Clinical trial NCT05166577
Conditions: Nasopharyngeal Carcinoma EBV-Related Gastric Carcinoma EBV-Related Leiomyosarcoma EBV Related Carcinoma EBV-Related Sarcoma
Sponsor: Viracta Therapeutics, Inc.
Start date: 2021-10-08; Completion date: 2025-01-10
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety and efficacy of nanatinostat in combination with valganciclovir in patients with relapsed/refractory EBV-positive solid tumors and in combination with pembrolizumab in patients with recurrent/metastatic nasopharyngeal carcinoma

Detailed description:
This is an open-label, multicenter Phase 1b/2 study evaluating nanatinostat in combination with valganciclovir alone and in combination with pembrolizumab. Nanatinostat is a selective class I HDAC inhibitor which induces EBV early lytic phase protein generation, activating (val)ganciclovir to its cytotoxic form.

The Phase 1b dose escalation portion is designed to evaluate safety and to determine the recommended Phase 2 dose (RP2D) in patients with EBV+ RM-NPC followed by a Project Optimus \| FDA (https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus) cohort to confirm the RP2D. Up to 60 patients with EBV+ RM-NPC will be randomized 1:1 to receive nanatinostat in combination with valganciclovir at the confirmed RP2D with or without pembrolizumab to evaluate safety, overall response rate, and potential pharmacodynamic markers in the Phase 2 dose expansion part of the study. Additionally, patients with other EBV+ solid tumors will be enrolled to receive nanatinostat in combination with valganciclovir at the RP2D in a Phase 1b cohort.

The study was prematurely terminated after the end of Phase 1b and did not proceed to Phase 2.

Arms: arm 1: Phase 1b: Nanatinostat dose escalation starting at 20 mg orally daily, 4 days per week, and valganciclovir starting at 900 mg orally daily, then Phase 2: Nanatinostat and valganciclovir at the confirmed recommended Phase 2 dose arm 2: Phase 2: Nanatinostat and valganciclovir at the confirmed recommended Phase 2 doses in combination with pembrolizumab 200 mg intravenous (IV) every 3 weeks
Interventions: intervention 1: Nanatinostat intervention 2: Valganciclovir intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: Phase 1b: Nanatinostat dose escalation starting at 20 mg orally daily, 4 days per week, then Phase 2: Nanatinostat at the confirmed recommended Phase 2 dose intervention 2: Phase 1b: Valganciclovir starting at 900 mg orally daily, then Phase 2: Valganciclovir at the confirmed recommended Phase 2 dose intervention 3: Phase 2: Pembrolizumab (anti-PD-1) dosed at 200 mg intravenous (IV) every 3 weeks

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol VT3996-301 
Nanatinostat (VRx-3996) 
IND 154400 
Viracta, Inc. 
Version 4.0 (22 Sep 2023) 
CONFIDENTIAL 
Page 1 of 127 
An Open-Label, Multicenter Phase 1b/2 Study of Nanatinostat 
and Valganciclovir in Patients with Advanced Epstein-Barr 
Virus-Positive (EBV+) Solid Tumors and in Combination with 
Pembrolizumab in Patients with Recurrent/Metastatic 
Nasopharyngeal Carcinoma 
Protocol Number:  VT3996-301 
Sponsor Name and Legal 
Registered Address: 
Viracta Therapeutics, Inc. 
2533 S. Coast Hwy 101 
Suite 210 
Cardiff, CA 92007 
(858) 400-8470
Sponsor Contact: Darrel P. Cohen, MD, PhD 
Chief Medical Officer 
DCohen@Viracta.com 
Investigational Drugs: Nanatinostat, VRx-3996 
Valganciclovir 
Pembrolizumab 
Short Title: Nanatinostat and Valganciclovir in EBV+ Solid Tumors 
Regulatory Agency 
Identifying Number(s): 
IND Number 154400 
Original Protocol: Version 1.0; 10 Jun 2021 
Amendment 1: Version 2.0; 19 Jul 2021 
Amendment 2: Version 3.0; 24 Aug 2022 
Amendment 3: Version 4.0; 22 Sep 2023 
This study will be conducted according to the principles of Good Clinical Practice as described 
in International Council for Harmonisation guidelines, including the archiving of 
essential documents. 
Confidentiality Statement 
The information contained in this document and all information provided to you related to 
nanatinostat are the confidential and proprietary information of Viracta Therapeutics, Inc. 
(“Viracta”) and except as may be required by federal, state, or local laws or regulations, may not 
be disclosed to others without prior written permission of Viracta. The Investigator may, 
however, disclose such information to supervised individuals working on nanatinostat, provided 
such individuals agree to be bound to maintain the confidentiality of such drug information. 
(NCT05166577)




Clinical Study Protocol VT3996-301 
Nanatinostat (VRx-3996) 
IND 154400 
Viracta, Inc. 
Version 4.0 (22 Sep 2023) 
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INVESTIGATOR’S AGREEMENT 
By signing below, the Investigator agrees to adhere to the protocol as written and agrees that 
any changes to the protocol must be approved by Viracta Therapeutics, Inc. before seeking 
approval from the Institutional Review Board/Research Ethics Board/Independent Ethics 
Committee (IRB/REB/IEC). 
The study will be conducted in accordance with the current International Council for 
Harmonisation (ICH) Guidelines, the Guidelines for Good Clinical Practice (GCP), the 
Declaration of Helsinki, national and local ethical and legal requirements. 
The information contained in this protocol is proprietary and provided to the Investigator in 
confidence, and may not be disclosed to any other party, in any form, without prior authorization 
from Viracta Therapeutics, except to the extent necessary for the conduct of the study at this 
investigational site. 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
 
 
 
Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol VT3996-301 
Nanatinostat (VRx-3996) 
IND 154400 
Viracta, Inc. 
Version 4.0 (22 Sep 2023) 
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PROTOCOL SYNOPSIS 
Protocol Number 
VT3996-301 
Study Title 
An Open-Label, Multicenter Phase 1b/2 Study of Nanatinostat and Valganciclovir in Patients 
with Advanced Epstein-Barr Virus-Positive (EBV+) Solid Tumors and in Combination with 
Pembrolizumab in Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma 
Sponsor  
Viracta Therapeutics, Inc. 
Investigational 
Drugs 
Nanatinostat (VRx-3996) 
Valganciclovir 
Pembrolizumab 
Study Phase 
Phase 1b/2 
Primary objectives 
 
Phase 1b: 
• 
To determine the recommended Phase 2 dose (RP2D) of nanatinostat in combination 
with valganciclovir  
Phase 2: 
• 
To confirm the RP2D of nanatinostat in combination with valganciclovir  
• 
To estimate the objective response rate (ORR) of nanatinostat and valganciclovir alone 
and in combination with pembrolizumab 
Secondary 
objectives 
 
• 
To characterize the safety and tolerability of nanatinostat and valganciclovir alone and in 
combination with pembrolizumab 
• 
To characterize the pharmacokinetic (PK) properties of nanatinostat in combination with 
valganciclovir 
• 
To evaluate additional preliminary efficacy parameters of nanatinostat and valganciclovir 
alone and in combination with pembrolizumab 
 
Exploratory 
objectives 
• 
To evaluate potential biomarkers of activity of nanatinostat and valganciclovir with or 
without pembrolizumab  
• 
To evaluate the safety, tolerability, PK, pharmacodynamics, and antitumor activity of 
nanatinostat in combination with valganciclovir in patients with non-nasopharyngeal 
(NPC) EBV+ solid tumors 
Primary endpoints Phase 1b: 
• 
Incidence of dose-limiting toxicities (DLTs) during the DLT evaluation period 
Phase 2: 
• 
Incidence of DLTs plus other safety parameters, tolerability, PK, and plasma EBV DNA 
concentrations at the RP2D and <RP2D of nanatinostat in combination with 
valganciclovir  
• 
ORR - defined as the percentage of patients with a complete response (CR) or partial 
response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST), 
version 1.1 (v1.1) 
Secondary 
endpoints 
• 
Incidence and severity of treatment-emergent adverse events per National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
• 
PK parameters (eg, time to maximum plasma concentration, maximum plasma 
concentration, and area under the plasma concentration-time curve) of nanatinostat, its 
metabolites, and ganciclovir (primary active hydrolytic product of valganciclovir) 
• 
Duration of response (DOR) - defined as the interval from date of first observed CR or 
PR to the date of documented disease progression or death due to any cause, whichever 
occurs first 


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IND 154400 
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• 
Disease control rate (DCR)- defined as the percentage of patients having a CR, PR, or 
stable disease at any time during treatment 
• 
Progression-free survival (PFS) - defined as the interval from the start of study drug 
treatment to the date of first documented disease progression or death from any cause, 
whichever occurs first 
• 
Overall survival (OS) - defined as the interval of time from the start of study drug 
treatment to date of death for any reason 
Exploratory 
endpoints 
• 
Plasma Epstein-Barr virus (EBV) DNA levels (real-time quantitative polymerase chain 
reaction [PCR])  
• 
Expression of EBV gene products (ie, lytic cycle antigens) in both pre-study and during 
study tumor biopsies 
• 
Programmed cell death-ligand 1 expression on tumor cells and tumor-infiltrating immune 
cells 
• 
Histone H3 acetylation 
• 
Incidence of DLTs plus other safety parameters, tolerability, PK, and plasma EBV DNA 
concentrations of nanatinostat in combination with valganciclovir in non-NPC solid 
tumors 
Study Design 
Phase 1b/2, open-label, multicenter study.  
Phase 1b: 
A traditional 3+3 dose escalation design will be used to determine the RP2D of nanatinostat 
and valganciclovir; approximately 27 to 60 patients with recurrent and/or metastatic 
nasopharyngeal carcinoma (RM-NPC) will be enrolled; cohorts of 3 to 6 patients with RM-
NPC will be enrolled sequentially at escalating nanatinostat doses starting with a 20 mg once 
daily dose on Days 1 to 4 per week (intermittent dosing) with valganciclovir 900 mg daily. 
Dose escalation of nanatinostat will continue with i) a total daily dose of 30 and 40 mg 
administered as a single dose on Days 1 to 4 per week with valganciclovir 900 mg once 
daily,  ii) as a divided nanatinostat dose twice daily on Days 1 to 4 per week with 
valganciclovir 900 mg once daily or twice daily for 21 days followed by a subsequent dose 
reduction to 900 mg once daily, then iii) as a split daily dose (SDD) of nanatinostat starting at 
20 mg and valganciclovir at 450 mg twice daily 4 hours apart on Days 1 to 7 per week 
(continuous daily dosing) until the RP2D is determined. 
 
Phase 2: 
Phase 2 will begin with a randomized dose optimization lead-in cohort to assess the safety, 
PK, pharmacodynamics, and antitumor activity of nanatinostat and valganciclovir and 
confirm its RP2D in patients with RM-NPC. Patients will be randomly assigned 1:1 to each 
treatment group (up to 20 patients in each treatment group; for approximately 40 patients 
total) during the dose optimization cohort period. The starting doses of nanatinostat for the 
treatment groups will be the RP2D and another dose level below the RP2D (‘<RP2D’) 
together with valganciclovir 450 mg twice daily based on the Safety Monitoring Committee’s 
(SMC) review of the totality of data from the previous Phase 1b cohorts.  
After the nanatinostat and valganciclovir RP2D has been confirmed by the SMC based on the 
results of the dose optimization cohort, up to 60 patients with RM-NPC will be randomly 
assigned 1:1 to receive nanatinostat and valganciclovir at that RP2D with or without 
pembrolizumab (n = 30 per cohort) to assess the preliminary antitumor activity, safety, and 
tolerability of each regimen in the Phase 2 dose expansion period. Randomization will be 
stratified by prior anti-programmed cell death 1 (PD-1) treatment exposure. Pembrolizumab 
will be administered at 200 mg intravenously every 3 weeks for those patients randomly 
assigned to the nanatinostat, valganciclovir, and pembrolizumab group. An early safety 
analysis after the first 6 patients randomized to this treatment group and followed for at least 
2 cycles (7 weeks) will be performed. 


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IND 154400 
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In addition, up to 10 patients with advanced EBV+ non-nasopharyngeal carcinoma (NPC) 
solid tumors (gastric cancer, lymphoepithelioma-like carcinoma, and leiomyosarcoma) will 
be enrolled in a Phase 1b exploratory proof-of-concept cohort to characterize the safety and 
PK of the nanatinostat and valganciclovir combination in other solid tumors. Enrollment in 
this proof-of-concept cohort will begin when the appropriate RP2D for this population is 
determined in consultation with the SMC, while enrollment in this proof-of-concept cohort 
may be stopped before 10 patients are treated if a) evidence of safety or tolerability issues 
arise, or b) Phase 2 of the study completes enrollment. 
Tumor responses will be assessed at Week 8 and then every 6 weeks for the first 26 weeks 
(6 months) and every 12 weeks thereafter by the Investigator per RECIST v1.1. A scan to 
confirm an unconfirmed PR or unconfirmed CR ≥4 weeks later may also be performed. 
Patients will continue to receive study treatment until the development of progressive disease 
(per Investigator assessment), unacceptable toxicity, withdrawal of consent, Investigator’s 
discretion, initiation of new antineoplastic therapy, or study termination by the Sponsor 
(maximum treatment duration of pembrolizumab is 24 months). 
Upon discontinuation of the protocol-specified treatments, patients will enter the Follow-up 
period. All patients must complete safety follow-up assessments at 30 and 90 days after 
receiving their last dose of study treatment (permanent discontinuation). All AEs for patients 
treated with nanatinostat, valganciclovir, and pembrolizumab and only serious adverse events 
(SAEs) for all other patients will be collected up to and including 90 days after the last dose 
of study treatment or until the start of a new antineoplastic therapy, whichever occurs first. 
All patients enrolled in the study will be followed for survival.  
Population  
Phase 1b: Patients with EBV+ RM-NPC and EBV+ non-NPC solid tumors (exploratory 
proof-of-concept cohort only) 
Phase 2: Patients with EBV+ RM-NPC  
Inclusion Criteria 
1. Adult patients age ≥18 years.  
2. Willing and able to give informed consent. 
3. Histologically or cytologically documented EBV+ tumor cells by Epstein-Barr virus 
encoded RNA – in situ hybridization (EBER-ISH) or latent membrane protein (LMP) 
-1 (according to local guidelines) per an archival tumor sample taken within 2 years 
prior to screening otherwise a de novo biopsy may be required. Formalin fixed, 
paraffin embedded (FFPE)  tissue block(s) or at least 10 unstained slides are 
requested. It is encouraged (but not required) that patients with a site of disease 
accessible to biopsy and who are candidates for tumor biopsy according to local 
practice guidelines undergo a new tumor biopsy at baseline and during treatment.  
4. Patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) 
(excluding patients in the Phase 1b exploratory proof-of-concept cohort) for whom 
no potentially curative options are available, who have received at least 1 prior line of 
platinum-based chemotherapy, and no more than 3 prior lines of therapy for RM-
NPC.  
Note: The following clinical scenarios are not considered to be separate lines of 
therapy:  
a. 
Maintenance therapy: drug therapy (including chemotherapy, targeted therapy, 
or immunotherapy including vaccines, cellular therapy, and checkpoint 
inhibitors) that is started with maintenance intent in patients who have recently 
completed one line of chemotherapy without experiencing disease progression 
b. Drug rechallenge: patients who have been “rechallenged” with the same drug 
therapy(s) previously used to treat recurrent or metastatic NPC. 
5. Patients who developed recurrent or metastatic disease within six months following 
radical concurrent chemoradiotherapy in combination with neoadjuvant and/or 
adjuvant therapy for non-metastatic NPC are eligible as long as no potentially 
curative options are available. 


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6. For Phase 1b exploratory proof-of-concept cohort only: Patients with 
advanced/metastatic EBV+ non-NPC solid tumors (gastric cancer, 
lymphoepithelioma-like carcinoma, leiomyosarcoma) that have progressed despite 
standard therapy for which no effective therapies exist. 
7. Radiologically measurable disease per RECIST v1.1. 
8. All acute toxic effects of any prior anti-neoplastic therapy resolved to at least Grade 1 
before initiation of study treatment (excluding alopecia, and Grade 2 sensory 
neuropathy, hypothyroidism [stable on thyroid hormone supplementation], 
chronic/stable xerostomia, hearing loss, lymphedema, and taste changes [all 
Grade 2]). 
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
10. Life expectancy ≥3 months. 
11. Adequate laboratory parameters (in the absence of transfusion or growth factor 
support within 3 weeks of Screening) including: 
a. 
Absolute neutrophil count (ANC) ≥1500/mm3. 
b. Platelet (PLT) count ≥100,000/mm3. 
c. 
Hemoglobin ≥9.0 g/dL. 
d. Aspartate aminotransferase (AST)/serum glutamine oxaloacetic transaminase 
(SGOT), alanine aminotransferase (ALT)/serum glutamic- pyruvic 
transaminase (SGPT) ≤2.5 × upper limit of normal (ULN) (≤5 × ULN if 
known liver involvement by tumor). 
e. 
Total bilirubin ≤2.0 × ULN unless considered due to Gilbert’s syndrome in 
which case, ≤3.5 × ULN. 
f. 
Estimated glomerular filtration (eGFR) rate ≥60 mL/min by Cockcroft-Gault 
equation (see Section 5.6.2 for formula to calculate creatinine clearance). 
g. Prothrombin time (PT) or international normalized ratio (INR) ≤1.5 × ULN. 
h. Serum potassium and magnesium should be within normal limits for 
institution or treatment to correct out of range values should be instituted. 
12. For human immunodeficiency virus (HIV) positive patients:  
a. 
CD4 count ≥350 cells/μL. 
b. On an established antiretroviral therapy (ART) for ≥4 weeks.  
c. 
An undetectable HIV viral load. 
d. No prior acquired immunodeficiency syndrome (AIDS)-defining opportunistic 
infections within the past 12 months. 
13. Willingness to comply with study requirements. 
14. Women of childbearing potential (ie, reached menarche, and not post-menopausal [no 
menses for 12 months without an alternative medical cause] or surgically sterile) 
must have the following:  
a. 
Understand that the study medication is expected to have teratogenic risk. 
b. Have a negative serum beta human-chorionic gonadotropin (β-hCG) 
pregnancy test at screening. 
c. 
Commit to continued abstinence from heterosexual intercourse (excluding 
periodic abstinence or the withdrawal method) or commit to the use of 2 forms 
of birth control with at least one highly effective method of birth control with a 
Pearl-Index <1%, and one effective barrier method such as a male condom, 
female condom, cervical cap, diaphragm, or contraceptive sponge with 
spermicide, without interruption, throughout the study dosing period and for 6 
months after the last dose of study treatment. Apart from abstinence, highly 
effective methods of birth control include the following: 
i. Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (ie, intravaginal, transdermal). 
Please note: Although the potential for drug interactions and risk of venous 


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thromboembolism is low (see Section 5.7.2.3), the use of an alternative 
method of contraception is recommended. 
ii. Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable). 
iii. Intrauterine device (IUD). 
iv. Intrauterine hormone-releasing system (IUS). 
v. Bilateral tubal occlusion. 
vi. Vasectomized partner. 
15. Male patients must agree to use condoms during intercourse throughout the study 
dosing period and for 90 days after the last dose of study treatment.  
Exclusion Criteria 
1. 
Anti-tumor treatment with cytotoxic drugs, biologic therapy (eg, monoclonal 
antibody), immunotherapy or other investigational drugs within 4 weeks or >5 half-
lives, whichever is shorter.  
2. Corticosteroids within 7 days prior to dosing (unless ≤10 mg/day of prednisone or 
equivalent). 
3. For NPC:  
a. 
Active parenchymal or leptomeningeal metastases. 
b. Base of skull disease that poses a risk of significant bleeding (eg, proximity to 
carotid artery) as judged by the Investigator. 
c. 
Invasive disease for which there is a potential risk of significant bleeding as 
judged by the Investigator.  
4. For non-NPC cancers: Active central nervous system disease (CNS)/metastases.  
5. Nasopharyngeal cancer patients who have received prior therapy with an anti-PD-1 
agent are not excluded, except for those who experienced prior Grade 3 or higher 
immune-related toxicity that resulted in permanent drug discontinuation (patients 
with prior temporary drug interruptions due to endocrinopathies etc. are eligible). 
6. Less than 14 days from prior locoregional radiotherapy. Palliative radiotherapy 
outside the head and neck is allowed as long as the lesions are not target lesions. 
7. Tumor mutational burden (TMB) -high advanced malignancies and/or microsatellite 
instability (MSI) -high malignancies who would otherwise be eligible for 
pembrolizumab (unless patients have progressed on pembrolizumab) in accordance 
with local standards (ie, only if such biomarkers are performed as standard of care in 
the participating center). 
8. Major surgery, open biopsy, or significant traumatic injury within 28 days prior to 
starting study treatment. In case of recent major surgery, the patient must have 
recovered adequately from the procedure and/or any complications prior to starting 
study treatment. 
9. Is currently participating in or has participated in an interventional study of an 
investigational agent or has used an investigational device within 4 weeks prior to the 
first dose of study treatment. 
Note: Individuals who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent. 
10. Diagnosis of any other malignancy within 3 years prior to enrollment, except for the 
following if adequately treated: 
• local basal cell or squamous cell carcinoma of the skin, or related localized 
non-melanoma skin cancer. 
• carcinoma in situ of the breast or of the cervix. 
• superficial bladder cancer. 
• Low grade (Gleason 6 or below) prostate cancer undergoing surveillance with no 
plans for treatment intervention or previously fully resected. 


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11. Gastrointestinal abnormalities including the following:
•
Inability to take oral medication.
•
Malabsorption syndrome or any other gastrointestinal condition (nausea, 
diarrhea, vomiting) that may impact the absorption of nanatinostat and 
valganciclovir.
•
Prior surgical procedures affecting absorption including total gastric resection.
•
Active gastrointestinal bleeding (hematemesis, hematochezia, or melena) in the 
past 3 months without documentation of resolution by endoscopy/colonoscopy.
12. Positive surface antigen unless quantitative DNA PCR is undetectable, and patient is 
stable on antiviral prophylaxis against hepatitis B virus (HBV) reactivation. Patients 
who are hepatitis B core antibody positive must have undetectable quantitative DNA 
PCR and be monitored according to the local standard-of-care/institutional guidelines.
13. Positive hepatitis C virus (HCV) on RNA PCR.
14. Known SARS-CoV-2 positivity at time of screening (patients can be re-screened once 
negative by PCR).
15. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to valganciclovir or nanatinostat.
16. Active infection requiring systemic therapy.
17. Prolongation of corrected QT interval using Fridericia’s formula (QTcF)  to
>480 msec, requires the coadministration of drugs known to prolong QT (Class Ia
[disopyramide, quinidine, procainamide] and Class III [sotalol, dofetilide, ibutilide] 
antiarrhythmic agents) (Drew 2010), and/or has a history of Torsades de Pointes
(TdP).
18. Receiving potentially nephrotoxic drugs (eg, cyclosporin)
19. Receiving concomitant drugs that are inhibitors of P-glycoprotein (P-gp) and breast 
cancer resistance protein (BCRP) , unless they can be held for 2 weeks or 5 half-lives, 
whichever is longer, prior to administration of nanatinostat. See Appendix 1, Table 2 
for a list of drugs.
20. Receiving tenofovir (unless can be switched to an alternative ART).
21. Psychiatric illness/social situations/substance abuse disorder that would interfere with 
compliance with study requirements.
22. Active autoimmune disease that has required systemic therapy with modifying 
agents, corticosteroids, or immunosuppressive agents.
23. Prior or ongoing clinically significant illness, medical condition, physical finding, 
electrocardiogram (ECG) finding, or laboratory abnormality that, in the Investigator’s 
opinion, could affect the safety of the patient, impair the assessment of study results, 
interfere with the patient’s participation for the full duration of the study, or is not in 
the best interest of the patient to participate.
24. Females who are pregnant or breastfeeding or expecting to conceive children within 
the projected duration of the study, starting with the screening visit through 6 months 
after the last dose of study treatment.
Sample Size, 
Location 
Sample size: up to a maximum of 170 patients  
For Phase 1b, approximately 27 to 60 patients total will be enrolled during the dose 
escalation period. An additional 100 patients may be enrolled in Phase 2; up to 40 patients 
will be enrolled during the dose optimization cohort period and up to 60 patients in the dose 
expansion period with or without pembrolizumab. Up to an additional 10 patients total will 
be enrolled in the exploratory proof-of-concept cohort of other EBV+ solid tumors. 
The reported ORR for PD-1 inhibitors in RM-NPC patients has ranged from 20% to 30%. 
Assuming that the pembrolizumab ORR for RM-NPC patients in this study will be around 
25%, a sample size of 30 patients would provide a 95% CI that excludes 10% as the lower 
ORR. A total of 60 patients (30 per randomized treatment group) is sufficient to provide 


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adequate estimates of tumor response for each group and provide initial indicators of safety 
and tolerability. These estimates will be utilized in planning for future studies in this patient 
population. The sample size of N=30 per randomized treatment group was determined using 
the nQuery Advisor tool (www.statsols.com; Statistical Solutions, Ltd, Cork, Ireland). 
Location: Global 
Study Treatments, 
Dose, Route of 
Administration, 
Treatment Regimen 
Nanatinostat (VRx-3996) oral – Starting dose: 20 mg once daily on Days 1 to 4 per week; 
Dose escalation: up to a total daily dose of 40 mg (Days 1 to 4 per week), then from 40 mg to 
80 mg as a SDD twice daily 4 hours apart (Days 1 to 7) (RP2D to be determined during the 
study) 
Valganciclovir 900 mg oral once daily or twice daily for 21 days followed by a subsequent 
dose reduction to 900 mg once daily when administered with nanatinostat on Days 1 to 4 per 
week (intermittent dosing) and 450 mg twice daily when administered with nanatinostat on 
Days 1 to 7 per week (split daily dosing). (RP2D to be determined during the study) 
Pembrolizumab 200 mg IV every 3 weeks 
(See Section 3, Study Design for additional details on dosing regimens to be evaluated) 
For Phase 2 dose expansion, pembrolizumab will be administered initially 7 days after the 
start of nanatinostat and valganciclovir, and thereafter every 3 weeks. (Dosing schemas are 
provided in Section 5.3.3). 
Dosing Cycles: Cycle 1: 28 days. Cycles 2+: 21 days. 
Efficacy 
Assessment(s) 
ORR: defined as the percentage of patients with a CR or PR within the first 26 weeks (6 
months) of treatment as assessed by the Investigator using RECIST v1.1. ORR will be 
summarized by dosing regimen with 95% confidence interval (CI) obtained by Clopper-
Pearson Exact methods and stratified by prior anti-PD-1 treatment exposure.  
DOR: defined as the interval from date of first observed CR or PR to the date of documented 
disease progression, or death due to any cause, whichever occurs first. All patients who have 
not progressed will be censored at the last non-missing tumor assessment. Estimates of 
median DOR with 95% CI will be determined by dosing regimen using Kaplan-Meier 
methods. 
DCR: defined as the percentage of patients having a CR, PR, or stable disease at any time 
during treatment, as assessed by the Investigator using RECIST v1.1. DCR will be 
summarized by dosing regimen with 95% CI obtained by Clopper-Pearson Exact methods. 
PFS: defined as the interval from the start of study drug treatment to the date of first 
documented disease progression or death from any cause, whichever occurs first. Responding 
patients and patients who are lost to follow-up will be censored at their last tumor assessment 
date. Estimates of median PFS with 95% CI will be determined by dosing regimen using 
Kaplan-Meier methods. The 95% CI around the PFS and OS rates at 12 months (56 weeks) 
will also be presented.  
OS: defined as the interval from the start of study drug treatment to date of death for any 
reason. Surviving patients and patients who are lost to follow-up will be censored at their 
contact date. Estimates of median OS with 95% CI will be determined by dosing regimen 
using Kaplan-Meier methods. 
Safety 
Assessment(s) 
The safety and tolerability of study drug treatments will be evaluated by means of adverse 
event (AE) reports (number and severity); dose holds, modifications, or discontinuations; 
laboratory safety evaluations; vital sign measurements; 12 lead resting ECGs; physical 
examinations; and ECOG performance status.  
Laboratory and AE toxicities will be graded according to NCI CTCAE v5.0. 
Pharmacokinetics 
•
PK sampling for nanatinostat and its metabolites
•
PK sampling for ganciclovir (primary active hydrolytic product of valganciclovir)
Biomarker 
Assessments 
The exploratory biomarker analyses outlined in this study are intended to foster an 
understanding of how baseline expression of certain pharmacodynamic markers may impact 
the activity of combination therapy with nanatinostat, valganciclovir and pembrolizumab, 
and how pharmacodynamic markers, such as plasma EBV DNA levels, may correlate with 


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clinical efficacy. Potential predictive markers will be studied to identify patients with optimal 
responses to nanatinostat and valganciclovir. The impact of study drug administration on 
B-cell/T-cell/NK cell/myeloid cell populations will be evaluated over time.  
Statistical Methods 
and Data Analysis 
Safety Analysis: The safety analysis population will include all patients who received at least 
one dose of any study drug. Safety analysis will be based on all patients in the Safety 
population and will be summarized overall, by dosing regimen, and by any other relevant 
subgroup (eg, solid tumor type). AEs will be summarized using System Organ Class and 
Preferred Term. Tabulations and listings of values for laboratory safety evaluations, vital 
signs, and ECGs, will be presented. Any abnormal or out-of-range values from laboratory 
safety evaluations or physical examinations will be presented in data listings.  
Efficacy Analysis: The Full Analysis Set population will consist of all patients with 
measurable disease at baseline who receive at least one dose of nanatinostat and 
valganciclovir with or without pembrolizumab and who have at least one post-baseline tumor 
assessment. Patients will be analyzed according to the dosing regimen to which they have 
been assigned. The full analysis set will be used for summaries of tumor response and 
survival metrics.  
The modified Intent-to-Treat (mITT) population is defined as all RM-NPC patients who have 
received at least one dose of study treatment (nanatinostat, valganciclovir, or 
pembrolizumab), have a confirmed diagnosis of EBV+ by central pathology review, met all 
inclusion criteria, and have baseline (screening) and at least one post-baseline tumor 
assessment for efficacy. 
The number and percentage of patients with each response and overall (CR and PR) will be 
presented for each time point for the Full Analysis Set population with Clopper-Pearson 
Exact 95% CIs. 
The results from this study will be presented using descriptive statistical methods. Kaplan-
Meier statistics will be used to display DOR, PFS and OS; Clopper-Pearson Exact methods 
will be used to display DCR.  


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TABLE OF CONTENTS 
SPONSOR’S PROTOCOL SIGNATURE PAGE ...........................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS.................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................12 
List of Tables .................................................................................................................................18 
List of Figures ................................................................................................................................18 
LIST OF ABBREVIATIONS ........................................................................................................20 
1.
INTRODUCTION ......................................................................................................23 
1.1. 
EBV and Cancer .........................................................................................................23 
1.2. 
Overview of EBV-positive (EBV+) Solid Tumors and Current Treatments ..............23 
1.2.1. 
EBV+ Nasopharyngeal Carcinoma .............................................................................23 
1.2.2. 
Other EBV+ Solid Tumors ..........................................................................................25 
1.2.2.1. 
EBV+ Gastric Cancer ..................................................................................................25 
1.2.2.2. 
EBV+ Lymphoepithelioma-like Carcinomas ..............................................................26 
1.2.2.3. 
EBV+ Leiomyosarcoma ..............................................................................................26 
1.3. 
Purpose of the Study ...................................................................................................26 
1.4. 
Overview of Investigational Treatment ......................................................................27 
1.4.1. 
Nanatinostat (VRx-3996) ............................................................................................27 
1.4.1.1. 
Nonclinical Experience with Nanatinostat Monotherapy ...........................................27 
1.4.1.2. 
Clinical Experience with Nanatinostat Monotherapy .................................................28 
1.4.2. 
Valganciclovir .............................................................................................................28 
1.4.3. 
Pembrolizumab ...........................................................................................................29 
1.5. 
Rationale for the Choice of Combination Treatments ................................................29 
1.5.1. 
HDAC Inhibitors and Antiviral Agents for EBV+ Malignancies ...............................30 
1.5.1.1. 
Clinical Experience with Nanatinostat and Valganciclovir in EBV+ 
Lymphoma ..................................................................................................................31 
1.5.2. 
Rationale for Adding Pembrolizumab to Nanatinostat and Valganciclovir ...............33 
1.5.3. 
Rationale for the Doses of Nanatinostat, Valganciclovir, and Pembrolizumab 
in this Study ................................................................................................................34 
1.5.3.1. 
Nanatinostat Dose .......................................................................................................34 
1.5.3.2. 
Valganciclovir Dose ...................................................................................................37 
1.5.3.3. 
Pembrolizumab Dose ..................................................................................................37 


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1.6. 
Potential Benefits and Risks .......................................................................................37 
1.6.1. 
Potential Benefits ........................................................................................................37 
1.6.2. 
Potential Risks ............................................................................................................38 
1.6.3. 
Risks Related to Study Procedures .............................................................................38 
1.6.4. 
Risk Management Strategies ......................................................................................38 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................39 
3. 
STUDY DESIGN .......................................................................................................40 
3.1. 
Description of Study Design .......................................................................................40 
3.1.1. 
Screening Period .........................................................................................................45 
3.1.2. 
Treatment Period ........................................................................................................45 
3.1.3. 
Safety Follow-up Period .............................................................................................45 
3.1.3.1. 
Disease Progression Follow-up Period .......................................................................46 
3.1.3.2. 
Survival Follow-up Period ..........................................................................................46 
3.1.4. 
End of Study ...............................................................................................................46 
3.2. 
Duration of Study .......................................................................................................46 
3.3. 
Discussion of Study Design ........................................................................................46 
3.4. 
Dosing Considerations ................................................................................................47 
3.4.1.1. 
Nanatinostat and Valganciclovir .................................................................................47 
3.4.1.2. 
Nanatinostat, Valganciclovir, and Pembrolizumab ....................................................48 
4. 
SELECTION OF STUDY POPULATION ................................................................48 
4.1. 
Patient Population .......................................................................................................48 
4.2. 
Inclusion Criteria ........................................................................................................48 
4.3. 
Exclusion Criteria .......................................................................................................50 
5. 
STUDY TREATMENT INFORMATION .................................................................53 
5.1. 
Nanatinostat ................................................................................................................53 
5.1.1. 
Dosage Form, Composition, and Packaging ...............................................................53 
5.1.2. 
Nanatinostat Study Drug Storage ...............................................................................53 
5.1.3. 
Nanatinostat Administration .......................................................................................54 
5.2. 
Valganciclovir .............................................................................................................54 
5.2.1. 
Dosage Form, Composition, and Packaging ...............................................................54 
5.2.2. 
Valganciclovir Study Drug Storage ............................................................................54 
5.2.3. 
Valganciclovir Administration ...................................................................................54 
5.3. 
Pembrolizumab ...........................................................................................................55 


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5.3.1. 
Pembrolizumab Study Drug Storage ..........................................................................55 
5.3.2. 
Pembrolizumab Administration ..................................................................................55 
5.3.3. 
Sequence of Study Drug Administration ....................................................................56 
5.4. 
Additional Dosing Guidelines for Pharmacokinetic Sampling ..................................60 
5.5. 
Dose Escalation Guidelines ........................................................................................60 
5.5.1. 
Provisional Dose Levels .............................................................................................60 
5.5.2. 
Guidelines for Dose Escalation ..................................................................................61 
5.5.3. 
Dose-Limiting Toxicities (DLTs) ...............................................................................63 
5.5.3.1. 
Phase 1b: Nanatinostat and Valganciclovir ................................................................64 
5.5.3.2. 
Phase 2: Nanatinostat and Valganciclovir With or Without Pembrolizumab ............64 
5.5.3.3. 
Assessment of Toxicity During Phase 2 Dose Expansion ..........................................65 
5.6. 
Dose Modification Guidelines for Study Treatment-Related Toxicities ....................66 
5.6.1. 
Criteria for Suspension of Study Drug Treatment Due to Treatment-Related 
Toxicities ....................................................................................................................70 
5.6.2. 
Dose Modifications for Patients with Renal Impairment ...........................................71 
5.6.3. 
Missed or Vomited Doses ...........................................................................................71 
5.7. 
Prior and Concomitant Medications ...........................................................................72 
5.7.1. 
Supportive Care Guidelines and Permitted Concomitant Medications ......................72 
5.7.1.1. 
Pembrolizumab Infusion-Related Reactions ..............................................................72 
5.7.1.2. 
Hematopoietic Growth Factors ...................................................................................73 
5.7.2. 
Concomitant Therapy Requiring Caution and/or Action ............................................73 
5.7.2.1. 
Corticosteroids ............................................................................................................73 
5.7.2.2. 
Proton Pump Inhibitors ...............................................................................................73 
5.7.2.3. 
Concomitant Therapies to be Used with Caution with Nanatinostat ..........................73 
5.7.3. 
Concomitant Therapies to be Used with Caution with Valganciclovir ......................74 
5.7.4. 
Prohibited Therapies ...................................................................................................74 
5.8. 
Patient Numbering & Treatment Assignment ............................................................75 
5.8.1. 
Patient Numbering ......................................................................................................75 
5.8.2. 
Treatment Assignment (Including Randomization) ...................................................75 
5.8.3. 
Treatment Blinding .....................................................................................................76 
5.9. 
Study Drug Preparation and Dispensation ..................................................................76 
5.9.1. 
Study Drug Packaging and Labelling .........................................................................76 
5.9.2. 
Drug Supply and Storage ............................................................................................76 


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5.9.3. 
Study Drug Compliance and Accountability ..............................................................76 
5.9.3.1. 
Study Drug Compliance .............................................................................................76 
5.9.3.2. 
Study Drug Accountability .........................................................................................76 
5.9.4. 
Study Drug Handling and Disposal ............................................................................77 
6. 
SCHEDULE OF EVENTS .........................................................................................77 
7. 
ENROLLMENT AND STUDY PROCEDURES ......................................................83 
7.1. 
Informed Consent .......................................................................................................83 
7.2. 
Screening Period .........................................................................................................84 
7.2.1. 
Demographic Information ..........................................................................................84 
7.2.2. 
Physical Examinations ................................................................................................84 
7.2.3. 
Medical History ..........................................................................................................84 
7.2.4. 
Tumor Specimen .........................................................................................................84 
7.2.5. 
Baseline Disease Assessments ....................................................................................85 
7.2.6. 
Eligibility Determination and Patient Registration .....................................................85 
7.2.6.1. 
Screen Failures ............................................................................................................85 
7.3. 
Treatment Period ........................................................................................................85 
7.3.1. 
Treatment Cycles ........................................................................................................85 
7.3.2. 
Unscheduled Visit(s) ..................................................................................................85 
7.3.3. 
Discontinuation of Study Treatment ...........................................................................86 
7.3.4. 
End of Treatment ........................................................................................................86 
7.3.5. 
Safety Follow-up Visit ................................................................................................87 
7.3.6. 
Long-term Follow-up Visits .......................................................................................87 
7.3.7. 
Lost to Follow-up .......................................................................................................88 
7.4. 
Assessments During the Treatment Phase ..................................................................88 
7.4.1. 
Efficacy Assessments .................................................................................................88 
7.4.1.1. 
Baseline Evaluation ....................................................................................................88 
7.4.1.2. 
Tumor Response Assessments ....................................................................................88 
7.4.2. 
Safety and Tolerability Assessments ..........................................................................89 
7.4.2.1. 
Laboratory Evaluations ...............................................................................................90 
7.4.2.2. 
Clinical Laboratory (Safety) Testing ..........................................................................90 
7.4.2.3. 
Pregnancy Testing ......................................................................................................91 
7.4.2.4. 
Vital Signs ..................................................................................................................91 
7.4.2.5. 
Cardiac Assessments: Electrocardiograms (ECGs) ....................................................92 


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7.4.2.6. 
Physical Examination .................................................................................................92 
7.4.2.7. 
Height and Weight ......................................................................................................92 
7.4.2.8. 
ECOG Performance Status .........................................................................................93 
7.4.3. 
Pharmacokinetics ........................................................................................................93 
7.4.4. 
Exploratory Biomarker Assessments ..........................................................................93 
7.4.4.1. 
Rationale for Biomarker Assessments ........................................................................93 
7.4.4.2. 
Pharmacodynamic Assessments in Blood ..................................................................94 
7.4.4.3. 
Additional Biomarker Assessments ............................................................................94 
8. 
ADDITIONAL SAFETY CONSIDERATIONS ........................................................95 
8.1. 
Monitoring, Recording and Reporting of Adverse Events .........................................95 
8.1.1. 
Clarification in Reporting of Deaths ...........................................................................96 
8.1.2. 
Clarification in Reporting of Disease Progression as an Adverse Event ....................96 
8.1.3. 
Laboratory Test Abnormalities ...................................................................................96 
8.2. 
Serious Adverse Event ................................................................................................96 
8.2.1. 
Reporting of Serious Adverse Events .........................................................................97 
8.3. 
Severity of the Event ..................................................................................................97 
8.4. 
Relationship to Study Drugs .......................................................................................98 
8.5. 
Expectedness ...............................................................................................................98 
8.6. 
Reporting Adverse Events ..........................................................................................99 
8.7. 
Reporting of Pregnancy ..............................................................................................99 
8.7.1. 
Females of Childbearing Potential ..............................................................................99 
8.7.2. 
Male Patients ............................................................................................................100 
8.8. 
Reporting of Overdose ..............................................................................................100 
8.9. 
Emergency Measures ................................................................................................100 
8.10. 
Unanticipated Problems ............................................................................................101 
9. 
STATISTICAL ANALYSES ...................................................................................101 
9.1. 
Overview ...................................................................................................................101 
9.2. 
Statistical and Analytical Plans ................................................................................101 
9.3. 
Definition of Analysis Populations ...........................................................................101 
9.4. 
Sample Size and Power Considerations ...................................................................102 
9.5. 
Baseline Characteristics and Subject Disposition .....................................................102 
9.6. 
Efficacy Analysis ......................................................................................................102 
9.6.1. 
Primary Efficacy Endpoint Analysis ........................................................................102 


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9.6.2. 
Secondary Efficacy Endpoints Analysis ...................................................................103 
9.6.3. 
Exploratory Endpoints ..............................................................................................103 
9.7. 
Safety Analysis .........................................................................................................103 
9.8. 
Interim Analysis ........................................................................................................104 
10. 
STUDY COMMITTEES AND COMMUNICATIONS ..........................................104 
11. 
LABORATORY REQUIREMENTS .......................................................................104 
12. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ........................104 
12.1. 
Ethics ........................................................................................................................105 
12.1.1. 
Ethics Committee ......................................................................................................105 
12.2. 
Ethical Conduct of the Study ....................................................................................106 
12.2.1. 
Patient Information and Informed Consent ..............................................................106 
12.2.2. 
Maintaining Patient Confidentiality .........................................................................106 
12.2.3. 
Use of Research Samples and Data ..........................................................................107 
12.3. 
Data Handling and Recordkeeping ...........................................................................108 
12.3.1. 
Data Collection Responsibilities and Access to Source Data ...................................108 
12.3.2. 
Retention of Records ................................................................................................108 
12.3.3. 
Study Monitoring ......................................................................................................108 
12.3.4. 
Audits and Inspections ..............................................................................................109 
12.3.5. 
Quality Control and Quality Assurance ....................................................................109 
12.4. 
Investigational Product Accountability ....................................................................110 
12.5. 
Financial Disclosure .................................................................................................110 
12.6. 
Compensation for Injury and Insurance ...................................................................110 
12.7. 
Study Termination and Site Closure .........................................................................110 
12.8. 
Use of Study Information and Publication ...............................................................111 
13. 
REFERENCES .........................................................................................................112 
14. 
APPENDICES ..........................................................................................................118 
APPENDIX 1. CONCOMITANT THERAPIES TO BE USED CAUTIOUSLY WITH 
NANATINOSTAT ...................................................................................................119 
APPENDIX 2. ESTABLISHED AND OTHER POTENTIALLY SIGNIFICANT 
DRUG INTERACTIONS WITH GANCICLOVIR .................................................120 
APPENDIX 3. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST V1.1) .........................................................................................................121 
APPENDIX 4. IMMUNOLOGIC RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS ..................................................................................................................124 


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List of Tables 
Table 1: 
Study VT3996-201: Grade 3/4 Treatment-Emergent Adverse Events 
Experienced by ≥3 (5%) Patients (as of 27 Oct 2021) ...............................................33 
Table 2: 
Percent of Subjects With Response to Nanatinostat for ≥ 6 Hours Based on 
Dosing Regimen .........................................................................................................35 
Table 3: 
Objectives and Endpoints ...........................................................................................39 
Table 4: 
Phase 1b: Dose Levels – Nanatinostat and Valganciclovir ........................................60 
Table 5: 
Phase 1b Dose Escalation Rules for Nanatinostat in Combination with 
Valganciclovir* ...........................................................................................................61 
Table 6: 
Early Stopping Boundaries for Toxicity .....................................................................66 
Table 7: 
Dose Modification Guidelines for Study Treatment-Related Toxicity ......................67 
Table 8: 
Pembrolizumab Recommended Dose Modifications for Immune-Mediated 
Adverse Reactions ......................................................................................................69 
Table 9: 
Valganciclovir Dose Adjustments for Patients with Renal Impairment .....................71 
Table 10: Pembrolizumab Infusion-Related Reaction Treatment Guidelines ............................73 
Table 11: Schedule of Events .....................................................................................................78 
Table 12: Required Laboratory Tests .........................................................................................91 
Table 13: ECOG Performance Status .........................................................................................93 
Table 14: Biomarker Sample Collection Plan ............................................................................94 
Table 15: Sponsor’s Medical Monitor ........................................................................................97 
List of Figures 
Figure 1: 
Comparing the Antitumor Activity and Expression of vPK (BGLF4) in 
EBV+ Gastric Cancer Tumor Samples with Split Daily Dose vs. Single 
Daily Dose of Nanatinostat in Combination with Ganciclovir ...................................36 
Figure 2: 
Continuous Daily Dosing of Nanatinostat Provides Better Antitumor 
Activity Relative to 4 Days On/3 Days Off ................................................................36 
Figure 3: 
Study Design ...............................................................................................................43 
Figure 4: 
Structural Formula and Key Features of Nanatinostat ...............................................53 
Figure 5: 
Valganciclovir Hydrochloride Structural Formula .....................................................54 
Figure 6: 
Dosing Sequence: Nanatinostat and Valganciclovir (Phase 1b Dose Levels 1 
through 3) ....................................................................................................................57 
Figure 7: 
Divided Dosing Sequence: Nanatinostat (Dose Levels 4 and 5) ................................57 


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Figure 8: 
Divided Dosing Sequence: Nanatinostat and Valganciclovir (Dose Levels 6 
and 7) ..........................................................................................................................58 
Figure 9:  Split Daily Dosing Sequence: Nanatinostat and Valganciclovir (Dose Levels 
8 through 13) ...............................................................................................................58 
Figure 10: Dosing Sequence: Nanatinostat, Valganciclovir, and Pembrolizumab – Phase 
2 Dose Expansion .......................................................................................................59 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
Ab 
antibody 
AE 
adverse event 
Ag 
antigen 
AIDS 
acquired immunodeficiency syndrome 
AITL 
angioimmunoblastic T-cell lymphoma 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ART 
antiretroviral therapy 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BCRP 
breast cancer resistance protein 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CMV 
cytomegalovirus 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax  
maximum plasma concentration 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete response 
CrCl 
creatinine clearance 
CRT 
chemoradiation therapy 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP, CYP450 
cytochrome P450 
DCR 
disease control rate 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DRESS 
Drug Rash with Eosinophilia and Systemic Symptoms 
EBER 
Epstein-Barr virus-encoded RNA 
EBER-ISH 
Epstein-Barr virus encoded RNA – in situ hybridization 
EBV 
Epstein-Barr virus 
EBV+ 
Epstein-Barr virus positive 
EBV-CTL 
Epstein-Barr virus-specific cytotoxic T lymphocyte 
EBV-PK 
Epstein-Barr virus-encoded protein kinase 
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 


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Abbreviation 
Definition 
ENKTL 
Extranodal NK/T-cell lymphoma 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
G-CSF 
granulocyte-colony stimulating factor 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDAC 
histone deacetylase  
IA-LPD 
immunodeficiency-associated lymphoproliferative disorders 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
iCPD 
immune confirmed progressive disease 
iCR 
immune complete response 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
INR 
international normalized ratio 
iPR 
immune partial response 
IR 
immediate-release 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
iRECIST 
immune-modified Response Evaluation Criteria in Solid Tumors 
iSD 
immune stable disease 
iUPD 
immune unconfirmed progressive disease 
IV 
intravenous(ly) 
LELC 
lymphoepithelioma-like carcinoma 
LMP 
latent membrane protein 
MDR1 
multidrug resistance 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMF 
mycophenolate mofetil 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer 
NPC 
nasopharyngeal carcinoma 
NSAID 
non-steroidal anti-inflammatory drug 


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Abbreviation 
Definition 
NSCLC 
non-small cell lung cancer 
NTL 
nontarget lesion 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD-1 
programmed cell death-1 
PD 
progressive disease 
PD-L1 
programmed cell death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PLELC 
pulmonary lymphoepithelioma-like carcinoma 
PR 
partial response 
PT 
prothrombin time 
PTCL-NOS 
peripheral T-cell lymphoma not otherwise specified 
qPCR 
quantitative polymerase chain reaction 
QTcF 
corrected QT interval using Fridericia’s method  
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RM-NPC 
recurrent and/or metastatic nasopharyngeal carcinoma 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SDD 
split daily dose 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SJS 
Stevens-Johnson Syndrome 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
t1/2 
terminal elimination half-life 
TdP 
Torsades de Pointes 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TIL 
tumor-infiltrating lymphocyte 
TL 
target lesion 
tmax  
time to maximum plasma concentration 
TMB 
tumor mutational burden 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cells 
WHO 
World Health Organization 


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1.
INTRODUCTION
1.1. 
EBV and Cancer
Epstein-Barr virus (EBV), a member of the γ-herpesvirus family, was the first virus directly 
implicated in the development of a human tumor (Epstein 1964) and is formally classified as a 
carcinogenic agent by the World Health Organization (WHO). Primary infection with EBV 
typically occurs in childhood and is generally asymptomatic; however, infection later in life may 
manifest as infectious mononucleosis (Thompson 2004). Once infected, individuals remain 
lifelong carriers of the virus, with >90% of the world’s population asymptomatically infected 
with EBV. 
Latent infection and intermittent reactivation are 2 important characteristics of the EBV 
lifecycle. The maintenance of latent EBV infection requires the expression of a small subset of 
genes. Specific expression patterns (Types I – III) of these genes are associated with specific 
EBV-driven malignancies (Saha 2011). EBV is associated with a wide spectrum of lymphoid 
malignancies, including B-cell, T/natural killer (NK)-cell and Hodgkin lymphomas, and solid 
tumors such as nasopharyngeal carcinoma (NPC), gastric cancer (and other 
lymphoepithelioma-like cancers [LELCs] involving the lung and other organs), and 
leiomyosarcomas (Li 2018, Neparidze 2014).  
1.2. 
Overview of EBV-positive (EBV+) Solid Tumors and Current 
Treatments 
1.2.1. 
EBV+ Nasopharyngeal Carcinoma 
NPC is one of the most commonly reported cancers of the head and neck worldwide. While it is 
prevalent in Southeast Asian countries and in native populations of the Artic region, North 
Africa, and the Middle East, with incidence rates of 15 to 50 per 100,000 in southern China and 
East Malaysia (Du 2020, Hutajulu 2014), NPC represents a rare disease in the Western countries 
(such as Europe and USA), Latin America and Japan, affecting less than 1 in 100,000 people 
(Perri 2019, Carioli 2017). Using the Global Cancer Observatory database, 129,079 new cases of 
NPC and 72,987 NPC-related deaths globally were estimated in 2018 (Bray 2018). The WHO 
has categorized NPC into 3 histopathologic subtypes: keratinizing squamous cell carcinoma 
(WHO type I), with varying degrees of differentiation; nonkeratinizing squamous cell carcinoma 
(WHO type II), retaining epithelial cell shape and growth pattern; and undifferentiated 
carcinoma (WHO type III), which does not produce keratin and lacks a distinctive growth 
pattern (Hutajulu 2014). Contributors to the etiology of NPC include genetic background (one-
third of patients harbor major histocompatibility complex [MHC] class I gene aberrations), 
environmental factors such as diet (salt preserved fish), tobacco, alcohol consumption, and EBV 
infection. Males are 2 to 3 times more likely to develop NPC than females. The peak age of 
incidence is between 50 and 60 years. Non-keratinizing NPC is consistently associated with EBV 
and accounts for the majority of NPC cases in endemic areas (Wu 2018).  
The main prognostic factor affecting the overall survival (OS) of NPC is the stage of the disease 
at presentation (Sun 2014), with 5-year OS rates for Stage 1 disease reported at 95% compared 
with 60% for Stage 4 disease (Li 2014). Because NPC is frequently asymptomatic, most patients 
(80%) present with advanced stage disease at diagnosis (Li 2014). 


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Circulating cancer-derived EBV DNA is a well-established tumor marker for NPC, with a 
sensitivity of 96% and a specificity of 93% (Leung 2014, Lo 1999). Plasma EBV DNA is 
detected in >95% of patients with advanced stage disease and is recognized as an independent 
prognostic biomarker in NPC (Lo 2000a, Ma 2018, Kim 2017), with high pre-treatment levels of 
EBV DNA correlating with a high risk of disease recurrence and distant metastasis (Chan 2002, 
Lo 2000b). In addition, patients with detectable plasma EBV DNA following chemoradiotherapy 
are at high risk of locoregional treatment failure (Chan 2018).  
EBV is considered the primary etiologic agent in the pathogenesis of NPC; both EBV DNA and 
EBV gene expression are detected in precursor lesions and tumor cells (Raab-Traub 2002). NPC 
cells express a type II latency pattern in which Epstein-Barr virus-encoded RNA 1/2 (EBER1/2), 
Epstein-Barr nuclear antigen 1 (EBNA1), and 2 integral membrane proteins, latent membrane 
protein (LMP)-1 and LMP-2, along with the BamHI-A fragment of the EBV genome are 
expressed (Tsao 2015). The diagnosis of EBV+ NPC is based on histologic examination and 
Epstein-Barr virus encoded RNA – in situ hybridization (EBER-ISH) or immunohistochemical 
staining for LMP (National Comprehensive Cancer Network [NCCN] Guidelines, Head and 
Neck Cancers 2021).  
EBV-associated NPC typically presents with an enhanced degree of lymphocyte infiltration and 
overexpression of programmed cell death-ligand 1 (PD-L1) (Zhang 2015), which initiated the 
clinical treatment evaluation of various checkpoint inhibitors in early phase clinical trials for 
recurrent and/or metastatic nasopharyngeal cancer (RM-NPC), with objective response rates 
(ORRs) reported in the range of 20% to 30% (Wang 2021, Ma 2018, Hsu 2017). 
The standard first-line treatment for NPC is radiotherapy for early-stage disease and 
chemoradiotherapy for more advanced disease (including cisplatin plus gemcitabine induction 
therapy for patients with high risk, locally advanced or metastatic disease) (Zhang 2019, 
Neparidze 2014). Neoadjuvant chemotherapy is sometimes used to down-stage locally advanced 
NPCs for radiotherapy. Although response rates to concurrent chemoradiotherapy with cisplatin-
based regimens are high and result in 5-year OS rates of approximately 85% (Yang 2015), 
disease subsequently relapses locally or more commonly with distant metastases in 30% to 40% 
of patients. No standard treatment options exist for second or later lines of therapy; treatment 
options are based on the general status of the patient and prior therapies received. The preferred 
initial regimen for patients with prior chemoradiation therapy (CRT) is gemcitabine/cisplatin, 
with a reported median progression-free survival (PFS) of 7.0 months (Zhang 2016). 
Single-agent options for RM-NPC include capecitabine, paclitaxel, docetaxel, and carboplatin 
(NCCN Guidelines, Head and Neck Cancers 2021). In addition, many patients in communities 
without access to chemotherapy in advanced medical facilities could benefit by alternative safe 
and effective treatment options that improve disease-free survival. 
As EBV is present in virtually all poorly differentiated and undifferentiated NPC, targeting EBV 
may be a potential therapeutic option (Chow 2019, Hong 2018). Various EBV-targeted treatment 
approaches have been evaluated in patients with recurrent or metastatic NPC, including inducing 
EBV lytic activation with gemcitabine and valproic acid followed by treatment with ganciclovir, 
an antiviral drug (Wildeman 2012), and adoptive transfer of EBV-specific cytotoxic T 
lymphocytes (EBV-CTLs) (Huang 2017, Louis 2010, Comoli 2005), with some clinical 
responses reported. For EBV-CTL therapy, modest clinical response rates of 10% to 20% were 


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observed in a limited number of patients with metastatic disease reporting a median PFS in the 
range of 2 to 3 months (Huang 2017, Louis 2010).  
Because PD-L1 is highly expressed by NPC cells and a correlation exists between tumor PD-L1 
expression with shorter OS, recurrence-free survival, and treatment failure (Hsu 2010), anti- 
programmed cell death-1 (PD-1) antibodies have been evaluated for the treatment of patients 
with RM-NPC. An ORR of 25.9% with a median PFS of 6.5 months was reported in a 
Phase 1b/2 trial (Keynote-028) in 27 patients with relapsed or metastatic PD-L1+ NPC treated 
with pembrolizumab (Hsu 2017). A Phase 2 trial evaluating nivolumab in 45 patients with 
RM-NPC who were not selected for PD-L1 expression reported an ORR of 20.5% (median PFS 
2.8 months) (Ma 2018). More recently, an ORR of 20.5% with a median duration of response 
(DOR) of 12.8 months (median PFS of 1.9 months) was reported for a Phase 2 study of 
toripalimab, a humanized IgG4 monoclonal antibody against PD-1, in 190 patients with RM-
NPC (Wang 2021). A decrease of 50% or more in the plasma EBV DNA copy number on Study 
Day 28 was associated with a significantly improved ORR (P=0.0001); tumor mutation burden 
had no predictive value for response. Therefore, combining a PD-1 inhibitor with EBV-targeted 
therapy may have the potential to augment anti-tumor activity for the treatment of RM-NPC. 
1.2.2. 
Other EBV+ Solid Tumors 
1.2.2.1. 
EBV+ Gastric Cancer 
Gastric cancer is the second leading cause of cancer death worldwide. Although relatively 
uncommon in the United States (US) with an estimated 27,600 new cases and 11,010 deaths in 
2020 (American Cancer Society 2020) and an overall incidence of 5.6 per 100,000 in North 
America, a high incidence is reported in East Asia, with an average incidence of 32.1 per 
100,000 (males) and 13.2 per 100,000 (females) (Rawla 2019, Van Cutsem 2016). Gastric cancer 
is classified into 4 subtypes according to its molecular biology in the Cancer Genome Atlas: 
EBV-positive, microsatellite instability, genomically stable, and chromosomal instability 
(Wang 2019). EBV-associated gastric carcinoma results from clonal growth of EBV-infected 
gastric epithelial cells and is characterized by atrophic gastritis in the background mucosa 
(Abe 2015). EBV+ gastric cancer is traditionally identified by the EBER-ISH assay (Sun 2020). 
The frequency of EBV infection in gastric carcinoma varies from 2% to 20% with an average of 
10% (Camargo 2011). Two subtypes of EBV-associated gastric carcinoma are recognized 
including LELC and conventional gastric adenocarcinoma (Nepardize 2014). EBV-associated 
gastric carcinoma is more common in males, is predominantly located in the proximal and 
middle regions of the stomach (Corvalan 2001, Takada 2000), and has a younger onset of disease 
(40 years [range: 21-45 years]) compared with 69 years (range: 50-90 years) for EBV-negative 
gastric cancer (Moore 2020). Risk factors include Helicobacter pylori infection and smoking. 
Surgical resection is the only curative therapy for localized gastric cancer; however, many 
patients have recurrence afterwards. EBV+ gastric carcinoma is associated with a significantly 
lower frequency of lymph node metastasis compared with EBV-negative gastric cancer and a 
more favorable survival. A recent retrospective analysis of 4599 gastric cancer patients 
diagnosed between 1976 and 2010 from 13 international centers reported a median OS of 
8.5 years for patients with EBV+ tumors compared with 5.3 years for patients with EBV-negative 
tumors (Carmargo 2014). Recently, nivolumab in combination with chemotherapy was approved 
by the FDA for the first-line treatment of gastric cancer. Median survival was 13.8 months for 


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patients who received nivolumab plus chemotherapy compared with 11.6 months for patients 
who received chemotherapy alone. In addition, pembrolizumab received accelerated approval in 
combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the 
first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive 
gastric or gastroesophageal junction (GEJ) adenocarcinoma with an ORR of 74%. Advanced 
gastric cancer has a poor prognosis despite the availability of chemotherapy, targeted therapies 
such as trastuzumab, ramucirumab, apatinib, and more recently, PD-1 inhibitors. Pembrolizumab 
showed an ORR of 11.6% for the treatment of patients with third-line gastric cancer (not selected 
for PD-L1) (Fuchs 2018). However, many patients relapse after these treatments (Zhao 2019), 
additional therapies are needed.  
1.2.2.2. 
EBV+ Lymphoepithelioma-like Carcinomas 
LELCs are rare tumors with morphologic and genetic features similar or identical to those of 
undifferentiated NPC that occur outside of the nasopharynx, and have been described in several 
different organs, with lung, stomach, thymus, and salivary gland LELCs being most consistently 
associated with EBV infiltration (Iezzoni 1995). Pulmonary lymphoepithelioma-like carcinoma 
(PLELC) accounts for <1% of all lung cancers and is more prevalent in Asia, primarily affecting 
younger non-smoking individuals (Li 2020); over 90% of cases are EBV+. No clinical practice 
guideline specifically for the treatment of PLELC exists owing to its rarity (Hu 2020). In general, 
treatment is similar to that of non-small cell lung cancer (NSCLC). Surgical resection with or 
without adjuvant chemotherapy is recommended by some clinicians. For resectable cases with 
and without standard adjuvant NSCLC chemotherapy, the 36-month recurrence-free survival is 
73%, and for those with stage III to IV disease at presentation, a median OS of >3 years has been 
reported after multimodality therapy (Lin 2016, Huang 2012). However, patients with locally 
advanced stage PLELC may benefit from a more aggressive multimodality approach (Hu 2020). 
Like NPC, plasma EBV DNA levels have been reported to reflect tumor burden in PLELC and 
may be useful for predicting outcome (eg, risk of disease progression) and monitoring (Li 2020). 
LELCs of the thymus and salivary glands are very rare, the latter being reported primarily in 
China (Saw 1986). 
1.2.2.3. 
EBV+ Leiomyosarcoma 
EBV-associated leiomyosarcomas are very rare neoplasms that are generally seen in 
immunocompromised (HIV-positive or post-transplant) patients, reported to occur primarily in 
the liver, brain, gastrointestinal, and respiratory tracts (Boman 1997). A recent review reported 
on 64 cases of AIDS-associated smooth muscle tumors from 53 articles (Purgina 2011). Clinical 
outcome was variable and included surgical resection primarily with radiotherapy, 
chemotherapy, and highly active retroviral therapy as less frequently used options. Surgical 
resection was more recently reported to be the preferred treatment option, as these tumors tend to 
be resistant to chemotherapy (Hussein 2014). 
1.3. 
Purpose of the Study 
Although response rates to CRT for first-line EBV+ NPC are high, patients tend to relapse with 
advanced disease, and no standard treatment options are available beyond the first-line setting for 
patients with platinum-refractory RM-NPC. The combination of histone deacetylase (HDAC) 


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inhibitors and ganciclovir has been reported to inhibit tumor growth in murine xenograft models 
of EBV+ nasopharyngeal and gastric cancer (Hui 2016).  
Nanatinostat (also known as VRx-3996 and CHR-3996) is an orally administered hydroxamic 
acid-based, selective and potent inhibitor of histone deacetylase (HDAC) Class I enzymes, 
originally discovered and developed by Chroma Therapeutics. Nanatinostat is currently being 
developed by Viracta Therapeutics, Inc (Sponsor) in combination with valganciclovir, an oral 
prodrug of ganciclovir, in patients with EBV-associated lymphoma. Nanatinostat and 
valganciclovir have been safely co-administered to more than 90 heavily pre-treated recurrent 
EBV+ lymphoma patients with complete and partial responses reported in a variety of B- and 
T/NK non-Hodgkin lymphoma (NHL) subtypes (summarized in Section 1.5.1.1). Therefore, 
nanatinostat and valganciclovir hold promise for the treatment of patients with EBV+ solid 
tumors. Phase 1b of this study will identify the recommended Phase 2 dose (RP2D) for 
nanatinostat in combination with valganciclovir in patients with recurrent or metastatic EBV+ 
NPC which will be confirmed in Phase 2.  
NPC cells highly express PD-L1, and response rates of 20 to 30% have been reported with PD-1 
inhibitors for the treatment of advanced NPC, including an ORR of 25.9% for pembrolizumab 
and an ORR of 20.5% for toripalimab in PD-1 positive RM-NPC (Wang 2021, Ma 2018, 
Hsu 2017). Pembrolizumab has been safely combined with various cytotoxic chemotherapies as 
well as HDAC inhibitors (Gray 2019). 
As discussed in Section 1.5.2, there is a compelling rationale to suggest that exposure to 
nanatinostat will result in enhancement of immune destruction of EBV-positive solid tumors. In 
order to explore the hypothesis that concurrent treatment with a PD-1 inhibitor together with an 
EBV-targeted treatment regimen may result in potentially greater anti-tumor activity for the 
treatment of RM-NPC, pembrolizumab will be administered concomitantly with nanatinostat and 
valganciclovir and compared with nanatinostat and valganciclovir alone during Phase 2 of the 
study.  
1.4. 
Overview of Investigational Treatment 
1.4.1. 
Nanatinostat (VRx-3996) 
Nanatinostat (VRx-3996) is a selective and potent HDAC Class I inhibitor with activity against 
HDAC1, HDAC2, and HDAC3. Nanatinostat is also a potent inducer of EBV protein kinase and 
tyrosine kinase. In tumor cell lines and tumor xenograft models, nanatinostat inhibited tumor 
growth across a wide spectrum of human tumor types and demonstrated synergistic activity in 
combination with agents such as erlotinib, decitabine, and tosedostat (Banerji 2012). 
1.4.1.1. 
Nonclinical Experience with Nanatinostat Monotherapy 
1.4.1.1.1. Nonclinical PK and Metabolism of Nanatinostat 
Nonclinical studies have shown that nanatinostat, as a single agent, has good oral bioavailability 
in rats and dogs (30% to 40%), and demonstrates good tissue penetration in rat models. 
Nanatinostat metabolism is not cytochrome P450 (CYP)-mediated, does not induce CYP450 
isoforms, and appears to be a poor inhibitor of CYP450 isoforms, using model substrates and 
inhibitors across all studies. 


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1.4.1.1.2. Pharmacodynamics of Nanatinostat 
The pharmacodynamics of nanatinostat, as a single agent, were evaluated by acetylation of 
histone H3 in peripheral blood mononuclear cells (PBMCs). An increase in acetylation was seen 
by 4 hours and returned towards baseline by 24 hours. Data suggest both a dose relationship and 
then a plateau in biologic response, with increased acetylation apparent at the 20 mg/day dose 
level and plateauing at levels ≥40 mg/day. 
1.4.1.2. 
Clinical Experience with Nanatinostat Monotherapy 
The safety and preliminary efficacy of nanatinostat as a single agent were evaluated in a 
Phase 1 study in 39 patients with refractory solid tumors (Banerji 2012). Nanatinostat was 
administered orally once daily as single doses of 5 mg (n=3), 10 mg (n=4), 20 mg (n=3), 40 mg 
(n=10), 80 mg (n=10), 120 mg (n=4), and 160 mg (n=5) on a 28-day cycle. Dose-limiting 
toxicities (DLTs) reported (by nanatinostat dose) included thrombocytopenia (160 mg), fatigue 
(80 and 120 mg), elevations in serum creatinine (80 mg and 120 mg), and atrial fibrillation (40 
mg). The maximum tolerated dose (MTD) was determined to be 80 mg/day, and the RP2D was 
40 mg daily. Most adverse events (AEs) were low grade (Grade 1 or 2); the most commonly 
reported AEs were fatigue and nausea. One partial response (PR) was seen in the 160 mg dose 
group in a patient with metastatic acinar pancreatic carcinoma. 
Nanatinostat was rapidly absorbed with a median time to maximum plasma concentration (tmax) 
of 1 hour (range 1 to 4 hours). Although there was pronounced variability in exposure across the 
dose levels, area under the plasma concentration-time curves (AUCs) were broadly proportional 
over the administered dose range. The median terminal elimination half-life (t½) was 1.8 hours. 
No clear differences were observed between Day 1 and Day 28 in pharmacokinetic (PK) 
parameters, suggestive of no apparent accumulation. 
Additional details regarding clinical and nonclinical experience with nanatinostat, are provided 
in the latest version of the nanatinostat Investigator’s Brochure (IB). 
1.4.2. 
Valganciclovir 
Valganciclovir (VALCYTE®), an oral prodrug of ganciclovir, is approved internationally for 
treatment of cytomegalovirus (CMV) retinitis in adult patients with AIDS and prevention of 
CMV disease in kidney, heart, and kidney-pancreas high-risk transplant patients, including 
treatment of high-risk pediatric kidney and heart transplant patients.  
The recommended adult dosage of valganciclovir for treatment of CMV retinitis is 900 mg orally 
twice daily for 21 days followed by a maintenance dose of 900 mg once daily. Oral 
valganciclovir is well absorbed (approximately 60%) and converted to ganciclovir by first-pass 
intestinal or hepatic metabolism with peak plasma concentrations achieved in 1 to 3 hours. The 
major elimination pathway is renal excretion through glomerular filtration and active tubular 
secretion. Dose reductions based on creatinine clearance are recommended for patients with 
renal impairment. Reported AEs of note related to valganciclovir include cytopenias (leukopenia, 
neutropenia, anemia, thrombocytopenia) and acute renal failure. Elderly patients, patients 
receiving nephrotoxic drugs, and inadequately hydrated patients are at higher risk for renal 
dysfunction (Valcyte [valganciclovir] Prescribing Information, 2021). 


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1.4.3. 
Pembrolizumab 
Pembrolizumab (KEYTRUDA®) is a potent humanized IgG4 monoclonal antibody with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. 
Based on nonclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1. Pembrolizumab is in clinical development as an intravenous (IV) 
immunotherapy for advanced malignancies and is currently approved in more than 90 countries 
for one or more advanced malignancies (Merck & Co., Inc Corporate Responsibility Report, 
2019/2020). Notable toxicities associated with the use of pembrolizumab as a single agent or in 
combination treatment include a variety of immune-mediated adverse reactions such as 
pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, and skin and 
infusion reactions (Keytruda [pembrolizumab] Prescribing Information, 2023). Modest responses 
to PD-1-targeted monotherapy with pembrolizumab have been reported in patients with RM-
NPC. In a recent Phase 2 study evaluating pembrolizumab in patients with PD-L1-positive RM-
NPC, patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease 
progression or unacceptable toxicity (Hsu 2017). The primary endpoint was ORR. In 27 patients 
evaluable for efficacy, the ORR was 25.9% (no patient had a complete response [CR]). Drug-
related AEs occurred in 20 patients (74.1%); the most commonly reported were rash and pruritis 
(25.9% each), pain (22.2%), fatigue (18.5%), and hypothyroidism (18.5%). Grade 3/4-related 
AEs occurred in 8 patients; only pneumonitis was reported in 2 or more patients. Ten patients 
were reported to have immune-related AEs, including hepatitis (n=4), hypothyroidism (n=2), and 
pneumonitis (n=2).  
When used as part of combination therapy, the recommended dosage of pembrolizumab is 
200 mg IV every 3 weeks or 400 mg IV every 6 weeks until disease progression, unacceptable 
toxicity or up to 24 months across the approved indications (Keytruda [pembrolizumab] 
Prescribing Information, 2023). 
1.5. 
Rationale for the Choice of Combination Treatments 
The rationale for the proposed combination treatment approach with nanatinostat and 
valganciclovir for EBV+ solid tumors in this study is based upon both nonclinical and clinical 
data supporting the complementary activities of class I HDAC inhibitors and the antiviral 
ganciclovir in EBV+ malignancies. Nanatinostat, a Class I-selective oral hydroxamate HDAC 
inhibitor active against HDAC1, HDAC2, and HDAC3, induces the expression of EBV protein 
kinases that activate the anti-viral nucleoside analogue ganciclovir via mono- and tri-
phosphorylation. This leads to inhibition of both viral and cellular DNA synthesis in 
EBV+ tumor cells and potentially in surrounding EBV- tumor cells as well (bystander effect), 
causing apoptosis. 
Clinical efficacy has previously been reported in patients with a variety of relapsed/refractory 
EBV+ lymphomas in early phase clinical studies using the combination of the HDAC inhibitor 
arginine butyrate with ganciclovir (Perrine 2007) and more recently with nanatinostat in 
combination with valganciclovir (Porcu 2020; reviewed in Section 1.5.1.1). Several of these 
EBV lymphoma subtypes shown to be susceptible to this combination therapy in clinical trials 
express the same EBV latency patterns found in NPC and gastric carcinoma (latency patterns II 
and III). This same expression indicates nanatinostat should be capable of inducing the EBV in 
NPC and gastric cancers out of the latent stage, resulting in expression of the target gene/enzyme 


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EBV-encoded protein kinase (EBV-PK). This inducement has been demonstrated in nonclinical 
studies using NPC and gastric carcinoma cell lines (data on file). Expression of EBV-PK is 
sufficient to render cells sensitive to ganciclovir. Ganciclovir triphosphate, the active metabolite 
of ganciclovir produced by EBV-PK, is toxic to all replicating mammalian cells. EBV-specific 
killing of NPC and gastric carcinoma cell lines was demonstrated in nonclinical studies using the 
combination of nanatinostat and ganciclovir (data on file). 
In addition, the plasma EBV DNA level has been reported to be closely correlated with survival 
and the response to therapy in patients with RM-NPC (Wang 2021, Wang 2010). A recent study 
evaluating the PD-1 inhibitor toripalimab as monotherapy in patients with previously treated 
RM-NPC reported the association of a significantly higher overall response rate in patients with 
a ≥50% vs <50% reduction in the plasma EBV DNA copy number on day 28 (Wang 2021). 
Therefore, dynamic monitoring of the plasma EBV DNA level may be a useful adjunct to 
determining a dosing regimen for further evaluation. 
1.5.1. 
HDAC Inhibitors and Antiviral Agents for EBV+ Malignancies 
EBV exists in a latent form in EBV+ NPC; induction of the viral lytic phase renders the tumor 
cells susceptible to antiviral therapy. Typically, in a latent tumor, ganciclovir has no antiviral or 
cytotoxic activity; however, induction of the lytic cycle using an HDAC inhibitor triggers 
expression of EBV-PK, the enzyme responsible for phosphorylating ganciclovir into its active 
cytotoxic form.  
Inhibition of class I HDACs (HDAC-1, -2, or -3) is sufficient to disrupt EBV latency and 
activate expression of EBV-PK. In published time-course experiments, discontinuous exposure 
to the HDAC inhibitor sodium butyrate was found to induce viral gene expression and be 
sufficient for synergistic tumor cell killing with ganciclovir in the EBV+ Burkitt lymphoma cell 
line P3HR1 (Ghosh 2007). In vitro exposure of P3HR1 cells to the HDAC inhibitor sodium 
butyrate induced measurable EBV- thymidine kinase gene expression at 6 hours. Intermittent 
exposure of P3HR1 cells to sodium butyrate (6 hours daily for 3 days followed by 3 days with no 
treatment) was as effective as continuous exposure in sensitizing the lymphoma cells to 
ganciclovir, with significantly greater cytotoxicity observed with the combination compared with 
either butyrate or ganciclovir alone. Furthermore, intermittent dosing reduces the potential 
toxicities resulting from the continuous HDAC inhibitor treatment.  
Nonclinical proof of concept for combining an HDAC inhibitor (romidepsin) with an anti-viral 
drug (ganciclovir) was initially established in murine xenograft models of EBV+ NPC and gastric 
cancer, whereby the combination reduced tumor volume compared with either agent alone (Hui 
2016). Similarly, the combination of gemcitabine, the HDAC inhibitor valproic acid, and 
ganciclovir was reported to exhibit a strong synergistic effect on cytotoxicity in NPC cell lines 
and clinical responses were noted in 3 patients with RM-NPC who received this regimen 
(Wildeman 2012).  
Nanatinostat is a highly potent inhibitor of Class I HDACs (half-maximal inhibitory 
concentration = 3, 4, and 7 nM for HDACs 1, 2 and 3, respectively). As a monotherapy, 
nanatinostat in vitro induces cytotoxicity in P3HR1 cells after 6 days of exposure at or above 
320 nM. While these concentrations can be achieved in vitro, preliminary PK data from the 
ongoing Phase 1b/2 dose escalation/expansion study VT3996-201 (NCT03397706) demonstrate 
that while nanatinostat may reach these concentrations in human plasma at the doses tested, it is 


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rapidly eliminated from the circulation (t1/2 <2 hours). As a single agent in patients with 
advanced malignancies (n=39), nanatinostat was well-tolerated, but demonstrated only limited 
activity at daily doses up to 160 mg (one PR was reported in a patient with metastatic pancreatic 
cancer receiving 160 mg daily) (Banerji 2012, CHROMA CHR-3996-001 Clinical Study 
Report). To date, no HDAC inhibitor has been approved in solid tumor indications. While the in 
vitro data suggest that nanatinostat may induce tumor cell death as a single agent with prolonged 
exposure, the intermittent administration of nanatinostat four days per week in doses of 20 to 40 
mg daily is unlikely to do so. 
In vitro studies using EBV+ Burkitt lymphoma HH514-16 cells demonstrated induction of the 
EBV lytic cycle after approximately 8 hours of exposure to 50 nM of nanatinostat 
(corresponding to approximately 20 ng/mL). A murine PK study demonstrated that administering 
a divided dose of nanatinostat 4 hours apart increased the duration of exposure to nanatinostat 
>50nM by up to 40%. Treatment of NPC-43 cells, an EBV+ NPC-derived cell line, with varying
concentrations of nanatinostat (5 to 500 nM) efficiently induced the virus lytic cycle (data on
file).
Taken together, these data support the conclusion that the activity of nanatinostat in combination 
with ganciclovir is dependent on their coadministration and is superior to that of either 
compound alone, particularly at nanatinostat concentrations below those capable of inducing 
direct HDAC inhibitor-mediated cytotoxicity. In addition, the use of nanatinostat monotherapy 
(at the same doses/concentrations as used in the combination therapy) as a tumoricidal agent 
would be ineffective in the clinical setting. 
1.5.1.1. 
Clinical Experience with Nanatinostat and Valganciclovir in EBV+ Lymphoma 
The investigation of nanatinostat in combination with valganciclovir for the treatment of 
relapsed/refractory EBV+ lymphoid malignancies was designated as a Fast Track Development 
Program by the United States (US) Food and Drug Administration (FDA) on 06 Nov 2019. The 
combination treatment of nanatinostat with valganciclovir is currently being evaluated in patients 
with EBV+ relapsed/refractory lymphoma in a single arm Phase 1b/2 dose escalation/expansion 
study (Study VT3996-201). Patients ≥18 years of age with EBV+ lymphoma per local laboratory 
and ≥1 prior therapy are eligible. Baseline hematology labs required for enrollment were a 
hemoglobin ≥8.0 g/dL, absolute neutrophil count (ANC) ≥1000/mm3 and platelet count 
≥50,000/mm3. 
The following regimens were evaluated in the completed Phase 1b dose-escalation phase (n=25): 
•
Cohort 1 (n = 7): Nanatinostat 10 mg oral twice daily + valganciclovir 900 mg oral twice
daily (20 mg + 1800 mg)
•
Cohort 2a (n = 5): Nanatinostat 5 mg oral twice daily + valganciclovir 450 mg oral twice
daily (10 mg + 900 mg)
•
Cohort 2b (n = 4): Nanatinostat 10 mg oral once daily + valganciclovir 450 mg oral twice
daily (10 mg + 900 mg)
•
Cohort 2c (n = 4): Nanatinostat 10 mg oral once daily + valganciclovir 900 mg oral once
daily (10 mg + 900 mg)


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•
Cohort 3 (n = 5): Nanatinostat 20 mg oral once daily, Days 1 to 4 per week +
valganciclovir 900 mg oral once daily (20 mg + 900 mg)
In Cohort 1, 3 of the first 4 patients enrolled experienced DLTs (Grade 4 neutropenia × 29 days, 
Grade 3 thrombocytopenia × 6 days, Grade 3 thrombocytopenia × 13 days) and developed 
Grade 1/2 creatinine elevations. The reported cytopenias and creatinine elevations prompted 
a 50% dose reduction in valganciclovir to 450 mg twice daily; 3 more patients were subsequently 
enrolled into the cohort. Following the dose reduction, 1 patient experienced a DLT 
(uncomplicated Grade 3 thrombocytopenia × 7 days); therefore, Cohort 1 was considered to have 
exceeded the MTD. In Cohort 2, no DLTs were reported across the 3 sub cohorts (2a, 2b, 2c; 
n = 13). In Cohort 3, an intermittent dosing schedule was used for nanatinostat administration 
(20 mg daily, Days 1 to 4 per week) with valganciclovir 900 mg daily based on the 
recommendation of the study Safety Committee; no subsequent DLTs were reported; these doses 
were declared the RP2D. 
As of 27 Oct 2021, 55 patients (10 patients with B-cell NHL [B-NHL], 21 patients with T-cell 
NHL [T-NHL]), 11 patients with Hodgkin lymphoma, 13 patients with other lymphomas) were 
enrolled and followed for DOR for almost 12 months from the first dose of study treatment; 25 
patients in Phase 1b and 30 patients in the Phase 2 expansion cohort (7 additional patients 
enrolled to receive the nanatinostat tablet formulation in an ongoing PK cohort were not part of 
this analysis). Lymphoma subtypes (N=55) were diffuse large B-cell lymphoma (DLBCL; 7 
patients), extranodal NK/T-cell lymphoma (ENKTL; 9 patients), peripheral T-cell lymphoma not 
otherwise specified (PTCL-NOS; 5 patients), angioimmunoblastic T-cell lymphoma (AITL; 
6 patients), cutaneous T-cell lymphoma (1 patient), Hodgkin lymphoma (11 patients), other 
B-cell (3 patients), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD;
13 patients), including post-transplant lymphoproliferative disorder (PTLD; 4 patients),
HIV-associated (5 patients), and other (4 patients: systemic lupus erythematosus [2 patients],
common variable immunodeficiency/primary immunodeficiency [2 patients]). Patients had a
median of 2 prior therapies (range 1 to 11); 77% had received ≥2 prior therapies, 75% were
refractory to their most recent prior therapy, and 96% had exhausted all standard therapies in the
judgment of the Investigator. Forty-three patients were evaluable for efficacy. For T-NHL
(n = 15), the ORR was 60% (9 of 15 patients); 4 patients had CRs (27%). All T/NK-NHL
patients were refractory to their most recent prior therapy. ORR/CR rates by T-NHL subtype
were as follows: ENKTL 63% (5 of 8 patients)/ 13% (1 of 8 patients) and PTCL (including
PTCL-NOS, AITL) 67% (4 of 6 patients)/ 50% (3 of 6 patients). Two patients (1 ENKTL and 1
PTCL) were withdrawn at 3.5 and 5.8 months, respectively, by the investigators to undergo SCT.
For the other 3 responding PTCL patients, one remains in a CR (16.6 months), one remained in a
CR for 20.7 months after stopping study drug treatment, and one had a PR lasting 10.6 months.
For B-NHL overall (n = 8), the ORR/CR rates were 50% (4 of 8 patients)/ 25% (2 of 8 patients). 
Four of 6 DLBCL patients responded (2 CRs in patients with primary refractory DLBCL and 2 
PRs). For Hodgkin lymphoma (n=10), PR was the best response in 1 patient (5 stable disease; 
4 progressive disease), and for IA-LPD (n=10), responses included 2 patients with CRs and 1 
patient with a PR. The median DOR was 10.4 months (Haverkos 2021). 
The most frequently reported Grade 3/4 treatment-emergent adverse events (TEAEs) overall by 
study phase are presented in Table 1. 


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Table 1: 
Study VT3996-201: Grade 3/4 Treatment-Emergent Adverse Events 
Experienced by ≥3 (5%) Patients (as of 27 Oct 2021) 
Phase 1b (n=25) 
Phase 2 (n=30) 
Thrombocytopenia 
13 (52%) 
7 (23%) 
Neutropenia 
10 (40%) 
9 (30%) 
Anemia 
9 (36%) 
8 (27%) 
Lymphopenia 
6 (24%) 
4 (13%) 
Leukopenia 
5 (20%) 
5 (17%) 
Acute kidney injury 
4 (16%) 
2 (7%) 
GI hemorrhage 
2 (8%) 
2 (7%) 
Febrile neutropenia 
1 (4%) 
3 (10%) 
In total, 42 patients received study treatment at the RP2D (nanatinostat 20 mg daily, Days 1 to 
4 per week plus valganciclovir 900 mg daily) including 5 patients from Cohort 3 of Phase 1b, 
30 patients from the Phase 2 expansion cohort, and 7 patients in the tablet PK cohort. At the 
RP2D, the most commonly reported TEAEs (≥20% of patients) were nausea (43%), anemia and 
neutrophil count decreased (31% each), constipation and fatigue (26% each), and diarrhea 
(21%). In general, the RP2D had a favorable safety and tolerability profile. 
In summary, the combination of nanatinostat and valganciclovir has been associated with a 
favorable safety and tolerability profile at the RP2D and showed preliminary efficacy 
in a population of heavily pretreated patients with a variety of EBV+ lymphomas, the majority 
of whom had refractory disease to their last therapy prior to entering the study. Further 
information about the safety profile of nanatinostat in combination with valganciclovir can be 
found in the current version of the IB. 
1.5.2. 
Rationale for Adding Pembrolizumab to Nanatinostat and Valganciclovir 
As described in Section 1.2.1, NPC cells are high expressors of PD-L1, and response rates of 
20 to 30% have been reported with PD-1 inhibitors for the treatment of advanced NPC, including 
an ORR of 25.9% for pembrolizumab in PD-1 positive RM-NPC (Wang 2021, Ma 2018, 
Hsu 2017). Pembrolizumab has been safely combined with various cytotoxic chemotherapies as 
well as HDAC inhibitors (Gray 2019).  
While some HDAC inhibitors have been approved for treating hematopoietic malignancies 
(romidepsin, vorinostat, panobinostat, belinostat), they are generally ineffective as single agents 
for the treatment of solid tumors (Anne 2013, Siegel 2009, Whitehead 2009, Steele 2008, 
Stadler 2006). Class I HDAC inhibitors have been reported in vitro and in vivo to increase 
PD-L1 and programmed cell death-ligand 2 (PD-L2) expression in nonclinical melanoma models 
(Woods 2015) and enhance the activity of PD-1 inhibitors. Furthermore, the induction of EBV 
out of latency by nanatinostat, and the resulting expression of highly immunogenic EBV 
proteins/antigens on the tumor cells, should serve to enhance the recognition and destruction of 
EBV+ solid tumors by T-lymphocytes (the evolutionary rationale for establishment of latency by 
EBV after infection of cells is to avoid expression of viral antigens, thereby escaping recognition 
and destruction by T-lymphocytes). Taken together, the dual activities of nanatinostat on the 
enhancement of PD-1 inhibitor activity and the induction of viral antigen expression suggest that 


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combining anti-PD-1 therapy with the EBV-targeted regimen of nanatinostat and valganciclovir 
may have the potential for synergistic antitumor activity in EBV-associated NPC. 
1.5.3. 
Rationale for the Doses of Nanatinostat, Valganciclovir, and Pembrolizumab in 
this Study 
1.5.3.1. 
Nanatinostat Dose 
In the Phase 1b part of this study, the nanatinostat starting dose will be 20 mg once daily on 
Days 1 to 4 per week with food. This nanatinostat dose was determined to be the RP2D in 
combination with valganciclovir 900 mg once daily in patients with relapsed/refractory EBV+ 
lymphomas in the Phase 1b/2 VT3996-201 study. Preliminary data has shown a favorable safety 
and tolerability profile at that dose. 
Administering nanatinostat as a divided dose may allow for the administration of a higher total 
daily dose of valganciclovir for the first 21 days improving tolerability and increasing the 
potential activity. Furthermore, dividing the nanatinostat dose may prolong the duration of 
nanatinostat exposure above the experimentally determined threshold required for EBV lytic 
reactivation (see Section 1.5.1). Forty mg daily was identified as the RP2D and 80 mg daily the 
MTD for single agent treatment in a Phase 1 study in patients with advanced cancers 
(Banerji 2012, CHROMA CHR-3996-001 Clinical Study Report). Because 40 mg per dose on 
Days 1 to 4 was well-tolerated with no DLTs to date, the current planned dose escalation is up to 
a maximum daily dose of 80 mg in divided doses on Days 1 to 7 per week until the RP2D is 
identified with an allowance for dose reduction cohorts in the case of DLTs.  
1.5.3.1.1. Rationale for Split Daily Dosing of Nanatinostat 
One of the main rate-limiting steps for the mechanism of action of nanatinostat and 
valganciclovir is EBV lytic reactivation from latency. This step results in expression of the viral 
protein kinase, BGLF4, which phosphorylates the pro-prodrug valganciclovir into its active 
cytotoxic form. To maximize EBV lytic reactivation, in vitro studies were performed to assess 
the impact of nanatinostat exposure duration on expression of BZLF1, the principal lytic cycle 
switch protein. The experiment was performed in EBV-infected gastric cancer cells (SNU-719) 
and revealed that a minimum of 8 to 10 hours is necessary to achieve proper activation of the 
EBV lytic cycle.  
Considering the PK of nanatinostat and its rapid clearance from the circulation (~4 hours), it was 
hypothesized that splitting the daily dose of nanatinostat into 2 sequential doses would provide 
adequate exposure to the drug and effective EBV reactivation. To test this hypothesis, a PK 
study was conducted in a murine model to examine the potential of splitting the single daily dose 
of nanatinostat into two daily doses that were administered 2 or 4 hours apart. Splitting the 
nanatinostat dose successfully increased its exposure time by up to 40%. Additionally, modeling 
of the human PK data from the Phase 1b/2 EBV+ lymphoma trial (NCT03397706) suggested that 
splitting the nanatinostat dose into 2 doses 4 hours apart would likely increase exposure to 
nanatinostat above the experimentally determined threshold required for lytic reactivation (20 
ng/mL) by 3 hours relative to the same dose administered as a single dose (6 hours for single 
dose exposure in 55% of patients versus 9 hours for split dose exposure in 99% of patients) as 
shown in Table 2. 


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Table 2: Percent of Subjects With Response to Nanatinostat for ≥ 6 Hours Based on Dosing 
Regimen 
Nanatinostat Dosing 
Regimen 
Duration (hours) 
Subjects with Duration ≥ 6 
hours (%) 
Median 
5th percentile,  
95th percentile 
30 mg single dose 
6.18 
4.55, 11.9 
55.0 
20 mg + 10 mg divided 
dose (4 hours) 
8.55 
6.96, 13.7 
99.0 
15 mg + 15 mg divided 
dose (4 hours) 
9.09 
6.98, 14.3 
99.0 
The effect of splitting the dose of nanatinostat on tumor reduction was assessed in an EBV+ 
gastric cancer xenograft murine model. SNU-719 cells were inoculated subcutaneously in the 
right flank of nude mice (n=10 per group). Once the tumor reached an average of 100 mm3, the 
mice were treated with vehicle (0.001 N HCl), ganciclovir (30 mg/kg), and nanatinostat 
(20 mg/kg) plus ganciclovir. The nanatinostat dose was administered as a single dose or as a split 
dose 4 hours apart. The animals were dosed 4 consecutive days each week for 4 weeks. No 
marked weight loss was observed during treatment. Tumor volume was measured twice weekly. 
Suppression of tumor growth was observed in animals treated with the combination of 
nanatinostat and ganciclovir. Splitting the dose of nanatinostat resulted in significantly enhanced 
antitumor activity relative to the single dose (Figure 1A).  
In a follow-up experiment, animals were treated for 6 days only, sacrificed on the seventh day, 
and tumors were resected to study the level of the BGLF4 protein kinase transcripts. Using 
RNA-scope, splitting the dose of nanatinostat yielded a definite increase in the expression level 
of BGLF4 transcript compared to the single dose (Figure 1B). These results strongly suggest that 
administering nanatinostat as 2 sequential doses 2 to 4 hours apart daily markedly increases the 
expression of the viral protein kinase and significantly enhances the antitumor activity of 
nanatinostat and valganciclovir.  


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Figure 1: Comparing the Antitumor Activity and Expression of vPK (BGLF4) in EBV+ 
Gastric Cancer Tumor Samples with Split Daily Dose vs. Single Daily Dose of 
Nanatinostat in Combination with Ganciclovir 
**** p=0.0001 
To achieve better tumor growth inhibition, a comparison was conducted to determine the 
antitumor activity of nanatinostat and valganciclovir in animals treated 4 days a week 
(Figure 2A) versus animals treated daily (Figure 2B). Treating the animals with the 
combination of nanatinostat and valganciclovir 4 days per week resulted in less antitumor 
activity than with uninterrupted daily dosing. 
Figure 2: Continuous Daily Dosing of Nanatinostat Provides Better Antitumor Activity 
Relative to 4 Days On/3 Days Off 
Altogether, these results suggest that splitting the dose of nanatinostat in the nanatinostat and 
valganciclovir combination and continuous daily dosing of nanatinostat rather than intermittent 
dosing 4 days on/3 days off represent two novel approaches that are likely to improve the 
efficacy of nanatinostat and valganciclovir in solid tumors. 
A 
B 


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1.5.3.2. 
Valganciclovir Dose 
For Phase 1b, valganciclovir will be administered at a dose of 900 mg once or twice daily with 
food. Once and twice daily dosing (900 mg/dose) are consistent with the labeled indication for 
the prevention and treatment, respectively, of CMV disease in kidney, heart, and kidney-
pancreas transplant patients at high risk (Valcyte [valganciclovir] Prescribing Information, 
2020). Once daily dosing was associated with a favorable safety and tolerability profile from the 
ongoing Phase 1b/2 VT3996-201 study in relapsed/refractory EBV+ lymphoma in combination 
with nanatinostat. 
Twice daily dosing of valganciclovir for the first 21 days starting on Cycle 1 Day 1 with a 
subsequent reduction to 900 mg once daily will be introduced in dose level 6 (Table 4), in 
concert with a divided dose of nanatinostat starting at 10 mg twice daily. Although this dosing 
regimen was observed to have exceeded the MTD in the Phase 1b/2 VT3996-201 study in 
patients with relapsed/refractory lymphoma with 2 DLTs of grade 3 thrombocytopenia and 
1 grade 4 neutropenia (Section 1.5.1.1), baseline hematology laboratory levels required for 
eligibility (hemoglobin ≥8.0 g/dL, absolute neutrophil count ≥1000/mm3, platelet count 
≥ 50,000/mm3) were lower than those required for the current study (VT3996-301: Hemoglobin 
≥9.0 g/dL, absolute neutrophil count ≥1500/mm3, platelet count ≥ 100,000/mm3). Therefore, the 
previous toxicity observed with these doses of nanatinostat and valganciclovir may not manifest 
in a different patient population with higher baseline hematology values required for eligibility. 
Twice daily dosing of 450 mg valganciclovir (900 mg/day; each dose 4 or 8 hours apart) together 
with twice daily dosing of nanatinostat (each dose 4 hours apart) will be explored in dose levels 
6 and 7 and 8 – 13, to assess the impact of short-term “dose intensification” of valganciclovir 
upon safety, tolerability, and plasma EBV DNA levels. 
1.5.3.3. 
Pembrolizumab Dose 
In the Phase 2 dose expansion part of this study, the dose of pembrolizumab will be 200 mg IV 
every 3 weeks, initially beginning 7 days following the start of administration of nanatinostat and 
valganciclovir (coinciding with Cycle 1 Day 8). Although the Keynote-028 study evaluated 
pembrolizumab at a dose of 10 mg/kg administered every 2 weeks (Hsu 2017), early PK and 
pharmacodynamic data supported using either a once every 2 weeks or once every 3 weeks 
dosing schedule. In addition, this dose of pembrolizumab has been safely combined with a 
number of cytotoxic chemotherapy regimens, with a recommended dosage of pembrolizumab 
across the approved indications of 200 mg IV every 3 weeks or 400 mg IV every 6 weeks until 
disease progression, unacceptable toxicity, or up to 24 months when used as part of combination 
therapy (Keytruda [pembrolizumab] Prescribing Information, 2023).  
Section 5.3.2 describes specific information regarding the administration of pembrolizumab in 
combination with nanatinostat and valganciclovir.  
1.6. 
Potential Benefits and Risks 
1.6.1. 
Potential Benefits 
As described in Section 1.5.1.1, preliminary data from the Phase 1b/2 VT3996-201 study 
indicate that at the RP2D, the combination of nanatinostat and valganciclovir was well tolerated 
and demonstrated clinical activity in a population of heavily pretreated patients with a variety of 


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recurrent EBV+ lymphomas. The oral administration of both nanatinostat and valganciclovir is 
an added benefit to patients, allowing them to take their study treatment at home.  
Targeting EBV has been reported to improve clinical outcomes of patients with both EBV-
associated lymphomas (Porcu 2020, Perrine 2007) and NPC (Section 1.2.1). Therefore, the 
combination of nanatinostat and valganciclovir may have clinically relevant activity for patients 
with EBV+ NPC and other tumors. 
1.6.2. 
Potential Risks 
HDAC inhibitors are potent inducers of the EBV lytic cycle; the production of infectious virus 
by virtue of HDAC inhibitor-mediated induction of the tumor lytic cycle is a clinically 
documented AE described in a monotherapy clinical trial with the HDAC inhibitor romidepsin 
(ISTODAX® [romidepsin] Prescribing Information 2021). However, this potential safety issue 
can be abrogated by the coadministration of ganciclovir. In the Phase 1b/2 VT3996-201 study, 
patients’ EBV genome levels are monitored in a serial fashion. No cases of EBV reactivation 
have been reported to date, indicating that this combination is preventing EBV viremia. 
Pertaining to the coadministration of nanatinostat and valganciclovir, both drugs exhibit 
overlapping toxicities (ie, thrombocytopenia and renal dysfunction) that may be increased 
in frequency or severity in combination. In addition, other toxicities were reported in prior 
clinical studies for one or both agents including fatigue, atrial fibrillation, nausea/vomiting, 
anemia, leukopenia, and neutropenia. 
Toxicities reported for other HDAC inhibitors include thrombocytopenia, QTc prolongation, 
neutropenia, anemia, fatigue, and diarrhea (Gryder 2012). Medications with a known risk of 
prolonging the QT interval should be avoided (Section 5.7.4 ). 
Toxicities reported for pembrolizumab include immune-mediated adverse reactions (irAEs) such 
as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, and 
dermatologic adverse reactions, as well as gastrointestinal events (nausea, decreased appetite, 
constipation, and abdominal pain). Patients receiving nanatinostat and valganciclovir in 
combination with pembrolizumab will be closely monitored for any evidence of irAEs as well as 
renal dysfunction and enhanced gastrointestinal toxicity. 
Further information about the safety profile of nanatinostat as a single agent and in combination 
with valganciclovir can be found in the current IB. For pembrolizumab, please consult the 
prescribing information (Keytruda [pembrolizumab] Prescribing Information 2023). 
1.6.3. 
Risks Related to Study Procedures 
Potential study-related risks include (but are not limited to) collection of new tumor samples, 
blood draws, radiologic assessments, and concomitant medications in case of AEs. More 
information is provided in the consent form. 
1.6.4. 
Risk Management Strategies 
The risks to patients in this study will be minimized by compliance with the eligibility 
criteria (eg, use of an eligibility checklist to approve enrollment) and study procedures, attentive 
medical monitoring, use of concomitant medications appropriate for the situation (eg, to manage 
AEs), and following guidance for dose adjustments (outlined in Section 5.6). 


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The benefit-risk balance of the oral treatment regimen with nanatinostat and valganciclovir alone 
and with intravenous pembrolizumab is anticipated to be positive for the target study population 
of patients with advanced incurable EBV+ solid tumors. 
2.
OBJECTIVES AND ENDPOINTS
The study objectives and related endpoints are presented in Table 3. 
Table 3: 
Objectives and Endpoints 
Objective(s) 
Endpoint(s) 
Primary 
Refer to Section 9.6.1 for methods of analysis. 
Phase 1b: 
To determine the recommended phase 2 dose 
(RP2D) of nanatinostat in combination with 
valganciclovir 
Phase 1b: 
Incidence of dose-limiting toxicities (DLTs) during the DLT 
evaluation period 
Phase 2: 
•
To confirm the RP2D of nanatinostat in
combination with valganciclovir
•
To estimate the objective response rate
(ORR) of nanatinostat and valganciclovir
alone and in combination with
pembrolizumab
Phase 2: 
•
Incidence of DLTs plus other safety parameters,
tolerability, PK and plasma EBV DNA concentrations at
the RP2D and <RP2D of nanatinostat in combination
with valganciclovir
•
Objective response rate (ORR) defined as the percentage
of patients with a complete response (CR) or partial
response (PR) as assessed by Response Evaluation
Criteria in Solid Tumors (RECIST), version 1.1 (v1.1)
Secondary 
Refer to Section 9.6.2 and Section 9.7 for methods of 
analysis. 
To characterize the safety and tolerability of 
nanatinostat and valganciclovir alone and in 
combination with pembrolizumab 
Incidence and severity of treatment-emergent adverse events 
(TEAEs) per National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 
To characterize the pharmacokinetic (PK) 
properties of nanatinostat in combination with 
valganciclovir 
PK parameters (eg, time to maximum plasma concentration 
[tmax], maximum plasma concentration [Cmax], and area under 
the plasma concentration-time curve [AUC]) of nanatinostat, 
its metabolites, and ganciclovir (primary active hydrolytic 
product of valganciclovir) 
To evaluate additional preliminary efficacy 
parameters of nanatinostat and valganciclovir 
alone and in combination with pembrolizumab 
•
Duration of response (DOR) – defined as the interval
from the date of first observed CR or PR to the date of
documented disease progression or death due to any
cause, whichever occurs first
•
Disease control rate (DCR) – defined as the percentage of
patients having a CR, PR, or stable disease at any time
during treatment
•
Progression-free survival (PFS) – defined as the interval
from the start of study drug treatment to the date of first
documented disease progression or death from any cause,
whichever occurs first
•
Overall survival (OS) – defined as the interval of time
from the start of study drug treatment to date of death for
any reason


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Objective(s) 
Endpoint(s) 
Exploratory 
Refer to Section 9.6.3 for methods of analysis. 
To evaluate potential biomarkers of activity of 
nanatinostat and valganciclovir with or without 
pembrolizumab  
•
Plasma Epstein-Barr virus (EBV) DNA levels (real-time
quantitative polymerase chain reaction [PCR])
•
Expression of EBV gene products (ie, lytic cycle
antigens) in both pre-study and during-study tumor
biopsies
•
Programmed cell death-ligand 1 (PD-L1) expression on
tumor cells and tumor-infiltrating immune cells
•
Histone H3 acetylation
To evaluate safety, tolerability, PK, PD, and 
antitumor activity of nanatinostat in combination 
with valganciclovir in patients with non-NPC 
EBV+ solid tumors 
Incidence of DLTs plus other safety parameters, 
tolerability, PK and plasma EBV DNA concentrations of 
nanatinostat in combination with valganciclovir in
non-NPC solid tumors
3.
STUDY DESIGN
3.1. 
Description of Study Design 
This is a Phase 1b/2, open-label, multicenter study designed to evaluate the safety and 
preliminary efficacy of oral nanatinostat and valganciclovir alone and in combination with IV 
pembrolizumab in patients with EBV+ RM-NPC (Figure 3). 


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Phase 1b: 
A traditional 3+3 dose escalation design will be used to determine the RP2D of nanatinostat and 
valganciclovir; approximately 27 to 60 patients with RM-NPC will be enrolled; cohorts of 3 to 
6 patients with RM-NPC will be enrolled sequentially at escalating nanatinostat doses starting 
with a 20 mg once daily dose on Days 1 to 4 per week (intermittent dosing) with valganciclovir 
900 mg daily. Any patients in screening when the last patient is enrolled in a cohort may also be 
enrolled if eligible. Dose escalation will continue with i) a total daily nanatinostat dose of 30 and 
40 mg daily administered as a single dose on Days 1 to 4 per week with valganciclovir 900 mg 
once daily, ii) as a divided nanatinostat dose twice daily on Days 1 to 4 per week with 
valganciclovir 900 mg once daily or valganciclovir 900 mg twice daily for 21 days followed by a 
subsequent dose reduction to 900 mg once daily, or iii) as a split daily dose of nanatinostat 
starting at 20 mg with valganciclovir 450 mg twice daily, 4 hours apart on Days 1 to 7 per week 
until the RP2D is determined. Because plasma EBV DNA levels correlate closely with the 
presence of disease and response to therapy in RM-NPC, these data will be considered together 
with safety data in the selection of the RP2D. 
Phase 2: 
Following dose escalation, Phase 2 will begin with a dose optimization cohort to assess the 
safety, tolerability, PK, pharmacodynamics, and antitumor activity of nanatinostat and 
valganciclovir and to confirm its RP2D in patients with RM-NPC.  
Patients will be randomly assigned 1:1 to each treatment group (up to 20 patients in each 
treatment group for approximately 40 patients total) during the dose optimization cohort period. 
The starting doses of nanatinostat for the treatment groups will be the RP2D and another dose 
level below the RP2D (<RP2D) plus valganciclovir 450 mg twice daily, based on the Safety 
Monitoring Committee’s (SMC’s) review of the totality of the data from the previous Phase 
1b cohorts. 
After the nanatinostat and valganciclovir RP2D is confirmed by the SMC based on the results of 
the dose optimization cohorts, up to 60 patients with RM-NPC will be randomly assigned 1:1 to 
receive that RP2D of nanatinostat and valganciclovir with or without concomitant 
pembrolizumab to assess the preliminary antitumor activity, safety, and tolerability of each 
regimen in the Phase 2 dose expansion period. Randomization will be stratified by prior 
anti-PD-1 treatment exposure. 
Pembrolizumab will be dosed at 200 mg IV every 3 weeks for those patients randomly assigned 
to the nanatinostat, valganciclovir, and pembrolizumab group.  
An early safety analysis will be performed after the first 6 patients are randomized to receive 
nanatinostat and valganciclovir in combination with pembrolizumab and have been followed for 
at least 2 cycles (7 weeks) of treatment as described in Section 5.5.3.3. 
In addition, up to 10 patients with advanced EBV+ non-NPC solid tumors (gastric cancer, LELC, 
and leiomyosarcoma) will be enrolled in a Phase 1b exploratory proof-of-concept cohort to 
characterize the safety and PK of the nanatinostat and valganciclovir combination in other solid 
tumors. Enrollment in this proof-of-concept cohort will begin when the appropriate RP2D for 
this population is determined in consultation with the SMC, while enrollment in the proof-of-
concept cohort may be stopped before 10 patients are treated if a) evidence of safety or 
tolerability issues arise or b) Phase 2 of the study completes enrollment.  


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All patients will be monitored at weekly intervals for the first 6 weeks, and then at 3-week 
intervals thereafter starting at Week 8. Tumor responses will be assessed at Week 8 and then 
every 6 weeks for the first 26 weeks (6 months) and every 12 weeks thereafter by the 
Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). A 
scan to confirm an unconfirmed PR or unconfirmed CR ≥4 weeks later may also be performed. 
Patients will continue to receive study treatment until the development of progressive disease 
(per Investigator assessment), unacceptable toxicity, withdrawal of consent, Investigator’s 
discretion, initiation of new antineoplastic therapy, or study termination by the Sponsor. The 
maximum treatment duration with pembrolizumab is 24 months.  


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Figure 3: 
Study Design 
Informed Consent 
Screening [1] 
Phase 1b 
Dose Escalation  
Treatment Period 
Day -28  to - 1 [1] 
Dose Escalation for Nanatinostat and 
Valganciclovir Treatment  
Patients with EBV+RM - NPC  
Standar d  3 + 3 escalation design  
N = 3-6 patients/dose group [ 2 ]  
RP2D Determined  
Nanatinostat and Valgancic lovir 
Exploratory Proof- of- 
Concept Cohort 
Advanced EBV+ Non- 
NPC solid tumors [ 3] 
Nanatinostat and 
Valganciclovir  
n ≤ 10 patients
Dose Optimization Cohorts  
Nan a tin o stat  and Valganciclovir  doses from Phase 1b
Patients with EBV+   RM - NPC  
Nanatinostat (RP2D) 
Valganciclovir  
n ≤ 20  
Nanatinostat ( <RP2D) 
Valganciclovir  
n ≤
Safety Monitoring Committee  
Review of data from the Dose Optimization Cohorts to 
confirm the RP2D   
Nanatinostat  
Valganciclovir  
Pembrolizumab  [4 ]
n = 30  
Nanatinostat
Valganciclovir 
n = 30  
Safety Follow-up  
30  and 90 days after the last dose of study 
drug 
 
 (permanent discontinuation)   
Phase 2 
Follow -up  
DLT and Plasma EBV DNA levels  
(following 28 days for each dose) 
2 cycles 
Primary 
assessments: 
1 Safety 
2 Radiographic 
imaging for tumor 
burden beginning at 
Week 8, then every 
6 weeks for the first 
6 months, then 
every 12 weeks 
thereafter 
 
Treatment Discontinuation  
Disease Progression by RECIST 
v1.1, unacceptable toxicity, 
treatment discontinuation at the 
discretion of the investigator, or
withdrawal of consent 
Long -Term Follow- Up  [5] 
20 


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CT = computed tomography; DLT = dose-limiting toxicity; EBV = Epstein-Barr virus; MRI = magnetic resonance imaging; 
NPC = nasopharyngeal carcinoma; RECIST v 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; RM = recurrent and/or 
metastatic; RP2D = recommended Phase 2 dose; SDD = split daily dose 
[1] Patients must have a histologically confirmed diagnosis of EBV+ recurrent and/or metastatic NPC or other solid tumor type and received
previous systemic therapy for their cancer; have measurable disease determined by MRI or CT with contrast at screening; and have adequate 
bone marrow, liver, and renal function. 
[2] Starting nanatinostat dose is 20 mg once daily on Days 1 to 4 per week with valganciclovir 900 mg daily. Dose escalation of nanatinostat will 
continue with i)  a total daily dose of 30 and 40 mg daily administered as a single dose on Days 1 to 4 per  week with valganciclovir 900 mg
once daily, ii) as a divided nanatinostat dose twice daily on Days 1 to 4 per week with valganciclovir 900 mg once daily or twice daily for 21
days followed by a subsequent dose reduction to 900 mg once daily, then iii) as a SDD of nanatinostat starting at 20 mg and valganciclovir at 
450 mg twice daily 4 hours apart on Days 1 to 7  per week until the RP2D is determined.
[3] EBV+ non-NPC solid tumors may include gastric cancer, lymphoepithelioma, and leiomyosarcoma – dosing regimen for the proof-of-concept
cohorts will be determined on data collected and analyzed at or after the RP2D from Phase 1b is determined.
[4] Pembrolizumab: Standard 200 mg IV every 3 weeks 
[5] Long-term follow-up assessments include tumor evaluation and EBV DNA viral levels (for patients who discontinued treatment for reasons
other than disease progression), survival assessment until lost to follow-up, death, or withdrawal of consent, and subsequent anti-neoplastic 
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3.1.1. 
Screening Period 
At screening, the patient will provide a signed informed consent form prior to any study-related 
activities. Collection and shipment of a formalin-fixed paraffin-embedded (FFPE) tumor sample 
(archived tissue or new biopsy specimen) to the central pathology lab should occur as early as 
possible, and no later than 8 weeks following Cycle 1 Day 1. The tumor sample will be used for 
central confirmation of EBV status and exploratory assessments as described in Table 3. For 
tumor specimens >2 years old, the Sponsor’s Medical Monitor should be consulted to discuss 
eligibility. Additional screening evaluations must be performed within 28 days or 21 days 
before treatment start (Cycle 1 Day 1) as defined in the Schedule of Events (Table 11). At the 
time of screening, male patients should be informed about their options to store germ cells in 
advance of study treatment. 
3.1.2. 
Treatment Period 
The treatment period will begin on Cycle 1 Day 1. Cycle 1 will be 28 days; all subsequent cycles 
will be 21 days. Patients will be treated until unacceptable toxicity, death, progressive disease, 
treatment discontinuation at the discretion of the Investigator, or withdrawal of consent 
(maximum treatment duration with pembrolizumab is 24 months).  
Patients with first evidence of progressive disease and no clinical deterioration may continue 
study treatment until a repeat scan within 4 to 6 weeks confirms disease progression. 
To account for atypical disease response to immune therapy, Investigators are encouraged to 
follow immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria 
(criteria based on RECIST v 1.1 for response and progressive disease, but adapted to account for 
the tumor response seen with immunotherapeutic drugs as described in Appendix 3) for 
treatment decision making, including confirmation of unconfirmed progressive disease with 
additional imaging.  
3.1.3. 
Safety Follow-up Period 
Upon discontinuation of the protocol-specified treatments, patients will enter the Follow-up 
period. All patients must complete a safety follow-up assessment at 30 and 90 days after 
receiving their last dose of study treatment (permanent discontinuation) as described in Section 
7.3.5. All AEs for patients treated with nanatinostat, valganciclovir, and pembrolizumab and 
only serious adverse events (SAEs) for all other patients will be collected up to and including 90 
days after the last dose of study treatment or until the start of a new antineoplastic therapy, 
whichever occurs first. 
Information related to concomitant medications used to treat AEs and any anti-neoplastic 
therapies taken following permanent discontinuation of study treatment will be collected for 
90 days after the last dose of study treatment for all patients. If a new antineoplastic treatment is 
initiated before the 30-day safety evaluation, safety follow-up will occur immediately before 
starting the new treatment. If a patient withdraws consent after the End-of-Treatment visit, but 
prior to the 30-day safety evaluation, safety data should be collected on the patient up to the date 
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3.1.3.1. 
Disease Progression Follow-up Period 
All patients enrolled in the study who discontinue study treatment for any reason other than 
disease progression will have a tumor assessment every 12 weeks (±7 days) as detailed in Table 
11, up to 1 year from the date of the last dose of study treatment, disease progression, the 
initiation of subsequent anti-cancer therapies, or end of the study, whichever occurs first. Any 
newly started anti-neoplastic therapies should be recorded on the “antineoplastic therapy since 
discontinuation” electronic case report form (eCRF) page. 
3.1.3.2. 
Survival Follow-up Period 
All patients enrolled in the study will be followed for survival as described in Section 7.3.6 
(or more frequently if a survival update is required for safety or regulatory reasons) for disease 
progression (for those who discontinued treatment for reasons other than disease progression), 
OS and subsequent anti-neoplastic therapies. Survival information can be obtained by phone 
calls, e-mail, medical records, clinic visits, or public records, such as government census or death 
records, until the patient is lost to follow-up, death, or withdraws consent. 
3.1.4. 
End of Study 
The end of the study occurs when all patients have either progressed, discontinued, died, become 
lost to follow-up, or have maintained a CR, PR, or stable disease for at least 3 years, or when the 
trial is terminated by the Sponsor. 
Patients continuing to derive benefit from study treatment in the opinion of the Investigator at the 
end of the study may be able to continue receiving study treatment on an individual basis 
(eg, by separate protocol or post-trial access plan) with Sponsor’s Medical Monitor approval. 
3.2. 
Duration of Study 
The study enrollment period is anticipated to be approximately 2 years, and the total duration of 
the study period is expected to be up to approximately 4 years (maximum treatment duration 
with pembrolizumab is 24 months). 
3.3. 
Discussion of Study Design 
This is a Phase 1b/2, open-label, multicenter, multiple dose study designed to evaluate the safety 
and preliminary efficacy of nanatinostat and valganciclovir alone and in combination with 
pembrolizumab in adult patients with recurrent or metastatic EBV+ NPC and other solid tumors. 
PK and pharmacodynamic assessments are also planned. 
The purpose of Phase 1b is to determine the RP2D of nanatinostat in combination with 
valganciclovir for treatment in Phase 2. Because this is the first study evaluating the combination 
of nanatinostat and valganciclovir in patients with solid tumors, determination of the RP2D is 
necessary for safe dosing in Phase 2.  
In Phase 2, a dose optimization cohort period will occur where approximately 40 patients will be 
randomly assigned to one of two cohorts (up to 20 patients each) at the RP2D and a dose below 
the RP2D to confirm the recommended nanatinostat and valganciclovir dose for Phase 2. After 
review of the data by the SMC, up to 60 RM-NPC patients will be randomly assigned to receive 
nanatinostat and valganciclovir at the confirmed RP2D with or without pembrolizumab, and an 


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early safety analysis will be performed after the first 6 patients randomized to receive 
nanatinostat and valganciclovir with pembrolizumab have been followed for at least 2 cycles (7 
weeks) of treatment as described in Section 5.5.3.3. Randomization will be stratified for prior 
exposure to anti-PD-1 agents. In addition, an exploratory proof-of-concept cohort of patients 
with other non-NPC EBV+ solid tumors is included for a preliminary analysis of safety of the 
RP2D in additional EBV+ tumor types. 
Antitumor activity will be assessed by radiologic tumor assessments conducted at baseline, 
Week 8, then every 6 weeks for the first 26 weeks (6 months), and every 12 weeks thereafter 
(and at the end-of-treatment visit) using RECIST v1.1 as the primary measure for assessment 
with the recommendation to employ iRECIST guidelines for treatment decision-making in the 
Phase 2 pembrolizumab combination group. A scan to confirm an unconfirmed PR or 
unconfirmed CR ≥4 weeks later may also be performed. 
PK assessments will be conducted to evaluate nanatinostat and valganciclovir only; these 2 drugs 
do not have competing elimination/metabolism pathways with pembrolizumab. For this reason, a 
7-day lead-in period for nanatinostat and valganciclovir prior to pembrolizumab administration is 
included in Phase 2.
The assessments to evaluate safety, tolerability, PK, and antitumor activity planned for this study 
are commonly used in oncology studies. 
An FFPE tumor block or 10 unstained slides of a representative tumor specimen obtained within 
2 years prior to screening must be available (otherwise a de novo biopsy may be required) and 
submitted to the central pathology laboratory within 8 weeks after Cycle 1 Day 1. Central 
pathology assessment will include EBER-ISH to confirm EBV status and also pharmacodynamic/
biomarker studies as described in Section 7.4.4. Biomarker studies using both archival and 
optional on-study tumor biopsies (to be performed on Cycle 1 Day 15 and at end of treatment 
with relapse or progression, if agreed) will be conducted to evaluate the mechanism of action of 
nanatinostat and valganciclovir with or without pembrolizumab, as well as to understand 
potential mechanisms of resistance. 
3.4. 
Dosing Considerations 
3.4.1.1. 
Nanatinostat and Valganciclovir 
In Phase 1b, the nanatinostat starting dose of 20 mg orally once daily on Days 1 to 4 per week in 
combination with the standard valganciclovir dose 900 mg orally once daily is based on the 
preliminary results (as of 27 Oct 2021; n=55) from the Phase 1b/2 VT3996-201 study in patients 
with EBV+ relapsed or refractory lymphomas. This patient population was heavily pretreated 
(77% received ≥2 prior therapies; median number of prior therapies was 2, range 1-11), the 
majority (75%) of whom had disease that was refractory to their last therapy at study entry. Most 
patients received repeat cycles of various cytotoxic regimens, including alkylating agents, 
anthracyclines, vinca alkaloids, and various biologic agents; the majority of these agents are 
associated with cytopenias. Nanatinostat in combination with valganciclovir has been generally 
well tolerated in this patient population (Section 1.5.1.1).  
Based on the safety data from previous cohorts, dosing with nanatinostat and valganciclovir will 
continue in single or split daily doses of nanatinostat with single daily or split daily doses of 


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valganciclovir beginning with intermittent nanatinostat dosing on Days 1 to 4 and escalating to 
twice daily dosing of nanatinostat and valganciclovir on Days 1 to 7 per week until the RP2D is 
determined. 
3.4.1.2. 
Nanatinostat, Valganciclovir, and Pembrolizumab  
According to the prescribing information, the recommended dose and schedule of 
pembrolizumab is 200 mg IV every 3 weeks (Keytruda [pembrolizumab] Prescribing 
Information, 2023). This dose and schedule of pembrolizumab has been safely combined with a 
number of cytotoxic chemotherapy regimens and biologic agents. For valganciclovir, although 
most toxicities reported are mild to moderate in nature, the prescribing information carries a 
warning regarding the development of cytopenia and renal toxicity (Valcyte [valganciclovir] 
Prescribing Information, 2021).  
To date, the most commonly reported toxicities with nanatinostat and valganciclovir at the RP2D 
(n=42) in the VT3996-201 study include nausea and cytopenias (additional details are provided 
in the latest version of the nanatinostat IB). The potential for overlapping toxicities with 
nanatinostat, valganciclovir, and pembrolizumab may be highest for renal function (already 
mitigated by the frequent monitoring of renal function according to the prescribing information 
for valganciclovir) and gastrointestinal events such as nausea and vomiting.  
Following dose escalation, two additional cohorts with up to 20 patients each will be randomized 
to receive nanatinostat and valganciclovir in the dose optimization cohort period at the RP2D and 
<RP2D to be selected in consultation with the SMC. After a review of the data from the first two 
cycles of the dose optimization cohort period, enrollment into Phase 2 dose expansion will begin, 
supported by an early safety analysis of the first 6 patients randomized to receive nanatinostat 
and valganciclovir with pembrolizumab as described in Section 5.5.3.3. 
4.
SELECTION OF STUDY POPULATION
Patients must have a histologically confirmed diagnosis of EBV+ recurrent or metastatic NPC or 
other solid tumor type and received previous systemic therapy for their cancer; have measurable 
disease determined by magnetic resonance imaging (MRI) or computed tomography (CT) with 
contrast at screening; and have adequate bone marrow, liver, and renal function. 
4.1. 
Patient Population 
4.2. 
Inclusion Criteria 
To be eligible for study participation, patients must meet all of the following inclusion criteria: 
1.
Adult patients age ≥18 years.
2.
Willing and able to give informed consent.
3.
Histologically or cytologically documented EBV+ tumor cells by EBER-ISH or LMP-1
(according to local guidelines) per an archival tumor sample taken within 2 years prior to
screening, otherwise a de novo biopsy may be required. FFPE tissue block(s) or at least
10 unstained slides are requested. It is encouraged (but not required) that patients with a


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site of disease accessible to biopsy and who are candidates for tumor biopsy according to 
local practice guidelines undergo a new tumor biopsy at baseline and during treatment. 
4.
Patients with RM-NPC (excluding patients in the Phase 1b exploratory proof-of-concept
cohort) for whom no potentially curative options are available, who have received at least
1 prior line of platinum-based chemotherapy and no more than 3 prior lines of therapy for
RM-NPC.
Note: The following clinical scenarios are not considered to be separate lines of therapy:
a.
Maintenance therapy: drug therapy (including chemotherapy, targeted therapy, or
immunotherapy including vaccines, cellular therapy, and checkpoint inhibitors) that
is started with maintenance intent in patients who have recently completed one line
of chemotherapy without experiencing disease progression.
b. Drug rechallenge: patients who have been “rechallenged” with the same drug
therapy(s) previously used to treat recurrent or metastatic NPC.
5.
Patients who developed recurrent or metastatic disease within six months following
radical concurrent chemoradiotherapy in combination with neoadjuvant and/or adjuvant
therapy for non-metastatic NPC are eligible as long as no potentially curative options are
available.
6.
For Phase 1b exploratory proof-of-concept cohort only: Patients with
advanced/metastatic EBV+ non-NPC solid tumors (gastric cancer, LELC,
leiomyosarcoma) that have progressed despite standard therapy for which no curative
therapies exist.
7.
Radiologically measurable disease per RECIST v1.1.
8.
All acute toxic effects of any prior anti-neoplastic therapy resolved to at least Grade 1
before initiation of study treatment (excluding alopecia, Grade 2 sensory neuropathy,
hypothyroidism [stable on thyroid hormone supplementation], chronic/stable xerostomia,
hearing loss, lymphedema, and taste changes [all Grade 2]).
9.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
10. Life expectancy ≥3 months.
11. Adequate laboratory parameters (in the absence of transfusion or growth factor support
with 3 weeks of Screening) including:
a.
Absolute neutrophil count ≥1500/mm3.
b. Platelets count ≥100,000/mm3.
c.
Hemoglobin ≥9.0 g/dL.
d. Aspartate aminotransferase (AST)/serum glutamine oxaloacetic transaminase
(SGOT), alanine aminotransferase (ALT)/serum glutamic- pyruvic transaminase
(SGPT) ≤2.5 × upper limit of normal (ULN) (≤5 × ULN if known liver involvement
by tumor).
e.
Total bilirubin ≤2.0 × ULN unless considered due to Gilbert’s syndrome in which
case, ≤3.5 × ULN.
f.
Estimated glomerular filtration rate ≥60 mL/min by Cockcroft-Gault equation (see
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g. Prothrombin time (PT) or international normalized ratio ≤1.5 × ULN.
h. Serum potassium and magnesium should be within normal limits for institution or
treatment to correct out of range values should be instituted.
12. For HIV positive patients:
a.
CD4 count ≥350 cells/μL.
b.
On an established antiretroviral therapy (ART) for ≥4 weeks.
c.
An undetectable HIV viral load.
d.
No prior AIDS-defining opportunistic infections within the past 12 months.
13. Willingness to comply with study requirements.
14. Women of childbearing potential (ie, reached menarche, and not post-menopausal [no 
menses for 12 months without an alternative medical cause] or surgically sterile) must 
have the following:
a.
Understand that the study medication is expected to have teratogenic risk.
b.
Have a negative serum beta human-chorionic gonadotropin pregnancy test at 
screening.
c.
Commit to continued abstinence from heterosexual intercourse (excluding periodic 
abstinence or the withdrawal method) or commit to the use of 2 forms of birth 
control with at least one highly effective method of birth control with a Pearl-Index 
<1%, and one effective barrier method such as a male condom, female condom, 
cervical cap, diaphragm, or contraceptive sponge with spermicide, without 
interruption, throughout the study dosing period and for 6 months after the last dose 
of study treatment. Apart from abstinence, highly effective methods of birth control 
include the following:
i. Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (ie, intravaginal, transdermal). Please note: 
Although the potential for drug interactions and risk of venous thromboembolism 
is low (see Section 5.7.2.3), the use of an alternative method of contraception is 
recommended.
ii. Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable).
iii. Intrauterine device
iv. Intrauterine hormone-releasing system
v. Bilateral tubal occlusion.
vi. Vasectomized partner.
15. Male patients must agree to use condoms during intercourse throughout the study dosing 
period and for 90 days after the last dose of study treatment.
4.3. 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1.
Anti-tumor treatment with cytotoxic drugs, biologic therapy (eg, monoclonal antibody),
immunotherapy, or other investigational drugs within 4 weeks or >5 half-lives, whichever
is shorter.


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2.
Corticosteroids within 7 days prior to dosing (unless ≤10 mg/day of prednisone or
equivalent).
3.
For NPC:
a.
Active parenchymal or leptomeningeal metastases.
b. Base of skull disease that poses a risk of significant bleeding (eg, proximity to
carotid artery) as judged by the Investigator.
c.
Invasive disease for which there is a potential risk of significant bleeding as judged
by the Investigator.
4.
For non-NPC cancers: Active central nervous system (CNS) disease/metastases.
5.
Nasopharyngeal cancer patients who have received prior therapy with an anti-PD-1 agent
are not excluded, except for those who experienced prior Grade 3 or higher immune-
related toxicity that resulted in permanent drug discontinuation (patients with prior
temporary drug interruptions due to endocrinopathies etc. are eligible).
6.
Less than 14 days from prior locoregional site radiotherapy. Palliative radiotherapy
outside the head and neck is allowed as long as the lesions are not target lesions.
7.
Tumor mutational burden -high advanced malignancies and/or microsatellite instability-
high malignancies who would otherwise be eligible for pembrolizumab (unless patients
have progressed on pembrolizumab) in accordance with local standards, (ie, only if such
biomarkers are performed as standard of care in the participating center).
8.
Major surgery, open biopsy, or significant traumatic injury within 28 days prior to starting
study treatment. In case of recent major surgery, the patient must have recovered
adequately from the procedure and/or any complications prior to starting study treatment.
9.
Is currently participating in or has participated in an interventional study of an
investigational agent or has used an investigational device within 4 weeks prior to the first
dose of study treatment.
Note: Individuals who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent. 
10. Diagnosis of any other malignancy within 3 years prior to enrollment, except for the
following if adequately treated:
•
local basal cell or squamous cell carcinoma of the skin, or related localized
non-melanoma skin cancer.
•
carcinoma in situ of the breast or of the cervix.
•
superficial bladder cancer.
•
low grade (Gleason 6 or below) prostate cancer undergoing surveillance with no plans
for treatment intervention or previously fully resected.
11. Gastrointestinal abnormalities including the following:
•
Inability to take oral medication.
•
Malabsorption syndrome or any other gastrointestinal condition (nausea, diarrhea,


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vomiting) that may impact the absorption of nanatinostat and valganciclovir. 
•
Prior surgical procedures affecting absorption including total gastric resection.
•
Active gastrointestinal bleeding (hematemesis, hematochezia, or melena) in the past
3 months without documentation of resolution by endoscopy/colonoscopy.
12. Positive surface antigen unless quantitative DNA polymerase chain reaction (PCR) is
undetectable, and patient is stable on antiviral prophylaxis against hepatitis B virus (HBV)
reactivation. Patients who are hepatitis B core antibody positive must have undetectable
quantitative DNA PCR and be monitored according to the local standard-of-
care/institutional guidelines.
13. Positive hepatitis C virus on RNA PCR.
14. Known SARS-CoV-2 positivity at time of screening (patients can be re-screened once
negative by PCR).
15. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to valganciclovir or nanatinostat.
16. Active infection requiring systemic therapy.
17. Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to >480 msec,
requires the coadministration of drugs known to prolong QT (Class Ia [disopyramide,
quinidine, procainamide] and Class III [sotalol, dofetilide, ibutilide] antiarrhythmic
agents) (Drew 2010), and/or has a history of Torsades de Pointes (TdP).
18. Receiving potentially nephrotoxic drugs (eg, cyclosporin).
19. Receiving concomitant drugs that are inhibitors of P-glycoprotein (P-gp) and breast cancer
resistance protein (BCRP), unless they can be held for 2 weeks or 5 half-lives, whichever
is longer, prior to administration of nanatinostat. See Appendix 1, Table 2 for a list of
drugs.
20. Receiving tenofovir (unless can be switched to an alternative ART).
21. Psychiatric illness/social situations/substance abuse disorder that would interfere with
compliance with study requirements.
22. Active autoimmune disease that has required systemic therapy with modifying agents,
corticosteroids, or immunosuppressive agents.
23. Prior or ongoing clinically significant illness, medical condition, physical finding,
electrocardiogram (ECG) finding, or laboratory abnormality that, in the Investigator’s
opinion, could affect the safety of the patient, impair the assessment of study results,
interfere with the patient’s participation for the full duration of the study, or is not in the
best interest of the patient to participate.
24. Females who are pregnant or breastfeeding or expecting to conceive children within the
projected duration of the study, starting with the screening visit through 6 months after the
last dose of study treatment.


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5.
STUDY TREATMENT INFORMATION
For this study, the term “study treatment” refers to the combination of nanatinostat 
and valganciclovir in Phase 1b and nanatinostat and valganciclovir with or without 
pembrolizumab in Phase 2 only. 
5.1. 
Nanatinostat 
5.1.1. 
Dosage Form, Composition, and Packaging 
Nanatinostat is available as 10 mg tablets. Instructions for requesting and receiving nanatinostat 
from the Sponsor will be included in the Study Manual. 
Nanatinostat (VRx-3996) is a hydroxamic acid-based HDAC inhibitor (Moffat 2010). 
As is typical of this class, the structure of nanatinostat has 3 main components: a hydroxamic 
acid that coordinates with the Zn2+ ion in the active pocket of the enzyme, a spacer (azabicyclo 
pyrimidine) that fills out the narrow channel of the binding site, and a hydrophobic head group, 
amino methyl(fluoroquinoline), that interacts with the rim surrounding the pocket of the active 
site. 
Nanatinostat is an off-white to pale orange solid with a molecular formula of C20H19FN6O2, and 
a molecular weight of 394.41 Da. The structural formula is presented in Figure 4. 
Figure 4: 
Structural Formula and Key Features of Nanatinostat 
Nanatinostat film-coated immediate-release (IR) 10 mg tablets consisting of the active 
nanatinostat (VRx-3996), and inactive excipients (ie, mannitol, microcrystalline cellulose, 
croscarmellose sodium, and sodium stearyl fumarate). The tablets are film coated with non-
functional Opadry II white. 
All inactive ingredients in the drug product meet compendial requirements of the United States 
Pharmacopeia and/or National Formulary. 
5.1.2. 
Nanatinostat Study Drug Storage 
Nanatinostat should be stored at controlled room temperature (20 to 25ºC, 68 to 77ºF) in a secure 
location. Excursions are permitted to 15ºC to 30ºC (59ºF to 86ºF). Once the bottle seal is broken, 
bottles should be stored tightly capped. 


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5.1.3. 
Nanatinostat Administration 
All patients will receive nanatinostat orally once or twice daily (at breakfast or breakfast and 
lunch, respectively) on Days 1 to 4 per week (ie, 4 days on, 3 days off) or Days 1 to 7 per week. 
Following the completion of the 28-day Cycle 1, patients will continue dosing in 21-day cycles 
until discontinuation as described in Section 7.3.3. 
Because valganciclovir tablets should be taken with food per prescribing information (Valcyte 
[valganciclovir] Prescribing Information, 2021), patients should be instructed to take both 
valganciclovir and nanatinostat with food and not fasting.  
See Appendix 1 for medications to be used with caution with nanatinostat. 
5.2. 
Valganciclovir 
Valganciclovir is a cytomegalovirus nucleoside analogue DNA polymerase inhibitor. 
5.2.1. 
Dosage Form, Composition, and Packaging 
Valganciclovir is available as 450 mg tablets packaged in bottles. 
Valganciclovir hydrochloride is a white to off-white solid with a molecular formula of C14 H22 N6 
O5. HCl, and a molecular weight of 390.82 g/mol. The structural formula is presented in Figure 5. 
Figure 5: 
Valganciclovir Hydrochloride Structural Formula 
Valganciclovir tablets manufactured by Viracta or commercially sourced will be provided to the 
investigational sites. Valganciclovir film-coated IR 450 mg tablets consist of the active 
valganciclovir (as hydrochloride) and inactive excipients (ie, microcrystalline cellulose, 
povidone, crospovidone, and magnesium stearate). The tablets are film coated with a non-
functional coating. 
Instructions for requesting and receiving valganciclovir will be included in the Study Manual. 
5.2.2. 
Valganciclovir Study Drug Storage 
Valganciclovir should be stored at controlled room temperature (20ºC to 25ºC, 68ºF to 77ºF) in a 
secure location. Excursions are permitted to 15ºC to 30ºC (59ºF to 86ºF). Once the bottle seal is 
broken, bottles should be stored tightly capped. 
5.2.3. 
Valganciclovir Administration 
The daily oral dose of valganciclovir is 900 mg once daily; 900 mg twice daily for 21 days (at 
breakfast and dinner) followed by a subsequent dose reduction to 900 mg once daily; or 450 mg 
twice daily at breakfast and lunch, in combination with nanatinostat. Following the completion 


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of the 28-day Cycle 1, patients will continue to receive the combination of nanatinostat and 
valganciclovir in 21-day cycles until discontinuation as described in Section 7.3.3. 
Valganciclovir doses should be adjusted for patients who develop an elevated creatinine while on 
study (see Section 5.6). 
Because valganciclovir tablets should be taken with food per prescribing information (Valcyte 
[valganciclovir] Prescribing Information, 2021), patients should be instructed to take both 
valganciclovir and nanatinostat with food and not fasting.  
All dosages of study treatment prescribed and dispensed to the patient, and all dose adjustments 
made during the study, must be accurately recorded in the eCRFs. 
5.3. 
Pembrolizumab 
Pembrolizumab is a humanized monoclonal PD-1 inhibitor antibody (IgG4/kappa isotype with a 
stabilizing sequence alteration in the Fc region) produced in Chinese hamster ovary cells by 
recombinant DNA technology. 
Pembrolizumab is available for injection in 100 mg/4 mL (25 mg/mL) colorless to slightly 
yellow solution in a single-dose vial and will be provided from commercial sources. Instructions 
for pembrolizumab will be included in the Study Manual.  
5.3.1. 
Pembrolizumab Study Drug Storage 
Pembrolizumab solution (injection) will be supplied in cartons containing either one or two 
100 mg/4 mL (25 mg/mL) vials. Vials should be stored refrigerated (2°C to 8°C, 36°F to 46°F) 
in the original carton to protect from light. 
As described in Section 5.3.2, pembrolizumab solution is diluted in an IV bag of sodium 
chloride or glucose. The diluted pembrolizumab solution may be stored at room temperature 
(20ºC to 25ºC, 68ºF to 77ºF) for no more than 6 hours from the time of dilution (this time 
includes room temperature storage of the diluted solution and the duration of infusion) and 
refrigerated for no more than 96 hours from the time of dilution. If refrigerated, the IV solution 
should come to room temperature prior to administration.  
5.3.2. 
Pembrolizumab Administration 
Prior to administration, pembrolizumab solution is transferred into an IV bag of sodium chloride 
9 mg/mL (0.9%) or glucose 50 mg/mL (5%). The diluted solution is mixed by gentle inversion; 
the solution should not be shaken. The final concentration of the diluted solution is between 
1 mg/mL to 10 mg/mL. The infusion solution is administered by IV over 30 minutes. 
Pembrolizumab should not be co-administered with other drugs through the same infusion line.  
The dose of pembrolizumab is 200 mg IV every 3 weeks (Section 5.5.1). On treatment days, 
pembrolizumab should be administered within an hour following nanatinostat and valganciclovir 
(nanatinostat and valganciclovir are administered first). Additional administration information is 
provided in the pembrolizumab prescribing information (Keytruda [pembrolizumab] Prescribing 
Information, 2023).  


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5.3.3. 
Sequence of Study Drug Administration 
The intermittent weekly dosing sequence for nanatinostat in combination with valganciclovir in 
Phase 1b dose levels 1 through 3 (defined in Table 4)  is presented in Figure 6.  
For patients receiving divided dosing of nanatinostat and single dosing of valganciclovir (dose 
levels 4 and 5 defined in Table 4), the first dose of nanatinostat and the only dose of 
valganciclovir will be taken at approximately breakfast time; the second dose of nanatinostat 
4 hours later will be taken at approximately lunch time. The sequence for intermittent divided 
dosing of nanatinostat only is presented in Figure 7. 
For the first 21 days of Cycle 1, patients receiving divided dosing of both nanatinostat and 
valganciclovir (dose levels 6 and 7 defined in Table 4) will take the first dose of nanatinostat and 
valganciclovir at approximately breakfast time, the second dose of nanatinostat 4 hours later at 
approximately lunch time, and then the second dose of valganciclovir in the evening at 
approximately dinner time on Days 1 to 4 per week. Patients will continue to receive divided 
dosing of valganciclovir at breakfast and dinner on Days 5 to 7 per week. Following the first 
21 days, these patients will continue to receive divided dosing of nanatinostat on Days 1 to 4 per 
week, but subsequent valganciclovir dosing will be reduced to once daily at breakfast. The 
sequence for divided dosing of both nanatinostat and valganciclovir is presented in Figure 8. 
For patients receiving split daily dosing of both nanatinostat and valganciclovir (dose levels 8 
through 13 defined in Table 4), the first dose of nanatinostat and valganciclovir will be taken at 
approximately breakfast time and the second dose of nanatinostat and valganciclovir will be 
taken 4 hours later at approximately lunch time on Days 1 to 7. The sequence for split daily 
dosing of both nanatinostat and valganciclovir is presented in Figure 9. 
The dosing sequence for nanatinostat and valganciclovir during the two dose optimization 
cohorts following identification of the RP2D is presented in Figure 10. 
The dosing sequence for nanatinostat and valganciclovir in combination with pembrolizumab 
during Phase 2 is presented in Figure 10. During Cycle 1, pembrolizumab will be administered 
on Day 8 of the 28-day cycle. This sequence will allow for the collection of PK samples (for 
nanatinostat and valganciclovir) and may potentiate the efficacy of pembrolizumab based on the 
rationale provided in Section 1.5. The dosing sequence for nanatinostat and valganciclovir 
without pembrolizumab during Phase 2 is presented in Figure 9. 
Note: Following Cycle 1, pembrolizumab will be administered on Day 1 of each subsequent 
21-day cycle. Nanatinostat will continue to be administered on Days 1 to 4 or 1 to 7 per week 
and valganciclovir will be administered every day.


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Figure 6: 
Dosing Sequence: Nanatinostat and Valganciclovir (Phase 1b Dose Levels 1 
through 3) 
Figure 7: 
Divided Dosing Sequence: Nanatinostat (Dose Levels 4 and 5) 
Dose levels defined in Table 4. 
Note: If divided dosing for nanatinostat only is determined as the RP2D for Phase 2, pembrolizumab and 
valganciclovir dosing will not be split and will follow the sequence described in Figure 10. 


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Figure 8: 
Divided Dosing Sequence: Nanatinostat and Valganciclovir (Dose Levels 6 
and 7) 
Dose levels defined in Table 4. 
Note: If divided dosing for nanatinostat and valganciclovir is determined as the RP2D for Phase 2, pembrolizumab 
dosing will not be split and will follow the sequence described in Figure 10. 
Figure 9: Split Daily Dosing Sequence: Nanatinostat and Valganciclovir (Dose Levels 8 
through 13) 
Dose levels defined in Table 4. 
Note: refer to Figure 6 through Figure 8 if the dosing schedule returns to intermittent nanatinostat 
dosing. 
Divided Dosing: Nanatinostat and Valganciclovir
Cycle 1, Weeks 1 – 3 (first 21 days)
Day 
1
Breakfast: Nanatinostat and Valganciclovir
Lunch: Nanatinostat
Dinner: Valganciclovir
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Breakfast: Valganciclovir
Lunch: --
Dinner: Valganciclovir
Cycle 1, Week 4 and Subsequent Cycles/Weeks
Day 
1
Breakfast: Nanatinostat and Valganciclovir
Lunch: Nanatinostat
Dinner: --
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Breakfast: Valganciclovir
Lunch: --
Dinner: --
Split Daily Dosing: Nanatinostat and Valganciclovir 
Breakfast: Nanatinostat and Valganciclovir 
Lunch: Nanatinostat and Valganciclovir 


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Figure 10: 
Dosing Sequence: Nanatinostat, Valganciclovir, and Pembrolizumab – Phase 2 Dose Expansion 
Nanatinostat, Valganciclovir, and Pembrolizumab –Cycle 1 Only 
Note: refer to Figure 6 through Figure 8 if the confirmed RP2D returns to intermittent nanatinostat dosing. 
Pembrolizumab will continue to be administered as illustrated in Figure 10. 
Nanatinostat, Valganciclovir, and Pembrolizumab –Subsequent Cycles 


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5.4. 
Additional Dosing Guidelines for Pharmacokinetic Sampling 
In an effort to standardize food intake for the PK assessments, patients will be asked to consume 
one can of Ensure® meal replacement shake or equivalent, prior to the dose of study treatment 
(within 30 minutes) on days with pre- and post-dose PK assessments as outlined in Section 7.4.3. 
An Ensure equivalent is defined as any liquid nutrition that is at least 8 ounces in size containing 
at least 8 grams of protein and at least 6 grams of fat. Alternatively, patients may consume a light 
breakfast in place of consuming an Ensure or equivalent meal replacement shake. The meal 
should start 30 minutes before administration of valganciclovir and nanatinostat. 
Note that nanatinostat and valganciclovir should be taken at the same time, including on Cycle 1 
Day 1 (for divided dosing, the first doses of the day should be taken together in the morning at 
approximately breakfast). For patients receiving divided or split daily dosing of nanatinostat and 
valganciclovir (dose levels 4-13; Table 4), the 4-hour PK time point samples should be collected 
prior to administration of the second dose of nanatinostat (ie, at approximately lunch time). For 
patients receiving divided dosing of valganciclovir (dose levels 6 and 7), the 8-hour PK 
timepoint should be collected prior to administration of the second dose of valganciclovir (ie, at 
approximately dinner time). 
See Appendix 1 for medications to be used with caution with nanatinostat. 
5.5. 
Dose Escalation Guidelines 
5.5.1. 
Provisional Dose Levels 
Table 4 describes the starting doses and the provisional dose levels of nanatinostat and 
valganciclovir (Phase 1b) and nanatinostat and valganciclovir with pembrolizumab (Phase 2 
Dose Optimization and Phase 2 Expansion) to be evaluated. The actual dose levels will be 
determined based on available data following a discussion with Investigators during 
dose-escalation teleconferences. No intrapatient dose escalation will be permitted in the Phase 1b 
dose escalation. 
Table 4: 
Phase 1b: Dose Levels – Nanatinostat and Valganciclovir 
Dose Level 
Nanatinostat Oral Dose 
on Days 1-4/Week 
Valganciclovir Oral Dose Daily 
-1
10 mg once daily 
900 mg once daily 
1 
20 mg once daily 
900 mg once daily 
2 
30 mg once daily 
900 mg once daily 
3 
40 mg once daily 
900 mg once daily 
4 
20 mg and 10 mg divided dose 
900 mg once daily 
5 
20 mg twice daily 
900 mg once daily 
6 
10 mg twice daily 
900 mg twice daily × 21 days, then once daily 
7 
20 mg and 10 mg divided dose 
900 mg twice daily × 21 days, then once daily 
Nanatinostat Oral Dose Twice Daily 
on Days 1-7/Week 
Valganciclovir Oral Dose Twice Daily 
on Days 1-7/Week 
8a 
20 mg and 10 mg divided dose 
450 mg twice daily 


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9a 
20 mg and 20 mg divided dose 
450 mg twice daily 
10a 
30 mg and 20 mg divided dose 
450 mg twice daily 
11a 
30 mg and 30 mg divided dose 
450 mg twice daily 
12a 
40 mg and 30 mg divided dose 
450 mg twice daily 
13a 
40 mg and 40 mg divided dose 
450 mg twice daily 
DLT = dose-limiting toxicity; RP2D = recommended Phase 2 dose 
a: Dose levels 9, 11, and 13 are planned dose levels, while dose levels 8, 10, and 12 are planned provisional dose levels for 
stepping up or down based on the DLT profile to potentially better determine the RP2D. See Table 5 for further details. 
5.5.2. 
Guidelines for Dose Escalation 
During the DLT evaluation window of both phases of the study, patients who permanently 
discontinue study treatment prior to receiving 75% of the planned number of nanatinostat and 
valganciclovir doses or 2 pembrolizumab doses due to reasons other than study drug-related 
toxicity will not be considered evaluable for DLT and may be replaced. 
Phase 1b 
The RP2D of nanatinostat in Phase 1b will be defined as the highest dose administered with 
standard daily doses of valganciclovir (900 mg once or 450 mg twice daily) for which <33% of 
patients experience a DLT (defined in Section 5.5.3) during the first treatment cycle (28 days) 
up to a maximum daily dose of 80 mg administered with food either as a single daily dose 
administered intermittently (Days 1 to 4 per week) or as a split dose twice daily administered 
continuously (Days 1 to 7 per week). In addition to toxicity, PK, antitumor activity, plus 
pharmacodynamic markers of disease response (plasma EBV DNA levels) will be considered in 
the final determination of the RP2D in consultation with the SMC. Dose escalation rules during 
Phase 1b are presented in Table 5.  
Table 5: 
Phase 1b Dose Escalation Rules for Nanatinostat in Combination with 
Valganciclovir* 
Dose level 
Outcome 
Action 
-1
Nanatinostat 10 mg daily, 
Days 1-4/wk  
Valganciclovir 900 mg daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to expansion cohorts. 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level -1 
If 1 of 6 patients experiences a DLT 
Declare dose level -1 to be RP2D 
If ≥2/6 patients experience a DLT 
Convene safety review to discuss next steps. 
1 
Starting dose 
Nanatinostat 20 mg daily, 
Days 1-4/wk  
Valganciclovir 900 mg daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 2 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 1 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 2 
If ≥2/6 patients experience a DLT 
Decrease nanatinostat to dose level -1 and 
proceed.  
2 
Nanatinostat 30 mg daily, 
Days 1-4/wk  
Valganciclovir 900 mg daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 3 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 2. 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 3. 
If ≥2/6 patients experience a DLT 
Declare dose level 1 the RP2D. 


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Dose level 
Outcome 
Action 
3 
Nanatinostat 40 mg daily, 
Days 1-4/wk  
Valganciclovir 900 mg daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 6. 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 3. 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 6. 
If ≥2/6 patients experience a DLT 
Proceed to dose level 4. 
4 
Nanatinostat 20 mg + 10 mg 
divided dose, Days 1-4/wk  
Valganciclovir 900 mg daily 
If none of the first 3 patients experiences 
a DLT 
Declare 30 mg nanatinostat the RP2D* 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 4. 
If 1 of 6 patients experiences a DLT 
Declare 30 mg nanatinostat the RP2D* 
If ≥2/6 patients experience a DLT 
Declare dose level 2 the RP2D. 
5 
Nanatinostat 20 mg BID, 
Days 1-4/wk  
Valganciclovir 900 mg daily 
If none of the first 3 patients experiences 
a DLT 
Declare 40 mg nanatinostat the RP2D* 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 5. 
If 1 of 6 patients experiences a DLT 
Declare 40 mg nanatinostat the RP2D* 
If ≥2/6 patients experience a DLT 
Declare dose level 3 the RP2D. 
6 
Nanatinostat 10 mg BID, 
Days 1-4/wk  
Valganciclovir 900 mg BID for 
21 days, then daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 7. 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 6. 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 7. 
If ≥2/6 patients experience a DLT 
Proceed to dose level 5. 
7 
Nanatinostat 20 mg + 10 mg 
divided dose, Days 1-4/wk  
Valganciclovir 900 mg BID for 
21 days, then daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 9. 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 7. 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 8 if it has not been 
previously enrolled, otherwise declare dose 
level 7 the RP2D. 
If ≥2/6 patients experience a DLT 
Step down to dose level 6 and enroll a total of 6 
patients there. Alternatively, declare dose level 
6 the RP2D if it has already enrolled 6 patients. 
8 
Nanatinostat 20 mg + 10 mg 
divided dose, Days 1-7/wk 
Valganciclovir 450 mg twice 
daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 9 if it has not been 
previously enrolled, otherwise declare dose 
level 8 the RP2D and expand dose level 8 to 6 
patients to confirm RP2D determination. 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 8. 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 9 if it has not been 
previously enrolled, otherwise declare dose 
level 8 the RP2D. 
If ≥2 patients experience a DLT 
Step down to dose level 7 and enroll a total of 6 
patients there.  Alternatively, declare dose level 
7 the RP2D if it has already enrolled 6 patients. 
9 
Nanatinostat 20 mg + 20 mg 
divided dose, Days 1-7/wk 
Valganciclovir 450 mg twice 
daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 11. 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 9. 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 10 if it has not been 
previously enrolled, otherwise declare dose 
level 9 the RP2D. 
If ≥2 patients experience a DLT 
Step down to dose level 8 and enroll a total of 6 
patients there. Alternatively, declare dose level 
8 the RP2D if it has already enrolled 6 patients. 
10 
Nanatinostat 30 mg + 20 mg 
divided dose, Days 1-7/wk 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 11 if it has not been 
previously enrolled, otherwise declare dose 
level 10 the RP2D and expand dose level 10 to 
6 patients to confirm RP2D determination. 


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Dose level 
Outcome 
Action 
Valganciclovir 450 mg twice 
daily 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 10. 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 11 if it has not been 
previously enrolled, otherwise declare dose 
level 10 the RP2D. 
If ≥2 patients experience a DLT 
Step down to dose level 9 and enroll a total of 6 
patients there. Alternatively, declare dose level 
9 the RP2D if it has already enrolled 6 patients. 
11 
Nanatinostat 30 mg + 30 mg 
divided dose, Days 1-7/wk 
Valganciclovir 450 mg twice 
daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 13. 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients in dose level 11 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 12 if it has not been 
previously enrolled, otherwise declare dose 
level 11 the RP2D. 
If ≥2 patients experience a DLT 
Step down to dose level 10 and enroll a total of 
6 patients there. Alternatively declare dose 
level 10 the RP2D if it has already enrolled 6 
patients. 
12 
Nanatinostat 40 mg + 30 mg 
divided dose, Days 1-7/wk 
Valganciclovir 450 mg twice 
daily 
If none of the first 3 patients experiences 
a DLT 
Proceed to dose level 13 if it has not been 
previously enrolled, otherwise declare dose 
level 12 the RP2D and expand dose level 12 to 
6 patients to confirm RP2D determination. 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 12. 
If 1 of 6 patients experiences a DLT 
Proceed to dose level 13 if it has not been 
previously enrolled, otherwise declare dose 
level 12 the RP2D. 
If ≥2 patients experience a DLT 
Step down to dose level 11 and enroll a total of 
6 patients there. Alternatively, declare dose 
level 11 the RP2D if it has already enrolled 6 
patients. 
13 
Nanatinostat 40 mg + 40 mg 
divided dose, Days 1-7/wk 
Valganciclovir 450 mg twice 
daily 
If none of the first 3 patients experiences 
a DLT 
Declare dose level 13 the RP2D and expand 
dose level 13 to 6 patients to confirm RP2D 
determination 
If 1 of 3 patients experiences a DLT 
Enroll 3 more patients into dose level 13. 
If 1 of 6 patients experiences a DLT 
Declare dose level 13 the RP2D 
If ≥2 patients experience a DLT 
Step down to dose level 12 and enroll a total of 
6 patients there. Alternatively declare dose 
level 12 the RP2D if it has already enrolled 6 
patients. 
*The RP2D referenced in this table is equivalent to a maximum tolerated dose (MTD) or maximum administered dose, but
ultimate determination of the RP2D of nanatinostat will be based on the evaluation of additional parameters such as the
incidence and severity of AEs, tolerability, pharmacokinetic data, antitumor activity, and plasma EBV DNA levels in
consultation with the Safety Monitoring Committee.
AEs = adverse events; BID = twice daily; DLT = dose-limiting toxicity; EBV = Epstein-Barr virus; RP2D = recommended
Phase 2 dose; wk = week
5.5.3. 
Dose-Limiting Toxicities (DLTs) 
A DLT is defined as an AE or clinically significant abnormal laboratory value that is at least 
possibly related to study drugs and is not primarily related to disease, disease progression, 
concomitant medication(s), or intercurrent illness. DLTs will be assessed for each phase of the 
study and will include events that meet any of the criteria outlined in Section 5.5.3.1, Section 
5.5.3.2, and Section 5.5.3.3. National Cancer Institute (NCI) Common Terminology Criteria 
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Adverse Events (CTCAE) version 5.0 (v5.0) will be used for all AE grading for the purpose of 
dose-escalation decisions. 
5.5.3.1. 
Phase 1b: Nanatinostat and Valganciclovir 
The DLT evaluation period is 28 days. 
To be considered a DLT, an AE must meet one or more of the following criteria: 
1.
Hematologic DLTs:
•
Grade 4 neutropenia or thrombocytopenia lasting ≥7 days.
•
Grade ≥3 thrombocytopenia associated with clinically significant bleeding.
2.
Non-hematologic DLTs:
•
Grade ≥3 non-laboratory toxicities despite maximum supportive therapy.
•
Grade ≥3 clinically significant laboratory abnormality for which the patient is
symptomatic regardless of its duration, requires medical intervention, is not corrected
within 72 hours, or leads to hospitalization.
3.
Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of >38.3°C
(101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour.
4.
Any treatment-related toxicity that results in a dose hold of >7 consecutive days or causes
the patient to discontinue treatment.
5.
Any Grade 5 toxicity not clearly due to the underlying disease or extraneous causes
6.
Any Hy’s law case: ALT and/or AST >3 × ULN and total bilirubin >2 × ULN not
explained by other causes.
5.5.3.2. 
Phase 2: Nanatinostat and Valganciclovir With or Without Pembrolizumab 
The DLT evaluation period is 7 weeks. 
Phase 2 of the study will initially have a dose optimization cohort period to assess the safety of 
the RP2D and ‘<RP2D’ of nanatinostat and valganciclovir determined by the SMC’s review of 
the totality of the data from the previous Phase 1b cohorts. The dose optimization cohort period 
will be monitored by the study’s SMC composed of the lead study Investigators and the 
Sponsor’s Medical Monitor. The evaluation period will be 2 cycles post-initial study drug 
administration (7 weeks). When all patients enrolled in the dose optimization cohort have 
completed 2 cycles (7 weeks) of treatment (or discontinued earlier) recruitment will be paused 
until a safety data review is performed in the following situations: 
1.
If treatment was postponed due to the reasons listed below for more than 2 of the first
6 enrolled patients who received at least one dose of any study drug.
2.
If treatment was postponed due to the reasons listed below for 4 or more of the first
9 patients who have received at least one dose of any study drug.


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The SMC will review the clinical and laboratory data for any DLTs and/or emerging new or 
unexpected toxicities associated with the nanatinostat and valganciclovir dose to determine the 
next steps for dosing and continued enrollment. 
Following review of the data from the dose optimization cohorts and confirmation of the RP2D, 
enrollment into the Phase 2 dose expansion will begin, supported by an early safety analysis of 
the first 6 patients randomized to receive nanatinostat and valganciclovir with pembrolizumab 
as described in Section 5.5.3.3. Any DLTs and/or emerging new or unexpected toxicities 
associated with nanatinostat in combination with valganciclovir and pembrolizumab will be 
evaluated by the SMC who will determine the next steps for dosing and continued enrollment.  
To be considered a DLT, an AE must meet one of the following criteria, where the relationship 
to study drug(s) cannot be ruled out, and the AE is not primarily related to disease, disease 
progression, concomitant medication(s) or intercurrent illness: 
1.
Hematologic DLTs:
•
Grade 4 neutropenia or thrombocytopenia lasting ≥7 days.
•
Grade ≥3 thrombocytopenia associated with clinically significant bleeding.
2.
Non-hematologic DLTs:
a.
Grade ≥3 non-laboratory toxicities despite maximum supportive therapy.
b. Grade ≥3 clinically significant laboratory abnormality for which the patient is
symptomatic regardless of its duration, requires medical intervention, is not
corrected within 72 hours, or leads to hospitalization.
3.
Febrile neutropenia defined as ANC <1000/mm3 with a single temperature of >38.3°C
(101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour.
4.
Any treatment-related toxicity that causes the participant to discontinue treatment.
5.
Any Grade 5 toxicity not clearly due to the underlying disease or extraneous causes.
6.
Any Hy’s law case: ALT and/or AST >3 × ULN and total bilirubin >2 × ULN not
explained by other causes.
After the nanatinostat and valganciclovir RP2D is confirmed by the SMC based on the results of 
the dose optimization cohorts, the study will proceed to the Phase 2 dose expansion period. Up to 
60 patients with RM-NPC will be randomly assigned 1:1 to receive that RP2D of nanatinostat 
and valganciclovir with or without concomitant pembrolizumab 200 mg IV every 3 weeks to 
assess the preliminary antitumor activity, safety, and tolerability of each regimen.  
5.5.3.3. 
Assessment of Toxicity During Phase 2 Dose Expansion 
Sequential boundaries will be used to monitor the DLT rate during Phase 2 dose expansion 
(Ivanova 2005). The accrual will be halted if excessive numbers of DLTs (boundary) as defined 
in Section 5.5.3.2 are seen per arm, and the SMC will have the option of either discontinuing 
accrual in that arm or reducing the RP2D to reduce the level of toxicity. The boundaries at which 
accrual is halted or the RP2D is reduced are listed in Table 6. This is a Pocock-type stopping 
boundary that yields the probability of crossing the boundary at most 5% when the rate of dose-
limiting toxicity is equal to the acceptable rate of 30%. 


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Table 6: 
Early Stopping Boundaries for Toxicity 
Number of Patients 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Boundary 
- 
- 
- 
4 
5 
5 
6 
6 
7 
7 
8 
8 
9 
9 
9 
Number of Patients 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
Boundary 
10 
10 
11 
11 
12 
12 
12 
13 
13 
14 
14 
14 
15 
15 
15 
An early safety analysis of the first 6 patients randomized to receive nanatinostat and 
valganciclovir with pembrolizumab will be performed, and a more conservative early stopping 
boundary than is shown in Table 6 above will be applied if appropriate. If at least two of these 
patients experience DLTs during their first 2 cycles (7 weeks) of treatment, then patient accrual 
will be halted, and the SMC will have the option of either discontinuing accrual in that arm or 
reducing the RP2D to reduce the level of toxicity. 
5.6. 
Dose Modification Guidelines for Study Treatment-Related 
Toxicities 
Nanatinostat and Valganciclovir 
For patients who do not tolerate the protocol-specified dosing schedule or develop toxicities, 
dose adjustments of nanatinostat and valganciclovir are permitted. Dose adjustments, except for 
valganciclovir adjustments based on renal function (Section 5.6.2), must be approved by the 
Medical Monitor or Sponsor prior to implementing. These changes must be accurately recorded 
in the eCRFs. 
Given the expectation that both study drugs are required for activity, both agents will be held 
and restarted in parallel. Dose modification guidelines in case of study treatment-related 
toxicity for nanatinostat, valganciclovir, and pembrolizumab are presented in Table 7. 
Unless otherwise indicated in Table 7, any AE that requires a dose hold should resolve to 
Grade 1 or baseline generally within 14 days before resuming treatment at the current or a 
reduced dose. 
The management of patients requiring more than 2 dose reductions should be discussed with the 
Sponsor’s Medical Monitor. 
For patients in Phase 2 treated with nanatinostat and valganciclovir in combination with 
pembrolizumab, if pembrolizumab treatment is discontinued, nanatinostat and valganciclovir 
dosing may continue. If nanatinostat or valganciclovir are discontinued, the Sponsor’s Medical 
Monitor should be consulted about pembrolizumab treatment. 
Pembrolizumab 
Dose reduction of pembrolizumab will not be required in this study. For the management of 
specific immune-mediated adverse reactions, see Table 8. Otherwise, withhold pembrolizumab 
for severe (Grade 3) immune-mediated adverse reactions and permanently discontinue 
pembrolizumab for those that are life-threatening (Grade 4), recurrent Grade 3 that require 
systemic immunosuppressive treatment, or if not able to reduce corticosteroid dosing to 10 mg 
per day or less of prednisone or an equivalent within 12 weeks of initiating steroids.  


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If a patient requires a dose interruption of >6 weeks of pembrolizumab from the intended day of 
the next scheduled dose, pembrolizumab should be discontinued.  
Exceptions following a discussion between the Sponsor’s Medical Monitor and the Investigator 
may be possible. Reasons for a potential exception include, but are not limited to, the following: 
1. Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs.
2. Dosing delays lasting >6 weeks from the previous dose that occur for non-drug-related
reasons (eg, surgery) may be allowed.
Patients with permanent discontinuation of pembrolizumab due to adverse reactions may 
continue treatment with nanatinostat and valganciclovir provided that they could still potentially 
benefit from the treatment (in the opinion of the Investigator) until disease progression, 
occurrence of intolerable toxicity, death, Investigator’s decision, or voluntary withdrawal of the 
patient from the study. 
The Investigator must first discuss any decision about permanent drug discontinuation in 
advance with the Sponsor’s Medical Monitor. All doses of study treatment and all dose 
interruptions or modifications must be accurately recorded in the eCRFs.  
For additional details on pembrolizumab dosing, refer to the current prescribing information 
(Keytruda [pembrolizumab] Prescribing Information, 2023). 
Table 7: 
Dose Modification Guidelines for Study Treatment-Related Toxicity 
NCI CTCAE v5.0 
Toxicity Grade 
Recommended Dose Modifications for Nanatinostat and 
Valganciclovir 
Recommended Dose Modifications 
for Pembrolizumab 
Grade 4 neutropenia 
(ANC <0.5 × 109/L) 
1.
Interrupt nanatinostat/valganciclovir dosing.
2.
Resume nanatinostat/valganciclovir at the same doses
when ANC ≥1.0 × 109/L.
3.
If the grade 4 neutropenia lasts more than 7 days or
recurs, then decrease valganciclovir dose by 50% daily.
For dose levels 6 and 7: decrease twice daily
valganciclovir dosing to once daily dosing (take with
nanatinostat).
4.
If the decreased dose is tolerated for ≥4 weeks, then
resume previous daily valganciclovir dose.
5.
If Grade 4 neutropenia occurs again following a
valganciclovir dose reduction, then interrupt
nanatinostat/valganciclovir dosing and discuss with the
medical monitor.
6.
Use of growth factors (G-CSF, GM-CSF) is permitted per
the ASCO 2015 clinical practice guidelines (Smith 2015).
Withhold until resolution to Grade 0 
or 1. 
Grade 3 neutropenia 
(ANC 0.5 – <1.0 × 
109/L) 
1.
If persistent (>7 days) then interrupt
nanatinostat/valganciclovir dosing.
2.
Resume nanatinostat/valganciclovir at the same doses
when ANC ≥1.0 × 109/L.
3.
If recurs and persists >7 days, then consider reducing
daily valganciclovir dose by 50%. For dose levels 6 and
7: decrease twice daily valganciclovir dosing to once
daily dosing (take with nanatinostat).
4.
If persists, then decrease nanatinostat daily dose to the
next lowest nanatinostat dose level.
5.
Use of growth factors (G-CSF, GM-CSF) are permitted
per the ASCO 2015 clinical practice guidelines
(Smith 2015).
Maintain dose and schedule. 


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NCI CTCAE v5.0 
Toxicity Grade 
Recommended Dose Modifications for Nanatinostat and 
Valganciclovir 
Recommended Dose Modifications 
for Pembrolizumab 
Grade 4 
thrombocytopenia 
(Platelet count <25 
× 109/L) 
1.
Interrupt nanatinostat/valganciclovir dosing.
2.
If thrombocytopenia resolves to ≤Grade 2 (>50 × 109/L),
then restart both drugs.
3.
If recurs, then decrease daily valganciclovir dose by 50%.
For dose levels 6 and 7: decrease twice daily
valganciclovir dosing to once daily dosing (take with
nanatinostat). If the decreased dose is tolerated for ≥4
weeks, then resume previous daily valganciclovir dose.
4.
If Grade 4 thrombocytopenia occurs again following a
valganciclovir dose reduction, then interrupt
nanatinostat/valganciclovir dosing and discuss with the
medical monitor.
If ongoing at time of next scheduled 
pembrolizumab dose, omit 
scheduled dose. 
If asymptomatic, resolved to 
≤Grade 2 within ≤7 days and prior 
to scheduled dose, proceed with 
pembrolizumab dose. 
Grade 3 anemia 
(Hemoglobin 
<8.0 g/dL) 
1.
Continue nanatinostat and decrease valganciclovir dose as
follows: from 900 mg twice daily to 900 mg daily; from
900 mg daily to 450 mg daily; from 450 mg daily to
450 mg every 2 days; from 450 mg every 2 days to
450 mg twice weekly.
2.
If anemia persists, then decrease nanatinostat daily dose
to the next lowest nanatinostat dose level.
3.
If anemia resolves to ≤Grade 2 (≥8.0 g/dL), after (1), then
increase valganciclovir dose. Increase nanatinostat dose if
it was decreased per (2).
4.
If anemia recurs, then decrease valganciclovir dose as
outlined in (1) and maintain at the lower dose.
5.
Transfusion is recommended in patients with a
hemoglobin level <7-8 g/d L per institutional guidelines,
and/or with symptomatic anemia
Maintain dose and schedule. 
Grade 4 anemia 
1.
Hold both study drugs.
2.
Transfuse.
3.
Once anemia resolves to ≤Grade 2 (≥8.0 g/dL), resume
nanatinostat at the planned dose and valganciclovir at a
lower dose as follows: Decrease 900 mg twice daily to
900 mg daily; decrease 900 mg daily to 450 mg daily;
decrease 450 mg daily to 450 mg every 2 days; decrease
450 mg every 2 days to 450 mg twice weekly)
4.
If anemia persists, then decrease nanatinostat daily dose
to the next lowest nanatinostat dose level.
5.
If recurs, interrupt both drugs and discuss with the study’s
Medical Monitor.
Maintain dose and schedule. 
Febrile neutropenia 
(ANC <1.0 × 109/L, 
with a single 
temperature of 
≥38.3°C or 
a sustained 
temperature of 
≥38°C for more 
than 1 hour) 
1.
Interrupt nanatinostat/valganciclovir dosing.
2.
Resume nanatinostat/valganciclovir at the same doses
when ANC ≥1.0 × 109/L.
3.
Use of growth factors (G-CSF, GM-CSF) are permitted
per the ASCO 2015 clinical practice guidelines
(Smith 2015).
Withhold until resolution to Grade 0 
or 1. 
QTc prolongation 
For QTc interval >480 msec and <500 msec: 
1.
Check magnesium and potassium levels and correct any
abnormalities.
2.
If possible, stop any medications that may prolong the
QTc interval.
3.
Decrease nanatinostat to the next lowest nanatinostat dose
level.
4.
Resume nanatinostat/valganciclovir at the initial dose in
the next cycle provided that the QTc interval improves to
≤470 msec at the start of that cycle. Otherwise continue
nanatinostat at the next lowest nanatinostat dose level.
Maintain dose and schedule. 


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NCI CTCAE v5.0 
Toxicity Grade 
Recommended Dose Modifications for Nanatinostat and 
Valganciclovir 
Recommended Dose Modifications 
for Pembrolizumab 
For QTc interval >500 msec: 
1.
Check magnesium and potassium levels and correct any
abnormalities.
2.
Interrupt nanatinostat/valganciclovir dosing and stop any
medications that may prolong the QTc interval.
3.
If the QTc interval improves to ≤470 msec just prior to
the start of the next cycle, resume
nanatinostat/valganciclovir at the initial dose.
4.
If no other cause of QTc prolongation is identified,
decrease dose of nanatinostat to the next lowest
nanatinostat dose level. Otherwise continue to hold
nanatinostat/valganciclovir for as long as necessary.
Other study drug-
related Grade 3/4 
non-hematologic 
toxicity or Grade 
3/4 clinically 
significant 
laboratory 
abnormalities  
Grade 4 non-hematologic AE: 
1.
Discontinue nanatinostat/valganciclovir dosing.
2.
Following resolution of the toxicity to ≤Grade 1 or to the
patient’s baseline value, if the Investigator considers it to
be in the patient’s best interest to resume therapy, this
may be permitted at a lower dose level following
discussion with Sponsor’s Medical Monitor.
Grade 3 non-hematologic AE: 
1.
Resume nanatinostat/valganciclovir at the same dose
when toxicity resolves to ≤Grade 1.
See Table 8. 
Treatment-related 
Grade 5 toxicity 
1.
Pause further enrollment in the study pending a Safety
Monitoring Committee assessment.
Pause further enrollment in the 
study pending a Safety Monitoring 
Committee assessment. 
Dose levels for Phase 1b are defined in Table 4. 
AE = adverse event; ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; CTCAE = Common 
Terminology Criteria for Adverse Events; G-CSF = granulocyte-colony stimulating factor; GM-CSF = granulocyte 
macrophage-colony stimulating factor; NCI = National Cancer Institute; PO = orally; QD = once daily.  
Table 8: 
Pembrolizumab Recommended Dose Modifications for Immune-Mediated 
Adverse Reactions 
Adverse Reaction 
Severity 
Pembrolizumab Dose Modification 
Pneumonitis 
Grade 2 
Withhold1 
Grades 3 or 4 
Permanently discontinue 
Colitis 
Grades 2 or 3 
Withhold1 
Grade 4 
Permanently discontinue 
Hepatitis with no 
tumor involvement of 
the liver 
AST or ALT increases to >3 and up to 8 × ULN or  
total bilirubin increases to more than 1.5 and up to 3 × 
ULN 
Withhold1 
AST or ALT increases to more than 8 × ULN  
or 
Total bilirubin increases to more than 3 × ULN 
Permanently discontinue 
Hepatitis with tumor 
involvement of the 
liver2 
Baseline AST or ALT is more than 1 and up to 3 × ULN 
and increases to more than 5 and up to 10 × ULN 
or 
Baseline AST or ALT is more than 3 and up to 5 × ULN 
and increases to more than 8 and up to 10 × ULN 
Withhold1 
AST or ALT increases to more than 10 × ULN 
or 
Total bilirubin increases to more than 3 × ULN 
Permanently discontinue 


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Adverse Reaction 
Severity 
Pembrolizumab Dose Modification 
Endocrinopathies 
Grades 3 or 4 
Withhold until clinically stable or 
permanently discontinue depending on 
severity 
Nephritis with renal 
dysfunction 
Grade 2 or 3 increased creatinine 
Withhold1. Follow guidelines for 
valganciclovir dose reduction in 
Table 7. Resume in patients with 
complete or partial resolution (Grades 
0 to 1) after valganciclovir dose 
adjustment and/or corticosteroid taper 
Grade 4 increased creatinine 
Permanently discontinue 
Exfoliative 
dermatologic 
conditions 
Suspected SJS, TEN, or DRESS 
Withhold1 
Confirmed SJS, TEN or DRESS 
Permanently discontinue 
Myocarditis 
Grade 2, 3 or 4 
Permanently discontinue 
Neurological 
toxicities 
Grade 2 
Withhold1 
Grade 3 or 4 
Permanently discontinue 
Infusion-related 
reactions 
Grades 1 or 2 
Interrupt or slow the rate of infusion 
Grades 3 or 4 
Permanently discontinue 
Source: Keytruda [pembrolizumab] Prescribing Information, 2023 
1Resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper 
2If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA based on 
recommendations for hepatitis with no liver involvement. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; DRESS = Drug Rash with Eosinophilia and Systemic 
Symptoms; SJS = Stevens-Johnson Syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal 
Patients should be monitored until resolution of the toxicity. During a dose interruption, 
study days and procedures will continue to accrue until the end of the current cycle (see Schedule 
of Events in Section 6). If the dose interruption extends beyond the end of the cycle, the 
subsequent Cycle Day 1 will not begin until dosing has resumed. If the dose is held for more 
than 14 days, the Investigator should consult with the Sponsor’s Medical Monitor before dosing 
resumes. 
If a patient has multiple dose interruptions for study drug toxicity or has had to interrupt for more 
than 14 days, a dose reduction may be considered. Re-escalation of study drug dose may only be 
performed after approval by the Sponsor’s Medical Monitor. 
5.6.1. 
Criteria for Suspension of Study Drug Treatment Due to Treatment-Related 
Toxicities 
In the event of the following treatment-related toxicities, no additional patients should be 
enrolled until further review and assessment by the Safety Monitoring Committee: 
•
Death
•
Grade 4 QTc prolongation (Torsade de Pointes)
•
Occurring in ≥2 patients:
−
Grade 4 acute renal failure
−
Grade 4 multi-organ failure


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5.6.2. 
Dose Modifications for Patients with Renal Impairment 
Patients who develop an elevated creatinine while on study should have their dose of 
valganciclovir adjusted per Table 9. 
An estimated creatinine clearance in adults is calculated from serum creatinine by the following 
formulas: 
For serum creatinine measured in mg/dL: 
For males = (140 – age [years]) × (body weight [kg]) = XX mL/min 
(72) × (serum creatinine [mg/dL])
For females = (140 – age [years]) × (body weight [kg]) = XX mL/min × 0.85 
(72) × (serum creatinine [mg/dL])
For serum creatinine measured in μmol/L: 
For males = (140 – age [years]) × (body weight [kg]) × 1.23 = XX mL/min 
 Serum creatinine (µmol/L) 
For females = (140 – age [years]) × (body weight [kg]) × 1.23 = XX mL/min × 0.85 
Serum creatinine (µmol/L) 
For patients already receiving a dose of valganciclovir lower than that recommended in Table 9, 
the Investigator should discuss the amount of dose reduction with the Sponsor’s Medical 
Monitor. 
Table 9: 
Valganciclovir Dose Adjustments for Patients with Renal Impairment 
Creatinine 
Clearance 
(mL/minute) 
Valganciclovir Dose (daily) 
Valganciclovir Dose (twice daily) 
≥60 
900 mg once daily 
900 mg twice daily 
40–59 
450 mg once daily 
450 mg twice daily 
25–39 
450 mg every 2 days 
450 mg once daily 
10–24 
450 mg twice weekly 
450 mg every 2 days 
<10 (on 
hemodialysis) 
Not recommended (discuss with Medical 
Monitor) 
Not recommended (discuss with Medical 
Monitor) 
5.6.3. 
Missed or Vomited Doses 
For dose levels 1 to 3, if a scheduled dose of nanatinostat or valganciclovir is missed, the patient 
should take the missed dose(s) as soon as possible during the same day if within 8 hours of the 
missed dose. For dose levels 4 to 13, or if more than 8 hours has passed, the planned dosing 
schedule will be resumed the following day without a change in the daily dose or schedule; do 
not make up missed or vomited doses. 
If a scheduled dose of nanatinostat or valganciclovir is vomited, the patient should contact the 
site for consideration of anti-nausea medication and dosing should resume with the next 


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scheduled dose. No replacement dose should be given. If the situation persists, the site should 
consult with the Sponsor’s Medical Monitor. 
The prescribing information for pembrolizumab should be followed for any missed doses 
(Keytruda [pembrolizumab] Prescribing Information, 2023).  
5.7. 
Prior and Concomitant Medications 
Prior and concomitant medications include all vitamins, herbal remedies, over-the-counter, and 
prescription medications. 
No other anticancer therapies (including chemotherapy, radiation, antibody therapy, 
immunotherapy, or other experimental therapies) of any kind are permitted while the patient is 
receiving treatment with nanatinostat, valganciclovir, and pembrolizumab. Patients are not 
allowed to participate concurrently in any other therapeutic study. 
If a patient takes an exclusionary medication while on study, the event will be deemed a protocol 
deviation and continuation of that patient in the study will be decided by the Sponsor’s Medical 
Monitor.  
5.7.1. 
Supportive Care Guidelines and Permitted Concomitant Medications 
During the treatment period, medications required to treat AEs or manage cancer symptoms, and 
supportive care agents, such as antiemetics, antidiarrheal agents, and pain medications are 
allowed, except if specifically prohibited (Section 5.7.4). Patients may continue to use 
concomitant medications previously prescribed to treat non-cancer-related conditions provided 
that, in the Investigator’s judgment, they will not interfere with the study outcomes.  
Patients should receive appropriate supportive care measures deemed necessary by the treating 
Investigator including the following: 
•
Nausea and vomiting: If nausea and vomiting occur, consideration should be given to
using prophylactic antiemetic therapy in subsequent cycles according to local institutional
practice. Liberal oral fluid intake should be maintained if possible.
•
Diarrhea: All patients experiencing diarrhea should be advised to drink liberal
quantities of clear fluids. If this is not possible, IV fluid and electrolyte replacement
therapy should be utilized.
•
Neutropenia (See Section 5.7.1.2).
5.7.1.1. 
Pembrolizumab Infusion-Related Reactions 
Pembrolizumab has been reported to cause infusion-related reactions varying in severity from 
hypersensitivity to anaphylaxis in 0.2% of patients. Patients should be monitored for the signs 
and symptoms of infusion-related reactions (including rigors, chills, wheezing, pruritis, flushing, 
rash, hypoxemia, hypotension, and fever).  Table 10 provides infusion-related reaction treatment 
guidelines. For additional details, refer to the current prescribing information for 
pembrolizumab (Keytruda [pembrolizumab] Prescribing Information, 2023). 


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Table 10: 
Pembrolizumab Infusion-Related Reaction Treatment Guidelines 
Severity (CTCAE Grade) 
Action 
Grade 1 or 2 
Interrupt or slow the rate of the infusion. Increase the 
monitoring of vital signs until the patient is deemed medically 
stable in the opinion of the Investigator. The use of additional 
supportive therapies (IV fluid, antihistamines, NSAIDs, 
acetaminophen, narcotics) may be considered. 
For grade 2 reactions, patients may be pre-medicated prior to the 
next pembrolizumab infusion with acetaminophen 500-1000 mg 
oral (or an equivalent antipyretic) and diphenhydramine 50 mg oral 
(or an equivalent antihistamine). 
Grade 3 or 4 
Stop the infusion and permanently discontinue 
pembrolizumab. Monitor symptoms. Increase the monitoring of 
vital signs until the patient is deemed medically stable in the 
opinion of the Investigator. Additional appropriate supportive 
therapies may include IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, corticosteroids, and 
epinephrine. Hospitalization may be indicated. 
Source: Keytruda [pembrolizumab] Prescribing Information, 2023 
CTCAE = Common Terminology Criteria for Adverse Events; IV=intravenous; NSAID=nonsteroidal 
anti-inflammatory drug. 
5.7.1.2. 
Hematopoietic Growth Factors 
The prophylactic use of hematopoietic growth factors is prohibited unless the patient experiences 
an AE. Granulocyte colony-stimulating factor (G-CSF) agents may be administered in response 
to Grade ≥3 neutropenia (Table 7). The American Society of Clinical Oncology (ASCO) clinical 
practice guidelines should be followed (Smith 2015). Hematopoietic growth factors may not be 
used within 21 days of screening.  
5.7.2. 
Concomitant Therapy Requiring Caution and/or Action 
5.7.2.1. 
Corticosteroids 
Patients may receive topical or inhaled corticosteroids while on study, or prednisone ≤10 mg per 
day (or the equivalent). The use of systemic corticosteroids is discouraged because the potential 
anti-tumor effect may confound the interpretation of study drug-related activity. Patients who 
develop severe conditions requiring systemic corticosteroid therapy may be treated as such and 
are not required to discontinue participation in the study. 
5.7.2.2. 
Proton Pump Inhibitors 
The effect of gastric pH on nanatinostat absorption is not known. If possible, proton pump 
inhibitors and H2 antagonists should be excluded from patient use. If these medications must be 
given, do not administer proton pump inhibitors, H2 antagonists, or antacids within 2 hours prior 
to or within 4 hours after nanatinostat administration. 
5.7.2.3. 
Concomitant Therapies to be Used with Caution with Nanatinostat 
A study with recombinant human CYP450 suggests that nanatinostat is a direct inhibitor of 
CYP3A4 isoform. In vitro studies indicated that nanatinostat is not metabolized by or induces the 


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activity of CYP3A4. A potential for drug interactions between nanatinostat and drugs that are 
substrates of CYP3A4 is low, but cannot be ruled out (see Appendix 1, Table 1). Please refer to 
the IB for a detailed description. 
Select ARTs (saquinavir, tipranavir, darunavir, and idinavir) that are metabolized by CYP3A4 
should be administered with caution. Coadministration of these ARTs may result in an increase 
in their systemic exposures. Caution is recommended during the coadministration of these drugs 
with nanatinostat (particularly saquinavir and indinavir due to their narrow therapeutic index), as 
well as other CYP3A substrates relevant to the study population (cyclosporine, sirolimus, 
tacrolimus).  
As combined (estrogen-progesterone containing) oral contraceptives are metabolized by 
CYP3A4, caution is also recommended during the coadministration of these drugs with 
nanatinostat. Although the potential for drug interactions and risk of venous thromboembolism is 
low, the use of an alternative method of contraception is recommended. 
Transporter studies indicate nanatinostat is likely a substrate of multidrug resistance 1 (MDR1) 
and BCRP transporters, but not an inhibitor of these transporters. Therefore, the use of strong 
MDR1/P-gp and BCRP inhibitors should be approached with caution (see Appendix 1, Table 2). 
5.7.3. 
Concomitant Therapies to be Used with Caution with Valganciclovir 
Drug-drug interaction studies with ganciclovir and valganciclovir were conducted in patients 
with normal renal function. Therefore, with concomitant administration of valganciclovir and 
other renally excreted drugs, patients with impaired renal function may have increased 
concentrations of ganciclovir and/or the co-administered drug. Such patients should be closely 
monitored for toxicity of ganciclovir and the co-administered drug. Established and other 
potentially significant drug interactions conducted with ganciclovir are listed in Appendix 2. 
Patients receiving concomitant immunosuppressive agents such as cyclosporine, mycophenolate 
mofetil, sirolimus, and tacrolimus may be at risk for increased hematologic and/or renal toxicity. 
Coadministration of the antiretroviral agent didanosine may result in an increase in its 
concentration and patients should be monitored closely for toxicity (eg, pancreatitis). In patients 
who are receiving a concomitant medication considered to pose a risk of significant drug 
interaction with valganciclovir, additional monitoring should be conducted as outlined 
in Appendix 2. 
5.7.4. 
Prohibited Therapies 
Patients are prohibited from receiving the following therapies during the screening and treatment 
phases of this study: 
•
Anti-cancer systemic chemotherapy or biologic therapy.
•
Immunotherapy not specified in this protocol.
•
Chemotherapy not specified in this protocol.
•
Investigational agents other than nanatinostat, valganciclovir and pembrolizumab.
•
Radiation therapy.
•
Tenofovir (unless the patient can be switched to an alternative ART).


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•
Live vaccines within 30 days prior to the first dose of investigational treatment and while
participating in the study.
•
Medications with a known risk of prolonging the QTc interval/TdP (Class Ia
[disopyramide, quinidine, procainamide] and Class III [sotalol, dofetilide, ibutilide]
antiarrhythmic agents) (Drew 2010). If, during the course of this study, the concomitant
administration of drugs with a known potential to cause TdP is required and cannot be
avoided, study drug administration must be interrupted until an assessment of the
potential safety risk has been performed.
•
Corticosteroids for any reason other than those outlined in Section 5.7.2.1.
5.8. 
Patient Numbering & Treatment Assignment 
5.8.1. 
Patient Numbering 
At the time of consent, patients will be assigned a 7-digit identification number consisting of a 
4-digit site number (eg, 1001) followed by a 3-digit patient number (eg, 101). Patient numbers
will be assigned sequentially at each site starting with 101 (eg, 1001-101, 1001-102, 1001-103,
etc.) for patients enrolled in the Phase 1b portion of the study and starting with 201 (eg, 1001-
201, 1001-202, 1001-203, etc.) for patients enrolled in Phase 2.
5.8.2. 
Treatment Assignment (Including Randomization) 
Patients with EBV+ RM-NPC will be enrolled in groups of 3 to 6 in the Phase 1b escalating 
nanatinostat dose groups to determine the RP2D of nanatinostat in combination with 
valganciclovir (patients in screening when the last patient is enrolled in a cohort may also be 
enrolled if eligible).  
For Phase 2, following determination of the RP2D, approximately 40 patients will be 
randomized into one of two dose optimization cohorts receiving nanatinostat at the RP2D or 
at the ‘<RP2D’ and valganciclovir twice daily as shown in Figure 3.


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Following confirmation of the RP2D, patients with EBV+ RM-NPC will be randomly assigned 
1:1 using a centralized interactive randomization system to either nanatinostat and valganciclovir 
treatment or nanatinostat and valganciclovir with pembrolizumab treatment in the Phase 2 dose 
expansion period. Randomization will be stratified by prior anti-PD-L1 treatment exposure. 
Pembrolizumab will be administered at 200 mg IV every 3 weeks for those patients randomly 
assigned to the nanatinostat, valganciclovir, and pembrolizumab group. An early safety analysis 
after the first 6 patients are randomized to this treatment group and followed for at least 2 cycles 
(7 weeks) of treatment will be performed as described in Section 5.5.3.3.  
In addition, up to 10 patients with EBV+ non-NPC solid tumors will be enrolled into an 
exploratory proof-of-concept cohort. The dose and regimen will be based on data collected and 
analyzed from prior cohorts after an RP2D is determined in consultation with the SMC to predict 
the appropriate recommended dose for the non-NPC solid tumor population prior to 
commencing enrollment.  
5.8.3. 
Treatment Blinding 
This is an open-label study; therefore, treatment assignments will not be blinded. 
5.9. 
Study Drug Preparation and Dispensation 
5.9.1. 
Study Drug Packaging and Labelling 
The study treatment will be released upon receipt of all requested essential documents based on 
federal, state, and local regulations. Each bottle of study drug will have either a booklet or panel 
label describing the contents based on regulatory requirements and a place for the pharmacist 
to record the patient number. Additional information is described in Section 5.1 
(nanatinostat), Section 5.2 (valganciclovir), and Section 5.3 (pembrolizumab). 
5.9.2. 
Drug Supply and Storage 
Drug supply and storage is described in Section 5.1 (nanatinostat), Section 5.2 (valganciclovir) 
and Section 5.3 (pembrolizumab). Additional information is provided in the Study Pharmacy 
Manual. 
5.9.3. 
Study Drug Compliance and Accountability 
5.9.3.1. 
Study Drug Compliance 
Patient compliance with oral study drugs will be assessed by the Investigator and/or study 
personnel at each patient visit, and information provided by the patient and/or caregiver will be 
captured in the eCRF. This information must be captured in the source documents at each patient 
visit. Paper diaries will be utilized to record doses and collect tablet counts. 
5.9.3.2. 
Study Drug Accountability 
The Investigator or their representative will account for all study drugs supplied by the Sponsor. 
The Investigator shall maintain adequate records of the disposition of study drug, including 


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dates, quantity, lot numbers, and use by patients. Drug accountability will be reviewed during 
monitoring visits and at the completion of the study. 
5.9.4. 
Study Drug Handling and Disposal 
Upon completion of the study, all remaining study treatment at the sites will be accounted for 
and returned to the Sponsor, or their designee, via a traceable method (US Postal Service, FedEx, 
etc.) or disposed following institution’s Standard Operating Procedures (SOPs), if instructed by 
the Sponsor. 
6. 
SCHEDULE OF EVENTS
Scheduled study visits, assessments, and dosing of each study drug will occur according to the 
Schedule of Events provided in Table 11. Every effort should be made to follow the schedule 
outlined in this table. Allowed visit windows are specified as follows: 
1.
Screening assessments must occur within 28 days or 21 days of Cycle 1 Day 1:
a.
Vital signs, ECOG performance status, and physical exam should be performed
within 28 days of start of study drug (Cycle 1 Day 1).
b. Specified laboratory and radiologic assessments should be performed within 21 days
prior to the start of study drug (Cycle 1 Day 1).
2.
Radiologic assessments must be performed as indicated in Table 11. A visit window of
±7 days is allowed. Even if study treatment doses are held for a patient, radiologic
assessments should stay on schedule.
3.
All other assessments have a general ±3-day window for completion with the exception of
safety follow-up assessments that have a ±5-day window and the long-term follow-up
assessments that have a ±7-day window.
4.
A creatinine clearance determination should be performed monthly, and in case of a
creatinine elevation while on-study.


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Table 11: 
Schedule of Events 
Screeninga 
Cycle 1 
(28 days) 
Cycle 2 
(21 days) 
Cycle 3+ 
(21 days) 
EOTb 
Safety Follow-upc 
Long-Term Follow-upd 
Day(s) of Cyclee 
-28 to -1 -21 to -1
1 
8 
15 
22 
1 
8 
1 
30 Days 
(±5 Days) 
After Last 
Dose 
90 Days 
(±5 Days) 
After Last 
Dose 
Without PD 
(q12 weeks 
±7 days) 
With PD 
(q12 weeks 
±7 days) 
Study Day 
1 
8 
15 
22 
29 
36 
50+ 
Study Week 
1 
2 
3 
4 
5 
6 
8+ 
Obtain informed consent 
X 
Enrollment/ Randomization 
X 
Patient history 
Complete medical history 
X 
Demography 
X 
Prior antineoplastic therapies 
X 
Inclusion/exclusion criteria 
X 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xf 
Xf 
Physical examination 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
Height 
X 
ECOG performance status 
X 
X 
X 
Vital signsg 
X 
X 
X 
X 
X 
Laboratory assessments 
Hematologyh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistryi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid function testsj 
X 
Xqcycle2 
Creatinine clearance 
(Cockcroft-Gault estimation)k 
X 
X 
X 
X 
X 
Coagulationh 
X 
X 
Urinalysisl 
X 
Hepatitis serologym 
X 
Serum pregnancy testn 
X 
Serum or urine pregnancy 
testn 
X 
X 
X 
X 
X 
X0-6mo 
X0-6mo 


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Screeninga 
Cycle 1 
(28 days) 
Cycle 2 
(21 days) 
Cycle 3+ 
(21 days) 
EOTb 
Safety Follow-upc 
Long-Term Follow-upd 
Day(s) of Cyclee 
-28 to -1 -21 to -1 
1 
8 
15 
22 
1 
8 
1 
 
30 Days 
(±5 Days) 
After Last 
Dose 
90 Days 
(±5 Days) 
After Last 
Dose 
Without PD 
(q12 weeks 
±7 days) 
With PD 
(q12 weeks 
±7 days) 
Study Day 
 
 
1 
8 
15 
22 
29 
36 
50+ 
 
 
 
 
 
Study Week 
 
 
1 
2 
3 
4 
5 
6 
8+ 
 
 
 
 
 
Disease assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain CT or MRIo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor evaluation per 
RECIST v1.1 CT/MRI with 
contrast enhancemento 
 
X 
 
 
 
 
 
 
Xq6wks, 
wk26+ q12wks 
X 
 
 
Xq12wks 
 
Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
Xp 
 
Xp 
 
 
 
Xp 
 
 
Xp 
 
 
 
 
Adverse events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
 
 
CMVr 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
HIVr 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
EBV DNA levelsr 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samplings 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Biomarkerst 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunophenotype 
and functionsu 
 
 
X 
 
 
 
 
 
X qcycle3 
X  
 
 
 
 
Histone acetylationv 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Plasma biomarker analysis 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
Tumor Biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival FFPE tumor 
specimenw 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
De novo tumor biopsyx 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
On-Study Biopsy (optional 
with disease progression or 
relapse)y 
 
 
X 
 
 
 
 
Nanatinostat/valganciclovir 
dispensing/return 
 
 
Xz 
 
 
 
X 
 
X 
X 
 
 
 
 
Pembrolizumab dosing  
(Phase 2 only) 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 


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Screeninga 
Cycle 1 
(28 days) 
Cycle 2 
(21 days) 
Cycle 3+ 
(21 days) 
EOTb 
Safety Follow-upc 
Long-Term Follow-upd 
Day(s) of Cyclee 
-28 to -1 -21 to -1
1 
8 
15 
22 
1 
8 
1 
30 Days 
(±5 Days) 
After Last 
Dose 
90 Days 
(±5 Days) 
After Last 
Dose 
Without PD 
(q12 weeks 
±7 days) 
With PD 
(q12 weeks 
±7 days) 
Study Day 
1 
8 
15 
22 
29 
36 
50+ 
Study Week 
1 
2 
3 
4 
5 
6 
8+ 
Anti-neoplastic therapies since 
discontinuation of study 
treatment and responseaa 
X 
X 
Survival contactaa 
X 
AE = adverse event; CR = complete response; CT = computed tomography; CMV = cytomegalovirus; DNA = deoxyribonucleic acid; EBV = Epstein-Barr virus; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; FFPE = formalin-fixed paraffin embedded; HIV = human immunodeficiency virus; MRI = magnetic resonance 
imaging; PD = progressive disease; PK = pharmacokinetic; PR = partial response; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; TSH = thyroid stimulating 
hormone 
a.
Screening – The screening visit may be conducted over multiple days in the 28 days prior to Cycle 1 Day 1 or conducted as a single visit within 21 days of Cycle 1 Day 1.
b.
EOT visit – At the time patients discontinue study treatment, a visit should be scheduled as soon as possible and within 14 days after the last dose of study treatment.
c.
Safety Follow-up – Assessments will occur 30 and 90 days after the last dose of study treatment for all patients. Visits at 30 days after last dose will be conducted in person 
to complete assessments. The safety follow-up assessments at 90 days after last dose may be completed by phone or in person. In situations for which the patient has declined 
further testing, follow-up via phone call, e-mail, medical records, clinic visits, or public records such as government census or death records will be performed to collect as 
much information as possible. The first Long-Term Follow-up visit may coincide with the 90-day Safety follow-up assessments.
d.
Long-term Follow-up – Patients who discontinue treatment for reasons other than disease progression will have tumor and plasma EBV DNA level assessments every
12 weeks (3 months) ± 7 days for up to 1 year from the date of the last dose of study treatment, disease progression, the initiation of subsequent anti-cancer therapies, or end 
of the study, whichever occurs first. Scans performed during the Follow-up period should be performed on the same schedule with the same imaging modality as previously 
used. All patients enrolled in the study will be followed for survival every 12 weeks (3 months) according to Section 3.1.3.2 until withdrawal of consent, death, lost to follow-
up, completion of 3 years of follow-up, completion of 1 year after the last patient discontinues treatment, or the study is terminated by the Sponsor, whichever occurs first. 
For females of childbearing potential, long-term follow-up visits must be completed in person for the first 6 months following the last dose of study drugs to perform 
pregnancy testing.
e.
Visit windows – There is a ±3-day window allowable for each clinic visit following Cycle Day 1. The Safety Follow-up visit has a ±5-day allowable window, and Long-term 
Follow-up has a ±7-day allowable window. For disease assessments after Cycle Day 1, a ±7-day window is allowable.
f.
During Safety Follow-up, only concomitant medications used to treat AEs and any new antineoplastic therapies will be collected.
g.
Vital signs - Vital signs include heart rate, blood pressure, and temperature. For patients enrolled in Phase 1b dose levels 1-7 requiring serial PK draws and ECGs, vital signs 
should be collected following ECGs and prior to the PK blood draws on Cycle 1 Day 1 and Cycle 2 Day 1 at the following timepoints: pre-dose, just prior to the first dose of 
nanatinostat and valganciclovir, and post-dose at 1-, 2-, 4-, and 6-hours (±15 minutes). For patients enrolled in dose levels 8-13 and Phase 2 requiring serial PK draws and 
ECGs, vital signs should be collected following ECGs and prior to the PK blood draws on Cycle 2 Day 1 at the following timepoints: pre-dose, just prior to the first dose of 
nanatinostat and valganciclovir, and post-dose at 1-, 2-, 3-, 4-, 5-, and 6-hours (±15 minutes). At time points requiring ECGs, vital signs, and PK blood draws, assessments 
should be performed in as short of timeframe as possible and in this order: ECG, vital signs, then blood draw.
h.
Hematology and coagulation – Hematology includes complete blood count to include white blood cells (WBCs) with differential, hemoglobin (Hgb), and platelets. 
Coagulation includes prothrombin time (PT) or International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT).
i.
Chemistry – Chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose (non-fasting), calcium, phosphate, magnesium, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, total protein, alkaline phosphatase (ALP), albumin, and uric acid.


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j.
Free T3, free T4 and TSH will be performed at baseline (Cycle 1 Day 1 pre-dose for all Phase 2 patients). Subsequently, TSH should be assessed every 2 cycles starting at
Cycle 2 Day 1.
k.
Creatinine clearance (Cockcroft-Gault estimation) – The Cockcroft-Gault formula will be used to calculate estimated creatinine clearance (CrCl), and should be performed
at screening, monthly, and repeated locally in case of creatinine elevations while on study:
•
Males: CrCl (mL/min) = (140 – age) × (weight [kg]) / 72 × (serum creatinine [mg/dL]); for females, the formula is multiplied by 0.85.
•
By SI units, CrCl (mL/min) = (140 – age) × (weight [kg]) × 1.23 / (serum creatinine [μmol/L]); for females, the formula is multiplied by 0.85.
Valganciclovir dose will be adjusted based on CrCl as described in Section 5.6.2 for patients with creatinine elevations/impaired renal function.
l.
Urinalysis will be performed locally at each site.
m.
Hepatitis screening – Hepatitis B virus (HBV) surface antigen (Ag), HBV core and surface antibody (Ab), HBV DNA polymerase chain reaction (PCR; only for patients
with positive HBV core Ab or surface Ag), hepatitis C virus (HCV) Ab (any subject positive for HCV Ab will be evaluated by qPCR).
n.
Pregnancy testing – Pregnancy testing is only required for females of childbearing potential and will be performed locally at each site. Serum test must be performed during
screening. Serum or urine tests are to be performed at the beginning of each cycle, at EOT, and at the 30-day Safety Follow-up visit. Pregnancy tests will be conducted
during Long-term Follow-up visits until 6 months following last dose of study drug.
o.
Tumor evaluation per RECIST v1.1 CT/MRI will be conducted at screening, Week 8, and every 6 weeks for the first 26 weeks (6 months), then every 12 weeks (±7 days) up
to 1 year from the date of the last dose of study treatment, disease progression, the initiation of subsequent anti-cancer therapies, withdrawal of consent, lost to follow-up, or
end of the study, whichever occurs first. Copies of all scans and redacted radiology reports are to be submitted according to vendor / Sponsor requirements in a timely
manner. A scan to confirm an unconfirmed PR or unconfirmed CR ≥4 weeks later may also be performed.
The same imaging modality used at screening must be used throughout the study for each patient.
For patients who discontinue due to relapse/progression, the EOT visit imaging assessment is not needed if the last scan was within 4 weeks of the EOT visit.
For patients who discontinue treatment without relapse/disease progression, CT scan assessments will continue every 12 weeks for up to 1 year from the date of the last dose
of study drug during the follow-up period until disease progression, start of new anti-cancer therapy, or end of study, whichever occurs first.
p.
12-Lead ECG – All ECGs will be performed in triplicate. Average corrected QT interval using Fridericia’s method (QTcF) is to be calculated to confirm eligibility. ECGs
will be performed in triplicate as follows: 2 ECGs will be performed in triplicate pre-dose within 1 hour of dosing at least 15 minutes apart. For Phase 1b (dose levels 1-7),
post-dose ECGs will be performed prior to and as close as possible to PK blood draws at 1-, 2-, 4-, and 6-hours post-dose (±15 minutes) on Cycle 1 Day 1. For Phase 1b (dose
levels 8-13) and Phase 2, one set of triplicate ECGs will be performed on Cycle 1 Day 1 at 2 hours post-dose and on Cycle 2 Day 1 prior to and as close as possible to the PK
blood draws at 1-, 2-, 3-, 4-(pre-dose of second divided dose), 5-, and 6-hours post-dose (±15 minutes). Detailed instruction on ECGs is provided in Section 7.4.2.5.
q.
For patients in Phase 2 who are receiving nanatinostat, valganciclovir, and pembrolizumab, all AEs will be collected for up to and including 90 days after the last dose of
study treatment or until the start of a new antineoplastic therapy, whichever is first; for all other patients, only serious adverse events (SAEs) will be collected during this
safety follow-up time period.
r.
EBV DNA, CMV, HIV levels – Plasma samples will be collected to investigate circulating EBV DNA, CMV, and HIV (HIV+ patients only). EBV DNA levels will be
utilized for safety and biomarker analysis. For patients in Follow-up: If no relapse/disease progression, then patients will continue to have EBV DNA levels monitored every
12 weeks for up to 1 year from the date of the last dose of study drug during the follow-up period, until disease progression, start of new anti-cancer treatment, or end of
study, whichever occurs first.
s.
PK sample collection – For Phase 1b (dose levels 1-7), PK will be collected on Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose and 1-, 2-, 4-, 6-, and 8-hours post-dose (±15
minutes). For Phase 1b (dose levels 8-13) and Phase 2, PK will be collected on Cycle 2 Day 1 at pre-dose, and 1-, 2-, 3-, 4- (pre-dose of second divided dose), 5-, 6-, and 8-
hours post-dose (±15 minutes). For patients receiving divided or split daily dosing, the 4-hour PK time point samples should be collected prior to administration of the second
dose of nanatinostat or nanatinostat and valganciclovir (ie, at approximately lunch time) and the 8-hour PK time point should be collected prior to administration of the second
dose of valganciclovir (ie, at approximately dinner time; dose levels 6 and 7 only). At time points requiring ECG, vital signs, and PK blood draw, assessments should be
performed in as short of timeframe as possible and in this order: ECG, vital signs, then blood draw.
t.
Exploratory biomarkers – Blood draws for exploratory biomarkers should be taken prior to the patient taking study medication on that day.
u.
Immunophenotype and immune function – Peripheral blood mononuclear cells (PBMCs) will be collected pre-dose and every 3 cycles starting at Cycle 3 Day 1 (Day 1 of
Cycles 3, 6, 9, 12, etc.) and at End of Treatment. Cycle 1 Day 1 pre-dose sample may be collected during screening within 21 days of Cycle 1 Day 1.
v.
Histone acetylation – PBMCs for histone acetylation will be collected pre-dose and at 3 hours (±15 minutes) post-dose.


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w.
Archival Formalin-Fixed Paraffin-Embedded (FFPE) tumor specimen – Mandatory for all patients. Eligibility will be based on local pathology review; confirmation of 
diagnosis by central pathology laboratory is not required for entry or initiation of treatment. A FFPE tumor block and/or 10 unstained slides of a representative tumor specimen or 
lymph node must be confirmed to be available at the time of screening and must be submitted to the central pathology laboratory within 8 weeks after Cycle 1 Day 1. If an 
archival tumor sample taken within 2 years prior to screening is not available, a de novo biopsy may be required.
x.
Tumor specimens must meet the criteria described in Section 7.2.4. De novo study biopsies – Optional. Matched pre- and on-study tumor biopsies may be obtained pre-dose 
within 28 days of Cycle 1 Day 1 and on Cycle 1 Day 15; these specimens will be used for exploratory evaluation and will be provided to the central pathology laboratory, along 
with a frozen tissue specimen, if available. On-study biopsies for exploratory evaluation will be performed at the discretion of the Investigator when the disease site is accessible 
for biopsy and the patient is a candidate for tumor biopsy according to local practice guidelines.
y.
On-study biopsy – Optional. FFPE tumor specimens collected at relapse or disease progression should be provided to the central pathology laboratory, along with a frozen 
tissue specimen, if available.
z.
Drug dispensing – Depending on cohort assignment and dose schedule, additional bottles of study drug may be dispensed mid-cycle as needed.
aa. Subsequent anti-neoplastic therapies and response – Patients will be contacted by telephone call, e-mail, medical records, clinic visits, or public records such as
government census or death records for assessment of additional therapy, response status, and survival every 12 weeks (3 months) until withdrawal of consent, death, lost to 
follow-up, completion of 3 years of follow-up, completion of 1 year after the last patient discontinues treatment, or the study is terminated by the Sponsor, whichever 
occurs first. 


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7. 
Enrollment and Study Procedures
Study enrollment and procedures are summarized in the following subsections. The timing of all 
study procedures is provided in the Schedule of Events included in Table 11. 
7.1. 
Informed Consent 
The Investigator will provide for the protection of the patients following all applicable Good 
Clinical Practice (GCP) regulations. The informed consent form (ICF) must be reviewed and 
approved by the Sponsor and the Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC) before the informed consent process may begin. 
Prior to performing any study-specific screening or study-related procedures for any potential 
patient to be enrolled, the patient must be given or must complete the following: 
•
Be informed of all pertinent aspects of the study and all elements of informed consent
•
Be given time to ask questions and time to consider the decision to participate
•
Voluntarily agree to participate in the study
•
Sign and date an IRB/IEC approved Informed Consent Form
Study personnel must obtain documented consent from each potential patient prior to entering in 
a clinical study. Consent must be documented by obtaining the dated signature of both the patient 
and the person conducting the consent discussion on the consent form. If local law does not 
allow written consent, then oral consent, attested to by the dated signature of an impartial witness 
(someone not involved with the conduct of the study), is the required alternative.  
If the patient is illiterate, an impartial witness must be present during the entire informed consent 
reading and discussion. Afterward, the patient should sign and date the informed consent, if 
capable. The impartial witness should also sign and date the informed consent along with the 
individual who read and discussed the informed consent (ie, study staff personnel). If the patient 
is legally incompetent (ie, mentally incapacitated), the written consent of a legal guardian or 
legal representative must be obtained. Depending on local law or review committee requirements 
such consent may also need to be signed by an impartial witness. 
The information from the consent form should be translated and communicated to the patient in 
language understandable to the patient. When the study patient population includes non-English 
speaking people, a certified translated consent form or an appropriate equivalent will be provided 
to the patient. 
The initial informed consent form and any subsequent revised written informed consent form 
must receive approval and/or favorable opinion by the IRB/IEC in advance of use. The patient or 
his/her legally acceptable representative should be informed in a timely manner if new 
information becomes available that may be relevant to the patient’s willingness to continue 
participation in the study. The communication of this information should be documented. 
A copy of the signed ICF will be provided to the patient. The Investigator will retain all original 
versions of signed ICFs. 


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After informed consent is provided, patients who successfully complete all screening 
assessments and study entry criteria may be enrolled in the study. The period for completing 
screening assessments is 28 days.  
An optional supplemental consent for future use of blood and tissue samples for research 
purposes (biobanking) may be proposed to patients based on local regulatory requirements. 
The assessments to be conducted on these samples are described as exploratory endpoints in 
the protocol. 
Rescreening of patients is only allowed once per patient if the patient is not registered as entering 
the treatment phase (Cycle 1 Day 1). In this case, a new patient number will be assigned, and the 
patient will be identified with this number throughout their participation in the study. 
7.2. 
Screening Period 
Selected screening procedures are highlighted below. A summary of all screening assessments 
to be performed is provided in the Schedule of Events (Table 11). 
7.2.1. 
Demographic Information 
Standard demographic parameter information including age, gender, and race/ethnicity (recorded 
in accordance with local regulations) will be collected at the screening visit. 
7.2.2. 
Physical Examinations 
Physical examinations will be performed as specified in the Schedule of Events (Table 11). 
Documentation of the physical examination will be included in the source documentation at the 
investigational site. Any changes from the screening physical examination findings that meet the 
definition of an AE must be recorded on the AE eCRF. 
7.2.3. 
Medical History 
All relevant cancer-related history over the patient’s lifetime should be recorded, including: 
•
Initial diagnosis
•
Prior antineoplastic therapies (including surgery and radiotherapy) and dates
•
Responses to prior antineoplastic therapies
The non-cancer-related medical history should include any ongoing medical conditions 
and symptoms and should also include the toxicity grade NCI CTCAE Version 5.0. 
7.2.4. 
Tumor Specimen 
An FFPE tumor block or 10 unstained slides of a representative tumor specimen obtained 
≤2 years prior to screening must be available and submitted to the central pathology laboratory 
within 8 weeks after Cycle 1 Day 1. For available tumor specimens >2 years old, the Sponsor’s 
Medical Monitor should be consulted to discuss eligibility.  
The specimen must be representative of the current disease. If archival tumor tissue (tumor block 
or unstained slides) was not available prior to enrollment, a newly obtained tumor biopsy 
(excisional or core) may be required prior to enrollment. If a new biopsy is obtained to satisfy 


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eligibility, an FFPE tumor sample should be provided to the central pathology lab. De-identified 
pathology reports associated with these tissues are also required and must be sent to the central 
pathology laboratory with the tissue and/or slides. 
The process for submitting archived tissue and procedures for central pathology review is 
provided in a separate Study Manual. 
7.2.5. 
Baseline Disease Assessments 
Any imaging assessments already completed during the regular work-up of the patient within 
21 days prior to Cycle 1 Day 1, including before signing the main study ICF, can be considered 
as the baseline images if all imaging requirements for the study are met. 
The imaging modality used for evaluation at screening must be consistently used throughout the 
study for each patient (CT with contrast or MRI). If positron emission tomography (PET) is 
used, a contrast-enhanced CT scan must be included.  
7.2.6. 
Eligibility Determination and Patient Registration 
Investigative sites will submit patient registration materials for Sponsor’s Medical Monitor 
approval prior to the enrollment of the patient in the trial. Details on this process will be included 
in the Study Manual. 
Once all screening procedures are complete, an eligibility checklist must be completed by the 
Investigator or designee and provided to the Sponsor’s Medical Monitor with limited exceptions 
at least 72 hours prior to planned enrollment for review. Eligibility will be reviewed and 
approved by the Sponsor Chief Medical Officer or designee (eg, Sponsor’s Medical Monitor) 
prior to patient enrollment. 
7.2.6.1. 
Screen Failures 
Patients who sign an ICF but are later deemed to be ineligible for enrollment before taking any 
study medication will be considered screen failures. The eCRF completion requirement for 
screen failures is outlined in the eCRF Completion Guidelines. 
7.3. 
Treatment Period 
Patients will be treated until discontinuation of study treatment as described in Section 7.3.3. 
7.3.1. 
Treatment Cycles 
Patients will receive nanatinostat at the assigned dose once or as a divided dose twice daily on 
Days 1 to 4 per week or Days 1 to 7 per week and valganciclovir 900 mg orally once daily, twice 
daily (for 21 days, with a subsequent dose reduction to 900 mg daily), or 450 mg orally twice 
daily continuously for 21-day treatment cycles (excluding Cycle 1, which is 28 days). 
Pembrolizumab (200 mg IV) will be administered every 3 weeks starting on Cycle 1 Day 8. 
7.3.2. 
Unscheduled Visit(s) 
Unscheduled visits will be recorded in the eCRF. The specific tests and evaluations performed 
during an unscheduled visit will be determined by the Investigator. 


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7.3.3. 
Discontinuation of Study Treatment 
Patients will continue study treatment until disease progression, unacceptable toxicity, start of 
new anti-neoplastic therapy, withdrawal of consent by the patient, patient is lost to follow-up, or 
discontinuation from the study due to any other reason (eg, Sponsor terminates the study). 
Maximum treatment duration with pembrolizumab is 24 months. 
In case a patient voluntarily discontinues from study treatment, the Investigator must make every 
effort to determine the primary reason for the decision and record this information in the eCRF. 
If a patient withdraws consent for participation in the study, all data collected up to the point of 
withdrawal must be maintained in the database and included in subsequent analyses, as 
appropriate. A patient may withdraw from the interventional portion of the study, but agree to 
continue follow-up of associated clinical outcome information in which case this information 
would be collected and maintained in the clinical trial database. 
Patients who discontinue treatment without relapse/disease progression will continue to follow 
the CT scan assessment schedule until disease progression, start of new anti-neoplastic therapy, 
withdrawal of consent, completion of one year of follow-up, lost to follow-up, or end of study 
(see Table 11), whichever comes first. 
Patients may be withdrawn permanently from the study if any of the following occur: 
•
Adverse event
•
Progressive disease or relapse per RECIST v1.1 or iRECIST (for patients receiving
pembrolizumab only)
•
Lost to follow-up
•
Physician decision
•
Pregnancy
•
Withdrawal of consent
•
Study terminated by Sponsor
•
Any protocol deviation for which continuing participation in the study would result
in a significant risk to the patient’s safety
7.3.4. 
End of Treatment
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible 
and within 14 days after the last dose of study drug, at which time all assessments listed for the 
End of Treatment (EOT) visit will be performed. The EOT visit will be recorded in the eCRF 
with the date and reason for stopping the study treatment. At a minimum, all patients who 
discontinue study treatment, including those who refuse to return for a final visit, will be 
contacted for follow-up safety evaluations 30 and 90 days following the last dose of study 
drug(s). 
The assessments to be performed at EOT are listed in the Schedule of Events provided in Table 
11.


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7.3.5. 
Safety Follow-up Visit 
All patients must complete safety follow-up assessments at 30 (± 5) and 90 (± 5) days following 
the final administration of study treatment. If a patient withdraws consent after the EOT visit but 
prior to the 30-day safety evaluation, safety information should be collected on the patient up to 
the date of consent withdrawal. The 90-day safety follow-up assessments may coincide with the 
first Long-Term Follow-up visit. 
For each safety follow-up assessment, the following should be collected: 
•
30-day Safety Follow-up:
−
AEs
−
Prior/concomitant meds for AEs
−
Pregnancy testing (for women of childbearing potential)
−
EBV DNA levels
−
Any antineoplastic therapies
•
90-day Safety Follow-up:
−
AEs (for the Phase 2 patients receiving pembrolizumab)
−
SAEs (for all patients)
−
Prior/concomitant meds for AEs
−
Any antineoplastic therapies
AE information will be collected following the last dose of study treatment through the 
appropriate safety follow-up period described above or until the start of a new antineoplastic 
therapy, whichever occurs first.  
In addition to AEs, all concomitant medications given to a patient because of an AE during this 
period will be recorded on the Prior and Concomitant medication eCRF page.  
All new anti-cancer therapies given to a patient within 90 days after the last dose of study 
treatment must be recorded in the eCRF. If a new antineoplastic treatment is initiated before the 
30-day safety evaluation, safety follow-up will occur immediately before starting the new
treatment. If a patient withdraws consent after the EOT visit, but prior to the 30-day safety
evaluation, safety data should be collected on the patient up to the date of consent withdrawal.
7.3.6. 
Long-term Follow-up Visits 
The first Long-Term Follow-up visit may coincide with the 90-day safety follow-up assessment. 
Patients who discontinue treatment for reasons other than disease progression will have 
tumor imaging and plasma EBV DNA level assessments every 12 weeks (3 months) ±7 days as 
detailed in Table 11, for up to 1 year following the last dose of study drug treatment, until 
disease progression, the start of subsequent anti-cancer therapies, withdrawal of consent, lost to 
follow up, or end of study, whichever occurs first. Scans performed during the Follow-up period 
should be performed on the same schedule with the same imaging modality as previously used 
throughout the study.  


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Survival Follow-up: All patients enrolled in the study will be followed for survival every 
12 weeks (3 months) by phone call, e-mail, medical records, clinic visits, or public records, such 
as government census or death records, until the patient is lost to follow-up, death, withdraws 
consent, completion of 3 years of follow-up, completion of 1 year after the last patient 
discontinues study treatment, or the study is terminated by the Sponsor, whichever occurs first. 
Newly started anti-neoplastic therapies during this follow-up period must be recorded on the 
“Antineoplastic therapies since discontinuation” eCRF page. 
7.3.7. 
Lost to Follow-up 
Patients who do not complete scheduled visits and who are unable to be contacted following 
at least 3 documented attempts (one of which is contact by certified/registered mail) will be 
considered lost to follow-up. 
7.4. 
Assessments During the Treatment Phase 
Study treatment will start on Cycle 1 Day 1. Serial assessments of safety and efficacy will be 
performed as outlined in the Schedule of Events provided in Table 11. On scheduled visit days, 
the use of the central laboratory is preferred for all protocol-specified laboratory analyses; 
however, additional local laboratory assessments may be performed, as applicable, per site 
policy or for unscheduled visit days. Clinical decisions and dose modifications can be based on 
local laboratory results. 
7.4.1. 
Efficacy Assessments 
7.4.1.1. 
Baseline Evaluation 
The following radiologic assessments are to be performed in the screening period 
(within 21 days prior to the start of treatment): 
1.
For all patients: CT with contrast or MRI of the head to rule out CNS involvement.
2.
For NPC patients: CT with contrast or MRI of the nasopharynx, neck, chest, abdomen,
and pelvis. If PET is used, a contrast-enhanced CT scan must be included.
3.
For non-NPC patients: CT with contrast or MRI of the chest, abdomen, and pelvis.
7.4.1.2. 
Tumor Response Assessments 
Tumor responses will be assessed by the Investigator per RECIST v1.1 (MRI or CT with 
contrast) and iRECIST (for patients receiving pembrolizumab). The CT scans should be 
performed with contrast unless contraindicated for medical reasons, in which case MRI should 
be used.  
Although RECIST v1.1 will be the primary measure for assessment of tumor response and 
disease progression for efficacy endpoints, iRECIST guidelines should be used for treatment 
decision making for patients receiving pembrolizumab, including confirmation of unconfirmed 
progressive disease by RECIST v1.1 with additional imaging within 4 to 6 weeks (Appendix 3). 


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Investigator-determined response assessments at each assessment time point will be entered into 
the appropriate eCRF. Copies of all scans and redacted radiology reports are to be submitted 
according to vendor / Sponsor requirements in a timely manner. 
All MRI or CT scan assessments will be determined from date of first dose and will follow the 
counting of calendar days and not the dosing cycles. It is critical that the same imaging modality 
used at screening is used throughout the study for each subject. The scans will be performed 
as follows: 
•
At Week 8 and then every 6 weeks (±7 days) for the first 26 weeks (6 months), and
every 12 weeks thereafter for up to 1 year after permanent discontinuation of study
treatment, until disease progression, the start of new anti-cancer treatment,
withdrawal of consent, lost to follow-up, or the end of the study, whichever occurs
first. A scan to confirm an unconfirmed PR or unconfirmed CR ≥4 weeks later may
also be performed.
•
At the EOT visit (unless the previous scan is within 4 weeks of the EOT visit).
If local regulatory authorities mandate less frequent imaging, the minimum frequency must be 
every 12 weeks. 
All patients will be followed for disease progression or relapse using the schedule described in 
the Schedule of Events provided in Table 11. This includes patients who discontinue the 
protocol-specified treatments or the study early for any reason without documented evidence of 
progressive disease or relapse. 
The radiologic assessments (MRI or CT with contrast) are considered the primary method 
of response assessment.  
Patients who relapse or progress will continue to be followed for OS, all subsequent anti-
neoplastic therapy, and response, including disease progression/relapse to subsequent anti-
neoplastic therapy. 
For a patient receiving pembrolizumab deemed clinically stable at the time of initial progression 
by RECIST v1.1, Investigators may elect to keep the patient on treatment using the iRECIST 
guidelines to assist with patient management (Appendix 3). Tumor imaging should be repeated 
within 4 to 6 weeks to confirm disease progression using iRECIST. Patients who have confirmed 
disease progression per iRECIST will discontinue treatment unless continued treatment is 
approved by the Sponsor.  
7.4.2. 
Safety and Tolerability Assessments 
Study assessments of safety include AEs, clinical laboratory tests, ECGs, vital signs, physical 
examinations, and ECOG status.  
Safety data will be collected from the signing of the ICF up to and including 90 days post-last 
dose of study treatment according to the Schedule of Events in Table 11. 
Adverse event monitoring and collection, in addition to other safety considerations, are 
summarized in Section 8. Laboratory assessments, vital signs, ECGs, physical examinations, and 
ECOG performance status are described in the subsequent sections below. 


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Tolerability will be assessed by the incidence of AEs leading to dose modifications or study drug 
discontinuation. 
7.4.2.1. 
Laboratory Evaluations 
7.4.2.2. 
Clinical Laboratory (Safety) Testing 
Laboratory tests will be collected and analyzed in an accredited central or local/site laboratory 
in accordance with quality standards. 
On scheduled visit days, the use of the central laboratory is preferred for the analysis of all 
indicated safety laboratory analyses; however, local laboratory assessments may be performed, 
as applicable, per site policy or for unscheduled visit days. Clinical decisions and dose 
modifications can be based on local laboratory results.  
The required hematology, serum chemistry, urinalysis, serology, and other parameters to be 
collected at the time points described in the Schedule of Events (Table 11) are listed in Table 12. 
These tests may also be performed when clinically indicated (eg, patients who are hepatitis B 
core antibody positive should have HBV DNA PCR monitoring according to local guidelines). 
In addition, the investigative sites will provide archived and/or newly obtained tumor samples 
at baseline, and at Cycle 1 Day 15 and/or at the time of relapse or with disease progression, as 
applicable. 
Viral levels (EBV, CMV, and HIV [for HIV+ patients only]) will also be monitored to assess for 
viral reactivation. 


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Table 12: 
Required Laboratory Tests 
Laboratory Test Category 
Laboratory Tests 
Hematology 
Hemoglobin, platelets, WBC with differential (absolute neutrophils, absolute monocytes, 
absolute eosinophils, absolute lymphocytes, absolute basophils),  
Coagulation 
PT or INR, aPTT 
Serum Chemistry 
AST (SGOT) 
Bicarbonate 
ALT (SGPT) 
BUN 
Albumin 
Creatinine 
Total bilirubin 
Glucose (non-fasting) 
Sodium 
Chloride 
Potassium 
Calcium 
Magnesium 
Phosphate 
Total protein 
Uric acid 
ALP 
Thyroid function tests (TSH, free T3, 
free T4) 
Urinalysis 
Macroscopic panel (dipstick) 
Viral 
HBV surface Ag 
HBV DNA PCR1 
HBV core and surface Ab 
HCV Ab2 
EBV DNA, CMV, HIV levels 
Pregnancy 
Only for females of childbearing potential. Serum test must be performed during 
screening. Serum or urine tests are to be performed as described in the Schedule of Events. 
Pregnancy tests will be performed locally at each site. 
1HBV DNA PCR only for patients with positive HBV core Ab or surface Ag. 
2Any patient positive for HCV Ab will be evaluated by quantitative PCR. 
Ab = antibody; Ag = antigen; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; ALP = alkaline 
phosphatase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CMV=cytomegalovirus; EBV = Epstein-Barr 
virus; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; INR = international 
normalized ratio; PCR = polymerase chain reaction; PT = prothrombin time; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; TSH = thyroid stimulating hormone; WBC = white blood cell. 
7.4.2.3. 
Pregnancy Testing 
Pregnancy testing is only required for females of childbearing potential. A serum test must be 
performed during screening. Serum or urine tests are to be performed at the beginning of each 
cycle, at EOT, at the 30-day Safety Follow-up visit, and for up to 6 months post-last dose of 
study treatment. Pregnancy tests will be performed locally at each site. 
7.4.2.4. 
Vital Signs 
Vital signs (temperature, blood pressure, and heart rate) will be collected at the screening visit 
(Day -28 to Day -1), on Day 1 of each cycle, and at the EOT visit. For Phase 1b dose levels 1 
through 7, vital signs should be collected just prior to the first dose of valganciclovir and 
nanatinostat, and in concert with and just prior to PK blood draws on Cycle 1 Day 1 and Cycle 2 
Day 1 through the 6-hour post-dose time point. For Phase 1b dose levels 8 through 13 and Phase 
2, vital signs should be collected just prior to the first dose of valganciclovir and nanatinostat, 
and in concert with and just prior to PK blood draws on Cycle 2 Day 1 through the 6-hour post-
dose timepoint as shown in Table 11. On other indicated visit days, vital signs will be collected 
once (prior to dosing of study treatment, if administered in clinic). 
Investigators are to report any clinically significant abnormal findings as AEs. 


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7.4.2.5. 
Cardiac Assessments: Electrocardiograms (ECGs) 
All 12-lead ECGs will be conducted in triplicate. Average QTcF will be calculated to confirm 
eligibility. ECG tracings will be provided to a central laboratory, instructions are provided in the 
Study Manual. 
Triplicate 12-lead ECGs will be performed separated by approximately 1 minute at screening, on 
Cycle 1 Day 1 (Phase 1b, all dose levels, and Phase 2), Cycle 2 Day 1 (Phase 1b dose levels 8 
through 13 and Phase 2 only) and at the EOT visit. Average QTcF will be calculated to confirm 
eligibility. Careful skin preparation is essential to assure high quality ECGs. All ECGs should be 
collected using the same ECG machines and performed in as calm an environment as possible, 
not immediately following stressful procedures (ie, biopsies, etc.), with minimal distractions 
(talking, TV, etc.). Prior to each ECG, the patient should lie in a supine position in a calm 
environment for at least 5 minutes. 
When performed in concert with serial PK collection on Cycle 1, Day 1 for Phase 1b dose levels 
1 through 7, 2 ECGs will be performed pre-dose (within 1 hour of dose, separated by at least 15 
minutes). Post-dose ECGs will be performed prior to and as close as possible to each PK sample 
collection at approximately maximum plasma concentration (maximum plasma concentration 
[Cmax];1 and 2 hours), 4 hours, and 6 hours. If possible, patients should not consume additional 
food between dosing and the last ECG time point. 
One set of triplicate 12-lead ECGs will be performed on Cycle 1, Day 1 at 2-hours post-dose for 
Phase 1b dose levels 8 through 13 and Phase 2. When performed in concert with serial PK 
collection on Cycle 2 Day 1 for these patients, 2 ECGs will be performed pre-dose (within 1 hour 
of dose, separated by at least 15 minutes). Post-dose ECGs will be performed prior to and as 
close as possible to each PK sample collection at approximately maximum plasma concentration 
(Cmax; 1 and 2 hours), 3 hours, 4 hours, 5 hours, and 6 hours. 
At screening and at the EOT visit, the ECG may be performed at any time during the clinic visit. 
ECGs may also be performed when clinically indicated, irrespective of the time of study drug 
dosing. 
All ECGs will be independently reviewed by a central laboratory. Instructions for the collection 
and transmission of ECGs to the central ECG laboratory will be provided in the Study Manual. 
Clinically significant abnormalities present at screening should be reported on the Medical 
History eCRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events eCRF page. All eligibility and patient 
management decisions should be based on the local reading of the ECG. 
7.4.2.6. 
Physical Examination 
A physical examination should be conducted at screening, the beginning of each cycle, at the 
EOT visit, and any additional times deemed necessary by the Investigator. 
7.4.2.7. 
Height and Weight 
Height and weight will be measured at screening (Day -28 to Day -1) and weight will 
subsequently be measured on Day 1 of each cycle and at the EOT visit. 


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7.4.2.8. 
ECOG Performance Status 
The ECOG performance status according to Table 13 (Oken 1982) will be assessed at 
the screening visit (Day -28 to Day -1), on Cycle 1 Day 1, and at the EOT visit. 
Table 13: 
ECOG Performance Status 
Grade 
ECOG status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature (eg, light housework, office work) 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
7.4.3. 
Pharmacokinetics 
The scheduled time points for the PK evaluations (assessments of nanatinostat, its metabolites, 
and ganciclovir [the active hydrolytic product of valganciclovir]) are outlined in the Schedule 
of Events in Table 11. Pharmacokinetic parameters to be evaluated include tmax, Cmax, and AUC. 
Details for collection, shipment, and storage are provided in the Lab Manual. 
7.4.4. 
Exploratory Biomarker Assessments 
7.4.4.1. 
Rationale for Biomarker Assessments 
The exploratory biomarker analyses outlined in this study are intended to foster an understanding 
of how baseline expression of certain pharmacodynamic markers may impact the activity of 
combination therapy with nanatinostat, valganciclovir, and pembrolizumab, and how 
pharmacodynamic markers such as plasma EBV DNA levels may correlate with clinical 
efficacy. Potential predictive markers will be studied to identify patients with optimal responses 
to nanatinostat and valganciclovir. The impact of study drug administration on B-cell/T-cell/NK 
cell/myeloid cell populations will be evaluated over time. Although on-study biopsies will be 
performed at the discretion of the Investigator, it is anticipated that at least 10 consenting patients 
per arm in Phase 2 will have on-study tumor biopsies (timing: within 28 days prior to Cycle 1 
Day 1, Cycle 1 Day 15, and at relapse or with disease progression). 
The specific study procedures to be conducted for each patient enrolled in the study are 
presented in the Schedule of Events in Table 11. Cells from peripheral blood or tumor tissue will 
be sent to a central laboratory selected by the study Sponsor for analysis of viral DNA levels, 
gene expression, phenotypic alterations in B-cells/T-cells/NK cells/myeloid cells and mutation 
profile. 
Details on the collection procedure and timing for each procedure are described in Table 14 and 
will be provided in the Study Manual. The sample collection information must be entered on the 
appropriate sample collection log eCRF page(s) and requisition form(s). 


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Table 14: 
Biomarker Sample Collection Plan 
Sample Type 
Visit/Time Point 
Analyses 
Purpose 
Archival FFPE tumor 
sample (if an archival 
tumor sample taken 
within 2 years prior to 
screening is not 
available, a newly 
obtained tumor biopsy 
[excisional or core] 
may be required) 
Screening 
• IHC: PD-1, PD-L1 and other
immune checkpoint molecules
• TIL counts: CD3, CD4, CD8
• EBV-associated
genes/proteins: EBER, BZLF-
1/ZTA, LMP-1, BGLF-4/PK,
BXLF-1/TK, BRLF-1/Rta,
etc.
•
Tumor Associated gene
expression profiles
Identify possible 
predictive markers 
On-study tumor biopsy 
(Optional)  
•
Up to 28 days prior
to Cycle 1 Day 1
•
Cycle 1 Day 15
•
At relapse or with
disease progression
EBV-associated genes/proteins, 
TIL counts, PD-L1 and other 
immune checkpoint molecules; 
markers related to resistance 
Identify potential PD 
or resistance markers 
Plasma 
• Screening
• Cycle 1 and 2 Days 1,
8, 15, and Day 1 of
each subsequent cycle
• Every 3 months in
follow-up until
disease progression
•
EBV DNA levels (EBV viral
load by q-PCR)
•
Analysis of tumor-associated
genes (eg, BGLF4, p53,
MVC, KRAS, etc)
Pharmacodynamic 
effect (on- and off 
treatment) 
PBMC (whole blood) 
• Pre-dose Cycle 1 Day
1 (may be collected
during Screening) and
3 hours post-
nanatinostat
administration.
• Every 3 cycles
starting at Cycle 3
Day 1 (Day 1 of
Cycles 3, 6, 9, 12,
etc.) and at End of
Treatment.
• Histone H3 acetylation (prior
to and 3 hours post-
nanatinostat administration,
Cycle 1 Day 1 only)
• RNA expression of selected
immunological genes
• Flow cytometry for immune
cell markers
• Flow cytometry for
identification of circulating
tumor cells and single cell
RNAseq
Pharmacodynamic 
effect (on-treatment) 
EBER = Epstein-Barr encoded RNA; EBV = Epstein-Barr virus; FFPE = formalin-fixed paraffin-embedded; 
IHC = immunohistochemistry; PBMC = peripheral blood mononuclear cell; PD-1 = programmed cell death-1; 
PD-L1 = programmed death-ligand 1; qPCR = quantitative polymerase chain reaction; TIL = tumor-infiltrating lymphocyte 
7.4.4.2. 
Pharmacodynamic Assessments in Blood 
For pharmacodynamic assessment of acetylation of histone H3 in PBMCs, pre- and on-
treatment samples will be collected as indicated in the Schedule of Events provided in Table 11. 
These assessments are mandatory for all patients.  
7.4.4.3. 
Additional Biomarker Assessments 
If the patient agrees, any remaining tumor or blood samples and residual PK samples may be 
stored for up to 15 years and further analyzed to address pertinent scientific questions related to 


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EBV+ solid tumors. A decision to perform additional biomarker-related analyses would be based 
on outcome data from this study or from new reported discoveries, as well as reagent and assay 
availability. 
8.
ADDITIONAL SAFETY CONSIDERATIONS
8.1. 
Monitoring, Recording and Reporting of Adverse Events 
An AE is any untoward medical event that occurs to a patient following the start of 
administration of the study drugs, whether or not considered study drug related. An AE can, 
therefore, be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom or disease temporally associated with the use of a drug, whether or not considered 
related to the drug. For example, it may be a new intercurrent illness, a worsening concomitant 
illness, an injury, or any concomitant impairment of the patient’s health, including laboratory test 
values (as specified by the criteria below), regardless of etiology. Any worsening (ie, any 
clinically significant adverse change in the frequency or intensity of a pre-existing condition) 
should be considered an AE. A diagnosis or syndrome should be recorded on the Adverse Events 
eCRF rather than the individual signs or symptoms of the diagnosis or syndrome. 
If an overdose occurs, whether accidental or intentional, and is associated with an AE, the AE 
should be recorded on the Adverse Events eCRF and will be reported consistent with instructions 
in Section 8.8.  All overdoses, with or without an associated AE, will be recorded on the 
dosing eCRF. 
All patients will be monitored for AEs during the study. Assessments may include monitoring 
any or all of the following parameters: the patient’s clinical symptoms, laboratory, pathologic, 
radiologic, or surgical findings, physical examination findings, or other appropriate tests 
and procedures. All AEs reported during the study should be monitored until resolution, or until 
the event has stabilized or reached a new baseline (all follow up results are to be reported to the 
sponsor or designee). During a dose interruption, study days and procedures will continue to 
accrue until the end of the current cycle (see Schedule of Events in Section 6). 
All AEs will be recorded by the Investigator from the time the patient signs the informed 
consent. Adverse events and SAEs will be recorded on the Adverse Events eCRF and in the 
patient’s source documents. All SAEs must be reported to the pharmacovigilance clinical 
research organization within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form. 
If the Investigator becomes aware of an SAE after the study-specified safety follow-up period 
and considers the event related to study drug, the event will be reported within 24 hours 
according to the procedures detailed in Section 8.2.1. Pre-existing conditions are not considered 
an AE unless the condition worsens by at least one Grade following the start of administration of 
the study treatment. 
For all patients, excluding those in Phase 2 receiving nanatinostat, valganciclovir, and 
pembrolizumab, AEs will be recorded following the signing of the ICF up to and including 
30 days (90 days for SAEs) after the last dose of study treatment or until a new anticancer 
treatment is started, whichever occurs first. For patients in Phase 2 who are receiving 


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nanatinostat, valganciclovir, and pembrolizumab, all AEs will be recorded from the signing of 
the ICF and continue for up to and including 90 days after the last dose of study treatment or 
until a new anticancer treatment is started, whichever is first. 
8.1.1. 
Clarification in Reporting of Deaths 
Fatal events regardless of causality will be reported within 24 hours of the Investigator’s 
knowledge through the safety follow period or until a new anticancer treatment is started, 
whichever is first. Death is an outcome of an adverse event and not an adverse event in itself. All 
reports of death should include an adverse event term for the cause of death (if known).  
8.1.2. 
Clarification in Reporting of Disease Progression as an Adverse Event 
Disease progression is expected in this study population, and thus disease progression should not 
be reported as an adverse event/serious adverse event term.  If clinical disease progression is 
identified, the specific clinical event that identifies the disease progression should be reported as 
the adverse event for standard adverse event reporting. Death due to disease progression should 
be reported in the clinical database on the designated eCRF. 
8.1.3. 
Laboratory Test Abnormalities 
An abnormal laboratory value is an AE if the abnormality: 
•
Results in discontinuation from the study, or
•
Requires treatment, modification or interruption of study treatment, or any other
therapeutic intervention, or
•
Is judged to be of significant clinical importance.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
(Section 8.2) need to be documented as an SAE. 
If a laboratory abnormality is one component of a diagnosis or syndrome (eg, hyperuricemia 
with tumor lysis syndrome), only the diagnosis or syndrome should be recorded on the Adverse 
Events eCRF. If the abnormality is not a part of a diagnosis or syndrome, then the laboratory 
abnormality should be recorded as the AE. 
8.2. 
Serious Adverse Event 
An SAE is defined as one of the following: 
•
Is fatal or life-threatening
•
Requires inpatient hospitalization or prolongation of an existing hospitalization
•
Results in a persistent or significant disability/incapacity
•
Constitutes a congenital anomaly/birth defect
•
Is medically significant (ie, defined as an event that jeopardizes the patient or may
require medical or surgical intervention to prevent one of the outcomes listed above)
Events not considered to be SAEs are hospitalizations for the following: 


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•
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the
condition under investigation and has not worsened since signing the informed
consent.
•
Social reasons and respite care in the absence of any deterioration in the patient’s
condition.
•
Hospitalization or prolongation of hospitalization for technical, practical, or social
reasons, in absence of an AE.
•
The administration of blood or platelet transfusion as routine treatment of studied
indication. However, hospitalization or prolonged hospitalization for a complication
of such transfusion remains a reportable SAE.
Note that treatment on an emergency outpatient basis that does not result in admission to hospital 
and involves an event not fulfilling any of the SAE definitions above is not an SAE. 
8.2.1. 
Reporting of Serious Adverse Events 
All SAEs must be reported to the Sponsor within 24 hours of the Investigator becoming aware of 
the SAE. 
To report a SAE, sites will complete an SAE Report Form and submit the report to: 
PRA Health Sciences / ICON Pharmacovigilance e-mail at CHOSafety@iconplc.com 
(North/South America) or MHGSafety@iconplc.com (Europe/Asia/Pacific/Africa) 
or 
Fax to +888-772-6919 or 1-434-951-3482 (North/South America) 
+44-1792-525-720 (Europe/Asia/Pacific/Africa)
The Investigator should discuss with the Sponsor’s Medical Monitor any SAEs for which the 
issue of seriousness is unclear or questioned. Contact information for the Sponsor’s Medical 
Monitor is listed in Table 15. 
Table 15: 
Sponsor’s Medical Monitor 
Region 
Phone 
E-mail
All 
+1 858-337-6079
DCohen@Viracta.com 
SAEs must be reported by each site to their appropriate IRB/IEC in accordance with the 
timeframes and procedures required by their IRB Policy. 
The Sponsor will report SAEs to the US FDA and any other relevant regulatory authorities. 
SAEs will be recorded from the signing of the ICF up to and including 90 days after permanent 
study discontinuation or until the start of a new antineoplastic therapy, whichever occurs first. 
8.3. 
Severity of the Event 
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event. All AEs 
will be assessed by the Investigator using NCI CTCAE Version 5.0. 


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The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate, 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This criterion is not the same as “serious”, which is 
based on patient/event outcome or action criteria associated with events that pose a threat to 
a patient’s life or functioning. Seriousness, not severity, serves as a guide for defining regulatory 
obligations. 
8.4. 
Relationship to Study Drugs 
The Investigator will use his/her best medical judgment to determine the relationship of an AE 
to each study drug included in the protocol-defined study treatment. 
The relationship of an AE or SAE to study drugs will be classified using the following 
3 categories: 
•
Definitely related
•
Possibly related
•
Unrelated
To be classified as “definitely related,” an AE should occur in a timeframe relative to 
administration of study drug(s) that suggests a strong causal relationship between the study 
drug(s) and the AE. In addition, there should be no other reasonable explanations for the AE, 
such as underlying disease or other concurrent conditions. 
To be classified as “unrelated,” an AE should occur in a timeframe relative to administration of 
study drug(s) that suggests a causal relationship between the study drug(s) and the AE is very 
unlikely. In addition, there should be a reasonable explanation for the AE, such as underlying 
disease or other concurrent condition. 
To be classified as “possibly related,” an AE should not fall clearly into 1 of the above 
2 categories. This would include, for example, an AE that does not seem to occur in close 
temporal proximity to administration of study drug(s), but also has no other reasonable 
explanation. 
8.5. 
Expectedness 
For regulatory reporting, the Sponsor will determine the expectedness of events suspected of 
being related to nanatinostat and/or valganciclovir based on the effective version of the IB. The 
expectedness of events suspected of being related to pembrolizumab will be based upon the 
approved prescribing information. 
The Sponsor or its authorized representative will report in an expedited manner to Regulatory 
Authorities and Ethics Committees concerned, suspected unexpected serious adverse reactions 
(SUSARs) in accordance with country-specific requirements (eg, 21 Code of Federal 
Regulations [CFR] 312.32[c], Directive 2001/20/EC and the Detailed Guidance on collection, 
verification and presentation of adverse reaction reports arising from clinical trials on 
investigational products for human use [ENTR/CT3], or other applicable requirement). 


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8.6. 
Reporting Adverse Events 
For all patients, excluding those in Phase 2 receiving nanatinostat, valganciclovir, and 
pembrolizumab, any AEs which occur from the signing of the ICF up to and including 30 days 
(90 days for SAEs) after the last dose of study treatment or until the start of subsequent 
anticancer therapy, whichever occurs first, will be recorded.  
For patients in Phase 2 who are receiving nanatinostat, valganciclovir, and pembrolizumab, all 
AEs will be recorded from the signing of the ICF up to and including 90 days after the last dose 
of study treatment or until a new anticancer treatment is started, whichever is first. 
Unanticipated problems that require reporting to IRB might include the following: 
•
A single occurrence of a serious, unexpected event that is uncommon and strongly
associated with drug exposure.
•
A single occurrence, or more often small number of occurrences, of a serious,
unexpected event that is not commonly associated with drug exposure, but
uncommon in the study population.
•
Multiple occurrences of an AE that, based on an aggregate analysis, is determined to
be an unanticipated problem.
•
An AE that is described or addressed in the IB, protocol, or ICF, but occurs at
a specificity or severity that is inconsistent with prior observations.
•
An SAE that is described or addressed in the IB, protocol, or ICF, but for which the
rate of occurrence in the study represents a clinically significant increase in the
expected rate of occurrence.
•
Any other AE or safety finding that would cause the Sponsor to modify the IB, study
protocol, or ICF, or would prompt other action by the IRB to ensure the protection of
human subjects.
8.7. 
Reporting of Pregnancy
8.7.1. 
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female patient are considered immediately reportable events. A positive 
urine pregnancy test will be followed by a serum test for confirmation. Study treatment is to be 
discontinued immediately and patients instructed to return any unused portion of the study 
treatment to the Investigator. Female patients will be asked to consent to data collection until the 
outcome of a pregnancy, should a pregnancy occur during the study. 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Drug Safety 
immediately (within 24 hours) using the Pregnancy Initial Report Form provided by the Sponsor 
(Section 8.2.1). The female patient should be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 


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The Investigator will follow the female patient until completion of the pregnancy and must notify 
Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form. 
If the outcome of the pregnancy is abnormal (eg, spontaneous or therapeutic abortion), 
the Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets 
any of the seriousness criteria, it must be reported as an SAE to Drug Safety within 24 hours 
of the Investigator’s knowledge of the event using the SAE Report Form. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death after 30 days that the Investigator suspects 
is related to the in-utero exposure to the study treatment should also be reported to Drug Safety 
within 24 hours of the Investigator’s knowledge of the event using the SAE Report Form. 
Pregnancies may also be reported to the IRB/IEC per their requirements. 
8.7.2. 
Male Patients 
Female partners of male patients participating in the study are recommended to use 2 forms of 
birth control including at least one form of highly effective and one effective barrier method 
(defined in Section 4.2, inclusion criterion 14c) while their partner is treated on study and for 
6 months after the last administration of study drug. If a female partner of a male patient taking 
study treatment becomes pregnant, the male patient should notify the Investigator, and the 
pregnant female partner should be advised to call her healthcare provider immediately. Pregnant 
female partners will be requested to consent to be followed as described in Section 8.7.1. 
8.8. 
Reporting of Overdose 
An overdose is defined as any accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose. 
If an overdose occurs, whether accidental or intentional, and is associated with an AE, the AE 
(not the overdose) should be recorded on the Adverse Event eCRF. If an overdose occurs, with 
or without an AE, the additional doses taken will be recorded on the dosing eCRF. Adverse 
events associated with overdose, misuse, abuse, or medication error should be reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 8.2) even if the AEs do not 
meet seriousness criteria. 
8.9. 
Emergency Measures 
In the event of an emergency, standard emergency procedures will be employed. The 
Investigator is to be consulted and informed immediately. 
The Investigator will provide all the necessary emergency equipment and specially trained trial 
site personnel to handle emergency events during this study. 
The investigational site is responsible for ensuring 24-hour emergency availability. 
All cases of emergency must immediately be reported to the Sponsor’s medical monitor and to 
the clinical project manager and will be noted in the eCRF. 


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8.10. 
Unanticipated Problems 
An AE observed during the conduct of a study should be considered an unanticipated problem 
involving risk to human patients and reported to the IRB/IEC, only if it is unexpected, serious, 
and would have implications for the conduct of the study (eg, requiring a significant, and usually 
safety-related, change in the protocol such as revising inclusion/exclusion criteria or including a 
new monitoring requirement, informed consent, or IB). 
Therefore, any incident, experience, or outcome that meets all of the following criteria could be 
reported by the Investigator to the IRB/IEC as an unanticipated problem: 
•
Unexpected given the following:
a.
The research procedures that are described in the protocol-related documents; and
b. The characteristics of the subject population being studied.
•
Related or possibly related to participation in the research, and
•
Suggests that the research places subjects or others at a greater risk of harm than is
previously known or recognized.
9.
STATISTICAL ANALYSES
9.1. 
Overview
The objective of the statistical analysis is to evaluate the efficacy and safety of the 
coadministration of nanatinostat and valganciclovir, with or without pembrolizumab, in patients 
with relapsed/refractory EBV+ solid tumors without available therapies. All data will be 
summarized by dosing regimen, disease subtype, and overall.  
9.2. 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will present the detailed statistical methods and analyses for this 
study. 
9.3. 
Definition of Analysis Populations 
The following patient populations will be assessed: 
1.
Safety Analysis population: All patients who receive at least one dose of study treatment
(nanatinostat, valganciclovir, or pembrolizumab). The safety analysis population will be
used for all listings and all demographic and baseline summaries.
2.
Full Analysis Set: All patients with measurable disease at baseline who receive at least
one dose of nanatinostat and valganciclovir with or without pembrolizumab and who have
at least one post-baseline tumor assessment. Patients will be analyzed according to the
dosing regimen for which they have been assigned. The full analysis set will be used for
summaries of tumor response and survival metrics.
3.
Modified Intent-to-Treat (mITT) population: The mITT population is defined as all
RM-NPC patients who have received at least one dose of study treatment (nanatinostat,


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valganciclovir, or pembrolizumab), have a confirmed diagnosis of EBV+ by central 
pathology review, met all inclusion criteria, and have baseline (screening) and at least one 
post-baseline tumor assessment for efficacy. 
4.
PK population: All treated patients with at least one available PK parameter of interest.
9.4. 
Sample Size and Power Considerations 
For Phase 1b, approximately 27 to 60 patients will be enrolled for up to 13 dose escalations of 
nanatinostat and valganciclovir and up to 10 patients in the exploratory proof-of-concept cohort 
of other EBV+ solid tumor patients. 
The reported ORR for PD-1 inhibitors in RM-NPC patients has ranged from 20% to 30%. 
Assuming the pembrolizumab ORR in RM-NPC patients in this study will be around 25%, a 
sample size of 30 would provide a 95% confidence interval (CI) that excludes 10% as the lower 
ORR. A total of 60 patients (30 per randomized treatment group) is sufficient to provide 
adequate estimates of tumor response for each group and to provide initial indicators of safety 
and tolerability. These estimates will be utilized in planning for future studies in this patient 
population. The sample size of N=30 per randomized treatment group was determined from 
nQuery Advisor tool (www.statsols.com; Statistical Solutions, Ltd, Cork, Ireland). 
9.5. 
Baseline Characteristics and Subject Disposition 
Demographic and baseline (last non-missing observation prior to treatment) disease 
characteristics will be summarized by dosing regimen for the Safety population. Patients’ age, 
height, weight, and continuous baseline characteristics will be summarized using descriptive 
statistics (N, mean, standard deviation, median, minimum, maximum), while age classification 
(≤65 or >65 years), gender, ethnicity, histology, and other categorical variables will be provided 
using frequency tabulations (count, percent) by dosing regimen. Medical history data (coded by 
Medical Dictionary for Regulatory Activities [MedDRA] dictionary) will be provided in data 
listings. 
Patient disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases. A summary of patients enrolled by site will be provided. Major protocol 
deviations will be summarized using frequency tabulations for the Full Analysis Set population. 
Corresponding patient listings will be provided as well. 
9.6. 
Efficacy Analysis 
Efficacy analyses will be performed on the Full Analysis Set and the mITT population. 
As described in Section 7.4.1.2, tumor responses for efficacy analyses will be assessed using 
the Investigator per RECIST v1.1 (MRI or CT with contrast) and will involve all known or 
suspected disease sites.  
9.6.1. 
Primary Efficacy Endpoint Analysis 
For Phase 2, the primary efficacy endpoint is the determination of ORR, defined as the 
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assessed by the Investigator using RECIST v1.1. ORR will be summarized by dosing regimen 
with 95% CI obtained by Clopper-Pearson Exact methods and stratified by prior anti-PD-1 
treatment exposure.  
9.6.2. 
Secondary Efficacy Endpoints Analysis 
Secondary efficacy endpoints will include DOR, disease control rate (DCR), PFS, and OS: 
•
Duration of response (DOR): defined as the interval from date of first observed CR
or PR to the date of documented disease progression or death due to any cause,
whichever occurs first. All patients who have not progressed will be censored at the
last non-missing tumor assessment. Estimates of median DOR with 95% CI will be
determined by dosing regimen using Kaplan-Meier methods.
•
Disease control rate (DCR): defined as the percentage of patients having a CR, PR,
or stable disease at any time during treatment, as assessed by the Investigator using
RECIST v1.1. DCR will be summarized by dosing regimen with 95% CI obtained by
Clopper-Pearson Exact methods.
•
Progression-free survival (PFS): defined as the interval from the start of study drug
treatment to the date of first documented disease progression or death from any cause,
whichever occurs first. Responding patients and patients who are lost to follow-up
will be censored at their last tumor assessment date. Estimates of median PFS with
95% CI will be determined by dosing regimen using Kaplan-Meier methods. The
95% CI around the PFS and OS rates at 12 months (56 weeks) will also be presented.
•
Overall survival (OS): defined as the interval from the start of study drug treatment
to date of death for any reason. Surviving patients and patients who are lost to follow-
up will be censored at their contact date. Estimates of median OS with 95% CI will be
determined by dosing regimen using Kaplan-Meier methods.
9.6.3. 
Exploratory Endpoints 
All exploratory endpoints will be summarized by dosing regimen and overall. 
9.7. 
Safety Analysis 
Safety analysis will be based on all patients in the Safety population and will be summarized 
overall, by dosing regimen, and by any other relevant subgroup (eg, solid tumor type). 
Study medication exposure will be summarized for each patient and tabulated by dosing regimen 
including duration of study medication, total dose taken, and dose reductions. 
Adverse events, vital sign measurements, clinical laboratory measurements, and concomitant 
medications will be summarized overall and by dosing regimen. Tabulations and listings of 
values for dose holds, modifications, or discontinuations; vital signs; and laboratory safety 
evaluations will be presented. 
Adverse events will be coded according to MedDRA and classified using the NCI CTCAE v5.0. 
The incidence rates of AEs will be tabulated by System Organ Class and Preferred Term. Subsets 
of AEs to be summarized include SAEs, events of all CTCAE grade severities, suspected 


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treatment-related AEs, and events that resulted in withdrawal of study medication. The most 
severe grade of each preferred term for a patient will be utilized for summaries of AEs by NCI 
CTCAE grade. All AEs with corresponding attributes will be displayed in a by-patient listing. 
Adverse events leading to death or to discontinuation from treatment, events classified as NCI 
CTCAE Grade 3 or higher, suspected treatment-related events, all deaths, and SAEs will also be 
displayed in by-patient listings separately. 
Clinical laboratory results will be summarized descriptively by dosing regimen, which will also 
include a display of change from baseline. Laboratory values outside of the normal ranges will 
be identified. Clinically significant hematologic and non-hematologic laboratory abnormalities 
that meet Grade 3 or Grade 4 criteria according to the CTCAE will be listed and summarized. 
Graphical display of selective lab parameters over the course of study will be provided. 
Vital sign measurements will be listed for each patient at each visit. Descriptive statistics for 
vital signs, both observed values and changes from baseline, will be summarized by 
dosing regimen. 
9.8. 
Interim Analysis 
No interim analysis is planned. 
10.
STUDY COMMITTEES AND COMMUNICATIONS
A Safety Monitoring Committee comprising of the study lead Investigators and the Sponsor 
Safety Team will monitor the safety of treatment throughout the study. 
11.
LABORATORY REQUIREMENTS
All study-related laboratory and clinical data gathered in this protocol will be stored in a 
password-protected database. All patient information will be handled using anonymous 
identifiers. Linkage to patients’ study data is only possible after accessing a password-protected 
database. Access to the database is only available to individuals directly involved in the study. 
A written document containing the name, location, certification number, and date of certification 
of the laboratory to be used for laboratory assays and those of other facilities conducting tests 
must be submitted to the Sponsor prior to initiating the study. This document should be returned 
along with the Form FDA 1572 or Statement of Investigator. The Sponsor must be notified if the 
laboratory is changed or if any additional laboratory is to be used. 
12.
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS
The Investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and documents. 
All study-related information will be recorded on source documents. All required data will be 
recorded in the eCRFs. All eCRF data must be submitted to the Sponsor throughout and at the 
end of the study. 


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If an Investigator retires, relocates, or otherwise withdraws from conducting the study, the 
Investigator must notify the Sponsor. If an Investigator changes during the course of the study, 
the Sponsor and any local regulatory authorities, as applicable, must first approve the change of 
Investigator and the new Investigator must provide the Sponsor the documentation listed below. 
Before initiating the study, the Investigator must provide copies of the following documents to 
the Sponsor: 
•
Fully executed and signed Form FDA 1572 or Statement of Investigator, where
appropriate.
•
Fully executed clinical trial agreement.
•
Current curriculum vitae (also applies to all sub-Investigators listed on the
Form FDA 1572).
•
Current medical license (online verification is also acceptable) of the Investigator
(also applies to all sub-Investigators listed on the Form FDA 1572).
•
Financial disclosure (also applies to all sub-Investigators listed on the
Form FDA 1572).
•
Investigator-signed protocol signature page.
•
Investigator-signed acknowledgement of receipt of the current nanatinostat IB.
•
IRB approval letter for the protocol and informed consent including written assurance
of continuing approval (at least annually). A copy of the annual progress report
submitted to the IRB/IEC must also be provided.
•
IRB-approved ICF.
•
Where applicable, a list of the IRB/IEC members or a Federal-Wide Assurance/
Department of Health and Human Services (FWA/DHHS) number.
•
Additional documents as necessary per local requirements.
The Sponsor personnel or representatives may visit the study site, if necessary, before initiation 
of the study to review information with study site personnel about protocol requirements 
pertaining to the study drug, CRFs, monitoring, SAE reporting, and other relevant information. 
12.1. 
Ethics 
12.1.1. 
Ethics Committee 
Before initiating the study, the Investigator will obtain confirmation from the ethics committee 
(EC) that the EC is properly constituted and compliant with all requirements and 
local regulations.  
The Investigator will provide the EC with all appropriate material, such as the protocol, current 
nanatinostat IB, site specific informed consent form, and other written information provided to 
the patients. The study will not be initiated until the Investigator obtains appropriate EC approval 
in writing for the protocol and informed consent document, and copies are received by 
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EC approval will be obtained for any substantial protocol amendments and informed consent 
revisions before implementing the changes. The Investigator will provide appropriate reports on 
the progress of the study to the EC, per local requirements, and to the Sponsor or designee in 
accordance with applicable local regulations.  
12.2. 
Ethical Conduct of the Study 
The Investigator will ensure that this study is conducted in full conformity with regulations for 
the protection of human patients of research codified in the following: 
•
US CFR applicable to clinical studies: 45 CFR Part 46; 21 CFR Parts 11, 50, 54,
56, 312
•
International Council for Harmonisation (ICH) Guideline E6
•
Declaration of Helsinki
•
Applicable national and local legal and regulatory requirements
The Investigator will also be responsible for the following: 
−
Providing written summaries of the status of the study to the IRB/IEC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/IEC
−
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures
−
Providing oversight of the conduct of the study at the site and adherence to
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation
536/2014 for clinical studies (if applicable), and all other applicable
local regulations
12.2.1. 
Patient Information and Informed Consent 
The Principal Investigator(s) at each investigative site will ensure that the patient is given full 
and adequate oral and written information about the nature, purpose, possible risk, and benefit of 
the study. Patients must also be notified that they are free to discontinue from the study at any 
time. The patient should be given the opportunity to ask questions and allowed time to consider 
the information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any 
study procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the patient, and/or a signed original as required by local regulations. 
12.2.2. 
Maintaining Patient Confidentiality 
The Principal Investigator and designees, employees, and agents involved with this study will 
comply with relevant local, state, federal, and regional laws, as applicable, relating to the 
confidentiality, privacy, and security of patient’s health information. Data generated during this 
study or disclosed by the Sponsor to the Investigator will only be used as appropriate for the 


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execution, analysis, review, and reporting of this study. Such information shall not be used 
for any other purposes and will remain confidential. 
The study protocol, documentation, data, and all other information generated will be held 
in strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
The study patient’s contact information will be securely stored at each investigative site for 
internal use during the study. At the end of the study, all records will continue to be kept in 
a secure location for as long a period as dictated by local IRB and Institutional regulations. 
Study patient research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored by the Sponsor. This will not include the patient’s contact 
or identifying information. Rather, individual patients and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by investigative sites and by the Sponsor will be secured and password protected. At the 
end of the study, all study databases will be de-identified and archived by the Sponsor. Though 
the results of the study may be presented in reports, published in scientific journals, or presented 
at medical meetings, patient names will never be used. 
To ensure patient safety and in adherence with regulatory guidelines, personal medical 
information may be reviewed by representatives of the Sponsor, the IRB/IEC, or regulatory 
authorities. This personal information will not be reused or disclosed to any other person or 
entity, or for other research. 
12.2.3. 
Use of Research Samples and Data 
The Sponsor will be responsible for all stored samples generated during this study. 
Some samples will be stored with specific vendors as appropriate (eg, PK samples). Samples and 
data will be stored using codes assigned by the clinical data system. Data will be kept in 
password-protected computers. 
With the patient’s approval, as approved by local IRBs, and in compliance with local regulations, 
de-identified biological samples will be stored by the Sponsor. These samples may be analyzed 
during the study or stored for future research following study completion. These samples, and the 
data obtained from the analysis, will be shared with other researchers, some of whom may be 
outside of this study. 
During the conduct of the study, an individual patient can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent regarding 
biosample storage will not be possible after the study is completed. 
Data generated from patients and collected for this study will be analyzed and stored by the 
Sponsor or its designee. If a patient withdraws consent, no additional data or samples will be 
collected from the patient. Survival information may be collected as outlined in Section 3.1.3.2. 
After the study is completed, the de-identified, archived data will be maintained by the Sponsor 
and may be made available for use by other researchers including those outside of the study. 


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12.3. 
Data Handling and Recordkeeping 
12.3.1. 
Data Collection Responsibilities and Access to Source Data 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. 
Each participating site will maintain appropriate medical and research records for this study, 
in compliance with ICH E6 and regulatory and institutional requirements for the protection of 
confidentiality of patients. Each site will permit authorized representatives of the Sponsor 
and/or its designee and regulatory agencies to examine (and when permitted by applicable law, 
to copy) clinical records for the purposes of quality assurance reviews, audits, and evaluation 
of the study safety, progress, and data validity. 
This study will utilize a 21 CFR Part 11-compliant data capture system provided by the Sponsor 
or its designee for the purposes of data collection. Specific instructions on the system used for 
data collection will be provided in the Study Manual. Clinical data will be entered directly from 
the source documents. 
12.3.2. 
Retention of Records 
All essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational medicinal product or for 25 years whichever is longer. 
No records will be destroyed without the written consent of the Sponsor. It is the responsibility 
of the Sponsor to inform the Investigator when these documents no longer need to be retained. 
12.3.3. 
Study Monitoring 
Before an investigational site can enter a patient into the study, the Sponsor or its designee will 
qualify the investigational study site, which will include: 
•
Determining the adequacy of the facilities.
•
Discussing with the Investigator(s) and other personnel their responsibilities
regarding protocol adherence, and the responsibilities of the Sponsor or its
representatives. This will be documented in a Clinical Study Agreement between the
Sponsor and the Investigator.
During the study, a monitor from the Sponsor or its designee will have regular contacts with the 
investigational site, for the following: 
•
Provide information and support to the Investigator(s).
•
Confirm that facilities remain acceptable.
•
Confirm that the investigational team is adhering to the protocol, that data are being
accurately recorded in the eCRFs, and that investigational product accountability
checks are being performed.


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•
Perform source data verification. This includes a comparison of the data in the eCRFs
with the patient’s medical records at the hospital or practice, and other records
relevant to the study. This will require direct access to all original records for each
patient (eg, clinic charts).
•
Record and report any protocol deviations not previously sent to the Sponsor or
its designee.
•
Confirm AEs and SAEs have been properly documented on eCRFs and confirm any
SAEs have been reported, and those SAEs that met criteria for reporting have been
forwarded to the IRB.
The monitor will be available between visits if the Investigator(s) or other staff need information 
or advice. 
The clinical monitoring plan will outline the nature and frequency of site monitoring. Remote 
monitoring may be performed, which may include accessing and viewing medical records from a 
location outside of the study center, as allowed by national law. 
12.3.4. 
Audits and Inspections 
Authorized representatives of the Sponsor or its designee, a regulatory authority, or an IRB/IEC 
may visit the site to perform audits or inspections, including source data verification. 
The purpose of a Sponsor audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, 
and data were recorded, analyzed, and accurately reported according to the protocol, ICH GCP 
guidelines, and any applicable regulatory requirements. Remote audits or inspections may be 
performed, which may include accessing and viewing medical records from a location outside of 
the study center, as allowed by national law. The Investigator should contact the Sponsor or its 
designee immediately if contacted by a regulatory agency regarding an inspection. 
12.3.5. 
Quality Control and Quality Assurance 
The Sponsor or designee performs quality control and assurance checks on all clinical studies 
that it sponsors. Before enrolling any patients in this study, Sponsor personnel and the 
Investigator review the protocol, the current IB, the eCRFs and instructions for their completion, 
the procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs. A 
qualified representative of the Sponsor will monitor the conduct of the study. During these site 
visits, information recorded in the eCRFs is verified against source documents. 
Quality control procedures will be implemented against data collected centrally. Missing data 
or data anomalies will be communicated to the site(s) for clarification/resolution. 
Applicable procedures will follow written SOPs in compliance with the protocol, GCP, and the 
applicable regulatory requirements. 
The investigational site will provide direct access to all study-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor or its 
designee, and inspection by local and regulatory authorities. 


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12.4. 
Investigational Product Accountability 
The Investigator must maintain accurate records (including dates, quantities, and bottle 
identification numbers) of all study drug supplies received. All records must be made available 
to the Sponsor, authorized representatives, and appropriate regulatory agencies, upon request.  
Current ICH GCP guidelines require the Investigator to ensure that study drug deliveries from 
the Sponsor are received by a responsible person (eg, pharmacist). 
Drug inventory and accountability records for the study treatment will be kept by the 
Investigator/pharmacist. Study treatment accountability throughout the study must 
be documented. 
12.5. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
12.6. 
Compensation for Injury and Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the Investigator 
or designated alternate will be provided.  
If bodily injury is sustained, resulting directly from the use of the study drug or by required study 
procedures, the Sponsor will reimburse the study site for reasonable physician fees and medical 
expenses necessary for treatment of only the bodily injury that is not covered by the patient’s 
medical or hospital insurance, provided that the injury is the following: 
•
Not caused by the patient’s pre-existing medical condition or underlying disease,
•
Not due to a negligent or wrongful act or omission by the study doctor and study staff,
•
Not caused by the study doctor or study staff’s failure to follow the study protocol, other
written instructions provided by the Sponsor, applicable laws or regulations, and
•
Not requiring treatment that would have occurred as standard care if the patient was not
taking part in the study.
No other compensation of any type will be provided by the Sponsor. Financial compensation for 
lost wages, disability, or discomfort due to the study participation or procedures is not available. 
12.7. 
Study Termination and Site Closure 
If the Sponsor elects to terminate the study prematurely, it will provide appropriate notification 
to the Investigators, IRBs/ECs, and FDA and other relevant regulatory authorities, as applicable. 
The notification will include instructions for handling patients still on study drug, data collection 
procedures, and requirements for study close-down. If required by applicable regulations, 
the Investigator must inform the ethics board promptly and provide the reason for the suspension 
or termination. 


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If the Sponsor elects to terminate or suspend this study prior to completion, it will discuss the 
feasibility of continued administration of nanatinostat/valganciclovir with or without 
pembrolizumab with each participating Investigator for those patients that appear to be 
benefitting from nanatinostat/valganciclovir with or without pembrolizumab. 
The Sponsor will also cooperate with participating sites in terms of collecting outstanding study 
data sufficiently to allow for the generation of a study manuscript. 
If an Investigator suspends or terminates the study, the Investigator will promptly inform the 
Sponsor and the IRB/IEC and provide a detailed written explanation. The Investigator will also 
return all nanatinostat/valganciclovir/pembrolizumab containers, as well as any other study 
materials, to the Sponsor or designee, or will destroy the materials at the investigative site. Upon 
study completion, the Investigator will provide the Sponsor, IRB/IEC, and regulatory agency 
with final reports and summaries as required by regulations. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to the following: 
•
Failure of the Investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines
•
Inadequate recruitment of participants by the Investigator
•
Discontinuation of further study intervention development
The study will be considered complete when all patients complete study follow-up. 
12.8. 
Use of Study Information and Publication 
The Sponsor intends that the data from this study will be presented and published following 
completion of data analysis. This study will be registered in a publicly accessible database such 
as clinicaltrials.gov. by the Sponsor in keeping with the policy of the International Committee of 
Medical Journal Editors (ICMJE). Once completed, the results of the study will be posted on 
these publicly accessible databases as required by law.  
The results of the study may be published or presented by the Investigator(s) following review 
and agreement by the Sponsor. Each Investigator agrees to submit all manuscripts or congress 
abstracts and posters/presentations to the Sponsors prior to submission. Any publication or 
presentation of ancillary reports or local site outcome data must wait until the primary clinical 
publication is “in press.” The Sponsor reserves the right to withhold the presentation of 
confidential or proprietary information. 
Authorship will be based upon the principles outlined in the ICJME guidelines (ICMJE 2018). In 
addition, as a guideline, to ensure representation of centers making substantial contributions to 
this study, centers enrolling at least 5% of the study population will be invited to suggest an 
investigator for publication co-authorship. Other contributors not meeting authorship criteria will 
be acknowledged individually should they agree. Data derived from the study are the exclusive 
property of the Sponsor. 


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13.
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Siegel D, Hussein M, Belani C, Robert F, Galanis E, Richon VM, et al. Vorinostat in solid and 
hematologic malignancies. J Hematol Oncol. 2009 Jul 27;2:31. 


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Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. American Society of Clinical 
Oncology. Recommendations for the Use of WBC Growth Factors: American Society of Clinical 
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pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients 
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future perspectives. Front Oncol. 2020 Dec 14;10:583463. 
Sun X, Su S, Chen C, Han F, Zhao C, Xiao W, et al. Long-term outcomes of intensity-modulated 
radiotherapy for 868 patients with nasopharyngeal carcinoma: an analysis of survival and treatment 
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14.
APPENDICES


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Appendix 1. 
Concomitant Therapies to be Used Cautiously with 
Nanatinostat 
Appendix 1, Table 1: Examples of Sensitive Substrates of CYP3A 
Enzyme 
Therapeutic 
CYP3A 
alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, everolimus, ibrutinib, 
lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, 
tacrolimus, tipranavir, triazolam, vardenafil, budesonide, dasatinib, dronedarone, eletriptan, 
eplerenone, felodipine, indinavir, lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, 
tolvaptan 
Appendix 1, Table 2: Examples of Strong Inhibitors of P-gp and BCRP Transporters 
Enzyme 
Therapeutic 
P-gp
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and 
ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, verapamil 
BCRP 
curcumin, cyclosporine A, eltrombopag 


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Appendix 2. 
Established and Other Potentially Significant Drug 
Interactions with Ganciclovir 
Concomitant Drug 
Change in Concentration of 
Ganciclovir or Concomitant Drug 
Increased 
Monitoring Required 
Clinical Comment 
Imipenem-cilastatin 
Unknown 
If required, only 
administer as inpatient 
with close monitoring for 
seizure activity 
Risk of generalized 
seizures 
Cyclosporine or 
amphotericin B 
Unknown 
Monitor serum creatinine 
at least twice weekly for 
first week, followed by 
monitoring every week 
thereafter 
Risk of renal 
toxicity 
Mycophenolate 
Mofetil (MMF) 
No change in levels of ganciclovir 
or MMF in patients with normal 
renal function 
Monitor serum creatinine 
and complete blood count 
(CBC) at least twice 
weekly for first week, 
followed by monitoring 
every week thereafter 
Risk for 
hematological 
and renal toxicity 
Other drugs 
associated with 
myelosuppression 
or nephrotoxicity a 
Unknown 
Monitor serum creatinine 
and CBC at least twice 
weekly for first week, 
followed by monitoring 
every week thereafter 
Risk for increased 
hematological 
and renal toxicity 
Didanosine 
No change in ganciclovir 
Increased didanosine 
Serum amylase weekly 
for first month on 
combination, monthly 
thereafter 
Monitor closely for 
didanosine toxicity 
(eg, pancreatitis) 
Probenecid 
Increased ganciclovir 
Monitor CBC at least 
twice weekly for first 
week, followed by 
monitoring every week 
thereafter 
May require dose 
reduction of 
valganciclovir 
CBC = complete blood count. 
a Includes adriamycin, dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, 
trimethoprim/sulfamethoxazole, vinblastine, vincristine, and zidovudine. 
Adapted from Valcyte [valganciclovir] Prescribing Information, 2021. 


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Appendix 3. 
Response Evaluation Criteria in Solid Tumors (RECIST 
v1.1) 
Measurable disease/target lesions and non-measurable disease/non-target lesions are to be 
evaluated according to RECIST version 1.1. 
Method 
Computed tomography (CT) or magnetic resonance imaging (MRI) will be performed to 
evaluate tumor response. All measurements should be taken and recorded in metric notation 
(mm) using a ruler or calipers.
Computed tomography and MRI are the best currently available and reproducible methods to 
measure target lesions and qualitatively assess non-target lesions selected for response 
assessment. Conventional CT (non-spiral or non-helical) and conventional MRI (MRI performed 
without fast scanning techniques) should produce images contiguously reconstructed at 10 mm 
or less. Spiral (helical or multidetector) CT should produce images contiguously reconstructed 
between 5 and 8 mm. 
The same method of assessment and the same technique should be used to characterize each site 
of disease at baseline and during follow-up evaluations. 
Definitions of Measurable/Non-Measurable Lesions 
Measurable lesions 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
•
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) OR
•
10 mm by caliper measurement in clinical examination (lesions that cannot be accurately
measured by calipers should be recorded as non-measurable) OR
•
20 mm by chest X-ray
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At both baseline and follow-up, only the short axis 
will be measured and followed. 
Non-measurable lesions 
All other lesions, including small lesions (longest diameter of <10 mm or pathological lymph 
nodes of ≥10 to <15 mm in the short axis) as well as truly non-measurable lesions, are defined as 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 


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involvement of skin or lung, and abdominal mass/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques. 
Definitions of Target/Non-Target Lesions 
Target lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions in total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and should be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and be 
representative of all involved organs, and in addition, should be those that lend themselves to 
reproducible repeated measurements. The sum of the diameters (longest diameter for non-nodal 
lesions, short axis for nodal lesions) of all target lesions will be calculated and reported as the 
baseline sum diameter. If lymph nodes are included, only the short axis is added to the sum. 
Non-target lesions 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or, in rare cases, 
‘unequivocal progression’. 
Post-Baseline Assessment 
At every planned follow-up scan visit as described in the protocol after baseline, the investigator 
will assess the target lesions selected at baseline quantitatively, assess the non‑target lesions 
selected at baseline qualitatively, and search for new lesions. The lesion assessments are then 
combined into an assessment of the entire subject at that visit (called the visit response or the 
overall response). 
Definition of Target Lesion Response 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target lesions) must have reduction in the short axis to <10 mm. 
Partial response: At least a 30% decrease in the target lesion sum diameter versus the baseline 
sum diameter. 
Progressive disease (PD): At least a 20% increase in the target lesion sum diameter versus the 
smallest sum diameter obtained during the study (this includes the baseline sum if that is the 
smallest sum diameter obtained during the study). In addition to the relative increase of 20%, the 
sum diameter must also show an absolute increase of at least 5 mm. 
Stable disease (SD): Neither sufficient decrease to qualify as partial response nor sufficient 
increase to qualify as PD. 
Definition of Non-Target Lesion Response 


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CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph 
nodes must be non-pathological in size (< 10 mm in the short axis). 
Non-CR/non-PD: Persistence of 1 or more non-target lesions or tumor marker levels maintained 
above normal limits. 
PD: Unequivocal progression of existing non-target lesions or the appearance of 1 or more 
new lesions. 
Overall Response 
The following table shows the criteria for the assessment of overall response at each time point 
for subjects who have measurable lesions at baseline. 
Evaluation of Overall Response at Each Time Point 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not evaluated 
No 
PR 
SD 
Non-PD/not evaluated 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
Source: RECIST version 1.1 criteria. 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; RECIST = 
Response Evaluation Criteria in Solid Tumors; SD = stable disease. 
Best Overall Response 
Best overall response (BOR) in this study is defined as the BOR across all time points, eg, a 
subject who has SD at first assessment, partial response at second assessment, and PD at last 
assessment has a best overall assessment of PR. If SD is assessed as the BOR, it must also meet 
the SD criteria at least once after study entry at 6 weeks or longer from baseline. If SD is the best 
time point response and the minimum time requirement is not met, the subject’s best response 
will depend on subsequent assessments eg, a subject who has SD at first assessment and PD at 
second assessment and does not meet the minimum duration for SD, will have a best overall 
assessment of PD. The same subject lost to follow-up after the first SD assessment would be 
considered unevaluable. 


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Appendix 4. 
Immunologic Response Evaluation Criteria in Solid Tumors 
(Source: Seymour 2017) 
Immunologic Response Evaluation Criteria in Solid Tumors (iRECIST) is based on RECIST 
v1.1, but adapted to account for the tumor response seen with immunotherapeutic drugs. When 
feasible, Investigators are encouraged to keep patients on treatment until progression is 
confirmed by the Investigator, working with local radiology, according to the rules in this 
section. This allowance to continue treatment beyond the initial radiologic progressive disease 
(PD) factors in the observation that some patients may have a transient increase in tumor burden 
after starting immunotherapy and then experience subsequent disease response. 
A summary of the adaptations is provided here, with additional detail in the iRECIST 
publications (Seymour 2017). iRECIST should be used by the Investigator to assess tumor 
response and progression for the purpose of treatment decisions. These data will be captured in 
the clinical database. 
Assessment at Screening and Prior to RECIST v1.1 Progression 
Until radiographic progression based on RECIST v1.1, there is no distinct iRECIST assessment. 
Assessment and Decision at RECIST v1.1 Progression 
In patients who have an assessment of radiologic PD per RECIST v1.1, the Investigator will 
decide whether to continue a patient on study treatment until repeat imaging is obtained (using 
iRECIST to guide treatment decisions). This decision would be based upon the patient’s overall 
clinical condition meeting the criteria for clinical stability defined by the following: 
•
Absence of symptoms and signs indicating clinically significant progression
of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia,
radiation, or other palliative care
•
Absence of rapid progression of disease
Any patient deemed clinically unstable should be discontinued from study treatment and tumor 
imaging would not be repeated for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the patient may continue to receive study 
treatment, and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per investigator assessment. 
iRECIST defines new response categories, including immune unconfirmed progressive disease 
(iUPD;unconfirmed PD) and immune confirmed progressive disease (iCPD;confirmed PD). For 
the purposes of iRECIST assessment, the first visit showing progression per RECIST v.1.1 
criteria will be assigned an overall response of iUPD. 
At this visit, the initial target and nontarget lesions identified at baseline will be assessed as 
usual, with collection of lesion measurements on the target lesion eCRF and tumor states on the 
nontarget lesion eCRF.  


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For data collection per iRECIST, the main difference is in the assessment of new lesions, 
which are classified as measurable or nonmeasurable, using the same size criteria as for baseline 
lesion assessment in RECIST v1.1 (at least 10 mm in long axis [or 15 mm in short axis for nodal 
lesions]). From measurable new lesions, up to 5 lesions total (up to 2 per organ), may be selected 
as “new lesions – target.” The sum of diameters of these lesions will be calculated but kept 
distinct from the sum of diameters of target lesions identified at baseline. All other new lesions 
will be followed qualitatively as “new lesions – nontarget.” 
Assessment at the Confirmatory Imaging (4-8 Weeks After Assessment of RECIST PD) 
Confirmatory imaging should be performed at least 4 weeks, but no longer than 8 weeks 
following initial iUPD assessment. On the confirmatory imaging, the outcomes of tumor 
evaluation by iRECIST can be (1) confirmation of progression (with an overall response of 
iCPD), (2) persistence of unconfirmed progression (with an overall response of iUPD), 
(3) disease stability (iSD), or (4) response (immune partial response [iPR]/immune complete
response [iCR]) as illustrated in Figure 1.
Appendix 4, Figure 1: Assessment of Tumor Response Using iRECIST 
iCPD =immune confirmed progressive disease; iCR = immune complete response; iPR = immune partial 
response; iSD = immune stable disease; iUPD = immune unconfirmed progressive disease; NTL = nontarget 
lesion; PD = progressive disease; TL = target lesion 
iRECIST Criteria for Confirmation of Progression 
Progression is considered as confirmed, with an overall response of iCPD, if ANY of the 
following occurs: 
•
Worsening of any of the individual component responses (target lesion, nontarget
lesion, or new lesion) that were the basis for the initial overall iUPD determination:


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−
Target lesions: worsening is a further increase in the sum of diameters of ≥5 mm,
compared with any prior iUPD timepoint.
−
Nontarget lesions: worsening is any significant growth in lesions overall,
compared with a prior iUPD timepoint; this does not have to meet the
“unequivocal” standard of RECIST v1.1
−
New lesions: worsening is any of the following:
o
An increase in the measurable new lesion sum of diameters by ≥5 mm from a
prior iUPD timepoint.
o
Visible growth of non-measurable new nontarget lesions
o
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST v1.1
Persistence of iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if the following 
is observed: 
•
No worsening of existing tumor burden (target, nontarget, and new lesions) as
described above occurs AND
•
The target lesion sum of diameters (target lesions identified at baseline) remains
above the RECIST-defined threshold for target lesion progression.
The second factor would be applicable only in cases where the target lesion increases at the 
initial assessment of iUPD met the criteria for progression (≥20% and ≥5 mm increase from 
nadir). Cases where initial iUPD was based upon progression of nontarget lesions or 
identification of new lesions, but target lesion change does not meet PD criteria would be 
covered by the section below on Resolution of iUPD. 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which 
the iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with possible 
outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, 
according to the following: 
•
No worsening of existing tumor burden (nontarget and new lesion) AND
•
The target lesion sum of diameters (target lesions identified at baseline) is not above
the RECIST-defined threshold for target lesion progression.
The response is classified as iSD or iPR (depending upon the sum of diameters of the target 
lesions), or iCR if all lesions resolve. iCR, iPR, and iSD can all be assigned after iUPD has been 
documented, as long as iCPD was not confirmed. Following a determination of iSD, iPR, or iCR, 
the next visit that shows radiographic progression, whenever it occurs, is again classified as 


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iUPD by iRECIST, and the confirmation process is repeated before a response of iCPD can be 
assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
patient continues to be clinically stable, then study treatment may continue following the regular 
imaging schedule. If PD is confirmed, then patients should be discontinued from study treatment. 
If an iCPD as defined above, but the patient is achieving a clinically meaningful benefit, and no 
further increase in the tumor burden is seen at the confirmatory tumor imaging, then an exception 
to continue study treatment may be considered following consultation with the Sponsor. If study 
treatment is continued, then tumor imaging should continue to be performed. 
Determination of Progression after Assessment of iSD/iPR/iCR 
After achieving a response of iSD/iPR/iCR, subsequent iUPD is indicated by any of the 
following: 
•
Target lesions
−
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from
nadir). The nadir is always the smallest sum of diameters observed throughout the
entire study.
•
Nontarget lesions
−
If nontarget lesions have never shown unequivocal progression, their doing so for
the first-time results in iUPD.
−
If nontarget lesions had shown previous unequivocal progression, and this
progression has not resolved, iUPD results from any significant further growth of
nontarget lesions, taken as a whole.
•
New lesions
−
New lesions appear for the first time.
−
Additional new lesions appear.
−
Previously identified measurable new lesions show an increase of ≥5 mm in the
new lesion sum of diameters, from the nadir value of that sum.
−
Previously identified non-measurable new lesions show any significant growth.
If any of the factors above indicate iUPD, the iUPD evaluation process is repeated, similar to the 
first occurrence of iUPD. iUPD must be confirmed before iCPD can occur. 

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STATISTICAL ANALYSIS PLAN 
Viracta Therapeutics, Inc. 
VT3996-301 
Protocol Title: 
An Open-Label, Multicenter Phase 1b/2 Study of Nanatinostat 
and Valganciclovir in Patients with Advanced Epstein-Barr 
Virus-Positive (EBV+) Solid Tumors and in Combination with 
Pembrolizumab in Patients with Recurrent/Metastatic 
Nasopharyngeal Carcinoma 
Protocol Version 
and Date: 
Version 4.0; 22 September 2023 
Sponsor: 
Viracta Therapeutics, Inc. 
2533 S. Coast Hwy 101 
Suite 210 
Cardiff, CA 92007 
Prepared By: 
Sarah Parisi 
Emanate Biostats, Inc. 
5800 Armada Drive 
Suite 210 
Carlsbad, CA 92008 
Document 
Version and Date 
Version 1.0; 22 November 2024 
(NCT05166577)


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STATISTICAL ANALYSIS PLAN APPROVAL 
Sponsor: 
Viracta Therapeutics, Inc. 
Clinical Protocol Number: VT3996-301 
Protocol Title: 
An Open-Label, Multicenter Phase 1b/2 Study of 
Nanatinostat and Valganciclovir in Patients with 
Advanced Epstein-Barr Virus-Positive (EBV+) Solid 
Tumors and in Combination with Pembrolizumab in 
Patients with Recurrent/Metastatic Nasopharyngeal 
Carcinoma 
Document File and Name: 
Viracta_VT3996-301_SAP_v1.0_2024-11-22.pdf 
Document Version and 
Effective Date: 
Version 1.0; 22 November 2024 
Approved By: 
Darrel P. Cohen, MD, PhD 
Chief Medical Officer 
Viracta Therapeutics, Inc. 
Sarah Parisi 
Associate Director, Biostatistics 
Emanate Biostats, Inc. 
(NCT05166577)


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Confidential 
 
Page 3 of 32 
 
TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN APPROVAL ........................................................ 2 
TABLE OF CONTENTS ............................................................................................... 3 
TABLE OF TABLES .................................................................................................... 5 
TABLE OF FIGURES ................................................................................................... 5 
ABBREVIATIONS ....................................................................................................... 6 
1. 
INTRODUCTION ................................................................................................. 8 
2. 
STUDY OBJECTIVES .......................................................................................... 8 
2.1 
Primary Study Objectives................................................................................ 8 
2.2 
Secondary Study Objectives............................................................................ 8 
2.3 
Exploratory Study Objective ........................................................................... 9 
3. 
INVESTIGATIONAL PLAN ................................................................................ 9 
3.1 
Overall Study Design ...................................................................................... 9 
3.2 
Schedule of Assessments .............................................................................. 13 
3.3 
Treatments ..................................................................................................... 13 
3.3.1 
Treatments Administered ....................................................................... 13 
3.3.2 
Method of Assigning Patients to Treatment Groups.............................. 14 
3.3.3 
Blinding Procedures ............................................................................... 15 
3.4 
Efficacy and Safety Variables ....................................................................... 15 
3.4.1 
Efficacy Variables .................................................................................. 15 
3.4.2 
Safety Variables ..................................................................................... 16 
3.4.3 
Pharmacokinetic Variables .................................................................... 17 
3.4.4 
Pharmacodynamic Variables ................................................................. 18 
3.5 
Data Quality Assurance ................................................................................. 18 
4. 
STATISTICAL METHODS ................................................................................ 18 
4.1 
General Methodology .................................................................................... 18 
4.1.1 
Reporting Conventions .......................................................................... 18 
4.1.2 
Summarization by Visit ......................................................................... 19 
4.1.3 
Data Handling Rules .............................................................................. 19 
4.1.4 
Baseline Value ....................................................................................... 19 
4.1.5 
Standard Calculations ............................................................................ 20 
4.2 
Analysis Sets ................................................................................................. 20 
4.3 
Study Patients ................................................................................................ 21 
4.3.1 
Disposition of Patients ........................................................................... 21 
4.3.2 
Protocol Deviations ................................................................................ 21 
4.4 
Demographic and Other Baseline Characteristics ......................................... 21 
4.5 
Efficacy Evaluation ....................................................................................... 22 


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4.5.1 
Datasets Analyzed .................................................................................. 22 
4.5.2 
Measurements of Treatment Compliance .............................................. 22 
4.5.3 
Primary Efficacy Endpoint Analysis Methods ...................................... 23 
4.5.4 
Secondary Efficacy Endpoint Analysis Methods .................................. 23 
4.5.5 
Statistical/Analytical Issues ................................................................... 23 
4.5.6 
Plasma Concentrations ........................................................................... 25 
4.5.7 
Pharmacokinetic Analysis ...................................................................... 25 
4.5.8 
Pharmacodynamic Analysis ................................................................... 25 
4.6 
Safety Evaluation .......................................................................................... 25 
4.6.1 
Extent of Exposure ................................................................................. 25 
4.6.2 
Adverse Events ...................................................................................... 25 
4.6.3 
Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events 28 
4.6.4 
Clinical Laboratory Evaluation .............................................................. 29 
4.6.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 30 
4.7 
Determination of Sample Size....................................................................... 31 
4.8 
Changes in the Conduct of the Study or Planned Analyses .......................... 31 
5. 
REFERENCE LIST ............................................................................................. 32 
 
 
 


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TABLE OF TABLES 
Table 1 
List of Abbreviations ................................................................................... 6 
Table 2 
Conventions for Censoring for DOR and PFS .......................................... 24 
 
TABLE OF FIGURES 
Figure 1  Study Design.............................................................................................. 11 
 
 


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ABBREVIATIONS 
Table 1 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ATC  
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CI 
confidence interval 
CR 
complete response 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
EBV+ 
Epstein-Barr Virus-Positive 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
End of Treatment 
ET 
Early Termination 
FFPE 
formalin-fixed paraffin-embedded 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
iRECIST 
Immunologic Response Evaluation Criteria in Solid Tumors 
IV 
intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamic 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
Q1 
1st quartile (25th percentile) 
Q3 
3rd quartile (75th percentile) 


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Abbreviation 
Definition 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RM-NPC 
recurrent/metastatic nasopharyngeal carcinoma 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SI 
Système International 
SMC 
Safety Monitoring Committee 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
 
 


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1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide comprehensive and 
detailed descriptions of the methods and presentation of data analyses proposed for 
Viracta Therapeutics, Inc. Protocol VT3996-301 (An Open-Label, Multicenter Phase 
1b/2 Study of Nanatinostat and Valganciclovir in Patients with Advanced Epstein-Barr 
Virus-Positive [EBV+] Solid Tumors and in Combination with Pembrolizumab in 
Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma). Descriptions of 
planned analyses are provided in order to avoid post hoc decisions that may affect the 
interpretation of the statistical analysis. The statistical methods applied in the design 
and planned analyses of this study are consistent with the International Council for 
Harmonisation (ICH) guidelines Statistical Principles for Clinical Trials (E9) (1998) 
and Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity 
Analysis in Clinical Trials (E9[R1]) (2021). 
This SAP will be finalized prior to data analysis and before database lock to provide 
comprehensive details of the tables, figures, and listings to be presented in the Clinical 
Study Report (CSR). Any changes between the statistical methods provided in the 
clinical study protocol and this SAP will be explained herein; any changes or deviations 
from this SAP relative to the final analysis will be fully documented in the CSR. Minor 
changes or deviations from the templates for tables, figures, and listings need not be 
documented in the CSR. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Study Objectives 
The primary objectives of this study include the following: 
• Phase 1b: To determine the recommended Phase 2 dose (RP2D) of nanatinostat 
in combination with valganciclovir; and 
• Phase 2:  
o To confirm the RP2D of nanatinostat in combination with 
valganciclovir; 
o To estimate the objective response rate (ORR) of nanatinostat and 
valganciclovir alone and in combination with pembrolizumab. 
2.2 
Secondary Study Objectives 
The secondary objectives of this study include the following: 
• To characterize the safety and tolerability of nanatinostat and valganciclovir 
alone and in combination with pembrolizumab; 
• To characterize the pharmacokinetic (PK) properties of nanatinostat in 
combination with valganciclovir; and 


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• To evaluate additional preliminary efficacy parameters of nanatinostat and 
valganciclovir alone and in combination with pembrolizumab. 
2.3 
Exploratory Study Objective 
The exploratory objectives of this study include the following: 
• Evaluate potential biomarkers of activity of nanatinostat and valganciclovir 
alone and in combination with pembrolizumab; and 
• Evaluate the safety, tolerability, PK, pharmacodynamic (PD), and antitumor 
activity of nanatinostat in combination with valganciclovir in patients with non-
NPC EBV+ solid tumors. 
3. 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
This is a Phase 1b/2, open-label, multicenter study designed to evaluate the safety and 
preliminary efficacy of oral nanatinostat and valganciclovir alone and in combination 
with IV pembrolizumab in patients with EBV+ recurrent/metastatic nasopharyngeal 
carcinoma (RM-NPC). The safety and tolerability of study drug treatments will be 
evaluated by means of adverse event (AE) reports, laboratory safety evaluations, vital 
sign measurements, 12-lead resting electrocardiograms (ECGs), physical examinations, 
and Eastern Cooperative Oncology Group (ECOG) performance status. The efficacy of 
study drug treatments will be evaluated for Phase 2 patients per tumor response 
measurements. Pharmacokinetic and pharmacodynamic assessments are also planned.  
Phase 1b 
A traditional 3+3 dose escalation design will be used to determine the RP2D of 
nanatinostat and valganciclovir; approximately 27 to 60 patients with RM-NPC will be 
enrolled; cohorts of 3 to 6 patients with RM-NPC will be enrolled sequentially at 
escalating nanatinostat doses starting with 20 mg daily on Days 1 to 4 per week 
(intermittent dosing) with valganciclovir 900 mg daily. Any patients in screening when 
the last patient is enrolled in a cohort may also be enrolled if eligible. Dose escalation 
of nanatinostat will continue as described below until the RP2D is identified: 
• Total daily nanatinostat dose of 30 and 40 mg daily administered as a single 
dose on Days 1 to 4 per week with valganciclovir 900 mg once daily; or 
• Divided nanatinostat dose twice daily on Days 1 to 4 per week with 
valganciclovir 900 mg once daily or valganciclovir 900 mg twice daily for 21 
days followed by a subsequent dose reduction to 900 mg once daily; or 
• Split daily dose of nanatinostat starting at 20 mg with valganciclovir 450 mg 
twice daily, 4 hours apart on Days 1 to 7 per week. 
Because plasma EBV deoxyribonucleic acid (DNA) levels correlate closely together 
with the presence of disease and response to therapy in RM-NPC, these data will be 
considered together with safety data in the selection of the RP2D. 


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Phase 2 
Following dose escalation, Phase 2 will begin with a dose optimization cohort to assess 
the safety, tolerability, PK, PD, and antitumor activity of nanatinostat and 
valganciclovir and to confirm its RP2D in patients with RM-NPC. 
Patients will be randomly assigned 1:1 to each treatment group (up to 20 patients in 
each treatment group for approximately 40 patients total) during the dose optimization 
cohort period. The starting doses of nanatinostat for the treatment groups will be the 
RP2D and another dose level below the RP2D (<RP2D) plus valganciclovir 450 mg 
twice daily, based on the Safety Monitoring Committee’s (SMC’s) review of the totality 
of the data from the previous Phase 1b cohorts. After the nanatinostat and 
valganciclovir RP2D is confirmed by the SMC based on the results of the dose 
optimization cohorts, up to 60 patients with RM-NPC will be randomly assigned 1:1 to 
receive that RP2D of nanatinostat and valganciclovir with or without concomitant 
pembrolizumab to assess the preliminary antitumor activity, safety, and tolerability of 
each regimen in the Phase 2 dose expansion period. Randomization will be stratified by 
prior anti programmed cell death protein 1(PD-1) treatment exposure. 
Pembrolizumab will be dosed at 200 mg intravenous(ly) (IV) every 3 weeks for those 
patients randomly assigned to the nanatinostat, valganciclovir, and pembrolizumab 
group. An early safety analysis will be performed after the first 6 patients are 
randomized to receive nanatinostat and valganciclovir in combination with 
pembrolizumab and have been followed for at least 2 cycles (7 weeks) of treatment as 
described in Section 5.5.3.3 of the clinical study protocol. 
In addition, up to 10 patients with advanced EBV+ non-NPC solid tumors (gastric 
cancer, lymphoepithelioma-like carcinoma, and leiomyosarcoma) will be enrolled in a 
Phase 1b exploratory proof-of-concept cohort to characterize the safety and PK of the 
nanatinostat and valganciclovir combination in other solid tumors. Enrollment in this 
proof-of-concept cohort will begin when the appropriate RP2D for this population is 
determined in consultation with the SMC, while enrollment in the proof-of-concept 
cohort may be stopped before 10 patients are treated if a) evidence of safety or 
tolerability issues arise or b) Phase 2 of the study completes enrollment. 
All patients will be monitored at weekly intervals for the first 6 weeks, and then at 3-
week intervals thereafter starting at Week 8. Tumor responses will be assessed at Week 
8 and then every 6 weeks for the first 26 weeks (6 months) and every 12 weeks 
thereafter by the Investigator per Response Evaluation Criteria in Solid Tumors version 
1.1 (RECIST v1.1). A scan to confirm an unconfirmed partial response (PR) or 
unconfirmed complete response (CR) ≥4 weeks later may also be performed. 
Patients will continue to receive study drug until the development of progressive 
disease (per Investigator assessment), unacceptable toxicity, withdrawal of consent, 
Investigator’s discretion, initiation of new antineoplastic therapy, or study termination 
by the Sponsor. The maximum treatment with pembrolizumab is 24 months. 
The study design is summarized in Figure 1 on the next page. 
 


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Figure 1  
Study Design 
 
CT = computed tomography; DLT = dose-limiting toxicity; EBV = Epstein-Barr virus; MRI = magnetic resonance 
imaging; NPC = nasopharyngeal carcinoma; RECIST v 1.1 = Response Evaluation Criteria in Solid Tumors Version 
1.1; RM = recurrent and/or metastatic; RP2D = recommended Phase 2 dose; SDD = split daily dose 
[1] Patients must have a histologically confirmed diagnosis of EBV+ recurrent or metastatic NPC or other solid tumor 
type and received previous systemic therapy for their cancer; have measurable disease determined by magnetic 
resonance imaging (MRI) or computed tomography with contrast at screening; and have adequate bone marrow, 
liver, and renal function. 
[2] Starting nanatinostat dose is 20 mg once daily on Days 1 to 4 per week with valganciclovir 900 mg daily. Dose 
escalation of nanatinostat will continue with i) a total daily dose of 30 and 40 mg daily administered as a single dose 
on Days 1 to 4 per week with valganciclovir 900 mg once daily, ii) as a divided nanatinostat dose twice daily on 
Days 1 to 4 per week with valganciclovir 900 mg once daily or twice daily for 21 days followed by a subsequent 
dose reduction to 900 mg once daily, then iii) as a SDD of nanatinostat starting at 20 mg and valganciclovir at 450 
mg twice daily 4 hours apart on Days 1 to 7 per week until the RP2D is determined.  


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[3] EBV+ non-NPC solid tumors may include gastric cancer, lymphoepithelioma-like carcinoma, and 
leiomyosarcoma - dosing regimen for the proof-of-concept cohorts will be determined on data collected and analyzed 
at or after the RP2D from Phase 1b is determined. 
[4] Pembrolizumab: Standard 200 mg IV every 3 weeks.  
[5] Long-term follow-up assessments include tumor evaluation and EBV DNA viral levels (for patients who 
discontinued treatment for reasons other than disease progression), survival assessment until lost to follow-up, death, 
or withdrawal of consent, and subsequent anti-neoplastic therapies. 
Screening Period 
At screening, the patient will provide a signed informed consent form prior to any 
study-related activities. Collection and shipment of a formalin-fixed paraffin-embedded 
(FFPE) tumor sample (archived tissue or new biopsy specimen) to the central pathology 
laboratory should occur as early as possible, and no later than 8 weeks following Cycle 
1 Day 1. The tumor sample will be used for central confirmation of EBV status and 
exploratory assessments as described in Table 3 of the clinical study protocol. For 
tumor specimens >2 years old, the Sponsor’s Medical Monitor should be consulted to 
discuss eligibility. Additional screening evaluations must be performed within 28 days 
or 21 days before treatment start (Cycle 1 Day 1) as defined in the Schedule of Events 
(Table 11). At the time of screening, male patients should be informed about their 
options to store germ cells in advance of study treatment. 
Treatment Period 
The treatment period will begin on Cycle 1 Day 1. Cycle 1 will be 28 days; all 
subsequent cycles will be 21 days. Patients will be treated until unacceptable toxicity, 
death, progressive disease, treatment discontinuation at the discretion of the 
Investigator, or withdrawal of consent (maximum treatment duration with 
pembrolizumab is 24 months). Patients with first evidence of progressive disease and 
no clinical deterioration may continue study treatment until a repeat scan within 4 to 6 
weeks confirms disease progression. To account for atypical disease response to 
immune therapy, Investigators are encouraged to follow immune-modified Response 
Evaluation Criteria in Solid Tumors (iRECIST) criteria (criteria based on RECIST v 
1.1 for response and progressive disease, but adapted to account for the tumor response 
seen with immunotherapeutic drugs as described in Appendix 3 of the clinical study 
protocol) for treatment decision making, including confirmation of unconfirmed 
progressive disease with additional imaging. 
Safety Follow-Up Period 
Upon discontinuation of the protocol-specified treatments, patients will enter the 
Follow-up period. All patients must complete a safety follow-up assessment at 30 and 
90 days after receiving their last dose of study drug. All AEs for patients treated with 
nanatinostat, valganciclovir, and pembrolizumab and only serious AEs (SAEs) for all 
other patients will be collected up to and including 90 days after the last dose of study 
treatment or until the start of a new antineoplastic therapy, whichever occurs first. The 
90-day safety follow-up assessment may coincide with the first Long-Term Follow-Up 
visit. 
Information related to concomitant medications used to treat AEs and any anti-
neoplastic therapies taken following permanent discontinuation of study treatment will 
be collected for 90 days after the last dose of study treatment for all patients. If a new 


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antineoplastic treatment is initiated before the 30-day safety evaluation, safety follow-
up will occur immediately before starting the new treatment. If a patient withdraws 
consent after the End of Treatment (EOT) visit, but prior to the 30-day safety 
evaluation, safety data should be collected on the patient up to the date of consent 
withdrawal. 
Long-Term Follow-Up Visit 
All patients enrolled in the study will be followed for survival every 12 weeks (or more 
frequently if a survival update is required for safety or regulatory reasons) until 
withdrawal of consent, death, loss to follow-up, completion of 3 years of follow-up, 
completion of 1 year after the last patient discontinues study treatment, or the study is 
terminated by the Sponsor, whichever occurs first. Patients will also be followed during 
this period for disease progression (for those who discontinued treatment for reasons 
other than disease progression), overall survival, and subsequent anti-neoplastic 
therapies, including response.  
Patients enrolled in the study who discontinue study treatment for any reason other than 
disease progression will have a tumor assessment every 12 weeks (±7 days), up to 1 
year from the date of the last dose of study treatment, until disease progression, the 
initiation of subsequent anti-cancer therapies, withdrawal of consent, loss to follow up, 
or end of the study, whichever occurs first. Any newly started anti-neoplastic therapies 
should be recorded on the Antineoplastic Therapy Since Discontinuation electronic case 
report form (eCRF) page. 
End of Study 
The end of the study occurs when all patients have either progressed, discontinued, 
died, become lost to follow-up, or have maintained a complete response, partial 
response, or stable disease for at least 3 years, or when the trial is terminated by the 
Sponsor. Patients continuing to derive benefit from study treatment in the opinion of 
the Investigator at the end of the study may be able to continue receiving study 
treatment on an individual basis (e.g., by separate protocol or post-trial access plan) 
with Sponsor’s Medical Monitor approval. 
3.2 
Schedule of Assessments 
For the complete schedule of assessments, refer to Section 6 (Schedule of Events) in 
the clinical study protocol. 
3.3 
Treatments 
3.3.1 Treatments Administered 
3.3.1.1 Nanatinostat (VRx-3996) 
Nanatinostat (VRx-3996) is a hydroxamic acid-based histone deacetylase inhibitor and 
is available as 10-mg tablets. 
All patients will receive nanatinostat orally once or twice daily (at breakfast or at 
breakfast and lunch, respectively) on Days 1 to 4 per week (i.e., 4 days on, 3 days off), 


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or Days 1 to 7 per week. Following the completion of the 28-day Cycle 1, patients will 
continue dosing in 21-day cycles until discontinuation.  
3.3.1.2 Valganciclovir 
Valganciclovir is a cytomegalovirus nucleoside analogue DNA polymerase inhibitor 
and is available as 450-mg tablets packaged in bottles. 
The daily oral dose of valganciclovir is 900 mg once daily; 900 mg twice daily for 21 
days (at breakfast and dinner) followed by a subsequent dose reduction to 900 mg once 
daily; or 450 mg twice daily at breakfast and lunch, in combination with nanatinostat. 
Following the completion of the 28-day Cycle 1, patients will continue to receive the 
combination of nanatinostat and valganciclovir in 21-day cycles until discontinuation.  
Valganciclovir doses should be adjusted for patients who develop an elevated creatinine 
level while on study. 
3.3.1.3 Pembrolizumab 
Pembrolizumab is a humanized monoclonal PD-1 inhibitor antibody (IgG4/kappa 
isotype with a stabilizing sequence alteration in the Fc region) produced in Chinese 
hamster ovary cells by recombinant DNA technology. Pembrolizumab is available for 
injection in 100 mg/4 mL (25 mg/mL) in a single-dose vial. 
The starting provisional dose of pembrolizumab is 200 mg IV every 3 weeks. 
3.3.1.4 Sequence of Study Drug Administration 
Patients will be administered study drugs on a treatment schedule determined by study 
phase and dose level. For a detailed description of different dosing administration 
schedules for each dose level, refer to Section 5.3.3 (Sequence of Study Drug 
Administration) of the clinical study protocol. 
3.3.2 Method of Assigning Patients to Treatment Groups 
Patients with EBV+ RM-NPC will be enrolled in groups of 3 to 6 in the Phase 1b 
escalating nanatinostat dose cohorts to determine the RP2D of nanatinostat in 
combination with valganciclovir. Patients in screening when the last patient is enrolled 
in a cohort may also be enrolled if eligible.  
For Phase 2, following determination of the RP2D, approximately 40 patients will be 
randomized into one of two dose optimization cohorts receiving nanatinostat at the 
RP2D or at the ‘<RP2D’ and valganciclovir twice daily. 
Following confirmation of the RP2D, patients with EBV+ RM-NPC will be randomly 
assigned 1:1 using a centralized interactive randomization system to either nanatinostat 
and valganciclovir treatment or nanatinostat and valganciclovir in combination with 
pembrolizumab treatment in the Phase 2 dose expansion period. Randomization will be 
stratified by prior anti-PD-L1 treatment exposure. Pembrolizumab will be administered 
at 200 mg IV every 3 weeks for those patients randomly assigned to the nanatinostat, 
valganciclovir, and pembrolizumab arm. An early safety analysis after the first 6 


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patients are randomized to this treatment arm and followed for at least 2 cycles (7 
weeks) of treatment will be performed. 
In addition, up to 10 patients with EBV+ non-NPC solid tumors will be enrolled into an 
exploratory proof-of-concept cohort. The dose and regimen will be based on data 
collected and analyzed from prior cohorts after an RP2D is determined in consultation 
with the SMC to predict the appropriate recommended dose for the non-NPC solid 
tumor population prior to commencing enrollment. 
3.3.3 Blinding Procedures 
This is an open-label study so treatment assignments will not be blinded. 
3.4 
Efficacy and Safety Variables 
3.4.1 Efficacy Variables  
3.4.1.1 Primary Efficacy Variable 
Tumor responses will be assessed by the Investigator per RECIST v1.1 using MRI or 
CT scan assessments. For patients receiving pembrolizumab, tumor responses will also 
be assessed per immunologic RECIST (iRECIST). Tumor imaging will be repeated to 
confirm disease progression using iRECIST.  
The primary efficacy endpoint is ORR, defined as the percentage of patients with a CR 
or PR as assessed by RECIST v1.1 within the first 26 weeks (6 months) of treatment. 
The ORR will also be calculated using iRECIST for patients receiving pembrolizumab. 
3.4.1.2 Secondary Efficacy Variables  
Secondary efficacy endpoints include the following: 
• Time to response (TTR) – defined as the interval from the start of study drug 
treatment to the date of first documented CR or PR per RECIST or iRECIST. 
• Duration of response (DOR) – defined as the interval of time from the date of 
first observed CR or PR to the date of documented disease progression or death 
due to any cause, whichever occurs first. Dates of progression and censoring 
will be determined as described in Section 4.5.5.2; 
• Disease control rate (DCR) – defined as the percentage of patients having a CR, 
PR, or stable disease (SD) at any time during treatment; 
• Progression-free survival (PFS) – defined as the interval of time from the start 
of study drug treatment to the date of first documented disease progression, 
initiation of new antineoplastic therapy, withdrawal of consent, loss to follow-
up, or death due to any cause, whichever occurs first. Dates of progression and 
censoring will be determined as described in Section 4.5.5.2; and 
• Overall survival (OS) – defined as the interval of time from the start of study 
drug treatment to the date of death due to any cause. Patients without 


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documentation of death at the time of analysis will be censored at the date the 
patient was last known to be alive. 
3.4.2 Safety Variables 
3.4.2.1 Adverse Events 
An AE is any untoward medical event that occurs to a patient following the start of 
administration of the study treatment, whether or not the event is considered study drug 
related. Any worsening (i.e., any clinically significant adverse change in the frequency 
or intensity of a pre-existing condition) should be considered an AE. 
For all patients (excluding those in Phase 2 receiving nanatinostat, valganciclovir, and 
pembrolizumab), AEs will be recorded from the signing of the informed consent form 
(ICF) up to and including 30 days (90 days for SAEs) after the last dose of study 
treatment or until the start of subsequent anticancer therapy, whichever occurs first. For 
patients in Phase 2 who receive nanatinostat, valganciclovir, and pembrolizumab, AEs 
will be recorded from the signing of the ICF up to and including 90 days after the last 
dose of study treatment or until a new anticancer treatment is started, whichever is first.  
3.4.2.2 Laboratory Parameters 
Laboratory tests will be collected and analyzed in central or local laboratories. 
Assessments include hematology, coagulation, serum chemistry, urinalysis, viral 
levels, and pregnancy testing (only for females of childbearing potential). Specific 
parameters include the following: 
• Hematology: Hemoglobin, platelets, and white blood cell count with differential 
(absolute neutrophils, absolute monocytes, absolute eosinophils, absolute 
lymphocytes, absolute basophils); 
• Coagulation: prothrombin time or international normalized ratio, and activated 
partial thromboplastin time; 
• Serum Chemistry: aspartate aminotransferase, alanine aminotransferase, 
albumin, total bilirubin, sodium, potassium, magnesium, total protein, alkaline 
phosphatase, bicarbonate, blood urea nitrogen, creatinine, glucose (non-
fasting), chloride, calcium, phosphate, uric acid, and thyroid function tests 
(Phase 2 only [thyroid-stimulating hormone, free T3, free T4]) 
• Urinalysis (Dipstick): pH, specific gravity, glucose, bilirubin, ketones, blood, 
protein, urobilinogen, nitrite/nitrate, leukocytes/leukocyte esterase; and 
• Viral: Hepatitis B virus (HBV) surface antigen, HBV core and surface antibody, 
HBV DNA polymerase chain reaction (for patients with positive HBV core 
antibody or surface antigen), Hepatitis C virus (HCV) antibody (for patients 
with positive HCV antibody), and EBV DNA, cytomegalovirus, and human 
immunodeficiency virus levels (HIV), for HIV+ patients only. 


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3.4.2.3 Other Safety Variables 
All 12-lead ECGs will be conducted in triplicate. Triplicate 12-lead ECGs will be 
performed separated by approximately 1 minute at screening, on Cycle 1 Day 1 (Phase 
1b, all dose levels, and Phase 2), Cycle 2 Day 1 (Phase 1b dose levels 8 through 13 and 
Phase 2 only) and at the EOT visit. Prior to each ECG, the patient will lie in a supine 
position in a calm environment for at least 5 minutes.  
When performed in concert with serial PK collection on Cycle 1 Day 1 (for Phase 1b 
dose levels 1 through 7), two ECGs will be performed pre-dose (within 1 hour of dose, 
separated by at least 15 minutes). Post-dose ECGs will be performed prior to and as 
close as possible to each PK sample collection at approximately maximum plasma 
concentration (1 and 2 hours), 4 hours, and 6 hours.  
When performed in concert with serial PK collection on Cycle 1 Day 1 (for Phase 1b 
dose levels 8 through 13 and Phase 2), two ECGs will be performed pre-dose (within 1 
hour of dose, separated by at least 15 minutes) and one set of triplicate 12-lead ECGs 
will be performed on Cycle 1 Day 1 at 2-hours post-dose. When performed in concert 
with serial PK collection on Cycle 2 Day 1 for these patients, two ECGs will be 
performed pre-dose (within 1 hour of dose, separated by at least 15 minutes). Post-dose 
ECGs will be performed prior to and as close as possible to each PK sample collection 
at approximately maximum plasma concentration (1 and 2 hours), 3 hours, 4 hours, 5 
hours, and 6 hours. 
At screening and at the EOT visit, the ECG may be performed at any time during the 
clinic visit. ECGs may also be performed when clinically indicated, irrespective of the 
time of study drug dosing. 
Vital signs (temperature, blood pressure, and heart rate) will be collected at the 
screening visit (Day -28 to Day -1), on Day 1 of each cycle, and at the EOT visit. On 
visit days requiring serial PK collection, vital signs will be collected just prior to the 
first dose of valganciclovir and nanatinostat, and in concert and just prior to PK blood 
draws. On other indicated visit days, vital signs will be collected once (prior to dosing 
of study treatment if administered in clinic). 
A physical examination will be conducted at the screening visit, at the beginning of 
each cycle, at the EOT visit, and at any additional times deemed necessary by the 
Investigator. Height and weight will be measured at the screening visit and weight will 
be subsequently measured on Day 1 of each cycle and at the EOT visit. 
The ECOG performance status will be assessed at the screening visit, on Cycle 1 Day 
1, and at the EOT visit. 
3.4.3 Pharmacokinetic Variables 
Pharmacokinetic endpoints include observed plasma concentrations and estimated PK 
parameters for nanatinostat and ganciclovir, and these will be described in a separate 
analysis plan. 


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3.4.4 Pharmacodynamic Variables 
Pharmacodynamic endpoints include selected biomarkers of nanatinostat and 
valganciclovir activity with or without pembrolizumab (e.g., plasma EBV DNA levels), 
and these will be described in a separate analysis plan. 
3.5 
Data Quality Assurance 
Report summaries will be generated using validated Base SAS® software, version 9.4 
or higher, on a PC or server-based platform. Additional validated software may be used 
to generate analyses, as needed.  
All SAS programs that create outputs or supporting analysis datasets will be validated 
by a second statistical programmer or biostatistician. At a minimum, validation of 
programs will consist of a review of the program log, review of output or dataset format 
and structure, and independent confirmatory programming to verify output results or 
dataset content. Additionally, all outputs will undergo a review by a senior level team 
member before finalization. 
The content of the source data will be reviewed on an ongoing basis by project statistical 
programmers and statisticians. Data will be checked for missing values, invalid records, 
and extreme outliers through defensive programming applications, analysis-based edit 
checks, and other programmatic testing procedures. All findings will be forwarded to 
the project data manager for appropriate action and resolution. 
4. 
STATISTICAL METHODS 
4.1 
General Methodology 
Data will be analyzed by Emanate biostatistics personnel. Statistical analyses will be 
reported with tables, figures, and listings, presented in rich text format, and using 
recommended ICH numbering. Output specifications for all tables, figures, and listings 
will be in conformance with guidelines specified by the ICH in Appendix 7 of the 
Electronic Common Technical Document Specification (Apr 2003). 
4.1.1 Reporting Conventions 
The Phase 1b and Phase 2 portions of the study will be analyzed separately. Tables and 
figures will be summarized by dosing regimen. In general, all data collected, and any 
derived data will be presented in patient data listings, for all enrolled patients. Listings 
will be ordered by phase, site, patient number, treatment regimen, and assessment or 
event date. The dosing regimen presented in listings will be based on the planned 
assignment, unless otherwise noted. 
In general, continuous variables will be summarized to indicate the study population 
sample size (N), number of patients with available data (n), mean, SD, median, first 
(Q1) and third (Q3) quartiles, minimum, and maximum values. Categorical variables 
will be summarized by the population size (N), number of patients with available data 
(n), number of patients in each category, and the percentage of patients in each category. 
Unless otherwise noted, and in order to determine the percentage of patients in each 
category, the denominator will be based on the number of patients with available data. 


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Select ordinal data may be summarized using both descriptive statistics and counts and 
percentages of patients in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form (i.e., on the electronic case report 
form [eCRF] or as provided within an external file) and are outlined as follows: 
• The mean and median will be rounded to one more decimal place than the 
precision of the variable of summarization; 
• Measures of variability (e.g., standard deviation, standard error) will be rounded 
to two more decimal places than the precision of the variable of summarization; 
and 
• Minimum and maximum values will be presented using the same precision as 
the variable of summarization. 
Other statistics (e.g., CIs) will be presented using the same general rules outlined above 
or assessed for the most appropriate presentation based on the underlying data. 
No formal statistical analysis will be performed to compare treatment regimens. This 
study is exploratory in nature; descriptive statistics will be tabulated by treatment 
regimen and reviewed to evaluate all study endpoints. 
4.1.2 Summarization by Visit 
Data summarized by study visit will be based on the nominal, scheduled visit label as 
reported on the eCRF. Data collected for the last patient visit completed will be 
summarized separately, and this summary will be labeled as “End of Treatment.” 
Data collected at unscheduled visits will not be included in by-visit summaries but will 
be considered when endpoint derivations potentially include multiple visits (e.g., 
determination of baseline value, determination of worst post-baseline value, etc.). All 
data will be included in patient listings. 
4.1.3 Data Handling Rules 
Unless otherwise noted, values reported as greater than or less than some quantifiable 
limit (e.g., “< 1.0”) will be summarized with the sign suppressed in summary tables and 
figures, using the numeric value reported. Data will display on patient listings to include 
the sign. 
4.1.4 Baseline Value 
Unless otherwise noted, the baseline value will be defined as the last value reported 
prior to first dose of any study drug. 


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4.1.5 Standard Calculations 
Where appropriate, the calculated study day of each assessment or event will be 
presented with the assessment or event date on patient data listings, where study day 
will be determined as: 
• The assessment/event date minus the date of first dose of study drug, if the 
assessment/event date is prior to the date of first dose; and 
• The assessment/event date minus the date of first dose of study drug, plus one, 
if the assessment/event date is on or after the date of first dose. 
Other variables requiring calculations will be derived using the following formulas: 
• Days: A duration between two dates expressed in days will be calculated using 
the following conventions: 
o Later date – earlier date + 1, if the earlier date is on or after the date of 
first dose of study drug; or 
o Later date – earlier date, if the earlier date is prior to the date of first 
dose of study drug. 
• Months: A duration expressed in months will be calculated by dividing the 
duration in days by (365.25 / 12). 
• Years: A duration expressed in years will be calculated by dividing the duration 
in days by 365.25. 
• Change from Baseline: Change from baseline will be calculated as the post 
baseline value minus the baseline value. 
• Percentage Change from Baseline: Percentage change from baseline will be 
calculated as the change from baseline divided by the baseline value, multiplied 
by 100. 
4.2 
Analysis Sets 
The analysis sets are defined as follows:  
• Safety Analysis Population: Includes all patients who receive at least one dose 
of study treatment (nanatinostat, valganciclovir, or pembrolizumab). The Safety 
Analysis Population will be used for all summaries of safety, demographic, and 
baseline summaries. 
• Full Analysis Set: Includes all patients with measurable disease at baseline who 
receive at least one dose of nanatinostat and valganciclovir with or without 
pembrolizumab and who have at least one post-baseline tumor assessment. 
Patients will be analyzed according to the dosing regimen for which they have 
been assigned. The Full Analysis Set will be used for summaries of tumor 
response and survival metrics. 


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Modified Intent-to-Treat Population: Includes all RM-NPC patients who receive at least 
one dose of study treatment (nanatinostat, valganciclovir, or pembrolizumab), have a 
confirmed diagnosis of EBV+ by central pathology review, met all eligibility criteria, 
and have baseline (screening) and at least one post-baseline tumor assessment for 
efficacy. 
4.3 
Study Patients 
4.3.1 Disposition of Patients 
Patient disposition will be summarized for all enrolled patients by dosing regimen and 
over all patients combined. Summaries will include the number and percentage of 
patients in each analysis set as well as the number and percentage of patients 
discontinuing the treatment or study by the primary reason for discontinuation. 
4.3.2 Protocol Deviations 
Important protocol deviations will be summarized by dosing regimen and over all 
patients combined for the Full Analysis Set. Important protocol deviations are protocol 
deviations captured on study that are deemed by the Sponsor to potentially impact the 
safety or efficacy conclusions of the study.  
Any important protocol deviations will be determined and appropriately categorized 
prior to database lock. The number and percentage of patients with any important 
protocol deviations as well as the number and percentage of patients with deviations 
within each category will be presented. Corresponding patient listings will be provided. 
4.4 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized for the Safety Analysis 
Population, Full Analysis Set, and modified Intent-to-Treat Population by dosing 
regimen and over all patients combined. 
Demographic variables include age as collected on the eCRF, age category (<65 or ≥ 
65 years), sex at birth, childbearing potential (if female), ethnicity, and race. Age will 
be summarized using descriptive statistics. Sex, ethnicity, and race will be summarized 
with the number and percentage of patients in each parameter category. 
Baseline characteristics include height, weight, body mass index (BMI), medical 
history, ECOG performance status, primary cancer diagnosis at study entry, time since 
initial primary cancer diagnosis, stage of disease at study entry, histology, and number 
of prior systemic therapies. Body mass index will be calculated as: weight (kg) / [height 
(cm) / 100]2. 
Height, weight, and BMI at baseline will be summarized using descriptive statistics. 
ECOG performance status will be summarized with the number and percentage of 
patients in each category.  
Medical history conditions will be mapped to preferred terms and system organ classes 
using the Medical Dictionary for Regulatory Activities (MedDRA, version 27.1). 


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Frequency counts and percentages to summarize patients reporting abnormal medical 
history by system organ class will be presented. 
For primary cancer history, diagnosis when patient entered the study (RM-NPC, Not 
NPC [gastric cancer, lymphoepithelioma-like carcinoma, leiomyosarcoma, etc.]), stage 
at study entry, histology, and number of prior systemic therapies will be summarized 
with the number and percentage of patients in each category. The time since the date of 
original primary cancer diagnosis will be summarized using descriptive statistics. All 
other primary cancer history will be included in patient data listings. 
4.5 
Efficacy Evaluation 
4.5.1 Datasets Analyzed 
Efficacy summaries will be produced as described in Section 4.2. Efficacy summaries 
will be repeated for the modified Intent-to-Treat Population (if meaningfully different 
than the Full Analysis Set) as supportive evidence and to assess the robustness of 
efficacy findings. A data listing of patients excluded from the Full Analysis Set and 
modified Intent-to-Treat Population, to include the reason for exclusion, will be 
presented. 
4.5.2 Measurements of Treatment Compliance 
 
Compliance with both nanatinostat and valganciclovir will be determined as the total 
number of tablets taken divided by the expected number of tablets taken, multiplied by 
100.  
The expected number of tablets administered will be determined using the prescribed 
dosing information contained in Table 4 of the clinical study protocol, where 
nanatinostat and valganciclovir are dispensed in 10 mg and 450 mg tablets, 
respectively. The number of tablets expected will be calculated for each cycle and then 
multiplied by the number of cycles the patient completes. 
The total number of tablets taken will be determined using the data recorded on the 
Study Drug Exposure eCRF pages for nanatinostat and valganciclovir. If a patient is 
administered study drug as expected (with no changes to dose administered, no 
interruptions, delays, or missed doses), then the Study Drug Exposure eCRFs will 
include a record for that cycle that indicates “No Change to Dose.” In this case, the total 
number of tablets taken in each cycle will be calculated as the number of days in the 
cycle where the doses were administered (multiplied by two if a divided dose). Missed 
doses are recorded on the Study Drug Exposure eCRFs as “Missed/Dosing Error.” 
When calculating the number of missed doses, if a patient reports “Missed/Dosing 
Error” on the eCRF, it will be assumed no study drug was administered on that date.  
Compliance with pembrolizumab will be determined as the total number of infusions 
received divided by the number of expected infusions, multiplied by 100. The number 
of expected infusions will be determined using the dosing schedule provided in Figure 
10 of the clinical study protocol. The total number of infusions received will be 
determined using the Study Drug Administration Log - Pembrolizumab eCRF. 


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Dosing compliance will be summarized using descriptive statistics, for each dosing 
regimen based on the Safety Analysis Population. The number and percentages of 
patients who are <80% compliant and ≥80% compliant within each dosing regimen will 
be summarized. Treatment compliance will also be included in a by-patient data listing.  
4.5.3 Primary Efficacy Endpoint Analysis Methods 
Counts and percentages for each tumor response category assessed by the Investigator 
per RECIST v1.1 will be presented by dosing regimen. Separate summaries will also 
be produced by prior anti-PD-1 treatment exposure. Non-evaluable patients are 
considered non-responders and will be included in the denominator. ORR estimates, 
from the first post-baseline assessment, with corresponding binomial 95% confidence 
intervals using the Clopper-Pearson Exact method will also be presented. 
For patients receiving pembrolizumab, the analysis will be repeated using iRECIST.  
Results from tumor assessments will be provided in separate listings. 
4.5.4 Secondary Efficacy Endpoint Analysis Methods 
Disease control rate will be analyzed using the same statistical methodologies as 
applied to the primary efficacy endpoint in Section 4.5.3. 
Duration of response, PFS, and OS will be summarized in days using Kaplan-Meier 
methodology. The number of patients who experienced the event of interest and the 
number of patients censored will be presented, as will Kaplan-Meier product limit 
estimates of the 25th, 50th (median), and 75th percentiles with associated CIs (where 
estimable) using Greenwood’s formula. The range for all patients, as well as those who 
experience the event of interest will also be summarized. Kaplan-Meier estimates of the 
survival distribution function over time will be generated for all patients receiving study 
treatment. The PFS and OS at 12 months (56 weeks) with associated 95% CIs will also 
be presented. 
All derived efficacy measures will also be provided in a separate listing. 
4.5.5 Statistical/Analytical Issues 
4.5.5.1 Adjustments for Covariates 
There are no planned applications of covariate adjustments; all statistical results are 
descriptive in nature. 
4.5.5.2 Handling of Dropouts or Missing Data 
Objective response rate and disease control rate are based on those patients with 
available data (baseline and post-baseline response assessment). Non-evaluable 
patients are considered non-responders and will be included in the denominator. The 
analysis of PFS and DOR will be right-censored according to the conventions described 
in Table 2. These conventions are based on the FDA Guidance for Industry Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics (2018) and Clinical 


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Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics 
(2015). 
Table 2 
Conventions for Censoring for DOR and PFS 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments 
Randomization (if applicable), or 
enrollment 
Censored 
New anti-cancer treatment started 
before documentation of PD or 
death 
Date of last disease assessment 
without documentation of PD 
before start of new treatment 
Censored 
Death or progressive disease (PD) 
immediately after more than one 
consecutively missed disease 
assessment visit 
Date of last disease assessment 
visit without documentation of 
PD that is before the first missed 
visit 
Censored 
Alive and without PD 
documentation 
Date of last disease assessment  
Censored 
Treatment discontinuation for 
undocumented progression, 
toxicity, or other reason 
Date of last disease assessment 
without documentation of PD 
Censored 
Death or PD between planned 
disease assessments 
Date of death or first disease 
assessment showing PD, 
whichever occurs first 
Not 
Censored 
Death or PD after more than one 
missed visit 
Date of last disease assessment 
without documentation of PD 
Censored 
4.5.5.3 Interim Analyses and Data Monitoring 
There are no interim analyses planned for this study.  
4.5.5.4 Multicenter Studies 
This is a multicenter study with 19 sites participating. Efficacy data collected from all 
study sites will be pooled for data analysis. The effect of study site on the efficacy 
analysis results may be explored post-hoc, as needed. 
4.5.5.5 Multiple Comparisons/Multiplicity 
There will be no adjustments for multiple comparisons in the efficacy analysis for this 
study. Results are descriptive in nature, and there will be no formal comparisons made 
between treatment groups. 
4.5.5.6 Use of an “Efficacy Subset” of Patients 
The primary efficacy analysis will be performed on the Full Analysis Set, and the 
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4.5.5.7 Active-Control Studies Intended to Show Equivalence 
This study does not include an active-control product and is not intended to demonstrate 
equivalence between any two drug products. 
4.5.5.8 Examination of Subgroups 
The primary efficacy endpoint may be summarized by various Phase 2 study patient 
subgroups of interest based on baseline and demographic categories including age (<65 
years of age and ≥ 65 years of age), ECOG performance status at study entry (0 and 1), 
number of prior systemic therapies (1, 2, and 3 lines), gender, and race. Summaries by 
subgroup will only be produced if there are at least 6 patients in the category of interest. 
Additional subgroup analyses may be performed post-hoc, as appropriate. 
4.5.6 Plasma Concentrations 
Plasma concentration measurements will be summarized in a separate report and is 
outside the scope of this SAP. 
4.5.7 Pharmacokinetic Analysis 
Pharmacokinetic analysis will be summarized in a separate report and is outside the 
scope of this SAP. 
4.5.8 Pharmacodynamic Analysis 
Analysis of selected biomarkers (e.g., plasma EBV DNA levels) will be summarized in 
a separate report and is outside the scope of this SAP. 
4.6 
Safety Evaluation 
Safety analysis will be carried out for the Safety Analysis Population. Patients who do 
not complete the study, for whatever reason, will have all available data up until the 
time of termination included in the analysis. Safety analysis will be summarized by 
dosing regimen and overall patients combined. 
4.6.1 Extent of Exposure 
Extent of exposure to nanatinostat, valganciclovir, and pembrolizumab will be 
summarized for the Safety Analysis Population by dosing regimen. The duration of 
exposure for each drug will be presented in days and calculated as the date of last dose 
of study drug minus the date of first dose of study drug, plus one. Duration of exposure 
and total dose received will be summarized using descriptive statistics. Patients with 
dosing interruptions greater than 14 days will be flagged in associated patient data 
listings. 
4.6.2 Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those AEs with onset after 
the first dose of study drug or existing events that worsened after the first dose during 
the study. Treatment-emergent AEs will be summarized by phase and treatment group. 
Events reported with a partial onset date (e.g., month and year are reported but the day 


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is missing) will be considered to be treatment-emergent if it cannot be confirmed that 
the event onset was prior to the first dose of study drug based on the available date 
entries. 
Verbatim terms on case report forms will be mapped to preferred terms and system 
organ classes using MedDRA, version 27.1)   
Summaries that are displayed by system organ class and preferred terms will be ordered 
by descending incidence of system organ class and preferred term within each system 
organ class. Summaries displayed by preferred term only will be ordered by descending 
incidence of preferred term. Summaries of the following types will be presented: 
• Overall summary of number of unique TEAEs and patient incidence of TEAEs 
meeting various criteria; 
• Overall summary of number of unique treatment-emergent SAEs (TESAEs) and 
patient incidence of TESAEs meeting various criteria; 
• Patient incidence of TEAEs by MedDRA system organ class and preferred 
term; 
• Patient incidence of the most frequently occurring TEAEs (i.e., TEAEs 
occurring in ≥ 10% of the Safety Analysis Population) by MedDRA preferred 
term; 
• Patient incidence of TEAEs by Common Terminology Criteria for Adverse 
Events (CTCAE) grade, MedDRA system organ class, and preferred term; 
• Patient incidence of TEAEs by relationship to nanatinostat, MedDRA system 
organ class, and preferred term;  
• Patient incidence of TEAEs by relationship to valganciclovir, MedDRA system 
organ class, and preferred term; 
• Patient incidence of TEAEs by relationship to pembrolizumab, MedDRA 
system organ class, and preferred term; 
• Patient incidence of TEAEs related to nanatinostat by CTCAE grade, MedDRA 
system organ class and preferred term;  
• Patient incidence of TEAEs related to valganciclovir by CTCAE grade, 
MedDRA system organ class and preferred term;  
• Patient incidence of TEAEs related to nanatinostat or valganciclovir by CTCAE 
grade, MedDRA system organ class and preferred term;  
• Patient incidence of TEAEs related to pembrolizumab by CTCAE grade, 
MedDRA system organ class and preferred term; 


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• Patient incidence of the most frequently occurring TEAEs related to 
nanatinostat (i.e., related TEAEs occurring in ≥ 10% of the Safety Analysis 
Population) by MedDRA preferred term; 
• Patient incidence of the most frequently occurring TEAEs related to 
valganciclovir (i.e., related TEAEs occurring in ≥ 10% of the Safety Analysis 
Population) by MedDRA preferred term; 
• Patient incidence of the most frequently occurring TEAEs related to 
nanatinostat or valganciclovir (i.e., related TEAEs occurring in ≥ 10% of the 
Safety Analysis Population) by MedDRA preferred term; 
• Patient incidence of the most frequently occurring TEAEs related to 
pembrolizumab (i.e., related TEAEs occurring in ≥ 10% of the Safety Analysis 
Population) by MedDRA preferred term; 
• Patient incidence of TEAEs leading to dosing interruption of nanatinostat by 
MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs leading to dose reduction of nanatinostat by 
MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs leading to dosing interruption of valganciclovir by 
MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs leading to dose reduction of valganciclovir by 
MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs leading to dosing interruption of nanatinostat or 
valganciclovir by MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs leading to dose reduction of nanatinostat or 
valganciclovir by MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs leading to dosing interruption of pembrolizumab 
by MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs leading to dose reduction of pembrolizumab by 
MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs related to nanatinostat leading to discontinuation of 
study drug by MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs related to valganciclovir leading to discontinuation 
of study drug by MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs related to nanatinostat or valganciclovir leading to 
discontinuation of study drug by MedDRA system organ class and preferred 
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• Patient incidence of TEAEs related to pembrolizumab leading to 
discontinuation of study drug by MedDRA system organ class and preferred 
term; 
• Patient incidence of SAEs by MedDRA system organ class and preferred term; 
• Patient incidence of SAEs by CTCAE grade, MedDRA system organ class and 
preferred term; 
• Patient incidence of SARs (nanatinostat) by MedDRA system organ class and 
preferred term; 
• Patient incidence of SARs (valganciclovir) by MedDRA system organ class and 
preferred term; 
• Patient incidence of SARs (nanatinostat or valganciclovir) by MedDRA system 
organ class and preferred term; 
• Patient incidence of SARs (pembrolizumab) by MedDRA system organ class 
and preferred term; 
• Patient incidence of dose-limiting toxicities by MedDRA system organ class 
and preferred term; 
• Patient incidence of TEAEs leading to death by MedDRA system organ class 
and preferred term. 
Selected AE summaries may also be repeated for different age subgroups (<65 years 
old, ≥ 65 years old) if there are at least 5 patients enrolled in each age group. 
At each level of summarization (e.g., any AE, system organ class, and preferred term), 
patients experiencing more than one TEAE will be counted only once. In the summary 
of TEAEs by severity grade, patients will be counted once at the highest severity 
reported at each level of summarization; in the summary of TEAEs by relationship, 
patients will be counted once at the closest relationship to study drug. Related events 
include those reported as “Possibly Related” or “Definitely Related” to each study drug; 
events considered not related are those reported as “Not Related” to each study drug 
For summaries of treatment-related TEAEs by CTCAE grade, a column summarizing 
patients with at least one treatment-related Grade ≥3 TEAE will also be presented. 
Adverse event data will be presented in data listings by patient, treatment regimen, and 
event. Serious AEs and AEs leading to permanent discontinuation of the study drugs 
will also be presented in separate data listings. 
4.6.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
All deaths during the study, including the post treatment follow-up period, will be listed 
by patient, to include the primary cause of death. Serious TEAEs and other significant 
AEs, including those that led to withdrawal, interruption, or dose reduction of each 


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study drug and those classified as CTCAE Grade 3 or higher will be provided in 
separate patient data listings. 
4.6.4 Clinical Laboratory Evaluation 
All descriptive summaries of laboratory results will be based on data analyzed by the 
central or local laboratory and presented in Système International (SI) units, as 
suggested by the Center for Biologics Evaluation and Research and the Center for Drug 
Evaluation and Research Position on Use of SI Units for Lab Tests (Oct 2013). All data 
will be included in by-patient data listings. Laboratory measurements identified as 
abnormal (i.e., outside the normal range) will also be listed separately by patient, 
laboratory test, and unit. In addition, normal ranges provided by the central laboratory 
will be presented in a separate listing. 
Clinical laboratory measurements, including serum chemistry, hematology, and 
coagulation will be summarized by dosing regimen. Descriptive statistics will be 
presented for observed values and changes from baseline at each visit where parameters 
were scheduled to be collected per the clinical study protocol.  
Where applicable, laboratory results will be classified as “low,” “normal,” or “high” 
with respect to the parameter-specific reference ranges (i.e., below the lower limit of 
the normal range, within the normal range, or above the upper limit of the normal 
range). Three-by-three contingency tables will be presented for each laboratory 
parameter to summarize the shift from the baseline category to the worst post-baseline 
measurement, defined as the value numerically farthest outside of the normal range 
across all post-baseline visits through the end of the study. 
Summary results will include the count and percentage of patients within each shift 
category and treatment group. 
The cumulative number and percentage of patients with liver function test abnormalities 
meeting drug-induced liver injury (DILI) criteria will be summarized by dosing 
regimen. Patients meeting DILI criteria will also be presented in a patient data listing. 
In addition, creatinine clearance will be calculated by the Cockcroft-Gault formula. For 
males, the creatinine clearance in mL/min is calculated as [(140 - age) × weight (kg)] / 
[72 ×serum creatinine (mg/dL)]. For females, the creatinine clearance in mL/min is 
calculated as 0.85 × the male value. The mean change from baseline over time for 
creatinine and creatinine clearance will be presented graphically over time by dosing 
regimen and over all patients combined. 
Where applicable, hematology, chemistry, and coagulation results for select parameters 
will be assigned a toxicity grade based on the U.S. Department of Health and Human 
Services Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (27 
Nov 2017). If the quantitative criteria for grading are equivalent for two grades and the 
differentiation is described by clinical interventions, the clinical intervention 
component will not be considered and the highest CTCAE grade will be assigned. 
Similarly, death related to AE (i.e., Grade 5) cannot be determined with available 
laboratory-based data collection and, thus, will not be summarized as a category. 
Laboratory parameters that include multiple sets of criteria for each direction (e.g., 


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separate criteria for potassium measures to assess hyperkalemia and hypokalemia) will 
be summarized separately to reflect each set of criteria. 
Five-by-five contingency tables will be presented for laboratory tests where toxicity 
grading can be applied, to summarize the shift from the baseline grade to the worst post-
baseline grade. Grades will be presented as none (Grade 0; i.e., measurements did not 
meet any CTCAE criteria for Grades 1 through 4), mild (Grade 1), moderate (Grade 2), 
severe (Grade 3), or life-threatening (Grade 4). Summary results will include the count 
and percentage of patients within each shift category. 
4.6.5 Vital Signs, Physical Findings, and Other Observations Related to Safety 
4.6.5.1 Vital Signs 
Descriptive statistics for vital sign parameter measurements will be presented for results 
and change from baseline at each visit where parameters were scheduled to be collected. 
4.6.5.2 12-Lead Electrocardiogram 
Descriptive statistics will be presented for observed values and changes from baseline 
at each visit where parameters were scheduled to be collected. All 12-lead ECGs will 
be conducted in triplicate. The average of the triplicate ECG interval parameters will 
be summarized by treatment regimen. 
Twelve-lead ECGs will be classified by the investigator as “normal,” “abnormal, not 
clinically significant,” or “abnormal, clinically significant.” The worst classification for 
each set of triplicate 12-lead ECGs will be used for analysis. Three-by-three 
contingency tables will be presented to summarize the shift from the baseline category 
to the worst post-baseline value. Summary results will include the count and percentage 
of patients within each shift category and treatment group. 
Prolonged QTc intervals will be summarized as QTc measurements (msec) that are 
>450, >480, and >500 msec averaged over each set of triplicate 12-lead ECGs at each 
visit where ECG is routinely collected per the clinical study protocol. Change from 
baseline categories will also be summarized for measurements that represent a change 
>30 or >60 msec relative to the baseline value. Summary results will include the 
percentage of patients within each category and treatment group. 
4.6.5.3 ECOG Performance Status 
Performance status will be assessed using the ECOG scale. Descriptive statistics will 
be presented for observed values and changes from baseline at each visit where 
assessments were scheduled to be collected per the clinical study protocol. Results will 
be presented in patient data listings. 
4.6.5.4 Prior and Concomitant Medications 
Medications will be coded using the latest version of the World Health Organization 
Drug Dictionary Enhanced (WHODDE). Medications entered on the eCRF will be 
mapped to Anatomical Therapeutic Chemical (ATC) drug class (level 4) and drug 
name.  


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VT3996-301 
Version 1.0; 22 November 2024 
 
 
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Page 31 of 32 
 
Prior and concomitant medications will be summarized separately, and the 
categorization of each medication will be determined programmatically based on 
medication start and end dates. A prior medication is defined as any medication 
administered prior to the date of the first dose of study drug with an end date prior to 
date of first dose of study drug. A concomitant medication is defined as any medication 
administered on or after the date of the first dose of study drug through 90 days after 
the last dose of study drugs. Any medication whose start date/time cannot be 
determined due to partial or missing medication start and/or end dates will be 
considered a concomitant medication. 
For both prior and concomitant medications summaries, the number and percentage of 
patients receiving any medication will be summarized by cohort, as will the number 
and percentage receiving any medication by ATC drug class and generic drug name. 
Prior medications will also be summarized over all patients combined. Patients 
reporting use of more than one medication at each level of summarization (any 
medication received, ATC class, and generic drug name) will be counted only once. 
ATC class terms will be displayed by descending order of incidence, as will generic 
drug names within each ATC class. The study phase during which each medication was 
received (e.g., prior, concomitant, or both) will be presented on the listing of prior and 
concomitant medications. 
4.7 
Determination of Sample Size 
For Phase 1b, approximately 27 to 60 patients will be enrolled for up to 13 dose 
escalations of nanatinostat and valganciclovir and up to 10 patients in the exploratory 
proof-of-concept cohort of other EBV+ solid tumors. 
Assuming the pembrolizumab ORR in RM-NPC patients in this study will be around 
25%, a sample size of 30 would provide a 95% confidence interval (CI) that excludes 
10% as the lower ORR. A total of 60 patients (30 per randomized treatment group) is 
sufficient to provide adequate estimates of tumor response for each group and to 
provide initial indicators of safety and tolerability. These estimates will be utilized in 
planning for future studies in this patient population. The sample size of N=30 per 
randomized treatment group was determined from nQuery Advisor tool 
(www.statsols.com; Statistical Solutions, Ltd, Cork, Ireland). 
4.8 
Changes in the Conduct of the Study or Planned Analyses 
Enrollment into Study VT3996-301 was discontinued after completion of the final 
Phase 1b dose level for business reasons unrelated to clinical factors or safety concerns. 
Patients who were receiving study drugs at the time of the study discontinuation notice 
continued to remain on study treatment as long as they derived clinical benefit, and they 
were to remain on study including and up to their final Safety Follow-Up Visit. Patients 
who were in the Long-Term Follow-Up period transitioned to End of Study. Reporting 
of serious adverse events continued per clinical study protocol Section 8.2.1.  
Consequently, study conduct did not proceed to Phase 2 after the recommended Phase 
2 dose of nanatinostat and valganciclovir was determined, and thus the Phase 2 study-
specific analyses described in this SAP will not be performed. The study will be 
considered complete when all patients have completed safety follow-up assessments.  


Viracta Therapeutics, Inc. 
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VT3996-301 
Version 1.0; 22 November 2024 
 
 
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Page 32 of 32 
 
The only changes to the study conduct or planned analyses identified within the 
development of this SAP relative to the descriptions provided within the clinical study 
protocol are described below: 
• Section 2 of the clinical study protocol only specified ORR as a primary efficacy 
endpoint for Phase 2, while ORR was added as a primary efficacy endpoint for 
Phase 1b in this SAP. 
• Section 9.1 of the clinical study protocol states that all data will be summarized 
by dosing regimen, disease subtype, and overall, but data summaries by disease 
subtype are unnecessary since Phase 1b only enrolled patients with RM-NPC, 
and the study did not proceed to Phase 2. 
 
5. 
REFERENCE LIST 
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Biologics Evaluation and Research (CBER) (US). Guidance for industry: 
Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and 
Biologics. April 2015. Available from: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/clinical-trial-endpoints-approval-non-
small-cell-lung-cancer-drugs-and-biologics 
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Biologics Evaluation and Research (CBER) (US). Guidance for industry: 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. December 
2018. Available from: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/clinical-trial-endpoints-approval-cancer-drugs-and-biologics 
ICH guideline Statistical Principles for Clinical Trials (E9) (1998) and Statistical 
Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in 
Clinical Trials (E9[R1], Rev 1) (2021).  
ICH in Appendix 7 of the Electronic Common Technical Document Specification (Apr 
2003) 
ICH guideline Structure and Content of Clinical Study Reports – Questions and 
Answers (E3[R1], 2013)