
The Jackson Laboratory for Genomic Medicine 
Farmington, CT   
Phone: 860.837.2062 
Email: Honey.Reddi@jax.org 
 
 
 
 

 
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APPENDIX J: CORRELATIVE TISSUE FORM FOR SHIPPING TO COH PATHOLOGY CORE  
 
A copy of this form should accompany the sample shipments to COH Pathology Core. 
Non‐COH sites: refer to Appendix D for shipping instructions to COH Pathology Core. 
 
COH IRB number: 17080 
Shipping date (MM‐DD‐YYYY):   ________/________/________ 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
Date of collection/ biopsy (MM‐DD‐YYYY):    ________/________/________ 
Time point:     
  Baseline       
  Progression 
Diagnosis: 
Tissue type (FFPE scrolls, slides, biopsies): 
Number of scrolls: 
Number of slides: 
 
 
 
 
CRA/Study Coordinator/Nurse Printed Name:   
CRA/Study Coordinator/Nurse Signature:   
Contact Number: 
 
 
 

 
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APPENDIX K: EXPEDITED REPORTING COVERSHEET 
NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT 
For Use by Participating Institutions Only 
THIS FORM ALONG WITH A COPY OF THE MEDWATCH 3500 OR IRB REPORTING FORM MUST BE EMAILED TO DCC@COH.ORG WITHIN 24 
HOURS OF KNOWLEDGE OF ONSET OF SERIOUS ADVERSE EVENT OR UNANCTICIPATED PROBLEM  
COH IRB #______‐ Participating Site IRB # ___________ 
From: 
Date: 
Phone No.: 
Email: 
Reporting Investigator: 
Event:  
Participant ID: 
Institution: 
Date Event Met Reporting Criteria (as defined in protocol):   
 
Type of Report: 
 Initial    Follow‐up 
CTCAE Grade:   
 G1/mild    G2/moderate     G3/severe    G4/life threatening   
 G5 
Attribution to pembrolizumab: 
 Unrelated   Unlikely   Possible    Probable   Definite 
Attribution to vorinostat: 
 Unrelated   Unlikely   Possible    Probable   Definite 
Historical/Known Correlation to 
pembrolizumab: 
 Expected    Unexpected 
Historical/Known Correlation to 
vorinostat: 
 Expected    Unexpected   
Meets Definition of Serious AE:       Serious      Non‐serious 
Meets Definition of 
Unanticipated Problem: 
   UP      Not a UP 
Has the event been reported to 
the following institution’s IRB? 
   No      Yes; Date:_____/____/_____ 
 
Authorized Investigator Signature:   
Date:____/____/____ 
 
 
 

 
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APPENDIX L: LYRIC CRITERIA 
Lugano Classification was developed based on treatment with cytotoxic agents 122. 
Immunotherapeutic drugs, may produce antitumor effects by potentiating endogenous cancer‐
specific immune responses. The response patterns seen with such an approach may extend beyond 
the typical time course of responses seen with cytotoxic agents, and can manifest as clinical 
responses after initial increases in tumor burden or even the appearance of new lesions. Thus, the 
2014 Lugano Classification may not provide an accurate assessment of response to 
immunotherapeutic agents. Provisional modification of the Lugano criteria (LYRIC Criteria) may be 
used to assess participants who meet progressive disease per Lugano Classification 28, 122. 
Complete Response 
Partial Response 
Progressive Disease 
Same as Lugano  
Same as Lugano  
As with Lugano with the following exceptions: 
 
Indeterminate response (IR) 
 IR1: ≥50% increase in SPD of up to 6 measurable lesions 
in first 12 weeks of therapy without clinical deterioration 
 IR2: <50% increase in the overall SPD with 
a. Appearance of a new lesion(s), or 
b. ≥50% increase in PPD of a lesion or set of lesions at 
any time during treatment 
 IR(3): Increase in FDG uptake without a concomitant 
increase in lesion size or number  
  
Patients with IR should continue on therapyand have repeat 
imaging after an additional 12 weeks (or sooner if clinically 
indicated). 
Progressive disease criteria in these patients will be met if:  
• 
IR1: An additional increase in the target SPD of ≥ 
10% between the first IR1 timepoint and the SPD 
being assessed; or an increase in ≥ 5mm in either 
dimension of at least one lesion for lesions ≤ 2cm 
and 10mm for lesions > 2cm. 
• 
IR2: the new or growing lesion(s) should be added 
to the target lesions (total of no more than 6) and 
there is PD if the SPD if the newly defined set of 
target lesions has increased ≥50% from their nadir 
value (which may precede the IR time point). 
• 
IR3: There is evidence of PD by an increase in lesion 
size or the development of new lesions. 
Abbreviations: SPD, sum of the product of the diameters; PPD, product of the perpendicular diameters. 
 
 
 

 
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References 
1. 
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma 
incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 
107(1): 265-276. e-pub ahead of print 2005/09/10; doi: 2005-06-2508 [pii] 
10.1182/blood-2005-06-2508 
 
2. 
Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E et al. Six 
versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients 
with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-
60). The lancet oncology 2008; 9(2): 105-116. doi: 10.1016/S1470-2045(08)70002-0 
 
3. 
Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M et al. Salvage 
regimens with autologous transplantation for relapsed large B-cell lymphoma in the 
rituximab era. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2010; 28(27): 4184-4190. doi: 10.1200/JCO.2010.28.1618 
 
4. 
Van Den Neste E, Schmitz N, Mounier N, Gill D, Linch D, Trneny M et al. Outcome 
of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage 
regimens in the International CORAL study. Bone marrow transplantation 2016; 
51(1): 51-57. doi: 10.1038/bmt.2015.213 
 
5. 
Gribben JG. How I treat indolent lymphoma. Blood 2007; 109(11): 4617-4626. doi: 
10.1182/blood-2006-10-041863 
 
6. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
reviews. Cancer 2012; 12(4): 252-264. doi: 10.1038/nrc3239 
 
7. 
Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O'Donnell E et al. Integrative 
analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and 
further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary 
mediastinal large B-cell lymphoma. Blood 2010; 116(17): 3268-3277. doi: 
10.1182/blood-2010-05-282780 
 
8. 
Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML et al. PD-L1 expression 
is characteristic of a subset of aggressive B-cell lymphomas and virus-associated 
malignancies. Clinical cancer research : an official journal of the American 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
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Page 135 of 152 
 
 
 
Association for Cancer Research 2013; 19(13): 3462-3473. doi: 10.1158/1078-
0432.CCR-13-0855 
 
9. 
Carreras J, Lopez-Guillermo A, Roncador G, Villamor N, Colomo L, Martinez A et al. 
High numbers of tumor-infiltrating programmed cell death 1-positive regulatory 
lymphocytes are associated with improved overall survival in follicular lymphoma. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2009; 27(9): 1470-1476. doi: 10.1200/JCO.2008.18.0513 
 
10. 
Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O'Donnell E et al. Constitutive 
AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and 
posttransplant lymphoproliferative disorders: implications for targeted therapy. 
Clinical cancer research : an official journal of the American Association for Cancer 
Research 2012; 18(6): 1611-1618. doi: 10.1158/1078-0432.CCR-11-1942 
 
11. 
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M et al. Phase I 
safety and pharmacokinetic study of CT-011, a humanized antibody interacting with 
PD-1, in patients with advanced hematologic malignancies. Clinical cancer research : 
an official journal of the American Association for Cancer Research 2008; 14(10): 
3044-3051. doi: 10.1158/1078-0432.CCR-07-4079 
 
12. 
Westin JR, Chu F, Zhang M, Fayad LE, Kwak LW, Fowler N et al. Safety and activity 
of PD1 blockade by pidilizumab in combination with rituximab in patients with 
relapsed follicular lymphoma: a single group, open-label, phase 2 trial. The lancet 
oncology 2014; 15(1): 69-77. doi: 10.1016/S1470-2045(13)70551-5 
 
13. 
Moskowitz CH, Ribrag, V., Michot, J. M., et al. PD-1 Blockade with the Monoclonal 
Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma 
after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study 
(KEYNOTE-013). In. 
 
14. 
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M et al. PD-1 
blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. The New 
England journal of medicine 2015; 372(4): 311-319. doi: 10.1056/NEJMoa1411087 
 
15. 
Lesokhin AM, Ansell, S. M., Armand, P., et al. Preliminary Results of a Phase I Study 
of Nivolumab (BMS-936558) in Patients with Relapsed or Refractory Lymphoid 
Malignancies. Blood (ASH Annual Meeting Abstracts) 2014 124: 291.;  

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
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Page 136 of 152 
 
 
 
 
16. 
O'Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli 
B et al. Clinical experience with intravenous and oral formulations of the novel histone 
deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced 
hematologic malignancies. Journal of clinical oncology : official journal of the 
American 
Society 
of 
Clinical 
Oncology 
2006; 
24(1): 
166-173. 
doi: 
10.1200/JCO.2005.01.9679 
 
17. 
Kirschbaum MH, Goldman BH, Zain JM, Cook JR, Rimsza LM, Forman SJ et al. A 
phase 2 study of vorinostat for treatment of relapsed or refractory Hodgkin lymphoma: 
Southwest Oncology Group Study S0517. Leukemia & lymphoma 2012; 53(2): 259-
262. doi: 10.3109/10428194.2011.608448 
 
18. 
Chen R, Frankel P, Popplewell L, Siddiqi T, Ruel N, Rotter A et al. A phase II study 
of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory 
indolent non-Hodgkin lymphoma. Haematologica 2015; 100(3): 357-362. doi: 
10.3324/haematol.2014.117473 
 
19. 
Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V et al. Phase 
II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin's 
lymphoma and mantle cell lymphoma. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 2011; 29(9): 1198-1203. doi: 
10.1200/JCO.2010.32.1398 
 
20. 
Ogura M, Ando K, Suzuki T, Ishizawa K, Oh SY, Itoh K et al. A multicentre phase II 
study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin 
lymphoma and mantle cell lymphoma. British journal of haematology 2014; 165(6): 
768-776. doi: 10.1111/bjh.12819 
 
21. 
Straus DJ, Hamlin PA, Matasar MJ, Lia Palomba M, Drullinsky PR, Zelenetz AD et 
al. Phase I/II trial of vorinostat with rituximab, cyclophosphamide, etoposide and 
prednisone as palliative treatment for elderly patients with relapsed or refractory diffuse 
large B-cell lymphoma not eligible for autologous stem cell transplantation. British 
journal of haematology 2015; 168(5): 663-670. doi: 10.1111/bjh.13195 
 
22. 
Sigalotti L, Fratta E, Coral S, Maio M. Epigenetic drugs as immunomodulators for 
combination therapies in solid tumors. Pharmacology & therapeutics 2014; 142(3): 
339-350. doi: 10.1016/j.pharmthera.2013.12.015 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
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CONFIDENTIAL 
Page 137 of 152 
 
 
 
 
23. 
Woods DM, Sodre AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J. HDAC 
Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy 
with PD-1 Blockade. Cancer immunology research 2015; 3(12): 1375-1385. doi: 
10.1158/2326-6066.CIR-15-0077-T 
 
24. 
Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL et al. Eradication of metastatic 
mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-
derived cells. Proceedings of the National Academy of Sciences of the United States of 
America 2014; 111(32): 11774-11779. doi: 10.1073/pnas.1410626111 
 
25. 
Zheng H, Zhao W, Yan C, Watson CC, Massengill M, Xie M et al. HDAC Inhibitors 
Enhance T-Cell Chemokine Expression and Augment Response to PD-1 
Immunotherapy in Lung Adenocarcinoma. Clinical cancer research : an official 
journal of the American Association for Cancer Research 2016; 22(16): 4119-4132. 
doi: 10.1158/1078-0432.CCR-15-2584 
 
26. 
Metzner B, Pott C, Muller TH, Gebauer W, Casper J, Kraemer D et al. Long-term 
clinical and molecular remissions in patients with follicular lymphoma following high-
dose therapy and autologous stem cell transplantation. Annals of oncology : official 
journal of the European Society for Medical Oncology / ESMO 2013; 24(6): 1609-
1615. doi: 10.1093/annonc/mds657 
 
27. 
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L et al. PD-1 
blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 
515(7528): 568-571. doi: 10.1038/nature13954 
 
28. 
Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA et al. Refinement 
of the Lugano classification response criteria for lymphoma in the era of 
immunomodulatory therapy. Blood 2016. doi: 10.1182/blood-2016-05-718528 
 
29. 
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline 
of pediatric phase I trials: the rolling six design. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2008; 26(2): 190-195. doi: 
10.1200/JCO.2007.12.7712 
 
30. 
Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O et al. Incidence 
of hematologic malignancies in Europe by morphologic subtype: results of the 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 138 of 152 
 
 
 
HAEMACARE project. Blood 2010; 116(19): 3724-3734. doi: 10.1182/blood-2010-
05-282632 
 
31. 
Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T et al. Cancer treatment 
and survivorship statistics, 2012. CA: a cancer journal for clinicians 2012; 62(4): 220-
241. doi: 10.3322/caac.21149 
 
32. 
Brice P, Simon D, Bouabdallah R, Belanger C, Haioun C, Thieblemont C et al. High-
dose therapy with autologous stem-cell transplantation (ASCT) after first progression 
prolonged survival of follicular lymphoma patients included in the prospective GELF 
86 protocol. Annals of oncology : official journal of the European Society for Medical 
Oncology / ESMO 2000; 11(12): 1585-1590.  
 
33. 
Le Gouill S, De Guibert S, Planche L, Brice P, Dupuis J, Cartron G et al. Impact of the 
use of autologous stem cell transplantation at first relapse both in naive and previously 
rituximab exposed follicular lymphoma patients treated in the GELA/GOELAMS 
FL2000 
study. 
Haematologica 
2011; 
96(8): 
1128-1135. 
doi: 
10.3324/haematol.2010.030320 
 
34. 
Rohatiner AZ, Nadler L, Davies AJ, Apostolidis J, Neuberg D, Matthews J et al. 
Myeloablative therapy with autologous bone marrow transplantation for follicular 
lymphoma at the time of second or subsequent remission: long-term follow-up. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology 
2007; 25(18): 2554-2559. doi: 10.1200/JCO.2006.09.8327 
 
35. 
Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H, Johnsen HE et al. High-
dose therapy improves progression-free survival and survival in relapsed follicular non-
Hodgkin's lymphoma: results from the randomized European CUP trial. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2003; 
21(21): 3918-3927. doi: 10.1200/JCO.2003.10.023 
 
36. 
Sebban C, Brice P, Delarue R, Haioun C, Souleau B, Mounier N et al. Impact of 
rituximab and/or high-dose therapy with autotransplant at time of relapse in patients 
with follicular lymphoma: a GELA study. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology 2008; 26(21): 3614-3620. doi: 
10.1200/JCO.2007.15.5358 
 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
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CONFIDENTIAL 
Page 139 of 152 
 
 
 
37. 
Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES et al. 
Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP 
alternating with ABVD. The New England journal of medicine 1992; 327(21): 1478-
1484. doi: 10.1056/NEJM199211193272102 
 
38. 
Oza AM, Ganesan TS, Leahy M, Gregory W, Lim J, Dadiotis L et al. Patterns of 
survival in patients with Hodgkin's disease: long follow up in a single centre. Annals 
of oncology : official journal of the European Society for Medical Oncology / ESMO 
1993; 4(5): 385-392.  
 
39. 
Smith SD, Moskowitz CH, Dean R, Pohlman B, Sobecks R, Copelan E et al. 
Autologous stem cell transplant for early relapsed/refractory Hodgkin lymphoma: 
results from two transplant centres. British journal of haematology 2011; 153(3): 358-
363. doi: 10.1111/j.1365-2141.2011.08616.x 
 
40. 
Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M et al. Aggressive 
conventional chemotherapy compared with high-dose chemotherapy with autologous 
haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: 
a randomised trial. Lancet 2002; 359(9323): 2065-2071. doi: 10.1016/S0140-
6736(02)08938-9 
 
41. 
Kharfan-Dabaja MA, Hamadani M, Sibai H, Savani BN. Managing Hodgkin 
lymphoma relapsing after autologous hematopoietic cell transplantation: a not-so-good 
cancer after all! Bone marrow transplantation 2014; 49(5): 599-606. doi: 
10.1038/bmt.2013.226 
 
42. 
Shi M, Roemer MG, Chapuy B, Liao X, Sun H, Pinkus GS et al. Expression of 
Programmed Cell Death 1 Ligand 2 (PD-L2) Is a Distinguishing Feature of Primary 
Mediastinal (Thymic) Large B-cell Lymphoma and Associated With PDCD1LG2 
Copy Gain. The American journal of surgical pathology 2014; 38(12): 1715-1723. doi: 
10.1097/PAS.0000000000000297 
 
43. 
Xerri L, Chetaille B, Serriari N, Attias C, Guillaume Y, Arnoulet C et al. Programmed 
death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small 
lymphocytic lymphoma/chronic lymphocytic leukemia. Human pathology 2008; 39(7): 
1050-1058. doi: 10.1016/j.humpath.2007.11.012 
 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 140 of 152 
 
 
 
44. 
Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. Programmed death-1 (PD-1) is 
a marker of germinal center-associated T cells and angioimmunoblastic T-cell 
lymphoma. The American journal of surgical pathology 2006; 30(7): 802-810. doi: 
10.1097/01.pas.0000209855.28282.ce 
 
45. 
Krishnan C, Warnke RA, Arber DA, Natkunam Y. PD-1 expression in T-cell 
lymphomas and reactive lymphoid entities: potential overlap in staining patterns 
between lymphoma and viral lymphadenitis. The American journal of surgical 
pathology 2010; 34(2): 178-189. doi: 10.1097/PAS.0b013e3181cc7e79 
 
46. 
Zhan HQ, Li XQ, Zhu XZ, Lu HF, Zhou XY, Chen Y. Expression of follicular helper 
T cell markers in nodal peripheral T cell lymphomas: a tissue microarray analysis of 
162 
cases. 
Journal 
of 
clinical 
pathology 
2011; 
64(4): 
319-324. 
doi: 
10.1136/jcp.2010.084459 
 
47. 
Han L, Liu F, Li R, Li Z, Chen X, Zhou Z et al. Role of programmed death ligands in 
effective T-cell interactions in extranodal natural killer/T-cell lymphoma. Oncology 
letters 2014; 8(4): 1461-1469. doi: 10.3892/ol.2014.2356 
 
48. 
Shimauchi T, Kabashima K, Nakashima D, Sugita K, Yamada Y, Hino R et al. 
Augmented expression of programmed death-1 in both neoplastic and non-neoplastic 
CD4+ T-cells in adult T-cell leukemia/lymphoma. International journal of cancer. 
Journal international du cancer 2007; 121(12): 2585-2590. doi: 10.1002/ijc.23042 
 
49. 
Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D et al. Plasma 
cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression 
after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and 
MEK-dependent pathway. Blood 2007; 110(1): 296-304. doi: 10.1182/blood-2006-10-
051482 
 
50. 
Kronig H, Kremmler L, Haller B, Englert C, Peschel C, Andreesen R et al. Interferon-
induced programmed death-ligand 1 (PD-L1/B7-H1) expression increases on human 
acute myeloid leukemia blast cells during treatment. European journal of haematology 
2014; 92(3): 195-203. doi: 10.1111/ejh.12228 
 
51. 
Tamura H, Dan K, Tamada K, Nakamura K, Shioi Y, Hyodo H et al. Expression of 
functional B7-H2 and B7.2 costimulatory molecules and their prognostic implications 
in de novo acute myeloid leukemia. Clinical cancer research : an official journal of 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
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Page 141 of 152 
 
 
 
the American Association for Cancer Research 2005; 11(16): 5708-5717. doi: 
10.1158/1078-0432.CCR-04-2672 
 
52. 
Kondo A, Yamashita T, Tamura H, Zhao W, Tsuji T, Shimizu M et al. Interferon-
gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7-H1, 
via nuclear factor-kappaB activation in blasts in myelodysplastic syndromes. Blood 
2010; 116(7): 1124-1131. doi: 10.1182/blood-2009-12-255125 
 
53. 
Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR et al. 
Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is 
enhanced by treatment with hypomethylating agents. Leukemia 2014; 28(6): 1280-
1288. doi: 10.1038/leu.2013.355 
 
54. 
Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S et al. 
Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-
cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm 
phase 2 trial. The lancet oncology 2016. doi: 10.1016/S1470-2045(16)30167-X 
 
55. 
Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J et al. 
Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical 
Hodgkin Lymphoma After Brentuximab Vedotin Failure. Journal of clinical oncology 
: official journal of the American Society of Clinical Oncology 2016. doi: 
10.1200/JCO.2016.67.3467 
 
56. 
 MULTICOHORT 
PHASE 
2 
STUDY 
OF 
PEMBROLIZUMAB 
FOR 
RELAPSED/REFRACTORY CLASSICAL HODGKIN LYMPHOMA (R/R CHL): 
KEYNOTE-087. European Hematology Association Annual Congress; Copenhagen, 
Denmark, 2016. 
 
57. 
Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M et al. 
Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: 
Preliminary Results of a Phase Ib Study. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology 2016; 34(23): 2698-2704. doi: 
10.1200/JCO.2015.65.9789 
 
58. 
Crump M, Coiffier B, Jacobsen ED, Sun L, Ricker JL, Xie H et al. Phase II trial of oral 
vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 142 of 152 
 
 
 
lymphoma. Annals of oncology : official journal of the European Society for Medical 
Oncology / ESMO 2008; 19(5): 964-969. doi: 10.1093/annonc/mdn031 
 
59. 
Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM et al. 
Panobinostat in patients with relapsed/refractory Hodgkin's lymphoma after autologous 
stem-cell transplantation: results of a phase II study. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2012; 30(18): 2197-2203. 
doi: 10.1200/JCO.2011.38.1350 
 
60. 
Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M et al. Results from a 
pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-
cell lymphoma after prior systemic therapy. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2012; 30(6): 631-636. e-pub 
ahead of print 2012/01/25; doi: 10.1200/JCO.2011.37.4223 
 
61. 
Thompson CA. Belinostat approved for use in treating rare lymphoma. American 
journal of health-system pharmacy : AJHP : official journal of the American Society of 
Health-System Pharmacists 2014; 71(16): 1328. doi: 10.2146/news140056 
 
62. 
Workman JL, Kingston RE. Alteration of nucleosome structure as a mechanism of 
transcriptional regulation. Annual review of biochemistry 1998; 67: 545-579. doi: 
10.1146/annurev.biochem.67.1.545 
 
63. 
Arts J, de Schepper S, Van Emelen K. Histone deacetylase inhibitors: from chromatin 
remodeling to experimental cancer therapeutics. Current medicinal chemistry 2003; 
10(22): 2343-2350.  
 
64. 
Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nature 
reviews. Genetics 2002; 3(6): 415-428. doi: 10.1038/nrg816 
 
65. 
Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T et al. Phase I 
study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in 
patients with advanced cancer. Journal of clinical oncology : official journal of the 
American 
Society 
of 
Clinical 
Oncology 
2005; 
23(17): 
3923-3931. 
doi: 
10.1200/JCO.2005.14.167 
 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 143 of 152 
 
 
 
66. 
Chen T, Sun H, Lu J, Zhao Y, Tao D, Li X et al. Histone acetylation is involved in 
hsp70 gene transcription regulation in Drosophila melanogaster. Archives of 
biochemistry and biophysics 2002; 408(2): 171-176.  
 
67. 
Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N et al. Histone 
deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth 
factor signaling. Oncogene 2002; 21(3): 427-436. doi: 10.1038/sj.onc.1205108 
 
68. 
Johnstone RW, Licht JD. Histone deacetylase inhibitors in cancer therapy: is 
transcription the primary target? Cancer cell 2003; 4(1): 13-18.  
 
69. 
Maltepe E, Krampitz GW, Okazaki KM, Red-Horse K, Mak W, Simon MC et al. 
Hypoxia-inducible factor-dependent histone deacetylase activity determines stem cell 
fate in the placenta. Development 2005; 132(15): 3393-3403. doi: 10.1242/dev.01923 
 
70. 
Chen X, Singh TR, Shankar S, Srivastava RK. In vivo regulation of apoptosis and 
angiogenesis by histone deacetylase inhibitors and TRAIL in human prostate cancer. 
Proc Am Assoc Cancer Res 2003; 44: 4305.  
 
71. 
Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW et al. Histone deacetylases 
induce angiogenesis by negative regulation of tumor suppressor genes. Nature 
medicine 2001; 7(4): 437-443. doi: 10.1038/86507 
 
72. 
Neuzil J, Swettenham E, Gellert N. Sensitization of mesothelioma to TRAIL apoptosis 
by inhibition of histone deacetylase: role of Bcl-xL down-regulation. Biochemical and 
biophysical research communications 2004; 314(1): 186-191.  
 
73. 
Sun Y, Chin YE, Weisiger E, Malter C, Tawara I, Toubai T et al. Cutting edge: 
Negative regulation of dendritic cells through acetylation of the nonhistone protein 
STAT-3. 
Journal 
of 
immunology 
2009; 
182(10): 
5899-5903. 
doi: 
10.4049/jimmunol.0804388 
 
74. 
Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C et al. Phase 2 trial of oral 
vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell 
lymphoma (CTCL). Blood 2007; 109(1): 31-39. doi: 10.1182/blood-2006-06-025999 
 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 144 of 152 
 
 
 
75. 
Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA et al. A class of 
hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. 
Proceedings of the National Academy of Sciences of the United States of America 1998; 
95(6): 3003-3007.  
 
76. 
Richon VM, Webb Y, Merger R, Sheppard T, Jursic B, Ngo L et al. Second generation 
hybrid polar compounds are potent inducers of transformed cell differentiation. 
Proceedings of the National Academy of Sciences of the United States of America 1996; 
93(12): 5705-5708.  
 
77. 
Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G et 
al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. 
Blood 2003; 101(10): 4055-4062. doi: 10.1182/blood-2002-11-3514 
 
78. 
Amin HM, Saeed S, Alkan S. Histone deacetylase inhibitors induce caspase-dependent 
apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17). 
British journal of haematology 2001; 115(2): 287-297.  
 
79. 
Nimmanapalli R, O'Bryan E, Kuhn D, Yamaguchi H, Wang HG, Bhalla KN. 
Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream 
of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases. Blood 2003; 
102(1): 269-275. doi: 10.1182/blood-2002-12-3718 
 
80. 
Mitsiades CS, Mitsiades N, Richardson PG, Treon SP, Anderson KC. Novel 
biologically based therapies for Waldenstrom's macroglobulinemia. Seminars in 
oncology 2003; 30(2): 309-312. doi: 10.1053/sonc.2003.50065 
 
81. 
Zhang Y, Li N, Caron C, Matthias G, Hess D, Khochbin S et al. HDAC-6 interacts 
with and deacetylates tubulin and microtubules in vivo. The EMBO journal 2003; 
22(5): 1168-1179. doi: 10.1093/emboj/cdg115 
 
82. 
Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor 
selectively induces p21WAF1 expression and gene-associated histone acetylation. 
Proceedings of the National Academy of Sciences of the United States of America 2000; 
97(18): 10014-10019. doi: 10.1073/pnas.180316197 
 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 145 of 152 
 
 
 
83. 
Huang L, Pardee AB. Suberoylanilide hydroxamic acid as a potential therapeutic agent 
for human breast cancer treatment. Molecular medicine 2000; 6(10): 849-866.  
 
84. 
Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C et al. 
Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the 
growth of prostate cancer cells in vitro and in vivo. Cancer research 2000; 60(18): 
5165-5170.  
 
85. 
Peart MJ, Tainton KM, Ruefli AA, Dear AE, Sedelies KA, O'Reilly LA et al. Novel 
mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer research 
2003; 63(15): 4460-4471.  
 
86. 
He LZ, Tolentino T, Grayson P, Zhong S, Warrell RP, Jr., Rifkind RA et al. Histone 
deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute 
promyelocytic leukemia. The Journal of clinical investigation 2001; 108(9): 1321-
1330. doi: 10.1172/JCI11537 
 
87. 
Siddiqi T, Frankel P, Ruel C, Chen RW, Kelly KR, Tuscano J et al. Phase 1 Study of 
MLN8237, an Aurora KinaseA (AURKA) Inhibitor, Combined with Vorinostat, a 
Histone Deacetylase (HDAC) Inhibitor, in Lymphoid Malignancies. Blood 2014; 
124(21): 4483-4483.  
 
88. 
Siddiqi T, Scuto A, Beumer JH, Song JY, Frankel P, Ruel C et al. Results from a Phase 
1 Study and Expanded Cohort of an Interrupted Dosing Schedule of the Aurora Kinase 
a Inhibitor MLN8237 Combined with Vorinostat in Lymphoid Malignancies. Blood 
2015; 126(23): 2731-2731.  
 
89. 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. 
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New 
England 
journal 
of 
medicine 
2012; 
366(26): 
2443-2454. 
doi: 
10.1056/NEJMoa1200690 
 
90. 
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al. Specific recruitment 
of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts 
reduced survival. Nature medicine 2004; 10(9): 942-949. doi: 10.1038/nm1093 
 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 146 of 152 
 
 
 
91. 
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006; 313(5795): 1960-1964. doi: 10.1126/science.1129139 
 
92. 
Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R et al. Effector 
memory T cells, early metastasis, and survival in colorectal cancer. The New England 
journal of medicine 2005; 353(25): 2654-2666. doi: 10.1056/NEJMoa051424 
 
93. 
Bachireddy P, Hainz U, Rooney M, Pozdnyakova O, Aldridge J, Zhang W et al. 
Reversal of in situ T-cell exhaustion during effective human antileukemia responses to 
donor lymphocyte infusion. Blood 2014; 123(9): 1412-1421. doi: 10.1182/blood-2013-
08-523001 
 
94. 
Chang AY, Bhattacharya N, Mu J, Setiadi AF, Carcamo-Cavazos V, Lee GH et al. 
Spatial organization of dendritic cells within tumor draining lymph nodes impacts 
clinical outcome in breast cancer patients. Journal of translational medicine 2013; 11: 
242. doi: 10.1186/1479-5876-11-242 
 
95. 
Setiadi AF, Ray NC, Kohrt HE, Kapelner A, Carcamo-Cavazos V, Levic EB et al. 
Quantitative, architectural analysis of immune cell subsets in tumor-draining lymph 
nodes from breast cancer patients and healthy lymph nodes. PloS one 2010; 5(8): 
e12420. doi: 10.1371/journal.pone.0012420 
 
96. 
Reichel J, Chadburn A, Rubinstein PG, Giulino-Roth L, Tam W, Liu Y et al. Flow 
sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-
Sternberg cells. Blood 2015; 125(7): 1061-1072. doi: 10.1182/blood-2014-11-610436 
 
97. 
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al. Distinct types 
of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 
403(6769): 503-511. doi: 10.1038/35000501 
 
98. 
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI et al. The use of 
molecular profiling to predict survival after chemotherapy for diffuse large-B-cell 
lymphoma. The New England journal of medicine 2002; 346(25): 1937-1947. doi: 
10.1056/NEJMoa012914 
 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 147 of 152 
 
 
 
99. 
Slovak ML, Bedell V, Hsu YH, Estrine DB, Nowak NJ, Delioukina ML et al. 
Molecular karyotypes of Hodgkin and Reed-Sternberg cells at disease onset reveal 
distinct copy number alterations in chemosensitive versus refractory Hodgkin 
lymphoma. Clinical cancer research : an official journal of the American Association 
for Cancer Research 2011; 17(10): 3443-3454. doi: 10.1158/1078-0432.CCR-10-1071 
 
100. 
Steidl C, Telenius A, Shah SP, Farinha P, Barclay L, Boyle M et al. Genome-wide copy 
number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with 
correlations to treatment outcome. Blood 2010; 116(3): 418-427. doi: 10.1182/blood-
2009-12-257345 
 
101. 
Hartmann S, Martin-Subero JI, Gesk S, Husken J, Giefing M, Nagel I et al. Detection 
of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of 
classical Hodgkin's lymphoma by array-based comparative genomic hybridization. 
Haematologica 2008; 93(9): 1318-1326. doi: 10.3324/haematol.12875 
 
102. 
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ et al. Cancer 
immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-
small 
cell 
lung 
cancer. 
Science 
2015; 
348(6230): 
124-128. 
doi: 
10.1126/science.aaa1348 
 
103. 
Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A et al. Genetic 
basis for clinical response to CTLA-4 blockade in melanoma. The New England journal 
of medicine 2014; 371(23): 2189-2199. doi: 10.1056/NEJMoa1406498 
 
104. 
Lu YC, Yao X, Crystal JS, Li YF, El-Gamil M, Gross C et al. Efficient identification 
of mutated cancer antigens recognized by T cells associated with durable tumor 
regressions. Clinical cancer research : an official journal of the American Association 
for Cancer Research 2014; 20(13): 3401-3410. doi: 10.1158/1078-0432.CCR-14-0433 
 
105. 
Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C, Gartner J et al. Mining exomic 
sequencing data to identify mutated antigens recognized by adoptively transferred 
tumor-reactive T cells. Nature medicine 2013; 19(6): 747-752. doi: 10.1038/nm.3161 
 
106. 
Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J et al. An immune-
active tumor microenvironment favors clinical response to ipilimumab. Cancer 
immunology, immunotherapy : CII 2012; 61(7): 1019-1031. doi: 10.1007/s00262-011-
1172-6 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 148 of 152 
 
 
 
 
107. 
Ulloa-Montoya F, Louahed J, Dizier B, Gruselle O, Spiessens B, Lehmann FF et al. 
Predictive gene signature in MAGE-A3 antigen-specific cancer immunotherapy. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2013; 31(19): 2388-2395. doi: 10.1200/JCO.2012.44.3762 
 
108. 
Armand P, Oki Y, Neuberg DS, Faham M, Cummings C, Klinger M et al. Detection of 
circulating tumour DNA in patients with aggressive B-cell non-Hodgkin lymphoma. 
British journal of haematology 2013; 163(1): 123-126. doi: 10.1111/bjh.12439 
 
109. 
Oki Y, Neelapu SS, Fanale M, Kwak LW, Fayad L, Rodriguez MA et al. Detection of 
classical Hodgkin lymphoma specific sequence in peripheral blood using a next-
generation sequencing approach. British journal of haematology 2015; 169(5): 689-
693. doi: 10.1111/bjh.13349 
 
110. 
Roschewski M, Dunleavy K, Pittaluga S, Moorhead M, Pepin F, Kong K et al. 
Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-
cell lymphoma: a correlative biomarker study. The lancet oncology 2015; 16(5): 541-
549. doi: 10.1016/S1470-2045(15)70106-3 
 
111. 
Kurtz DM, Green MR, Bratman SV, Scherer F, Liu CL, Kunder CA et al. Noninvasive 
monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput 
sequencing. Blood 2015; 125(24): 3679-3687. doi: 10.1182/blood-2015-03-635169 
 
112. 
Sarkozy C, Huet S, Carlton V, Delmer A, Jardin F, Delfau-Larue MH et al. Quantitative 
Assessment of Circulating Clonal IG-VDJ Sequences in Plasma of Follicular 
Lymphoma at Diagnosis Is Highly Predictive of Progression Free Survival (PFS). ASH 
2015, abstract #2675  
 
113. 
 Noninvasive Genotyping And Assessment of Treatment Response in Diffuse Large B-
Cell Lymphoma. ASH 2015, abstract #126. 
 
114. 
 Dynamic Noninvasive Genome Monitoring for Outcome Prediction in Diffuse Large 
B-Cell Lymphoma. ASH 2015, abstract #130. 
 
115. 
Scherer F, Kurtz DM, Newman AM, Stehr H, Craig AF, Esfahani MS et al. Distinct 
biological subtypes and patterns of genome evolution in lymphoma revealed by 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 149 of 152 
 
 
 
circulating tumor DNA. Science translational medicine 2016; 8(364): 364ra155. doi: 
10.1126/scitranslmed.aai8545 
 
116. 
Rossi D, Diop F, Spaccarotella E, Monti S, Zanni M, Rasi S et al. Diffuse large B-cell 
lymphoma genotyping on the liquid biopsy. Blood 2017. doi: 10.1182/blood-2016-05-
719641 
 
117. 
Bohers E, Viailly PJ, Dubois S, Bertrand P, Maingonnat C, Mareschal S et al. Somatic 
mutations of cell-free circulating DNA detected by next-generation sequencing reflect 
the genetic changes in both germinal center B-cell-like and activated B-cell-like diffuse 
large B-cell lymphomas at the time of diagnosis. Haematologica 2015; 100(7): e280-
284. doi: 10.3324/haematol.2015.123612 
 
118. 
Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D et al. Phase 2 
study of panobinostat with or without rituximab in relapsed diffuse large B-cell 
lymphoma. Blood 2016; 128(2): 185-194. doi: 10.1182/blood-2016-02-699520 
 
119. 
Herrera AF, Kim HT, Kong KA, Faham M, Sun H, Sohani AR et al. Next-generation 
sequencing-based detection of circulating tumour DNA After allogeneic stem cell 
transplantation for lymphoma. British journal of haematology 2016. doi: 
10.1111/bjh.14311 
 
120. 
Vandenberghe P, Wlodarska I, Tousseyn T, Dehaspe L, Dierickx D, Verheecke M et 
al. Non-invasive detection of genomic imbalances in Hodgkin/Reed-Sternberg cells in 
early and advanced stage Hodgkin's lymphoma by sequencing of circulating cell-free 
DNA: a technical proof-of-principle study. The Lancet. Haematology 2015; 2(2): e55-
65. doi: 10.1016/S2352-3026(14)00039-8 
 
121. 
Camus V, Stamatoullas A, Mareschal S, Viailly PJ, Sarafan-Vasseur N, Bohers E et al. 
Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free 
circulating DNA of patients with classical Hodgkin lymphoma. Haematologica 2016; 
101(9): 1094-1101. doi: 10.3324/haematol.2016.145102 
 
122. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E et al. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. Journal of 
Clinical Oncology 2014. doi: 10.1200/jco.2013.54.8800 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 150 of 152 
 
 
 
 
123. 
Hutchings M, Loft A, Hansen M, Pedersen LM, Buhl T, Jurlander J et al. FDG-PET 
after two cycles of chemotherapy predicts treatment failure and progression-free 
survival in Hodgkin lymphoma. Blood 2006; 107(1): 52-59. doi: 10.1182/blood-2005-
06-2252 
 
124. 
Song MK, Chung JS, Lee JJ, Jeong SY, Lee SM, Hong JS et al. Metabolic tumor 
volume by positron emission tomography/computed tomography as a clinical 
parameter to determine therapeutic modality for early stage Hodgkin's lymphoma. 
Cancer Sci 2013; 104(12): 1656-1661. doi: 10.1111/cas.12282 
 
125. 
Kanoun S, Rossi C, Berriolo-Riedinger A, Dygai-Cochet I, Cochet A, Humbert O et 
al. Baseline metabolic tumour volume is an independent prognostic factor in Hodgkin 
lymphoma. Eur J Nucl Med Mol I 2014; 41(9): 1735-1743. doi: 10.1007/s00259-014-
2783-x 
 
126. 
Tseng D, Rachakonda LP, Su Z, Advani R, Horning S, Hoppe RT et al. Interim-
treatment quantitative PET parameters predict progression and death among patients 
with Hodgkin's disease. Radiation oncology 2012; 7: 5. doi: 10.1186/1748-717X-7-5 
 
127. 
Hussien AE, Furth C, Schonberger S, Hundsdoerfer P, Steffen IG, Amthauer H et al. 
FDG-PET Response Prediction in Pediatric Hodgkin's Lymphoma: Impact of 
Metabolically Defined Tumor Volumes and Individualized SUV Measurements on the 
Positive Predictive Value. Cancers 2015; 7(1): 287-304. doi: 10.3390/cancers7010287 
 
128. 
Cottereau AS, Versari A, Loft A, Casasnovas O, Bellei M, Ricci R et al. Prognostic 
value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the 
standard arm of the H10 trial. Blood 2018; 131(13): 1456-1463. doi: 10.1182/blood-
2017-07-795476 
 
129. 
Mettler J, Muller H, Voltin CA, Baues C, Klaeser B, Moccia A et al. Metabolic Tumor 
Volume for Response Prediction in Advanced-Stage Hodgkin Lymphoma. J Nucl Med 
2019; 60(2): 207-211. doi: 10.2967/jnumed.118.210047 
 
130. 
Kanoun S, Tal I, Berriolo-Riedinger A, Rossi C, Riedinger JM, Vrigneaud JM et al. 
Influence of Software Tool and Methodological Aspects of Total Metabolic Tumor 
Volume Calculation on Baseline [18F] FDG PET to Predict Survival in Hodgkin 
Lymphoma. PloS one 2015; 10(10). doi: ARTN e0140830 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
Page 151 of 152 
 
 
 
10.1371/journal.pone.0140830 
 
131. 
Casasnovas RO, Kanoun S, Tal I, Cottereau AS, Edeline V, Brice P et al. Baseline total 
metabolic volume (TMTV) to predict the outcome of patients with advanced Hodgkin 
lymphoma (HL) enrolled in the AHL2011 LYSA trial. Journal of Clinical Oncology 
2016; 34(15). doi: 10.1200/Jco.2016.34.15_Suppl.7509 
 
132. 
Moskowitz AJ, Schoder H, Gavane S, Thoren KL, Fleisher M, Yahalom J et al. 
Prognostic significance of baseline metabolic tumor volume in relapsed and refractory 
Hodgkin lymphoma. Blood 2017; 130(20): 2196-2203. doi: 10.1182/blood-2017-06-
788877 
 
133. 
Itti E, Meignan M, Berriolo-Riedinger A, Biggi A, Cashen AF, Vera P et al. An 
international confirmatory study of the prognostic value of early PET/CT in diffuse 
large B-cell lymphoma: comparison between Deauville criteria and DeltaSUVmax. Eur 
J Nucl Med Mol Imaging 2013; 40(9): 1312-1320. e-pub ahead of print 2013/05/08; 
doi: 10.1007/s00259-013-2435-6 
 
134. 
Mikhaeel NG, Smith D, Dunn JT, Phillips M, Moller H, Fields PA et al. Combination 
of baseline metabolic tumour volume and early response on PET/CT improves 
progression-free survival prediction in DLBCL. Eur J Nucl Med Mol Imaging 2016; 
43(7): 1209-1219. e-pub ahead of print 2016/02/24; doi: 10.1007/s00259-016-3315-7 
 
135. 
Schmitz C, Huttmann A, Muller SP, Hanoun M, Boellaard R, Brinkmann M et al. 
Dynamic risk assessment based on positron emission tomography scanning in diffuse 
large B-cell lymphoma: Post-hoc analysis from the PETAL trial. Eur J Cancer 2020; 
124: 25-36. e-pub ahead of print 2019/11/12; doi: 10.1016/j.ejca.2019.09.027 
 
136. 
Vercellino L, Cottereau AS, Casasnovas O, Tilly H, Feugier P, Chartier L et al. High 
total metabolic tumor volume at baseline predicts survival independent of response to 
therapy. Blood 2020; 135(16): 1396-1405. e-pub ahead of print 2020/01/25; doi: 
10.1182/blood.2019003526 
 
137. 
Cottereau AS, Nioche C, Dirand AS, Clerc J, Morschhauser F, Casasnovas O et al. 
(18)F-FDG PET Dissemination Features in Diffuse Large B-Cell Lymphoma Are 
Predictive of Outcome. J Nucl Med 2020; 61(1): 40-45. e-pub ahead of print 
2019/06/16; doi: 10.2967/jnumed.119.229450 

 
Pembrolizumab Plus Vorinostat for DLBCL, FL and HL  
City of Hope #: 17080  
Protocol Version‐Date:  10‐ 10/16/20 
 
CONFIDENTIAL 
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138. 
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L et al. 2006 
update of recommendations for the use of white blood cell growth factors: an evidence-
based clinical practice guideline. Journal of clinical oncology : official journal of the 
American 
Society 
of 
Clinical 
Oncology 
2006; 
24(19): 
3187-3205. 
doi: 
10.1200/JCO.2006.06.4451 
 
139. 
Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Mueller SP et 
al. Role of imaging in the staging and response assessment of lymphoma: consensus of 
the International Conference on Malignant Lymphomas Imaging Working Group. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2014; 32(27): 3048-3058. doi: 10.1200/JCO.2013.53.5229 
 
140. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. American journal of 
clinical oncology 1982; 5(6): 649-655. e-pub ahead of print 1982/12/01;