Clinical trial NCT05011058
Conditions: Epstein-Barr Virus Associated Lymphoma EBV-Positive DLBCL, NOS EBV-Related Non-Hodgkin Lymphoma EBV Related PTCL, NOS EBV-Related Hodgkin Lymphoma EBV-Related PTLD EBV-Related Lymphoproliferative Disorder
Keywords: Epstein-Barr virus (EBV) EBV-positive lymphomas EBV-positive T-cell lymphoma EBV-positive Hodgkin lymphoma EBV-positive diffuse large B-cell lymphoma (DLBCL) EBV-positive extranodal natural killer/T-cell lymphoma EBV-positive peripheral T-cell lymphoma (PTCL) EBV-positive post-transplant lymphoproliferative disorders
Sponsor: Viracta Therapeutics, Inc.
Start date: 2021-05-28; Completion date: 2025-01-31
Enrollment: 102 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 2 study to evaluate the efficacy of nanatinostat in combination with valganciclovir in patients with relapsed/refractory EBV-positive lymphomas

Detailed description:
Patients with EBV-associated lymphomas have inferior outcomes with standard-of-care therapies compared to those with EBV-negative disease. Nanatinostat is a selective class I HDAC inhibitor which induces EBV lytic phase protein generation, activating (val)ganciclovir to its cytotoxic form. This open-label, multicenter, multinational, single-arm, Phase 2 basket study employs a Simon's 2-stage design to allow termination of enrollment into cohorts where treatment appears futile, and will include the following cohorts of patients with EBV+ relapsed/refractory lymphomas:

1. Diffuse large B-cell lymphoma (DLBCL)
2. Extranodal natural killer/T-cell lymphoma (ENKTL)
3. Peripheral T-cell lymphoma (PTCL), including angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (PTCL-NOS)
4. Hodgkin lymphoma (HL)
5. Post-transplant lymphoproliferative disorders (PTLD)
6. Human immunodeficiency virus (HIV)-associated lymphomas (HIV-L)
7. EBV+ lymphomas other than the above

The study was terminated prematurely and did not reach its target enrollment.

Arms: arm 1: Patients will receive nanatinostat 20 mg orally once daily, days 1-4 per week with valganciclovir 900 mg orally once daily.

Up to 10 PTCL patients will receive nanatinostat 20 mg orally once daily, days 1-4 per week.
Interventions: intervention 1: Nanatinostat in combination with valganciclovir
Intervention descriptions: intervention 1: Drug: Nanatinostat, 20 mg orally once daily, 4 days per week in 28 day cycles

Drug: Valganciclovir, 900 mg orally once daily in 28 day cycles

Protocol documents:
Prot_000.pdf: 
Viracta Therapeutics, Inc. 
Clinical Study Protocol Amendment 5.1 
Nanatinostat and Valganciclovir 
VT3996-202 (NAVAL-1) 
Version 6.1 (26 October 2023) 
CONFIDENTIAL 
Page 1 of 100 
 
An Open-Label, Phase 2 Trial of Nanatinostat in Combination with 
Valganciclovir in Patients with Epstein-Barr Virus-Positive (EBV+) 
Relapsed/Refractory Lymphomas (NAVAL-1) 
Protocol Number: VT3996-202 
Sponsor Name and Legal 
Registered Address:
Viracta Therapeutics, Inc. 
2533 S. Coast Hwy 101 
Suite 210 
Cardiff, CA 92007 
(858) 400-8470 
Sponsor Contact:
Donald Strickland, MD 
Vice President, Clinical Development & Medical Director 
DStrickland@Viracta.com 
Investigational Drugs:
Nanatinostat (Nstat), VRx-3996 
Valganciclovir (VGCV) 
Short Title:
Nanatinostat and Valganciclovir in R/R EBV+ Lymphoma 
(“NAVAL-1”) 
Regulatory Agency 
Identifying Number(s):
IND Number 132679 
EUDRA CT Number: 2020-005197-10 
Original Protocol:
Version 1.0, 05 February 2021 
Amendment 1:
Version 2.0, 03 April 2021  
Amendment 2:
Version 3.0, 22 April 2021 
Amendment 3:
Version 4.0, 16 March 2022 
Amendment 3.1:
Version 4.1, 23 June 2022 
Amendment 4.1:
Version 5.1, 27 March 2023 
Amendment 5.1:
Version 6.1, 26 October 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. 
(NCT05011058)


Viracta Therapeutics, lnc. 
'-lanatinoslat and Valganciclovir 
Clinical Study Protocol ,\mendment 5.1 
VT3996-202 (Ni\ VAL-1) 
SPONSOR'S PROTOCOL SIGNATURE PAGE 
By signing below, the Sponsor declares that this study will be conducted in accordance 
with current lnternational Council for Harmonisation (ICH) Guidelines, Good Clinical Practice 
(GCP) standards, the Declaration of Helsinki and local ethical and legal requirements. 
This protocol has been reviewed and approved by: 
Darrel P. Cohen. MD. PhD 
ChiefMedical Officer 
Susan Spruill, MS, PStat® 
Statistician 
Datt:: 
Date 
-~ 
~{!f dfJ:J3,,_ 
Date 
Version 6.l (26 Octob.::r 2023) 
CONFIDENTfr\l , 
Page 2 of 100 


Viracta Therapeutics, Inc. 
Clinical Study Protocol Amendment 5.1 
Nanatinostat and Valganciclovir 
VT3996-202 (NAVAL-1) 
Version 6.1 (26 October 2023) 
CONFIDENTIAL 
Page 3 of 100 
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 me 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Viracta Therapeutics, Inc. 
Clinical Study Protocol Amendment 5.1 
Nanatinostat and Valganciclovir 
VT3996-202 (NAVAL-1) 
Version 6.1 (26 October 2023) 
CONFIDENTIAL 
Page 4 of 100 
PROTOCOL SYNOPSIS 
Protocol Number 
VT3996-202 
Study Title 
An Open-Label, Phase 2 Trial of Nanatinostat in Combination with Valganciclovir 
in Patients with Epstein-Barr Virus-Positive (EBV+) Relapsed/Refractory Lymphomas 
(NAVAL-1) 
Sponsor  
Viracta Therapeutics, Inc. 
Investigational 
Drugs 
Nanatinostat (Nstat, VRx-3996) 
Valganciclovir (VGCV) 
Study Phase 
Phase 2 
Objectives 
(Primary 
and Secondary) 
Primary: 
To evaluate the anti-tumor activity of the combination treatment of nanatinostat (Nstat) 
with valganciclovir (VGCV) based on objective tumor response rates. 
Secondary: 
 To determine the duration of tumor control. 
 To determine survival outcomes. 
 To describe the safety profile of the combination treatment of Nstat with VGCV. 
 To generate pharmacokinetic (PK) data with the intended commercial dose and 
administration of Nstat. 
Endpoints 
(Primary 
and Secondary) 
Primary: 
Objective response rate (ORR) as assessed by an Independent Review Committee (IRC) – 
defined as the proportion of patients who achieve a complete response (CR) or partial 
response (PR) using the 2007 International Working Group (IWG) criteria (Cheson 2007). 
Secondary: 
 Duration of response (DOR) – defined as the interval from date of first observed CR 
or PR to the date of disease progression, death due to any cause, or last adequate 
(radiographic) response assessment. 
 Time to next anti-lymphoma treatment (TTNLT) – defined as the interval from the start 
of study drug treatment to date of next anti-lymphoma 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. 
 Time to progression (TTP) – defined as the interval from the start of study drug 
treatment to date of disease progression. 
 Overall survival (OS) – defined as the interval from the start of study drug treatment to 
date of death, for any reason. 
 Incidence and severity of treatment-emergent adverse events (TEAEs). Adverse events 
(AEs) will be graded according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
 Pharmacokinetic parameters (eg, time to maximum plasma concentration [tmax], 
maximum plasma concentration [Cmax], area under the plasma concentration-time curve 
[AUC]). 
Study Design 
This is an open-label, multicenter, multinational single-arm, Phase 2 basket design study, 
utilizing Simon’s 2-stage design options for discontinuing enrollment into each cohort 
where treatment appears to be futile (Simon 1989). The study will include 7 cohorts of 
patients with the following EBV+ relapsed/refractory lymphomas: 


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 
Cohort 1: EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, 
NOS) 
 
Cohort 2: Extranodal NK/T-cell lymphoma (ENKTL) 
 
Cohort 3: Peripheral T-cell lymphoma (PTCL), including PTCL-NOS 
and angioimmunoblastic T-cell lymphoma (AITL): 
 
Cohort 3a: Nanatinostat monotherapy 
 
Cohort 3b: Nanatinostat + valganciclovir 
 
Cohort 4: Hodgkin lymphoma (HL) 
 
Cohort 5: Post-transplant lymphoproliferative disorder (PTLD) 
 
Cohort 6: Lymphomas associated with human immunodeficiency virus (HIV) 
infection (HIV-L): Plasmablastic, Burkitt, Hodgkin, and DLBCL 
 
Cohort 7: EBV+ lymphomas other than Cohorts 1, 3, 4, 5, and 6 above (Cohort 7 
will not enroll patients in France) 
In Stage 1, 6 cohorts (Cohorts 1, 2, 3b, 4, 5, and 6) will enroll up to 10 patients each. Any 
cohort that fails to enroll any patients within 1 year from the date the first patient is 
enrolled in the study will be considered for termination of enrollment. Enrollment in 
Cohorts 2, 4, and 6 has been closed as of 17 October 2023, 24 August 2023, and 24 
August 2023, respectively. Patients currently enrolled in these cohorts may continue to 
receive study treatment per protocol until which time treatment discontinuation is required 
as defined in Section 7.2.3. 
All cohorts that have a response in 2 or more patients in Stage 1 will continue to enroll 
patients in Stage 2, for a total of 21 patients in each cohort. If ≥7 responses are observed 
in the initial 21 patients in any cohort, then enrollment will be expanded to include up to 
120 additional patients in that cohort (N=141), with the possibility of performing an 
interim efficacy analysis in that cohort to be described in the statistical analysis plan. 
Cohort 3a will not enroll beyond the initial 10 patients, regardless of the number of 
responders in Stage 1.  
To evaluate the activity of single-agent nanatinostat, the first 20 patients enrolled with 
PTCL will be randomized 1:1 to either nanatinostat monotherapy (20 mg PO once daily 
on Days 1 to 4 per week in Cohort 3a) or nanatinostat plus valganciclovir (in Cohort 3b). 
Following a disease response assessment at 6 weeks, patients in Cohort 3a with a CR or 
PR will continue nanatinostat monotherapy. Those in Cohort 3a with stable disease at 
6 weeks or disease progression at any time (confirmed by CT or MRI) will have the 
option to cross over to combination therapy for the remainder of the study. Patients must 
complete the End of Monotherapy Disease assessment and qualify (labs, no sign of CNS 
disease progression, Eastern Cooperative Oncology Group [ECOG]) prior to beginning 
Cycle 1 Day 1 of the nanatinostat plus valganciclovir combination therapy. 
Cohort 7 will be closed to enrollment when all other cohorts are closed, regardless of the 
number of patients recruited at that time and will not be subject to the decision criteria of 
the Simon’s 2-stage design. 
It is thus estimated that up to 486 patients in Cohorts 1 to 6 may be enrolled for 
combination therapy, of which approximately 60 would be enrolled in Stage 1 and 66 
would be enrolled in Stage 2, and up to 360 would be enrolled into the post-Stage 2 
expansion cohorts. Additional patients (n=10) with PTCL will be enrolled in Cohort 3a 
for nanatinostat monotherapy, and patients with lymphoma subtypes other than those 
assigned to Cohorts 1, 3, 4, 5, and 6 may be enrolled into Cohort 7 (with the exception of 
France; see above).  
If 10 patients of a given lymphoma subtype are enrolled into Cohort 7, then the Simon’s 
decision criteria will be applied to determine whether or not to add patients in Stage 2 for 
that subtype. If none of the subtypes represented in Cohort 7 enrolls at least 10 patients, 


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efficacy data collected on those patients will be listed, but not summarized by group. All 
patients will be summarized for safety, regardless of decision to discontinue enrollment 
into any cohort. Patients enrolled in Cohorts 1 to 7 (with the exception of Cohort 3a), and 
patients crossed over from Cohort 3a will receive intermittent dosing of nanatinostat and 
continuous valganciclovir in 28-day cycles as follows: 
1. Nanatinostat 20 mg orally once daily on Days 1 to 4 per week (ie, 4 days on, 
3 days off) 
2. Valganciclovir 900 mg orally once daily. Patients with a CrCl 50-59 mL/min at 
study entry will receive valganciclovir 450 mg orally once daily as per Table 4. 
Patients who develop disease progression but, in the opinion of the Investigator, would 
still benefit from continuing study drug may continue treatment with nanatinostat and 
valganciclovir after agreement with the Sponsor, provided that they are i) asymptomatic 
from or have no overt signs of disease progression and ii) have a performance status of 
0-1. It is recommended to perform an interval follow-up radiologic disease assessment 
before the next scheduled time point. Such patients will be recorded as having had a PFS 
event. 
All patients will be monitored at weekly intervals through the first cycle of treatment, and 
then at 2-week intervals thereafter. Tumor response will be evaluated after every 2 cycles 
× 3, and after every 3 cycles thereafter. The responses will be assessed by both the 
Investigator and an IRC. 
The PK parameters of nanatinostat and its metabolites and ganciclovir (primary active 
hydrolytic product of valganciclovir) will be evaluated for patients enrolled in Stage 1 and 
sparse sampling will be collected during the Stage 2 part of the study at selected sites. 
Enrolled patients will receive treatment until disease progression (per Investigator 
assessment), unacceptable toxicity, withdrawal of consent, Investigator’s discretion, 
death, initiation of new antineoplastic therapy, discontinuation from the study for any 
reason, or study termination by the Sponsor. Patients receiving nanatinostat monotherapy 
who have disease progression will be offered the option to receive combination therapy 
with valganciclovir. All antineoplastic therapies given after the last dose of study drug 
(and time to next therapy) will be recorded in the electronic case report form (eCRF) 
(unless the patient withdraws consent or is lost to follow-up). Patients will be followed for 
survival regardless of treatment discontinuation reason (except if consent is withdrawn or 
patient is lost to follow-up). 
Population  
Patients with EBV+ relapsed/refractory lymphoma following prior systemic therapy(ies) 
with no available standard therapies as per the eligibility criteria. 
Inclusion Criteria 
1. Adult patients age ≥18 years or as permitted by applicable local regulations at the 
time of providing informed consent. Patients must be able to swallow whole tablets. 
a. For patients with PTLD: Age ≥12 years and weighing ≥40 kg.  
2. Histologically confirmed (by 2016 WHO classification (Swerdlow 2016)) EBV+ 
lymphoma* per local laboratory by EBER-ISH (or for PTLD only, by LMP-1 
immunohistochemistry) on a representative disease specimen. Any degree of EBER-
ISH or LMP-1 positivity is considered to be eligible (ie, there is no cut-off value for 
% positive cells).  
* 
Tumor cells are EBV+, with the exception of AITL, which is characterized by 
EBV-negative neoplastic T cells and EBV+ associated B-lineage cells (of 
immunoblastic/plasmablastic immunophenotype)  
a. 
A recent formalin-fixed paraffin-embedded (FFPE) specimen must be available 
for retrospective central review of diagnosis. FFPE tissue blocks are preferred; if 
a tissue block is not available, at least 15 unstained slides or freshly cut serial 


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sections (3−5 μm in thickness), preferably with an accompanying block punch 
will be accepted. The specifications for the age of the tumor samples are: 
 For patients with ENKTL, AITL, PTLD and HIV-L: preferably ≤1 year 
old. For tumor specimens >1 year old, please consult the Medical Monitor to 
discuss eligibility. 
 For patients with all other lymphoma subtypes: preferably ≤6 months old. 
For tumor specimens >6 months old, please consult the Medical Monitor to 
discuss eligibility. 
3. For patients with EBV+ DLBCL, NOS: Relapsed or refractory disease following 1 
or more prior systemic therapy(ies) with curative intent. Patients must have received 
at least one course of an anti-CD20 immunotherapy such as rituximab, and at least 
one course of anthracycline-based chemotherapy (unless contraindicated, in which 
case, an accepted anthracycline-free alternative for DLBCL was given).  
4. For patients with ENKTL: Relapsed or refractory disease following 1 or more prior 
systemic therapy(ies) with a curative intent. Patients must have failed an 
asparaginase-containing regimen. 
5. For patients with PTCL (PTCL, NOS and AITL): Relapsed or refractory disease 
following 2 or more prior systemic therapy(ies) with a curative intent. 
6. For patients with HL: Patients must have received at least one course of 
anthracycline-based chemotherapy (unless contraindicated, in which case, an accepted 
anthracycline-free alternative for HL was given). Patients with relapsed/refractory 
classical Hodgkin lymphoma(cHL) should have failed or be ineligible for an anti-PD-
1 agent (eg, pembrolizumab, nivolumab) and CD30-directed therapy (ie, brentuximab 
vedotin). 
7. For patients with PTLD: Patients with relapsed or refractory EBV+ PTLD who have 
received at least one prior therapy must have received at least one course of an anti-
CD20 immunotherapy such as rituximab. For solid-organ transplant (SOT) patients, 
prior therapy also includes chemotherapy, administered concurrently or sequentially, 
unless chemotherapy is inappropriate. 
8. For patients with the following lymphomas associated with HIV infection: 
plasmablastic, Burkitt, Hodgkin, and DLBCL. 
a. 
Prior therapy requirements for DLBCL and HL are specified in inclusion 
criteria 3 and 6. 
b. France only: For Burkitt and plasmablastic lymphoma - Patients must have 
received a regimen such as EPOCH (etoposide, prednisone, vincristine, 
cyclophosphamide, hydroxydaunorubicin), CODOX-M (original or 
modified; cyclophosphamide, vincristine, doxorubicin, and high-dose 
methotrexate) or Hyper-CVAD (cyclophosphamide, vincristine, 
doxorubicin, and dexamethasone), including CNS prophylaxis or therapy. 
9. Patients with HIV-L should meet the following criteria for inclusion:  
a. 
Currently on a stable regimen of anti-retroviral therapy (ART) 
b. Compliant with ART and follow-up according to the investigator  
c. 
No evidence of a worsening HIV viral load (as assessed by HIV quantitative 
polymerase chain reaction [qPCR]) 
d. CD4 count >50 cells/mm3 
10. No available standard therapies in the opinion of the Investigator. 
11. Not eligible for high-dose chemotherapy with allogeneic/autologous stem cell 
transplantation or CAR-T therapy at the time of study entry. 
12. Presence of at least one bi-dimensionally measurable lesion by computed tomography 
(CT) or magnetic resonance imaging (MRI): longest diameter (LDi) >1.5 cm for 
a nodal lesion; LDi >1.0 cm for an extranodal lesion within 28 days prior to start 
of treatment.  


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13. Able to provide a prior core or excisional biopsy for biomarker analysis at screening. 
If no tissue is available, then a new biopsy must be performed. 
14. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
15. All acute toxic effects of any prior anti-tumor therapy resolved to Grade ≤1 before 
initiation of study treatment (excluding alopecia and stable Grade 2 sensory 
neuropathy). 
16. Required baseline laboratory data (within 2 weeks prior to start of study drug 
administration) as shown in the table below: 
System 
Laboratory Value 
Hematology 
 
Absolute neutrophil count (ANC) 
≥1000/mm3 (no growth factor support within 
14 days) 
Platelets 
≥50,000/mm3 (no platelet transfusion within 
14 days) 
Hemoglobin 
≥8.0 g/dL (no red cell transfusion within 21 
days) 
Renal 
 
Creatinine clearance 
≥50 mL/min (Cockcroft-Gault) 
Hepatic 
 
Total bilirubin 
≤2.0 × upper limit of normal (ULN) 
(except patients with documented Gilbert’s 
syndrome [<3.5 × ULN]) 
Aspartate aminotransferase 
(AST [SGOT]) and alanine 
aminotransferase (ALT [SGPT]) 
≤3.0 × ULN (or ≤5.0 × ULN if liver 
involvement by primary disease)  
Coagulation 
 
International normalized ratio 
(INR) 
Activated partial thromboplastin 
time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy (as long as INR 
or aPTT are within the therapeutic range 
of intended use of anticoagulants) 
17. Life expectancy >3 months. 
18. Women of childbearing potential (ie, reached menarche, and not premenarchal or 
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 true abstinence from heterosexual intercourse: When this is in line 
with the preferred and usual lifestyle of the patient (Periodic abstinence [eg, 
calendar, ovulation, symptothermal, post-ovulation methods], declaration of 
abstinence for the duration of exposure to the investigational medicinal 
product [IMP], or the withdrawal method are not acceptable forms of 
contraception). Otherwise, begin a highly effective method of birth control 
with a Pearl-Index <1%, without interruption, throughout the study dosing 
period and for 6 months after the last dose of nanatinostat. 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 (oral, intravaginal, 
transdermal). Note: Although the potential for drug interactions and risk 
of venous thromboembolism is low (see Section 5.5.2.3), the use of an 
alternative method of contraception is recommended.


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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. 
19. Male patients must agree to use condoms during intercourse throughout the study 
dosing period and for 90 days after the last dose of nanatinostat. Female partners of 
male patients participating in the study are to consider the use of effective methods of 
contraception while their partner is treated on study and for 90 days after the last 
administration of nanatinostat. 
20. The patient is willing and able to provide informed consent and comply with the 
protocol. Assent must be obtained for adolescent patients <18 years old, or as 
permitted by applicable local regulations, and a parent/guardian must provide written 
consent. 
Exclusion Criteria 
1. Presence or history of central nervous system (CNS) involvement by lymphoma. 
2. Systemic anticancer therapy within 21 days prior to Cycle 1 Day 1 dosing. 
3. Antibody (anticancer) agents within 28 days of Cycle 1 Day 1 dosing. 
4. Less than 14 days from prior local site radiation therapy. 
5. Less than 60 days from prior autologous hematopoietic stem cell or solid organ 
transplant. 
6. Less than 21 days from prior CAR-T therapy (any AEs must be Grade 1 or less to be 
eligible for enrollment)  
7. Less than 90 days from prior allogeneic transplant. 
8. Receiving systemic corticosteroids during the last week prior to Cycle 1 Day 1, 
unless administered at a dose equivalent to ≤20 mg/day of prednisone. 
9. For recipients of prior allogeneic HSCT: Receiving systemic immunosuppressants as 
either prophylaxis or treatment for graft-versus-host disease (GvHD).  
10. Major surgery within 28 days within the first dose of study drug. In the case of recent 
major surgery, the patient must have recovered adequately from the procedure and/or 
any complications prior to starting study treatment. 
 
Note: Minor surgery (eg, minor biopsy of extracranial site, central venous 
catheter placement, shunt revision) is permitted within 3 weeks prior to 
enrollment. 
11. 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. 
12. History of other malignancy that could affect compliance with the protocol or 
interpretation of results. Patients with any malignancy appropriately treated with 
curative intent and the malignancy has been in remission without treatment for 
2 years prior to enrollment are eligible. Also eligible are the following: 
 
Curatively treated: 
i. 
Basal cell, squamous cell carcinoma, or melanoma of the skin (at any 
time prior to the study). 
ii. 
Cervical carcinoma in situ (at any time prior to the study). 
 
Low-grade early-stage prostate cancer (Gleason score 6 or below, stage 1 or 2) 
with no requirement for therapy at any time prior to study, or previously fully 
resected. 


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13. Inability to take oral medication, malabsorption syndrome or any other 
gastrointestinal condition (nausea, diarrhea, vomiting) that may impact the absorption 
of nanatinostat and valganciclovir. 
14. Active GvHD. 
15. Positive hepatitis B core antibody or surface antigen unless DNA qPCR is negative, 
and patient will be receiving prophylaxis for reactivation. 
16. Positive hepatitis C virus on RNA polymerase chain reaction (PCR). 
17. Known SARS-CoV-2 positivity by any testing method at time of screening. Patients 
with a positive PCR test should only be enrolled if ≥10 days have passed since 
COVID symptoms first appeared and they have recovered from symptoms or have 
mild symptoms. 
18. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to valganciclovir or nanatinostat. 
19. Active infection requiring systemic therapy (excluding viral upper respiratory tract 
infections). Patients may be receiving prophylactic antiviral, antifungal or 
antibacterial therapies at the discretion of the Investigator. 
20. 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). 
21. Receiving concomitant drugs that are inhibitors of P-glycoprotein (P-gp) and/or 
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). 
22. Psychiatric illness/social situations/substance abuse disorder that would interfere with 
compliance with study requirements. 
23. Has a prior or ongoing clinically significant illness such as New York Heart 
Association Class III or IV cardiac disease, myocardial infarction within the last 
6 months, unstable arrhythmias, or unstable angina, or pulmonary disease), 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 compliance with 
the protocol, or is not in the best interest of the patient to participate. 
24. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening visit through 6 months 
after the last dose of nanatinostat. 
Sample Size 
Calculations and 
Hypothesis Testing 
This multinational, multicenter study will employ a Simon’s 2-stage design to allow 
termination of enrollment into cohorts where treatment appears futile (Simon 1989). The 
decision to transition from Stage 1 to Stage 2 is dependent on the assumption of ORR: 
ORR ≤10% (poor response); ORR ≥35% (good response). The sample size estimation 
uses 1-sided alpha = 0.05 and targets statistical power = 85%. 
Using the Simon’s 2-stage design approach, the null hypothesis that the true response rate 
is 10% will be tested against a one-sided alternative. In the first stage, up to 10 patients 
will be accrued in each cohort. If there are 1 or fewer responses, the cohort will be 
discontinued. If the cohort fails to enroll any patients within 1 year from the enrollment of 
the first patient, the cohort will be considered for termination of enrollment. Otherwise, if 
at least 2 patients in a cohort respond, additional patients will be accrued for a total of 21 
in the cohort. The null hypothesis that the true response rate is 10% will be rejected in 
each cohort where 5 or more responses are observed in 21 patients. This design yields a 
type I error rate of 0.0440 and power of 86.2% within each cohort where the true response 
rate is 35%. 
If 10 patients of a given lymphoma subtype are enrolled into Cohort 7, then the Simon’s 
decision criteria will be applied to determine whether or not to add patients in Stage 2 for 


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that subtype. If none of the subtypes represented in Cohort 7 enrolls at least 10 patients, 
efficacy data collected on those patients will be listed, but not summarized by group. All 
patients will be summarized for safety, regardless of the decision to discontinue 
enrollment into any cohort. 
If at the end of Stage 2 there are at least 7 responders observed in the initial 21 patients in 
any cohort (ORR≥33.3%), enrollment will be expanded to include up to 120 additional 
patients in that cohort (N=141), with the possibility of performing an interim analysis in 
that cohort to be described in the statistical analysis plan. The maximum sample size 
estimated for the expanded cohort is dependent on the assumption of ORR ≥35% with the 
lower bound of its 95% CI excluding ORR 25%. 
Study Treatments, 
Dose, Route of 
Administration, 
Treatment 
Regimen 
Patients enrolled in Cohorts 1 to 7 (with the exception of Cohort 3a), and patients crossed 
over from Cohort 3a will receive intermittent dosing of nanatinostat and continuous 
valganciclovir in 28-day cycles as follows: 
1. Nanatinostat 20 mg orally once daily on Days 1 to 4 per week (ie, 4 days on, 3 days 
off). 
2. Valganciclovir 900 mg orally once daily for patients ≥17 years of age. Patients with a 
CrCl 50-59 mL/min at study entry will receive valganciclovir 450 mg orally once 
daily as per Table 4. The daily dose of valganciclovir for patients <17 years of age is 
based on body surface area (BSA) and CrCl derived from a modified Schwartz 
formula (see Section 5.2.2). 
Nanatinostat and valganciclovir should be taken at the same time following a light meal. 
On days with pre- and post-dose PK assessments, patients will be asked to consume one 
can of Ensure® or equivalent, prior to the dose of study drugs (within 30 minutes). 
Alternatively, patients may consume a light breakfast in place of consuming an Ensure 
equivalent and should start the meal 30 minutes before administration study drugs. 
For Cohorts 1, 2, 3b, 4, 5, 6, and 7, patients will receive nanatinostat/valganciclovir 
(nanatinostat 20 mg orally once daily on Days 1 to 4 per week and valganciclovir 900 mg 
orally once daily) continuously for 28-day treatment cycles. Patients with a CrCl 
50-59 mL/min at study entry will receive valganciclovir 450 mg orally once daily as per 
Table 4. During treatment Cycle 1, visits will occur on Days 1, 8, 15, and 22. Starting at 
Cycle 2, visits will occur on Days 1 and 15. Each scheduled clinic visit has an allowable 
±3-day window. 
For Cohort 3a, the PTCL patients randomized to monotherapy will begin with 6 weeks of 
nanatinostat monotherapy (20 mg orally once daily on Days 1 to 4 per week) with visits 
on Days 1, 15, 29, and 43. Each scheduled clinic visit has an allowable ±3-day window. If 
a patient has stable or progressive disease at the Day 43 visit (or progressive disease prior 
to Day 43), the patient will be offered the option to switch to nanatinostat/valganciclovir 
combination and follow the 28-day treatment cycles as described above. Patients must 
complete the End of Monotherapy Disease assessment and qualify (labs, no sign of CNS 
disease progression, ECOG) prior to beginning Cycle 1 Day 1 of the 
nanatinostat/valganciclovir combination therapy. If a patient has a response (complete or 
partial response) to nanatinostat monotherapy at the Day 43 visit, the patient will continue 
monotherapy treatment.  
Efficacy 
Assessment(s) 
Disease response assessments will be made every 8 weeks until 24 weeks, and then every 
12 weeks for the remainder of the study, according to the revised response criteria for 
malignant lymphoma based on the IWG-NHL guidelines (Cheson 2007). A scan to 
confirm an unconfirmed PR or unconfirmed CR ≥4 weeks later may also be performed. 
18FDG-PET/CT and a diagnostic contrast-enhanced CT scan (or MRI if a CT with contrast 
is contraindicated) will be performed at baseline, and for the 8-week and 16-week tumor 
assessments. Subsequent evaluations will be by CT with contrast (without PET) or MRI 
only. Patients with FDG-avid lymphoma at baseline may have an 18FDG-PET/CT 
performed to evaluate a possible CR or PR after Week 16 (unless prohibited by local 
practice) and may use a diagnostic contrast-enhanced CT for follow-up once a complete 


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metabolic response is obtained. 18FDG-PET/CT scans may also be obtained per 
investigator discretion (eg, in instances where extranodal disease may be inadequately 
imaged by contrast-enhanced CT). 
Efficacy will be evaluated in terms of ORR, DOR, PFS, OS, TTP, and TTNLT. ORR will 
be used to move from Stage 1 to Stage 2. 
Special Safety 
Assessment(s) 
The safety and tolerability of study drug treatments will be evaluated by means of AE 
reports (incidence, causality, and severity), ECOG performance status, physical 
examinations, 12-lead ECGs, and laboratory safety evaluations. 
Laboratory abnormalities and AE severity will be graded according to NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0.  
Pharmacokinetics 
 PK sampling for nanatinostat and its metabolites 
 PK sampling for ganciclovir 
Biomarker 
Assessments 
The biomarker analyses outlined in this study are intended to foster an understanding of 
how baseline expression of certain biomarkers may impact efficacy, as well as to evaluate 
the effect of combination therapy with nanatinostat and valganciclovir on 
pharmacodynamic markers of activity, such as plasma EBV DNA levels, and correlation 
with clinical efficacy. Potential predictive markers will be studied to identify patients with 
optimal responses to nanatinostat plus valganciclovir. The impact of study drug 
administration on B-cell/T-cell/NK cell/myeloid cell populations will be evaluated over 
time. Cells and plasma from peripheral blood, or tumor tissue (lymph nodes), will be sent 
to a central laboratory selected by the study sponsor for analysis of viral DNA levels, and 
gene expression, phenotypic alterations in B-cells/T-cells/NK cells/myeloid cells and 
mutation profile. 
Independent 
Review Committee 
An IRC will be established to provide an independent review of radiographic and 
pertinent clinical data to provide expert interpretation of changes in tumor status and 
response assessment 
Statistical Methods 
and Data Analysis 
Efficacy Analysis: The number and percentage of patients with EBV+ lymphoma with 
a CR or PR after initiation of treatment will be summarized overall and by cohort. Ninety-
five percent (95%) confidence intervals (CIs) around the ORR: CR + PR will be 
calculated using the ClopperPearson method. For patients who achieve CR/PR, the DOR, 
defined as the start of the response to documented disease progression, death due to any 
cause, or last adequate (radiographic) response assessment will be estimated using 
the KaplanMeier method. Any patient who does not need anti-lymphoma treatment, 
experiences disease progression, or death will be censored at the last non-missing 
assessment. Patients initiating anti-cancer therapy will be censored at the last adequate 
disease assessment prior to the start of therapy. 
Overall survival will be estimated using the Kaplan-Meier method and will include all 
enrolled patients. Patients still alive will be censored at the last non-missing assessment. 
The 95% CI around the OS rate at 12 months will be presented. Analyses of other 
time-to-event efficacy endpoints (DOR, TTP, PFS, and TTNLT) will be analyzed 
in a similar manner. All efficacy summaries will be presented by cohort and overall. 
Safety Analysis: AEs will be summarized by cohort and overall, by System Organ 
Class, and Preferred Term. Tabulations and listings of values for ECGs, vital signs, 
and laboratory safety evaluations will be presented. Any abnormal or out-of-range values 
from laboratory safety evaluations or physical examinations will be presented in data 
listings. 
 


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TABLE OF CONTENTS 
SPONSOR’S PROTOCOL SIGNATURE PAGE ...........................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................13 
LIST OF TABLES .........................................................................................................................18 
LIST OF FIGURES .......................................................................................................................18 
LIST OF ABBREVIATIONS ........................................................................................................19 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Overview of EBV+ Lymphomas and Current Treatment(s) .......................................25 
1.1.1. 
EBV+ Diffuse Large B-cell Lymphoma (EBV+ DLBCL, NOS) ................................26 
1.1.2. 
Peripheral T-Cell Lymphoma (PTCL) ........................................................................26 
1.1.3. 
Extranodal NK/T-Cell Lymphoma (ENKTL) ............................................................27 
1.1.4. 
Hodgkin Lymphoma (HL) ..........................................................................................28 
1.1.5. 
Post-Transplant Lymphoproliferative Disorders (PTLD) ..........................................28 
1.1.6. 
Lymphomas Associated with HIV infection (HIV-L) ................................................29 
1.2. 
Overview of Investigational Treatment ......................................................................30 
1.2.1. 
Overview of Nanatinostat ...........................................................................................30 
1.2.1.1. 
Nonclinical Experience with Nanatinostat .................................................................30 
1.2.1.2. 
Clinical Experience with Nanatinostat Monotherapy in Advanced Cancers ..............30 
1.2.2. 
Overview of Valganciclovir .......................................................................................31 
1.2.3. 
Rationale for the Combination of Nanatinostat (VRx-3996) and 
Valganciclovir .............................................................................................................31 
1.2.3.1. 
Nonclinical Experience with Nanatinostat and Valganciclovir ..................................31 
1.2.4. 
Clinical Experience with Nanatinostat Plus Valganciclovir in EBV+ 
Lymphoma ..................................................................................................................33 
1.3. 
Potential Benefits and Risks .......................................................................................35 
1.3.1. 
Potential Benefits ........................................................................................................35 
1.3.2. 
Potential Risks ............................................................................................................36 
1.3.3. 
Risks Related to Study Procedures .............................................................................37 
1.3.4. 
Risk Management Strategies ......................................................................................37 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................37 
3. 
STUDY DESIGN .......................................................................................................38 


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3.1. 
Description of Study Design .......................................................................................39 
3.1.1. 
Screening Period .........................................................................................................41 
3.1.2. 
Treatment Period ........................................................................................................41 
3.1.3. 
Safety Follow-up Period .............................................................................................41 
3.1.4. 
Long-term Follow-up Period ......................................................................................42 
3.1.5. 
Timing of Analyses .....................................................................................................42 
3.1.6. 
End of Study ...............................................................................................................42 
4. 
SELECTION OF STUDY POPULATION ................................................................42 
4.1. 
Patient Population .......................................................................................................43 
4.1.1. 
Inclusion Criteria ........................................................................................................43 
4.1.2. 
Exclusion Criteria .......................................................................................................46 
5. 
STUDY TREATMENT PRODUCT INFORMATION .............................................48 
5.1. 
Nanatinostat ................................................................................................................48 
5.1.1. 
Dosage Form and Composition ..................................................................................48 
5.1.2. 
Nanatinostat Study Drug Storage ...............................................................................48 
5.1.3. 
Nanatinostat Administration .......................................................................................48 
5.2. 
Valganciclovir .............................................................................................................49 
5.2.1. 
Valganciclovir Study Drug Storage ............................................................................49 
5.2.2. 
Valganciclovir Administration ...................................................................................49 
5.3. 
Additional Dosing Guidelines for Pharmacokinetic Sampling ..................................50 
5.4. 
Dose Modifications of Nanatinostat and Valganciclovir ............................................50 
5.4.1. 
Dose Modifications for Patients with Renal Impairment ...........................................52 
5.4.2. 
Missed or Vomited Doses ...........................................................................................53 
5.5. 
Prior and Concomitant Medications ...........................................................................53 
5.5.1. 
Permitted Concomitant Medications ..........................................................................53 
5.5.1.1. 
Hematopoietic Growth Factors ...................................................................................54 
5.5.2. 
Concomitant Therapy Requiring Caution and/or Action ............................................54 
5.5.2.1. 
Corticosteroids ............................................................................................................54 
5.5.2.2. 
Proton-Pump Inhibitors ..............................................................................................54 
5.5.2.3. 
Concomitant Therapies to be Used with Caution with Nanatinostat ..........................54 
5.5.3. 
Concomitant Therapies to be Used with Caution with Valganciclovir ......................55 
5.5.4. 
Prohibited Medications ...............................................................................................55 
5.6. 
Patient Numbering & Treatment Assignment ............................................................55 


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5.6.1. 
Patient Numbering ......................................................................................................55 
5.6.2. 
Treatment Assignment (Including Randomization) ...................................................55 
5.6.3. 
Treatment Blinding .....................................................................................................56 
5.7. 
Study Drug Preparation and Dispensation ..................................................................56 
5.7.1. 
Study Drug Packaging and Labelling .........................................................................56 
5.7.2. 
Drug Supply and Storage ............................................................................................56 
5.7.3. 
Study Drug Compliance and Accountability ..............................................................56 
5.7.3.1. 
Study Drug Compliance .............................................................................................56 
5.7.3.2. 
Study Drug Accountability .........................................................................................56 
5.7.4. 
Study Drug Handling and Disposal ............................................................................56 
6. 
SCHEDULE OF EVENTS .........................................................................................57 
6.1. 
Schedule of Events Tables ..........................................................................................58 
7. 
ENROLLMENT AND STUDY PROCEDURES ......................................................64 
7.1. 
Screening Period .........................................................................................................64 
7.1.1. 
Informed Consent .......................................................................................................64 
7.1.2. 
Demographic Information ..........................................................................................64 
7.1.3. 
Physical Examinations ................................................................................................65 
7.1.4. 
Medical History ..........................................................................................................65 
7.1.5. 
Tumor Specimen .........................................................................................................65 
7.1.6. 
Central Review of EBV Status and Verification of Lymphoma Subtype ..................65 
7.1.7. 
Baseline Disease Assessments ....................................................................................66 
7.1.7.1. 
18FDG-PET/CT and CT with Contrast .......................................................................66 
7.1.7.2. 
Bone Marrow Biopsy ..................................................................................................66 
7.1.8. 
Eligibility Determination and Patient Registration .....................................................66 
7.1.8.1. 
Screen Failures ............................................................................................................67 
7.2. 
Treatment Period ........................................................................................................67 
7.2.1. 
Treatment Cycles ........................................................................................................67 
7.2.2. 
Unscheduled Visit(s) ..................................................................................................67 
7.2.3. 
Discontinuation of Study Treatment ...........................................................................67 
7.2.4. 
End of Treatment ........................................................................................................68 
7.2.5. 
Safety Follow-up Visit ................................................................................................68 
7.2.6. 
Long-term Follow-up Visits .......................................................................................69 
7.2.7. 
Lost to Follow-up .......................................................................................................69 


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7.3. 
Assessments During the Treatment Phase ..................................................................69 
7.3.1. 
Efficacy Assessments .................................................................................................69 
7.3.1.1. 
Baseline Evaluation ....................................................................................................69 
7.3.1.2. 
Tumor Response Assessments ....................................................................................70 
7.3.2. 
Safety and Tolerability Assessments ..........................................................................71 
7.3.2.1. 
Physical Examination .................................................................................................71 
7.3.2.2. 
Vital Signs ..................................................................................................................71 
7.3.2.3. 
Height and Weight ......................................................................................................72 
7.3.2.4. 
ECOG Performance Status .........................................................................................72 
7.3.2.5. 
Laboratory Evaluations ...............................................................................................72 
7.3.2.6. 
Clinical Laboratory (Safety) Testing ..........................................................................72 
7.3.2.7. 
Pregnancy Testing ......................................................................................................73 
7.3.2.8. 
Cardiac Assessments: Electrocardiograms (ECGs) ....................................................73 
7.3.3. 
Pharmacokinetics ........................................................................................................74 
7.3.4. 
Biomarker Assessments ..............................................................................................74 
7.3.4.1. 
Rationale for Biomarker Assessments ........................................................................74 
7.3.4.2. 
Pharmacodynamic Assessments in Blood ..................................................................75 
7.3.4.3. 
Additional Biomarker Assessments ............................................................................76 
8. 
ADDITIONAL SAFETY CONSIDERATIONS ........................................................76 
8.1. 
Monitoring, Recording and Reporting of Adverse Events .........................................76 
8.1.1. 
Laboratory Test Abnormalities ...................................................................................77 
8.2. 
Serious Adverse Event ................................................................................................77 
8.2.1. 
Reporting of SAEs ......................................................................................................78 
8.3. 
Severity of the Event ..................................................................................................78 
8.4. 
Relationship to Study Drugs .......................................................................................79 
8.5. 
Expectedness ...............................................................................................................79 
8.6. 
Reporting Adverse Events ..........................................................................................80 
8.7. 
Reporting of Pregnancy ..............................................................................................80 
8.7.1. 
Females of Childbearing Potential..............................................................................80 
8.7.2. 
Male Patients ..............................................................................................................81 
8.8. 
Reporting of Overdose ................................................................................................81 
8.9. 
Emergency Measures ..................................................................................................81 
8.10. 
Unanticipated Problems ..............................................................................................81 


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9. 
STATISTICAL ANALYSES .....................................................................................83 
9.1. 
Overview .....................................................................................................................83 
9.2. 
Statistical and Analytical Plans ..................................................................................83 
9.3. 
Definition of Analysis Populations .............................................................................83 
9.4. 
Sample Size and Power Considerations .....................................................................83 
9.5. 
Baseline Characteristics and Patient Disposition .......................................................84 
9.6. 
Efficacy Analysis ........................................................................................................84 
9.6.1. 
Primary Efficacy Endpoint Analysis ..........................................................................84 
9.6.2. 
Secondary Efficacy Endpoints Analysis .....................................................................85 
9.6.3. 
Exploratory Endpoints ................................................................................................86 
9.7. 
Safety Analysis ...........................................................................................................86 
9.8. 
Interim Analysis ..........................................................................................................86 
10. 
STUDY COMMITTEES ............................................................................................87 
10.1. 
Study Steering Committee ..........................................................................................87 
10.2. 
Independent Review Committee .................................................................................87 
11. 
STUDY ADMINISTRATION ...................................................................................87 
11.1. 
Regulatory and Ethical Consideration ........................................................................87 
11.1.1. 
Ethical Conduct of the Study ......................................................................................87 
11.1.2. 
Ethics Review .............................................................................................................87 
11.1.3. 
Patient Information and Informed Consent ................................................................88 
11.1.4. 
Maintaining Patient Confidentiality ...........................................................................88 
11.1.5. 
Use of Research Samples and Data ............................................................................89 
11.2. 
Data Handling and Recordkeeping .............................................................................89 
11.2.1. 
Data Collection Responsibilities and Access to Source Data .....................................89 
11.2.2. 
Retention of Records ..................................................................................................89 
11.2.3. 
Study Monitoring ........................................................................................................90 
11.2.4. 
Audits and Inspections ................................................................................................90 
11.2.5. 
Quality Control and Quality Assurance ......................................................................91 
11.3. 
Study Termination and Site Closure ...........................................................................91 
11.4. 
Use of Study Information and Publication .................................................................91 
12. 
REFERENCES ...........................................................................................................92 
13. 
APPENDICES ............................................................................................................97 


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APPENDIX 1. CONCOMITANT THERAPIES TO BE USED WITH CAUTION 
WITH NANATINOSTAT ..........................................................................................98 
APPENDIX 2. ESTABLISHED AND OTHER POTENTIALLY SIGNIFICANT 
DRUG INTERACTIONS WITH GANCICLOVIR ...................................................99 
APPENDIX 3. RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA ........................100 
 
LIST OF TABLES 
Table 1: 
IC50 Values (nM) for Various HDAC Inhibitors ........................................................33 
Table 2: 
Objectives and Endpoints ...........................................................................................37 
Table 3: 
Dose Modification Guidelines for Study Treatment-Related Toxicity ......................50 
Table 4: 
Valganciclovir Dosing for Patients with Renal Impairment .......................................53 
Table 5: 
Visit/Evaluation Schedule ..........................................................................................58 
Table 6: 
Visit/Evaluation Schedule for Cohort 3a (Nanatinostat Monotherapy), 
Days 1-43 ....................................................................................................................63 
Table 7: 
ECOG Performance Status .........................................................................................72 
Table 8: 
Clinical Laboratory Tests ...........................................................................................73 
Table 9: 
Biomarker Sample Collection Plan ............................................................................75 
Table 10: ICON Medical Monitoring Support Center ................................................................78 
Table 11: Examples of Sensitive Substrates of CYP3A .............................................................98 
Table 12: Examples of Strong Inhibitors of P-gp and BCRP Transporters ................................98 
Table 13: Response Definitions for Clinical Trials ..................................................................100 
 
LIST OF FIGURES 
Figure 1: 
Cytotoxicity in P3HR1 Cells ......................................................................................32 
Figure 2: 
Study Design ...............................................................................................................41 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
Ab 
antibody 
ABVD 
doxorubicin, bleomycin, vinblastine, and dacarbazine 
AE 
adverse event 
Ag 
antigen 
AIDS 
acquired immunodeficiency syndrome 
AITL 
angioimmunoblastic T-cell lymphoma  
ALCL 
anaplastic large cell lymphoma  
allo-SCT 
allogeneic stem cell transplant 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ART 
antiretroviral therapy 
ASCO 
American Society of Clinical Oncology 
ASCT 
autologous stem cell transplant 
ASH 
American Society of Hematology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
β-hCG 
beta human-chorionic gonadotropin  
BCRP 
breast cancer resistance protein 
BEACOPP 
bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, 
and prednisone 
BID 
bis in die (twice daily) 
CAR 
chimeric antigen receptor 
cART 
combination antiretroviral therapy 
CBC 
complete blood count 
CI 
confidence interval 
CFR 
Code of Federal Regulations 
cHL 
classical Hodgkin Lymphoma 
Cmax  
maximum plasma concentration 
CMV 
Cytomegalovirus 
CNS 
central nervous system 


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Abbreviation 
Definition 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DHAP 
dexamethasone, cytarabine, and cisplatin  
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EBER-ISH 
Epstein-Barr virus encoded RNA – in situ hybridization 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EEA 
European Economic Area 
ENKTL 
extranodal NK/T-cell lymphoma 
EOT 
End of Treatment 
EPOCH 
Etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin 
ESHAP 
etoposide, solumedrol, high-dose cytarabine, cisplatin 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GCV 
Ganciclovir 
GvHD 
graft-versus-host disease  
HBV 
hepatitis B virus 
HCT 
hematopoietic cell transplantation 
HCV 
hepatitis C virus 
HDAC 
histone deacetylase  
HDACi 
histone deacetylase inhibitor 
HHV-6/HHV-8 
human herpesvirus-6/human herpesvirus-8  
HIV 
human immunodeficiency virus 
HIV-L 
HIV-associated lymphoma 


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Abbreviation 
Definition 
HL 
Hodgkin lymphoma 
IARC 
International Agency for Research on Cancer 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICE 
ifosfamide, carboplatin, and etoposide 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
Intent-to-Treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous(ly) 
IWG 
International Working Group 
JAK 
Janus kinase 
LDH 
lactate dehydrogenase 
LDi 
longest diameter 
LMP-1 
latent membrane protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMF 
mycophenolate mofetil 
mITT  
modified Intent-to-Treat 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
N 
number of patients 
n 
number of patients in the category 


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Abbreviation 
Definition 
NCI 
National Cancer Institute 
NF-κB 
nuclear factor-kappa B 
NHL 
non-Hodgkin lymphoma 
NK/T 
natural killer/T-cell 
Nstat 
Nanatinostat 
NOS 
not otherwise specified 
ORR 
objective response rate 
OS 
overall survival 
P-gp 
P-glycoprotein 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed cell death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
per os (orally) 
PR 
partial response 
PT 
prothrombin time 
PTCL 
peripheral T-cell lymphoma 
PTLD 
post-transplant lymphoproliferative disorder 
QD 
quaque die (once daily) 
qPCR 
quantitative polymerase chain reaction 
QTcF 
corrected QT interval using Fridericia’s method  
R-CHOP 
rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone 
RBC 
red blood cell 
REB 
Research Ethics Board 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAHA 
suberoylanilide hydroxamic acid (vorinostat, Zolinza®) 


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Abbreviation 
Definition 
SD 
stable disease 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SMILE 
dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SOT 
solid organ transplant 
SRC 
Safety Review Committee 
SSC 
Study Steering Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TdP 
Torsades de Pointes 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocyte 
TK 
thymidine kinase 
t½ 
terminal elimination half-life 
tmax  
time to maximum plasma concentration 
T-NHL 
T-cell non-Hodgkin lymphoma 
TTNLT 
time to next anti-lymphoma treatment  
TTP 
time to progression 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
VGCV 
Valganciclovir 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
Epstein-Barr virus-positive (EBV+) lymphomas are a heterogeneous group of malignancies that 
harbor latent EBV within the lymphoma cells, and are associated with variable clinical features, 
treatments, and prognoses. EBV positivity in lymphomas has been shown to be a poor prognostic 
indicator in some subtypes, and no established therapies for the treatment of EBV+ lymphomas. 
In a meta-analysis evaluating survival outcomes across several lymphoma types (Hodgkin 
lymphoma [HL], diffuse large B-cell lymphoma [DLBCL], natural killer/T-cell [NK/T] 
lymphoma, peripheral T-cell lymphoma [PTCL]), EBV+ disease was associated with 
significantly worse overall survival (OS) (Ding 2016). Irrespective of the lymphoma subtype, 
EBV positivity is associated with significantly reduced OS with standard therapy compared to 
patients who are EBV negative (EBV–). 
Nanatinostat (VRx-3996) is an orally administered hydroxamic acid-based, selective and potent 
inhibitor of histone deacetylase (HDAC) Class I enzymes HDAC1, HDAC2, and HDAC3, 
and a potent inducer of EBV kinases (thymidine kinase [TK] and protein kinase [EBV-PK]). 
These EBV kinases activate the antiviral nucleoside analog ganciclovir via mono-
phosphorylation (Gustafson 1998, Meng 2010), resulting in sensitization of tumor cells to 
ganciclovir (Ghosh 2012), leading 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. This dual or combination approach is predicted to have high tumor specificity 
based on targeting of EBV-containing cells, while sparing EBV– cells. 
Valganciclovir (VALCYTE® United States Prescribing Information (Genentech 2021) and 
Summary of Product Characteristics (Roche 2018)), an oral prodrug of ganciclovir, is approved 
internationally for the treatment of cytomegalovirus (CMV) retinitis in adult patients with 
acquired immunodeficiency syndrome (AIDS) and prevention of CMV disease in adult and 
pediatric kidney and heart transplant patients at high risk. Outside of its approved indication, 
valganciclovir has been shown to be effective in mitigating EBV viral load in EBV+ pediatric 
liver transplant patients at risk for development of a post-transplant proliferative disorder 
(Venturi 2009). 
EBV-associated lymphomas are often very aggressive and respond poorly to conventional 
treatments. Clinical support for combining an HDAC inhibitor (HDACi) with an antiviral drug 
was initially provided by a Phase 1/2 proof-of-concept study conducted with the pan-HDACi, 
arginine butyrate, in combination with ganciclovir in patients with recurrent EBV+ lymphomas, 
which demonstrated significant anti-tumor activity (4 complete responses and 6 partial 
responses) among 15 patients treated (Perrine 2007). In a Burkitt lymphoma cell line, P3HR1, 
induction of EBV-TK was observed at concentrations of nanatinostat approaching 1 μM, 
demonstrating approximately 1,000-fold greater potency compared to sodium butyrate. This 
unique combination approach thus allows nanatinostat to be used as an activator of specific 
EBV-associated genes present in malignant cells, which confers targeted susceptibility of the 
cell to the antiviral valganciclovir (an oral prodrug for ganciclovir), causing apoptosis. 
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 November 2019. 
In an ongoing Phase 1b/2 trial (VT3996-201), nanatinostat given in combination with 


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valganciclovir has been shown to have promising safety, tolerability, and anti-tumor activity 
in patients with EBV+ lymphomas (see Section 1.2.4). 
Based on these findings, as well as the urgent need for new therapies for EBV+ lymphoma, 
particularly for patients with relapsed or refractory T-cell non-Hodgkin lymphoma (T-NHL), this 
global Phase 2 study has been developed to continue the evaluation of nanatinostat with 
valganciclovir in patients with relapsed/refractory EBV+ lymphomas. 
1.1. 
Overview of EBV+ Lymphomas and Current Treatment(s) 
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 recognized as a carcinogenic agent by the 
World Health Organization (WHO) (Swerdlow 2016) and the International Agency for Research 
on Cancer (IARC) (Chen 2021). Primary infection with EBV typically occurs in childhood 
and is generally asymptomatic; however, infection later in life may manifest as infectious 
mononucleosis. 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, and specific expression patterns 
(Types I to III) of these genes are associated with specific EBV-driven malignancies (Saha 
2011). Epigenetic mechanisms play a major role in generating and maintaining the diverse 
patterns of viral gene expression that can expand tissue tropism, enable evasion of immune 
detection, and drive oncogenesis (Tempera 2014). 
The American Cancer Society estimates 77,240 new cases of non-Hodgkin lymphoma (NHL) 
and 8,480 new cases of HL in 2020, with 8,480 and 970 deaths, respectively (Siegel 2020). 
The proportion of EBV positivity varies with the lymphoma subtype. For example, within North 
America, 30% of HL, 70–80% of angioimmunoblastic T-cell lymphoma (AITL), 30–40% of 
peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and ≥80% of post-transplant 
lymphoproliferative disorders (PTLDs) are EBV+ (Roschewski 2012, Dojcinov 2018). 
The incidence of EBV+ disease varies with geographic location; Burkitt lymphomas are almost 
always EBV+ in tropical regions but less than 30% are positive in the US. EBV is associated 
with 5–10% of DLBCL in western countries (Tracy 2018) and 10–15% in Asia (Lu 2015). 
Outcomes in EBV+ lymphoma patients are typically inferior compared to EBV– lymphomas 
of the same subtype. EBV+ DLBCL patients have worse outcomes and share similar poor 
prognostic indicators, irrespective of age (Lu 2015). For PTCL, EBV+ patients have been 
reported to have a shorter OS than EBV– patients (13 vs 72 months respectively, p = 0.04) 
(Haverkos 2017). For HL patients, those who were EBV+ had inferior failure-free survival 
outcomes compared to EBV– patients (Kanakry 2013). 
As there is no established targeted treatment specific for EBV+ lymphoid malignancies, 
the standard of care therapy for each lymphoma subtype is utilized. Cytotoxic chemotherapy 
is the mainstay for front-line treatment of lymphomas with ancillary anti-CD20 antibodies 
and/or radiotherapy etc., depending on the diagnosis and stage of disease. Treatment options for 
recurrent lymphomas depend upon the subtype, but generally include “salvage” chemotherapy 
regimens, stem cell transplantation, brentuximab, chimeric antigen receptor (CAR) T-cell 
therapy, checkpoint inhibitors, and HDAC inhibitors, among others. However, the prognosis 


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in relapsed/refractory lymphoma is generally poor. Treatment of relapsed/refractory EBV+ 
lymphoma is therefore an unmet medical need. 
1.1.1. 
EBV+ Diffuse Large B-cell Lymphoma (EBV+ DLBCL, NOS) 
EBV+ diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS) per 
the WHO classification (Swerdlow 2016)) is the most common subtype of EBV+ NHL, 
and approximately 10% of DLBCL is EBV+. Originally considered to be a disorder of elderly 
patients and included as a provisional entity in the WHO classification in 2008 as “EBV+ 
DLBCL of the elderly”, the category was updated in 2016 to “not otherwise specified” as cases 
were increasingly noted in younger individuals. Patients with EBV+ DLBCL, NOS tend to be 
older when diagnosed, with a more advanced disease stage and higher rates of extranodal 
involvement (particularly with respect to the gastrointestinal tract, skin, and bone marrow) 
(Castillo 2018). 
There is no uniformly accepted treatment for EBV+ DLBCL beyond the current standard of 
care, the combination of the anti-CD20 monoclonal antibody rituximab with cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP). Limited data have been published 
comparing the outcomes of rituximab-based regimens in patients with EBV+ DLBCL 
and patients with EBV– DLBCL. One study reported that OS and progression-free survival (PFS) 
were significantly worse in EBV+ patients compared to EBV– patients who received 
CHOP/CHOP-like regimens (p = 0.0002 and p <0.0001, respectively) (Sato 2014). In contrast, 
another retrospective analysis reported similar survival outcomes for EBV+ and EBV– patients in 
the post-rituximab era, although complete response (CR) rates were lower in EBV+ patients 
(59% vs 73%) (Beltran 2018). The largest retrospective study reported the outcomes 
of 250 DLBCL patients, 35 (14%) were EBV+ (Lu 2015). EBV+ patients, irrespective of age 
(> or ≤50) had a significantly worse PFS (p <0001) and OS (p <0001) compared to the EBV– 
patients. However, given its aggressive nature, and the poor outcomes of EBV+ DLBCL (Lu 
2015, Sato 2014, Oyama 2007, Park 2007), other novel therapies are needed, particularly 
for patients who have relapsed or are refractory to therapy. Treatment options for patients with 
relapsed/refractory DLBCL are based upon the intention to proceed to autologous stem cell 
transplant (ASCT) or not, and initially may include various cisplatin-containing chemotherapy 
regimens such as DHAP (dexamethasone, cytarabine, and cisplatin), ESHAP (etoposide, 
solumedrol, high-dose cytarabine, cisplatin), ICE (ifosfamide, carboplatin, and etoposide), 
gemcitabine-containing regimens, or anti-CD19 CAR-T-cell therapy. More recently approved 
options for patients having received ≥2 prior therapies include Selinexor (US only) 
and polatuzumab vedotin + bendamustine/rituximab, and for those who are not eligible for 
ASCT, tafacitamab with lenalidomide (US only). 
1.1.2. 
Peripheral T-Cell Lymphoma (PTCL) 
Peripheral T-cell lymphomas comprise a heterogeneous group of aggressive malignancies, 
classified into nodal and extranodal subtypes. Nodal PTCLs are the most common and include 
PTCL, PTCL-NOS, AITL, and anaplastic large cell lymphoma (ALCL). Around 70% of 
patients with PTCL are refractory to first-line therapy or relapse of their disease (Dreyling 2013). 
Clinical practice guidelines (Dreyling 2013, NCCN 2022) and data from a recent prospective 
multicenter cohort study (Carson 2017) support use of an anthracycline-containing regimen 
(CHOP) +/- etoposide for initial therapy. Monotherapy options for recurrent disease in some 


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countries include the HDAC inhibitor, belinostat, and pralatrexate and bendamustine, with 26% 
to 47% overall response rates (11% to 29% CR rates) reported (reviewed in (Dreyling 2013, 
O'Connor 2015), or brentuximab vedotin (for CD30+ PTCL). While romidepsin was previously 
approved in the US for recurrent PTCL, a recent Phase 3 study evaluating romidepsin plus 
CHOP (Ro-CHOP) versus CHOP in first-line PTCL patients did not meet the primary efficacy 
endpoint of PFS, and the PTCL indication was withdrawn from the US market (Bachy 2022). 
Combination platinum-based regimens such as DHAP, ESHAP, ICE, or with gemcitabine-
containing regimens, followed by ASCT for consolidation are recommended with 
chemosensitive disease (Dreyling 2013, NCCN 2022). Allogeneic stem cell transplant (allo-
SCT) has so far offered the only curative treatment in relapsed/refractory PTCL. 
Single-agent therapies (eg, lenalidomide, belinostat, brentuximab vedotin) are recommended 
for palliative intent. Clinical trials are currently recommended for all lines of therapy for PTCL 
(Dreyling 2013, NCCN 2022). Most patients with relapsed or refractory PTCL have poor 
outcomes, with median PFS and median OS reported to be 3.7 and 6.5 months, respectively, for 
those who receive chemotherapy at relapse (Mak 2013). 
1.1.3. 
Extranodal NK/T-Cell Lymphoma (ENKTL) 
Extranodal NK/T-cell lymphoma (ENKTL) is a subtype of mature T- and NK-cell lymphoma 
included in the WHO classification (Swerdlow 2016), and while less prevalent than nodal PTCL, 
has a higher incidence in Asian and South American populations and is uncommon in other 
countries (Tse 2017). A defining feature of ENKTL is the infection of lymphoma cells with 
EBV, and the involvement of the nasal and upper pharyngeal regions. This is an aggressive 
malignancy that is resistant to anthracycline-containing regimens because of its expression of P-
glycoprotein (P-gp), and no standard treatment has been established based on the results of 
randomized clinical trials. Following greatly improved outcomes (objective response rate [ORR] 
79%) with L-asparaginase-based regimens for patients with recurrent disease (Yamaguchi 2011), 
it is currently recommended that first-line treatment of ENKTL should include L-asparaginase 
(eg, SMILE: dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) and local 
(nasopharyngeal) radiotherapy (Dreyling 2013, NCCN 2022), with hematopoietic stem cell 
transplantation recommended as front-line consolidation therapy for patients with advanced 
disease. However due to the aggressive nature of this disease, the 3-year OS of high-risk patients 
(per the PINK-E prognostic index for ENKTL) is less than 30% (Kim 2016). 
Nearly 50% of patients with newly diagnosed ENKTL develop disease progression, and for 
patients who have previously received regimens not containing L-asparaginase, salvage therapy 
with SMILE or similar regimens is effective. However, patients who have relapsed following 
or are refractory to L-asparaginase-based therapy have a very poor outcome with salvage 
chemotherapy, even after allogeneic stem cell transplantation, with a reported median PFS and 
OS of 2.3 and 4.9 months, respectively (Ahn 2013, Jeong 2018). 
NK/T-cell lymphoma cells express programmed death-ligand 1 (PD-L1), which is upregulated 
by the EBV latent membrane protein 1. Some preliminary responses in patients receiving 
anti-PD-L1 and anti-programmed cell death-1 (PD-1) inhibitors have been reported in early 
phase clinical trials with a limited number of patients (Li 2018, Kim 2020). Therefore, new 
treatment options are urgently needed for ENKTL patients with recurrent/persistent disease 
following first-line therapy due to a lack of available treatment options and very poor outcomes 
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1.1.4. 
Hodgkin Lymphoma (HL) 
EBV is associated with approximately one-third of HL cases, and in a contemporary 
retrospective population-based study, EBV positivity was demonstrated to be an independent 
adverse prognostic factor in patients >50 years of age with classic HL (Diepstra 2009). 
The standard treatment of EBV+ HL is not different from that for EBV– HL of the same stage, 
histology, and prognosis (Ansell 2018) and is guided by clinical stage and risk stratification. 
Systemic chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), 
followed by involved-field radiotherapy when indicated, is considered the standard of care. 
Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is 
also recommend as an alternative regimen for patients with advanced HL; 5-year PFS compared 
with ABVD was 82.2% versus 75.3% (HR 0.68 [95% CI 0.53-0.87]; p=0.0017) in a recently-
reported Phase 3 randomized controlled clinical trial (Straus 2021, NCCN 2022). The regimen of 
bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone 
(BEACOPP) is an alternative option for patients with high-risk, advanced-stage disease. Patients 
who are refractory to or have relapsed following these therapies have been treated with novel 
agents targeting CD30, PD-1, HDAC, nuclear factor-kappa B (NF-κB), Janus Kinase (JAK) 2, 
and mammalian target of rapamycin (mTOR), with varying degrees of success; ASCT remains 
the standard of care for curative therapy (Karantanos 2017). 
1.1.5. 
Post-Transplant Lymphoproliferative Disorders (PTLD) 
Post-transplant lymphoproliferative disorders (PTLD) occur in the setting of prolonged 
immunosuppression following hematopoietic stem cell or solid organ transplantation, with the 
majority associated with EBV. PTLD is classified into 4 general groups: monomorphic PTLD, 
B-cell type; polymorphic PTLD; monomorphic PTLD, T-cell type; and classical HL PTLD; 
about 85% are of B-cell origin. The evaluation of EBV status is an essential part of the 
diagnostic work-up, commonly performed by available lab-developed assays such as latent 
membrane protein 1 (LMP-1) or Epstein-Barr encoded region in situ hybridization (EBER-ISH). 
Given that recipient EBV seronegativity is considered a risk factor for the development of PTLD 
and given that the seroprevalence of EBV increases with age, younger patients post-transplant 
are particularly at risk.   
Treatment is largely dependent on the PTLD subtype. Due to a deficiency of randomized 
controlled trials and the heterogeneity of PTLD, the standard of care therapy has not been 
defined. The initial management of monomorphic PTLD, B-cell, and polymorphic PTLD 
involves the reduction of immunosuppressive therapy (RI) if possible, or a risk-stratified 
sequential approach to therapy with either rituximab alone for patients who would not be eligible 
for chemotherapy due to underlying comorbidities or chemoimmunotherapy (eg with R-CHOP) 
(Dierickx 2018). Using such approaches has resulted in reported CR rate of 70% with a median 
OS rate of 6.6 years (Trappe 2017).  
Responses to first-line therapy are not durable in most cases. In the hematopoietic cell 
transplantation (HCT) setting, approximately 50% of cases fail initial treatment. Patients whose 
disease is relapsed or refractory after treatment with first-line therapy have limited treatment 
options and rapidly decline with high mortality, often within 1 or 4 months, respectively (Sanz 
2021, Dharnidharka 2021). In solid organ transplant (SOT) patients who failed rituximab plus 
chemotherapy or cannot receive a chemotherapy regimen, the median survival was 


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approximately 3 months. In a recent retrospective cohort study of 18 HCT subjects, the median 
survival from diagnosis of rituximab-refractory disease was 1.7 months (Socié 2020). Analysis 
of an expanded multinational population in 2021 confirmed these findings: patients with EBV+ 
PTLD following HCT who failed rituximab have a median OS of 0.7 months (Sanz 2021), and 
patients with EBV+ PTLD following SOT who failed rituximab plus chemotherapy, the median 
survival was 4.1 months (Dharnidharka 2021).  
There are no established treatments for relapsed or refractory PTLD, although reduced-intensity 
chemotherapy, rituximab monotherapy, or other agents (interferon-α, anti-interleukin-6 
antibodies) (Zimmermann 2011) have been used, with variable and often limited success. EMA 
recently approved an EBV-specific allogeneic T-cell immunotherapy for adult and pediatric 
patients with relapsed or refractory EBV+ PTLD who have received at least one prior therapy. 
Treatment options for pediatric patients with PTLD follow the same treatment algorithms as 
adults with generally similar outcomes. Yet, new therapeutic options are urgently needed for 
PTLD, especially for patients with relapsed or refractory disease. 
1.1.6. 
Lymphomas Associated with HIV infection (HIV-L) 
In human immunodeficiency virus (HIV)-positive individuals, EBV-related lymphomas are 
more prevalent than in HIV-negative cases, despite effective control of viremia and 
improvement in CD4 counts with combination antiretroviral therapy (cART). The most 
common HIV-associated lymphomas according to the 2017 WHO classification of tumors of 
hematopoietic and lymphoid tissues include plasmablastic, Burkitt, DLBCL, and Hodgkin 
lymphoma (Swerdlow 2017). EBV is associated with DLBCL and HL in 30 to 90% and almost 
all cases respectively, as well as up to 50% of AIDS-related lymphomas (Carbone 1993, 
Shindiapina 2020). Classic HL in the setting of HIV is mostly the mixed cellularity subtype, 
although the prevalence of nodular sclerosing HL has increased with higher CD4 counts due to 
the impact of cART (Biggar 2006). The prevalence of EBV in HIV positive- cases of Burkitt 
lymphoma in a multicenter study in the US was reported to be 60% versus 20% in non-endemic 
HIV-negative cases (Mbulaiteye 2014). Clinically, these lymphomas tend to present with 
advanced stages of disease, and involve the gastrointestinal tract, central nervous system 
(although less frequently after the introduction of cART) and extranodal sites including the liver 
and bone marrow, and lymphoma remains the most frequent neoplastic cause of mortality in 
individuals with HIV (Grulich 2015). 
Although initially outcomes for HIV-associated lymphomas were inferior to HIV-negative 
individuals, the advent of cART boosting immune function has had a major impact on the 
tolerability of chemotherapy regimens, and therapeutic approaches to disease management are 
largely similar to standard of care in HIV-negative individuals (eg, for HL) (Dunleavy 2012). For 
aggressive HIV-associated B-cell lymphomas, although rituximab (if CD20+) with 
EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin) is the 
preferred regimen, R-CHOP is acceptable, with a risk-adapted approach to intrathecal therapy 
(NCCN 2022). For relapsed or refractory disease, salvage regimens include bortezomib-ICE or 
other regimens (see Section 1.1.1). 


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1.2. 
Overview of Investigational Treatment 
1.2.1. 
Overview of Nanatinostat 
Nanatinostat (VRx-3996) is a selective HDAC Class I inhibitor with activity against HDAC1, 
HDAC2, and HDAC3. In both 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). 
1.2.1.1. 
Nonclinical Experience with Nanatinostat 
1.2.1.1.1. Nonclinical PK and Metabolism of Nanatinostat 
Preclinical studies have shown that nanatinostat, as a single agent, has good oral bioavailability 
in rats and dogs, on the order of 30–40%, and demonstrates good tissue penetration in rat 
models. Nanatinostat metabolism is not CYP-mediated, does not induce CYP459 isoforms, 
and appears to be a poor inhibitor of CYP450 isoforms, using model substrates and inhibitors 
across all studies. 
1.2.1.1.2. 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 suggested both a dose relationship 
and plateau in biologic response, with increased acetylation apparent at the 20 mg per day dose 
level and plateauing at levels ≥40 mg/day. 
1.2.1.2. 
Clinical Experience with Nanatinostat Monotherapy in Advanced Cancers 
A Phase 1 study evaluating nanatinostat as a single agent was performed in 39 patients with 
refractory solid tumors (Banerji 2012). Nanatinostat was administered once daily (QD) orally 
(PO) at doses ranging from 5 to 160 mg on a 28-day cycle. Dose-limiting toxicities (DLTs) were 
thrombocytopenia (160 mg), fatigue (80 and 120 mg), elevations in serum creatinine 
(80 and 120 mg), and atrial fibrillation (40 mg). The maximum tolerated dose (MTD) was 
established as 80 mg. Most adverse events (AEs) were low grade (Grade 1 or 2), most commonly 
fatigue and nausea. Regarding efficacy, there was 1 partial response (PR) (160 mg dose group) 
and 9 had stable disease (SD). 
The pharmacokinetics (PK) of nanatinostat showed rapid absorption with peak plasma 
concentrations occurring at approximately 1 hour. Although there was pronounced variability in 
exposure across the dose levels, areas under the plasma concentration-time curve (AUCs) were 
broadly proportional over the administered dose range. The median terminal elimination half-life 
(t½) was approximately 2 hours. There were no apparent differences between Day 1 and Day 28 
PK parameters, suggestive of no apparent accumulation. 
For further details on clinical and nonclinical experience, please refer to the latest version of the 
nanatinostat (VRx-3996) Investigator’s Brochure (IB). 


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1.2.2. 
Overview of Valganciclovir 
Valganciclovir (VALCYTE®), an oral prodrug of ganciclovir, is approved internationally for 
treatment of CMV retinitis in adult patients with AIDS and prevention of CMV disease in adult 
and pediatric kidney and heart transplant patients at high risk. The antiviral activity of 
valganciclovir is based on the generation of ganciclovir-triphosphate, which is a competitive 
substrate for the CMV DNA polymerase. 
The recommended adult dosing for treatment of CMV retinitis is 900 mg orally twice daily 
(BID) for 21 days followed by a maintenance dose of 900 mg QD. 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. Dosage 
reductions based on creatinine clearance are recommended for patients with renal impairment. 
Notable AEs include cytopenias and acute renal failure. Elderly patients, patients receiving 
nephrotoxic drugs, and inadequately hydrated patients are at higher risk for renal dysfunction. 
1.2.3. 
Rationale for the Combination of Nanatinostat (VRx-3996) and Valganciclovir 
1.2.3.1. 
Nonclinical Experience with Nanatinostat and Valganciclovir 
The mechanism of action underlying the combination therapy approach to EBV+ lymphomas 
depends upon both drug components – nanatinostat as a virus gene-inducing agent, and 
ganciclovir as the prodrug that is activated by viral gene products induced by nanatinostat to 
cause tumor cytotoxicity. In published time-course experiments, discontinuous exposure to the 
HDACi 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). Exposure of P3HR1 cells to the HDACi butyrate in vitro induced measurable EBV-TK 
and protein kinase gene expression at 6 hours. Subsequently, 6-hour pulses daily for 1, 2, or 3 
days were shown to sensitize P3HR1 cells in vitro to ganciclovir, with significantly greater 
cytotoxicity observed with the combination compared to either butyrate or ganciclovir alone. 
The cytotoxic activity of the combination of nanatinostat plus ganciclovir has been demonstrated 
in in vivo models of EBV+ Burkitt lymphoma, substantially inhibiting tumor growth compared to 
the administration of either agent alone. In vitro, the combination of increasing concentrations of 
nanatinostat with a fixed dose of ganciclovir in P3HR1 cells increased cytotoxicity compared to 
either nanatinostat or ganciclovir alone (Figure 1). 


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Figure 1: 
Cytotoxicity in P3HR1 Cells 
 
Abbreviations: DMSO = dimethyl sulfoxide; GCV = ganciclovir; N = nanatinostat; Nstat = nanatinostat. 
7AAD is a cell viability assay. % 7AAD indicates the fraction of tumor cells that take up the dye 7AAD, resulting in 
fluorescence, and are therefore dead.
In an in vivo murine lymphoma model, 5 Balb/C nude mice per treatment group were injected 
with 1 × 107 P3HR1 cells in Matrigel® in the right flank and once tumors reached 100–150mm3, 
received 5 mg/kg nanatinostat on a 4 day/week intermittent dosing cycle as a monotherapy or in 
combination with daily ganciclovir (5 mg/kg nanatinostat + 100 mg/kg ganciclovir). Tumor 
volumes were reduced by approximately 32% by Day 30 for nanatinostat plus ganciclovir but 
were not significantly affected by either nanatinostat or ganciclovir alone (data on file). 
Similar effects have been demonstrated in xenograft models of EBV+ solid tumors. 
The combination of romidepsin and ganciclovir was reported to induce enhanced killing of 
EBV+ tumor cells in xenograft models of nasopharyngeal carcinoma (HA cell line) and gastric 
cancer (SNU-719 cell line) compared to either drug alone (Hui 2016). Similarly, the combination 
of nanatinostat plus ganciclovir induced significant cytotoxicity in murine xenograft models of 
EBV+ gastric cancer (SNU-719 cell line) compared to either drug alone. SNU-719 tumor cells 
were injected subcutaneously into immunocompromised B-NDG mice. Once tumors reached a 
volume of 100–150 mm3, treatment was initiated according to the following dosing groups 
(n = 8 mice/group): Control (saline), ganciclovir 50 mg/kg, nanatinostat 5 mg/kg, nanatinostat 
15 mg/kg, nanatinostat 5 mg/kg + ganciclovir 50 mg/kg, nanatinostat 15 mg/kg + ganciclovir 
50 mg/kg. Nanatinostat was administered 4 days/week and ganciclovir 7 days/week. The 
combination of nanatinostat 15 mg/kg + ganciclovir 50 mg/kg showed a significant reduction in 
tumor burden for SNU719 tumors at 32 days, compared to ganciclovir or nanatinostat alone. 
This anti-tumor effect of the combination was dose-dependent as the nanatinostat dose was 
increased (in combination with the fixed ganciclovir dose). 
The relative potency of nanatinostat compared to other clinically approved and experimental 
HDACi for inhibition of Class I HDAC is presented in Table 1. 


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Table 1: 
IC50 Values (nM) for Various HDAC Inhibitors 
Agent 
Nstat* 
Vorinostat* Panobinostat
Belinostat 
Entinostat Mocetinostat Givinostat
HeLa extract 
9 
60 
- 
- 
11,000 
1,850 
- 
HDAC1 (I) 
3 
90 
3 
41 
181 
34 
28 
HDAC2 (I) 
4 
25 
- 
- 
- 
- 
- 
HDAC3 (I) 
7 
150 
4 
30 
2311 
998 
21 
Abbreviations: HDAC = histone deacetylase; IC50 = half-maximal inhibitory concentration; Nstat = nanatinostat. 
*Data on file. Other data from literature (Beckers 2007, Moffat 2010). Nanatinostat was assayed using vorinostat 
(suberoylanilide hydroxamic acid [SAHA], Zolinza®) as a positive control; (-) indicates not determined.
It is well established that selective inhibition of HDAC-1, -2, and -3 by small interfering RNA 
or specific HDACi (eg, romidepsin, MS-275, and apicidin) can induce the latently infected EBV+ 
lymphoma cells into the EBV lytic cycle. This in turn mediates enhanced killing with ganciclovir 
in vitro and in vivo (Hui 2016). 
The observation that nanatinostat is a highly potent inhibitor of Class I HDAC supports the 
rationale for the combination of nanatinostat with ganciclovir at concentrations of nanatinostat 
below the level required to induce direct cytotoxicity to maximize cell killing through activation 
of EBV-PK and subsequent activation of ganciclovir. 
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, PK data from 
the VT3996-201 study has demonstrated that nanatinostat does not reach these concentrations 
at the doses tested in human plasma and it is rapidly eliminated from the circulation. These data 
suggest that while nanatinostat could be capable of inducing tumor cell death as a single agent, 
the concentrations of nanatinostat required would be much higher that observed or potentially 
achievable with the current dosing regimen. In addition, the nanatinostat dose for this study 
(20 mg daily, Days 1 to 4 per week) is <20% of the MTD (80 mg daily), as determined in a 
single agent Phase 1 study in patients with advanced solid tumors (Banerji 2012). 
Regarding valganciclovir as a monotherapy, during active EBV infections, EBV lytic phase 
protein kinases are required to convert the prodrug valganciclovir to an active antiviral drug. 
However, since EBV exists in its latent form in tumor cells, valganciclovir has no activity 
against EBV in the absence of EBV lytic phase protein kinases. Taken together, these data 
support the conclusion that the activity of nanatinostat and ganciclovir is dependent on their 
coadministration and is superior to that of either compound alone. 
1.2.4. 
Clinical Experience with Nanatinostat Plus Valganciclovir in EBV+ Lymphoma 
A single arm Phase 1b/2 dose escalation/expansion study of nanatinostat in combination with 
valganciclovir (Study VT3996-201) is being conducted in patients with relapsed/refractory EBV+ 
lymphoma. Key eligibility criteria for enrollment included age ≥18 with histologically confirmed 
EBV+ lymphomas, ≥1 prior lines of therapy and no curative treatment options per investigator. In 
Phase 1b (n=25), the RP2D of nanatinostat (20 mg daily, Days 1 to 4 per week) and 
valganciclovir (900 mg daily) was selected based on evaluation of the following dose levels: 
 Cohort 1 (n = 7): nanatinostat 10 mg oral twice daily + valganciclovir 900 mg oral twice 
daily (20+1800) 


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 Cohort 2a (n = 5): nanatinostat 5 mg oral twice daily + valganciclovir 450 mg oral twice 
daily (10+900) 
 Cohort 2b (n = 4): nanatinostat 10 mg oral once daily + valganciclovir 450 mg oral once 
daily (10+900) 
 Cohort 2c (n = 4): nanatinostat 10 mg oral once daily + valganciclovir 900 mg oral once 
daily (10+900) 
 Cohort 3 (n = 5): nanatinostat 20 mg oral once daily, Days 1 to 4/week + valganciclovir 
900 mg oral once daily (20+900) 
In Cohort 1, 3 of the first 4 patients enrolled developed DLTs (Grade 4 neutropenia × 29 days, 
Grade 3 thrombocytopenia × 6 days, Grade 4 thrombocytopenia × 8 days), and 3/4 patients 
developed Grade 1 and 2 creatinine elevations. The picture of 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 this, 1 patient developed a DLT 
(uncomplicated Grade 3 thrombocytopenia × 7 days), therefore, Cohort 1 was considered to have 
exceeded the MTD. In Cohort 2, across the 3 cohorts (2a, 2b, 2c; n = 13), there were no DLTs 
reported. The Safety Review Committee (SRC) made the recommendation to proceed in 
Cohort 3 with nanatinostat 20 mg daily using an intermittent schedule for administration 
(ie, 4 days on, 3 days off) with valganciclovir 900 mg once daily. The dosing regimen for 
Cohort 3 was subsequently declared to be the RP2D, as no DLTs were reported. 
As of the data cutoff date (04 May 2023), 64 patients (14 B-NHL, 25 T-NHL, 12 HL, 13 other) 
were enrolled; 25 in Phase 1b, and 39 patients received the RP2D (nanatinostat 20 mg daily, 
Days 1 to 4 per week plus valganciclovir 900 mg daily) in a Phase 2 expansion cohort; all 
patients had been followed for DoR for almost 12 months from first dose of study drug. Ten 
additional patients were planned to receive the nanatinostat tablet formulation in a PK cohort. 
Lymphoma subtypes were DLBCL (n=10), ENKTL (n=10), PTCL-NOS (n=5), AITL (n=8), 
cutaneous T-cell lymphoma (n=2), HL (n=12), other B-cell (n=4), and immunodeficiency-
associated lymphoproliferative disorders (IA-LPD; n=13), including PTLD (n=4), HIV 
associated (n=5), and other (n=4: systemic lupus erythematosus [n=2], common variable and 
primary immunodeficiency [n=1 each]). Patients had a median of 2 prior therapies (range 1 to 
13); 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. For all 
evaluable patients (n=50), the ORR/CR rate was 36% (18/50) / 16% (8/50), and the median 
duration of response (DOR) was 6.5 months.  
Responses were observed across multiple lymphoma subtypes, including AITL, DLBCL, IA-
LPD, PTCL, and PTLD. The lead lymphoma subtype of (8 evaluable) PTCL patients, the ORR, 
CRR, and median and mean DOR were 50%, 37.5%, and 17.1 months and 22.2 months, 
respectively. Of the 9 evaluable patients with DLBCL, 3 had a CR (both primary refractory 
DLBCL), and 3 had a PR; prior therapies and response durations in these patients are shown in 
Table 6. In most patients, responses were seen by the time of the first disease response 
assessment. Several durable responses were observed, as the median and mean DORs were 6.5 
and 15 months, respectively. The median DOR was 38.3 months in the AITL subgroup and 20.8 
months in the ENKTL subgroups, with the median not yet reached in the DLBCL cohort where a 
few patients continued on study treatment at the time of this analysis. Of note, one of the CRs 


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was achieved in an EBV+ PTCL patient whose disease never responded to second-line histone 
deacetylase inhibitor (HDACi) treatment, and one of the CRs was achieved in an EBV+ DLBCL 
patient whose disease never responded to first-line R-CHOP chemotherapy. Also notable, 2 
patients with DLBCL and 1 patient with ENKTL continued on treatment approximately 39+ 
months. Three patients (PTCL, ENKTL, HL), who at the time of enrollment in this study were 
not eligible for SCT or CAR-T-cell therapy, achieved adequate disease control and were able to 
proceed to SCT (n=1 autologous and n=1 allogeneic) or CAR-T-cell therapy (n=1), which are 
notable outcomes for heavily pretreated patients with poor prognoses. Four patients remained on 
study treatment at the time of data cutoff. 
As of the data cutoff date (04 May 2023), 64 patients overall were evaluable for safety 
(Phase 1b: 25 patients, Phase 2: 30 patients, nanatinostat tablet PK cohort: 9 patients). The most 
common (>20% of patients) treatment-emergent AEs (TEAEs) reported overall were platelet 
count decreased / thrombocytopenia (16 [25%] and 11 [17.2%]), nausea (25 [39.1%]), 
neutropenia / neutrophil count decreased (14 [21.9%] and 11 [17.2%]), anaemia (24 [37.5%]), 
fatigue (22 [34.4%]), constipation and diarrhea (19 patients each [29.7%]), increased blood 
creatinine (17 [26.6%]), and vomiting (15 [23.4%]). Most TEAEs were Grade 1 or 2 in severity. 
Most TEAEs were Grade 1 or 2 in severity.  
Across all cohorts, the most frequently reported Grade 3/4 TEAEs (>10% of patients) were 
neutropenia / neutrophil count decreased (12 [18.8%] and 9 [14.1%]), platelet count decreased / 
thrombocytopenia (6 [9.4%] and 8 [12.5%]), and anaemia (13 [20.3%]). Specifically, among the 
events of increased creatinine, all were Grade 1 or 2 in severity.  
No study drug-related deaths occurred. Serious adverse reactions (n=12) included febrile 
neutropenia and atrial fibrillation (each n=2, [3.1%]), and anemia, neutropenia, 
thrombocytopenia, pharyngitis, sepsis, myelodysplastic syndrome, tumor necrosis, and dyspnoea 
(each n=1 [1.6%]). Thirteen (20%) patients had adverse events resulting in drug withdrawal. 
The combination of nanatinostat and valganciclovir was well-tolerated and showed preliminary 
efficacy in a population of heavily pretreated patients with a variety of EBV+ lymphomas, 
the majority of whom were refractory to their last therapy prior to entering the study. 
Patients with relapsed/refractory T/NK-NHL and DLBCL showed the most promising response 
rates. Thus, the combination of nanatinostat and valganciclovir may be a potential therapy for 
patients with relapsed/refractory EBV+ lymphomas for whom effective therapies are urgently 
needed. 
1.3. 
Potential Benefits and Risks 
1.3.1. 
Potential Benefits 
As described in Section 1.2.4, preliminary data from the Phase 1b/2 VT3996-201 study indicate 
that at the RP2D, the combination of nanatinostat and valganciclovir was generally well-
tolerated and demonstrated clinical activity in a population of heavily pretreated patients with a 
variety of recurrent EBV+ lymphomas, the majority of whom were refractory to their last therapy 
prior to entering the study. Patients with relapsed/refractory DLBCL and ENKTL showed the 
most promising response rates, including CRs in 2 patients with primary refractory DLBCL. 
The combination appears to be highly active in patients with recurrent PTCL and ENKTL, 
including those who had failed stem cell transplantation. The oral administration of both 


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nanatinostat and valganciclovir is an added benefit to patients, as they can take their study 
treatment at home. The eligibility of adolescents (≥12 years of age) with PTLD in this study is 
supported by the guidance in which the histology and biologic behavior of the cancer under 
study is the same as adult patients, or when the molecular target of the investigational treatment 
is relevant to both adult and adolescent patients (federalregister.gov/d/2019-04582). 
1.3.2. 
Potential Risks 
HDAC inhibitors are potent inducers of the EBV lytic cycle; the production of infectious virus 
by virtue of HDACi-mediated induction of the tumor lytic cycle is a clinically documented AE 
described in a monotherapy clinical trial with the HDACi romidepsin, but this potential safety 
issue can be abrogated by the coadministration of ganciclovir (GCV). In the Phase 1b/2 
VT3996-201 study, patients’ EBV genome levels have been serially monitored. There have been 
no reported cases of EBV or CMV reactivation, and no significant elevations of plasma EBV 
DNA have been noted thus far in these patients receiving nanatinostat co-administered with 
valganciclovir, indicating that this combination is potentially preventing EBV viremia. 
EBV reactivation has been reported in 3 ENKTL patients receiving romidepsin as a monotherapy 
(Kim 2016). Romidepsin-induced EBV reactivation was also reported in 2 patients with relapsed 
PTCL who were receiving romidepsin in a Phase 2 trial (Ritchie 2009). The romidepsin 
prescribing information describes a risk of reactivation of DNA viruses, including EBV 
(ISTODAX® USPI 2021 (Celgene 2021)). Due to the reported activity of HDACi’s in PTCL, the 
potential anti-tumor activity of nanatinostat as a monotherapy will be evaluated in 10 patients 
with PTCL in this study. Because of the risk of EBV reactivation in patients with EBV+ 
lymphomas receiving monotherapy with HDACi’s, these patients will be monitored closely for 
clinical signs and lab evidence of EBV or other viral reactivation during their short course (6 
weeks) of monotherapy. 
Dosing for valganciclovir is consistent with the approved dose. Any necessary dose adjustments 
(eg, in the case of creatinine elevations) will be made according to the prescribing information. 
The safety profile for this dose of valganciclovir is well defined and appears acceptable as part of 
a treatment regimen for patients with relapsed/refractory lymphoma. Further information about 
valganciclovir can be found in the prescribing information (VALCYTE® USPI 2021 and SmPC 
2018 (Genentech 2021, Roche 2018). 
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, in prior clinical studies other toxicities reported for one or both agents include 
fatigue, atrial fibrillation, nausea/vomiting, anemia, leukopenia, and neutropenia. 
As QTc prolongation has been reported with other HDAC inhibitors, (Gryder 2012), medications 
with a known risk of prolonging the QT interval should be avoided (Section 5.5.4). 
As with any new combination, toxicities which have not been seen with either agent alone 
or with combinations of similar agents may become manifest. 
Available clinical data indicates a 2- to 2.5-fold higher systemic exposure of nanatinostat with 
the co-administration of valganciclovir, which is expected, as valganciclovir/ganciclovir is the 
MDR1 and BCRP inhibitor, and nanatinostat is the substate of MDR1 and BCRP transporters. 


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The systemic exposure of ganciclovir from nanatinostat and valganciclovir co-administration is 
consistent with that from valganciclovir monotherapy reported in the literature. 
Further information about the safety profile of nanatinostat as a single agent and in combination 
with valganciclovir can be found in the current IB. 
1.3.3. 
Risks Related to Study Procedures 
Potential study-related risks include (but are not limited to) collection of new tumor samples, 
blood draws, radiological assessments, and concomitant medications in case of AEs. More 
information can be found in the consent form. 
1.3.4. 
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 5.4). Patients receiving 
nanatinostat monotherapy will be closely monitored for potential EBV reactivation and will have 
a disease response assessment 2 weeks earlier than patients in the combination arm. 
The benefit-risk balance of the oral treatment regimen with nanatinostat and valganciclovir is 
anticipated to be positive for the target study population of relapsed/refractory EBV+ lymphoma 
patients who have previously received 1 or more prior therapies and in the opinion of the 
Investigator have exhausted all standard therapies. 
2. 
OBJECTIVES AND ENDPOINTS 
The study objectives and related endpoints are presented in Table 2. Details of the statistical 
analysis are described in Section 9. 
Table 2: 
Objectives and Endpoints 
Objective(s) 
Endpoint(s) 
Primary 
Refer to Section 9.6.1 for methods of analysis. 
To evaluate the anti-tumor 
activity of the combination 
treatment of nanatinostat (Nstat) 
with valganciclovir (VGCV) 
based on objective tumor 
response rates  
 Objective response rate (ORR) as assessed by an Independent Review 
Committee (IRC) – defined as the proportion of patients who achieve a 
complete response (CR) or partial response (PR) using the 2007 
International Working Group (IWG) criteria (Cheson 2007); Table 13. 
The Investigator will also use the 2007 IWG criteria for assessment of 
progression/relapse and for any clinical decisions requiring assessment of 
disease progression/relapse. 
Secondary 
Refer to Section 9.6.2 for methods of analysis. 
To determine the duration of 
tumor control 
 Duration of response (DOR) – defined as the interval from the date of first 
observed CR or PR to the date of disease progression, death due to any 
cause, or last adequate (radiographic) response assessment. 
 Time to next anti-lymphoma treatment (TTNLT) – defined as the interval 
from the start of study drug treatment to date of next anti-lymphoma 
treatment. 


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Objective(s) 
Endpoint(s) 
 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. 
 Time to progression (TTP) – defined as the interval from the start of study 
drug treatment to date of disease progression. 
To determine survival outcomes 
 Overall survival (OS) – defined as the interval from the start of study drug 
treatment to date of death, for any reason. 
To describe the safety profile of 
the combination treatment of 
Nstat with VGCV 
 Incidence and severity of treatment-emergent adverse events (TEAEs). 
Adverse events will be graded according to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
To generate pharmacokinetic 
(PK) data with the intended 
commercial dose and 
administration of Nstat 
 Pharmacokinetic (PK) parameters (eg, time to maximum plasma 
concentration [tmax], maximum plasma concentration [Cmax], area under the 
plasma concentration-time curve [AUC]). 
Exploratory 
Refer to Section 9.6.3 for methods of analysis. 
Explore correlation of baseline 
PD-L1 expression and other 
immune checkpoint molecules 
with outcome 
 Expression of PD-L1 and other immune checkpoint molecules in tumor 
 Tumor-infiltrating lymphocyte (TIL) counts (eg, CD3, CD4, CD8) 
 EBV-associated genes/proteins (eg, EBER, BZLF-1/ZTA, LMP-1, BGLF-
4/PK, BXLF-1/TK, BRLF-1Rta) 
Evaluate potential biomarkers 
of activity of combination 
therapy  
 Histone H3 acetylation 
 Plasma EBV DNA levels 
 RNA expression of selected immunological genes 
 Flow cytometry/IF/IHC for immune cell markers 
Identify potential resistance 
markers to therapy 
EBER, LMP-1, TIL counts, PD-L1 and other immune checkpoint molecules; 
markers related to resistance 
3. 
STUDY DESIGN 
The purpose of this study is to determine the efficacy of the combination treatment of 
nanatinostat with valganciclovir in patients with relapsed/refractory EBV+ lymphomas. 
No therapies are currently established for the treatment of EBV+ lymphoma; with use of standard 
therapies for the lymphoma subtypes, outcomes such as PFS and OS are increasingly recognized 
to be inferior for EBV+ lymphomas such as EBV+ DLBCL (NOS), HL, and PTCL, creating an 
unmet need for these patients. Promising preliminary safety and efficacy of the combination of 
oral nanatinostat and oral valganciclovir has been demonstrated in the VT3996-201 Phase 1b/2 
study in heavily previously treated (median of 2 prior therapies) patients with a variety of 
relapsed/refractory EBV+ lymphomas, 75% of whom were refractory to their most recent therapy 
prior to enrolling in the study (Porcu 2020, Haverkos 2021). 
Since there are no clinical monotherapy data with nanatinostat in lymphoma patients, and other 
HDAC inhibitors have demonstrated activity in patients with PTCL, nanatinostat will also be 
evaluated as monotherapy in patients with PTCL. The first 20 PTCL patients enrolled into the 
study will be randomized to receive nanatinostat monotherapy (n = 10) or nanatinostat plus 
valganciclovir combination therapy (n = 10). Patients receiving nanatinostat monotherapy may 
have the option to cross over to combination therapy (see Section 3.1). 


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An Independent Review Committee (IRC) will be established to determine the ORR. A Study 
Steering Committee (SSC) composed of study Investigators will be established to i) manage the 
overall stewardship of the study according to the protocol, and ii) to recommend and approve any 
modifications needed. 
3.1. 
Description of Study Design 
This is an open-label, multicenter, multinational single-arm, Phase 2 basket design study, 
utilizing Simon’s 2-stage design options for discontinuing enrollment into each cohort where 
treatment appears to be futile (Simon 1989). The study will include 7 cohorts of patients with the 
following EBV+ relapsed/refractory lymphomas: 
 Cohort 1: EBV+ DLBCL, NOS 
 Cohort 2: ENKTL 
 Cohort 3: PTCL, including PTCL-NOS and AITL 
 Cohort 3a: Nanatinostat monotherapy 
 Cohort 3b: Nanatinostat + valganciclovir 
 Cohort 4: HL 
 Cohort 5: PTLD 
 Cohort 6: Lymphomas associated with HIV infection (HIV-L): Plasmablastic, Burkitt, 
Hodgkin, and DLBCL 
 Cohort 7: EBV+ lymphomas other than Cohorts 1, 3, 4, 5, and 6 above (Cohort 7 will not 
enroll patients in France) 
In Stage 1, 6 cohorts (Cohorts 1, 2, 3b, 4, 5, and 6) will enroll up to 10 patients each. Any cohort 
that fails to enroll any patients within 1 year from the date the first patient is enrolled in the 
study will be considered for termination of enrollment. Enrollment in Cohorts 2, 4, and 6 has 
been closed as of 17 October 2023, 24 August 2023, and 24 August 2023, respectively. Patients 
currently enrolled in these cohorts may continue to receive study treatment per protocol until 
which time treatment discontinuation is required as defined in Section 7.2.3.  
All cohorts that have a response in 2 or more patients in Stage 1 will continue to enroll patients 
in Stage 2, for a total of 21 patients in each cohort (Figure 2). If ≥7 responses are observed in the 
initial 21 patients in any cohort, then enrollment will be expanded to include up to 120 additional 
patients in that cohort (N=141), with the possibility of performing an interim efficacy analysis in 
that cohort to be described in the statistical analysis plan.  Cohort 3a will not enroll beyond the 
initial 10 patients, regardless of the number of responders in Stage 1. 
To evaluate the activity of single-agent nanatinostat, the first 20 patients enrolled with PTCL will 
be randomized 1:1 to either nanatinostat monotherapy (20 mg PO once daily on Days 1 to 4 per 
week in Cohort 3a) or nanatinostat plus valganciclovir (in Cohort 3b). Following a disease 
response assessment at 6 weeks, patients in Cohort 3a with a CR or PR will continue nanatinostat 
monotherapy. Those in Cohort 3a with stable disease at 6 weeks or disease progression at any 
time (confirmed by CT or MRI) will have the option to cross over to combination therapy for the 
remainder of the study. Patients must complete the End of Monotherapy Disease assessment and 


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qualify (labs, no sign of CNS disease progression and Eastern Cooperative Oncology Group 
[ECOG]) prior to beginning Cycle 1 Day 1 of the nanatinostat plus valganciclovir combination 
therapy. 
Cohort 7 will be closed to enrollment when all other cohorts are closed, regardless of the number 
of patients recruited at that time and will not be subject to the decision criteria of the Simon’s 2-
stage design. 
It is thus estimated that up to 486 patients in Cohorts 1 to 6 may be enrolled for combination 
therapy, of which approximately 60 would be enrolled in Stage 1, 66 would be enrolled in Stage 
2, and up to 360 would be enrolled in the post-Stage 2 expansion cohorts. Additional patients 
(n=10) with PTCL will be enrolled in Cohort 3a for nanatinostat monotherapy, and patients with 
lymphoma subtypes other than those assigned to Cohorts 1, 3, 4, 5, and 6 may be enrolled into 
Cohort 7 (with the exception of France; see above). 
If 10 patients of a given lymphoma subtype are enrolled into Cohort 7, then the Simon’s decision 
criteria will be applied to determine whether or not to add patients in Stage 2 for that subtype. If 
none of the subtypes represented in Cohort 7 enrolls at least 10 patients, efficacy data collected 
on those patients will be listed, but not summarized by group. All patients will be summarized 
for safety, regardless of decision to discontinue enrollment into any cohort. 
Patients enrolled in Cohorts 1 to 7 (with the exception of Cohort 3a), and patients crossed over 
from Cohort 3a will receive intermittent dosing of nanatinostat and continuous valganciclovir 
in 28-day cycles as follows: 
a. Nanatinostat 20 mg orally once daily on Days 1 to 4 per week (ie, 4 days on, 3 days off) 
b. Valganciclovir 900 mg orally once daily. Patients with a CrCl 50-59 mL/min at study 
entry will receive valganciclovir 450 mg orally once daily as per Table 4. 
For adolescent patients, see Section 5.2.2 for appropriate dosing recommendations for 
valganciclovir.  Patients who develop disease progression but, in the opinion of the Investigator, 
would still benefit from continuing study drug may continue treatment with nanatinostat and 
valganciclovir after agreement with the Sponsor, provided that they are i) asymptomatic from or 
have no overt signs of disease progression; and ii) have a performance status of 0-1. It is 
recommended to perform an interval follow-up radiologic disease assessment before the next 
scheduled time point. Such patients will be recorded as having had a PFS event. 
All patients will be monitored at weekly intervals through the first cycle of treatment, and then at 
2-week intervals thereafter. Tumor response will be evaluated after every 2 cycles × 3, and after 
every 3 cycles thereafter. The responses will be assessed by both the Investigator and an IRC. 


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Figure 2: 
Study Design 
 
 
Note: Patients enrolled with PTCL will be randomized 1:1 to either nanatinostat monotherapy (in Cohort 3a) or 
nanatinostat plus valganciclovir (in Cohort 3b). 
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 
to the central pathology lab should occur as early as possible, and no later than 8 weeks 
following Cycle 1 Day 1 (see Section 4.1.1). The tumor sample will be used for central 
confirmation of EBV status and verification of lymphoma subtype. Additional screening 
evaluations must be performed within 28 days or 14 days before treatment start as defined in the 
Schedule of Events (Section 6.1). At the time of screening, patients should be advised around 
their options to store germ cells. 
3.1.2. 
Treatment Period 
Patient eligibility will be confirmed once all screening procedures are completed. 
Enrolled patients will receive treatment until disease progression (per Investigator assessment), 
unacceptable toxicity, withdrawal of consent, Investigator’s discretion, death, initiation of new 
antineoplastic therapy, discontinuation from the study for any reason, or study termination by the 
Sponsor. Patients receiving nanatinostat monotherapy who have disease progression will be 
offered the option to receive combination therapy with valganciclovir. All antineoplastic 
therapies given after the last dose of study drug (and time to next therapy) will be recorded in the 
electronic case report form (eCRF) (unless the patient withdraws consent or is lost to follow-up). 
Patients will be followed for survival regardless of treatment discontinuation reason (except if 
consent is withdrawn or patient is lost to follow-up). 
3.1.3. 
Safety Follow-up Period 
Upon discontinuation of the protocol-specified treatments, patients will enter the Follow-up 
period. All patients will be followed for AEs for 28 days after the last dose of study drug 
(permanent discontinuation) and complete the Safety Follow-up visit as described in 
Section 7.2.5, except if the patient is lost to follow-up or withdraws consent (see Section 8.1). 
 
 
 
 
 
 
 
   7. Other EBV+ 
 
lymphomas 
Enroll up to 10 patients per 
cohort: 
1. EBV+ DLBCL, NOS 
2. ENKTL 
3a. PTCL (Nanatinostat) 
3b. PTCL (Nanatinostat+VGCV) 
4. HL 
5. PTLD 
6. HIV-L 
If 0-1 responses of
10 patients 
If ≥ 2 responses of 
10 patients 
Drop cohort 
Enroll additional 
patients until 
N=21 per cohort 
Stage 1 
If ≥7 responses of 
21 patients 
Enroll additional 
patients up to 120 
per cohort (N=141) 
If ≤6 responses of
21 patients 
Drop cohort 
Stage 2 
Expansion 


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3.1.4. 
Long-term Follow-up Period 
In the Long-term Follow-up period, patients will be followed-up as described in Section 7.2.6 
(or more frequently if a survival update is required for safety or regulatory reasons) for disease 
progression, OS, subsequent anti-lymphoma therapies, and response (best overall responses 
and disease progression date) to subsequent lymphoma therapies. Survival information can be 
obtained by phone calls, clinic visits, or public records, such as government census or death 
records, until the patient is lost to follow-up, death, or withdraws consent. 
3.1.5. 
Timing of Analyses 
Because of the open-label single treatment regimen design elements, each cohort will be 
monitored individually for safety and efficacy. Therefore, each cohort may move from Stage 1 
to Stage 2 and complete Stage 2 at different rates. The decision to expand enrollment will also 
occur independently for each cohort. However, a study-wide analysis of response and safety over 
all cohorts will be performed once all cohorts have either discontinued or completed assessments 
of response at the end of Stage 2 and those with responses have been followed for up to 3 years. 
3.1.6. 
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 SD 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 drugs on an individual basis 
(eg, by separate protocol or post-trial access plan) with Sponsor approval. 
4. 
SELECTION OF STUDY POPULATION 
Patients must have a histologically confirmed diagnosis of relapsed EBV+ lymphoma, must have 
been previously treated for their lymphoma with systemic therapy, must be refractory to or have 
relapsed after their last treatment, must have at least one measurable lesion by computed 
tomography (CT) or magnetic resonance imaging (MRI) scan, and must have adequate bone 
marrow function, liver function, and renal function. 
The eligibility criteria are designed to limit enrollment to patients who have relapsed/refractory 
EBV+ lymphoma and who are sufficiently well to safely participate in study procedures 
and provide interpretable results. Prior therapy provisions are intended to define patient 
subgroups that have already received available/standard of care therapies with well-defined 
activities. 


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4.1. 
Patient Population 
4.1.1. 
Inclusion Criteria 
To be eligible for study participation, patients must meet all the following inclusion criteria: 
1. Adult patients age ≥18 years or as permitted by applicable local regulations at the time of 
providing informed consent. Patients must be able to swallow whole tablets. 
a. For patients with PTLD: Age ≥12 years and weighing ≥40 kg.  
2. Histologically confirmed (by 2016 WHO classification (Swerdlow 2016)) EBV+ 
lymphoma* per local laboratory by EBER-ISH (or for PTLD only, by LMP-1 
immunohistochemistry) on a representative disease specimen. Any degree of EBER-ISH 
or LMP-1 positivity is considered to be eligible (ie, there is no cut-off value for % 
positive cells). 
* Tumor cells are EBV+, with the exception of AITL, which is characterized by EBV-
negative neoplastic T cells and EBV+ associated B-lineage cells (of 
immunoblastic/plasmablastic immunophenotype)  
a. A recent FFPE specimen must be available for retrospective central review of 
diagnosis. FFPE tissue blocks are preferred; if a tissue block is not available, at least 
15 unstained slides or freshly cut serial sections (3−5 μm in thickness), preferably 
with an accompanying block punch will be accepted. The specifications for the age of 
the tumor samples are: 
 For patients with ENKTL, AITL, PTLD and HIV-L: preferably ≤1 year old. 
For tumor specimens >1 year old, please consult the Medical Monitor to discuss 
eligibility. 
 For patients with all other lymphoma subtypes: preferably ≤6 months old. 
For tumor specimens >6 months old, please consult the Medical Monitor to 
discuss eligibility. 
3. For patients with EBV+ DLBCL, NOS: Relapsed or refractory disease following 1 or 
more prior systemic therapy(ies) with curative intent. Patients must have received at least 
one course of an anti-CD20 immunotherapy such as rituximab, and at least one course of 
anthracycline-based chemotherapy (unless contraindicated, in which case, an accepted 
anthracycline-free alternative for DLBCL was given). 
4. For patients with ENKTL: Relapsed or refractory disease following 1 or more prior 
systemic therapy(ies) with a curative intent. Patients must have failed an asparaginase-
containing regimen. 
5. For patients with PTCL (PTCL, NOS and AITL): Relapsed or refractory disease 
following 2 or more prior systemic therapy(ies) with a curative intent.  
6. For patients with HL: Patients must have received at least one course of anthracycline-
based chemotherapy (unless contraindicated, in which case, an accepted anthracycline-
free alternative for HL was given). Patients with relapsed/refractory classical Hodgkin 
lymphoma(cHL) should have failed or be ineligible for an anti-PD-1 agent (eg, 
pembrolizumab, nivolumab) and CD30-directed therapy (ie, brentuximab vedotin). 


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7. For patients with PTLD: Patients with relapsed or refractory EBV+ PTLD who have 
received at least one prior therapy must have received at least one course of an anti-CD20 
immunotherapy such as rituximab. For solid-organ transplant (SOT) patients, prior 
therapy also includes chemotherapy, administered concurrently or sequentially, unless 
chemotherapy is inappropriate. 
8. For patients with the following lymphomas associated with HIV infection: plasmablastic, 
Burkitt, Hodgkin, and DLBCL.  
a. Prior therapy requirements for DLBCL and HL are specified in inclusion criteria 3 
and 6. 
b. France only: For Burkitt and plasmablastic lymphoma – Patients must have received 
a regimen such as EPOCH, CODOX-M (original or modified; cyclophosphamide, 
vincristine, doxorubicin, and high-dose methotrexate) or Hyper-CVAD 
(cyclophosphamide, vincristine, doxorubicin, and dexamethasone), including CNS 
prophylaxis or therapy. 
9. Patients with HIV-L should meet the following criteria for inclusion:  
a. Currently on a stable regimen of anti-retroviral therapy (ART) 
b. Compliant with ART and follow-up according to the investigator  
c. No evidence of a worsening HIV viral load (as assessed by HIV quantitative 
polymerase chain reaction [qPCR]) 
d. CD4 count >50 cells/mm3 
10. No available standard therapies in the opinion of the Investigator. 
11. Not eligible for high-dose chemotherapy with allogeneic/autologous stem cell 
transplantation or CAR-T therapy at the time of study entry. 
12. Presence of at least one bi-dimensionally measurable lesion by CT or MRI: longest 
diameter (Ldi) >1.5 cm for a nodal lesion; Ldi >1.0 cm for an extranodal lesion within 28 
days prior to start of treatment.  
13. Able to provide a prior core or excisional biopsy for biomarker analysis at screening. If 
no tissue is available, then a new biopsy must be performed. 
14. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
15. All acute toxic effects of any prior anti-tumor therapy resolved to Grade ≤1 before 
initiation of study treatment (excluding alopecia and stable Grade 2 sensory neuropathy). 


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16. Required baseline laboratory data (within 2 weeks prior to start of study drug 
administration) as shown in the table below: 
System 
Laboratory Value 
Hematology 
 
Absolute neutrophil count (ANC) 
≥1000/mm3 (no growth factor support within 14 days) 
Platelets 
≥50,000/mm3 (no platelet transfusion within 14 days) 
Hemoglobin 
≥8.0 g/dL (no red cell transfusion within 21 days) 
Renal 
 
Creatinine clearance 
≥50 mL/min (Cockcroft-Gault) 
Hepatic 
 
Total bilirubin 
≤2.0 × upper limit of normal (ULN) 
(except patients with documented Gilbert’s syndrome 
[<3.5 × ULN]) 
Aspartate aminotransferase 
(AST [SGOT]) and alanine 
aminotransferase (ALT [SGPT]) 
≤3.0 × ULN (or ≤5.0 × ULN if liver involvement by 
primary disease)  
Coagulation 
 
International normalized ratio (INR) 
Activated partial thromboplastin time 
(aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy (as long as INR or aPTT are 
within the therapeutic range of intended use of 
anticoagulants) 
17. Life expectancy >3 months. 
18. Women of childbearing potential (ie, reached menarche, and not premenarchal or 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 true abstinence from heterosexual intercourse: When this is in line with 
the preferred and usual lifestyle of the patient (Periodic abstinence [eg, calendar, 
ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the 
duration of exposure to the investigational medicinal product [IMP], or the 
withdrawal method are not acceptable forms of contraception). Otherwise, begin a 
highly effective method of birth control with a Pearl-Index <1%, without interruption, 
throughout the study dosing period and for 6 months after the last dose of 
nanatinostat. Apart from abstinence, highly effective methods of birth control include 
the following: 
o Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, transdermal). Please 
note: Although the potential for drug interactions and risk of venous 


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thromboembolism is low (see Section 5.5.2.3), the use of an alternative method 
of contraception is recommended. 
o Progestogen-only hormonal contraception associated with inhibition 
of ovulation (oral, injectable, implantable). 
o Intrauterine device (IUD). 
o Intrauterine hormone-releasing system (IUS). 
o Bilateral tubal occlusion. 
o Vasectomized partner. 
19. Male patients must agree to use condoms during intercourse throughout the study dosing 
period and for 90 days after the last dose of nanatinostat. Female partners of male patients 
participating in the study are to consider the use of effective methods of contraception 
while their partner is treated on study and for 90 days after the last administration of 
nanatinostat. 
20. The patient is willing and able to provide informed consent and comply with the protocol. 
Assent must be obtained for adolescent patients <18 years old, or as permitted by 
applicable local regulations, and a parent/guardian must provide written consent.  
4.1.2. 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. Presence or history of central nervous system (CNS) involvement by lymphoma. 
2. Systemic anticancer therapy within 21 days prior to Cycle 1 Day 1 dosing. 
3. Antibody (anticancer) agents within 28 days of Cycle 1 Day 1 dosing. 
4. Less than 14 days from prior local site radiation therapy. 
5. Less than 60 days from prior autologous hematopoietic stem cell or solid organ 
transplant. 
6. Less than 21 days from prior CAR-T therapy (any AEs must be Grade 1 or less for 
enrollment). 
7. Less than 90 days from prior allogeneic transplant. 
8. Receiving systemic corticosteroids during the last week prior to Cycle 1 Day 1, unless 
administered at a dose equivalent to ≤20 mg/day of prednisone. 
9. For recipients of prior allogeneic HSCT: Receiving systemic immunosuppressants as 
either prophylaxis or treatment for graft-versus-host disease (GvHD).  
10. Major surgery within 28 days within the first dose of study drug. In the case of recent 
major surgery, the patient must have recovered adequately from the procedure and/or any 
complications prior to starting study treatment. 
 Note: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter 
placement, shunt revision) is permitted within 3 weeks prior to enrollment. 


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11. 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. 
12. History of other malignancy that could affect compliance with the protocol or 
interpretation of results. Patients with any malignancy appropriately treated with curative 
intent and the malignancy has been in remission without treatment for 2 years prior to 
enrollment are eligible. Also eligible are the following: 
 Curatively treated: 
i. 
Basal cell, squamous cell carcinoma, or melanoma of the skin (at any time prior 
to the study). 
ii. 
Cervical carcinoma in situ (at any time prior to the study). 
 Low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with 
no requirement for therapy at any time prior to study, or previously fully resected. 
13. Inability to take oral medication, malabsorption syndrome or any other gastrointestinal 
condition (nausea, diarrhea, vomiting) that may impact the absorption of nanatinostat 
and valganciclovir. 
14. Active GvHD. 
15. Positive hepatitis B core antibody or surface antigen unless DNA qPCR is negative, and 
patient will be receiving prophylaxis for reactivation. 
16. Positive hepatitis C virus on RNA polymerase chain reaction (PCR). 
17. Known SARS-CoV-2 positivity by any testing method at time of screening. Patients with 
a positive PCR test should only be enrolled if ≥10 days have passed since COVID 
symptoms first appeared and they have recovered from symptoms or have mild 
symptoms. 
18. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to valganciclovir or nanatinostat. 
19. Active infection requiring systemic therapy (excluding viral upper respiratory tract 
infections). Patients may be receiving prophylactic antiviral, antifungal or antibacterial 
therapies at the discretion of the Investigator. 
20. 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). 
21. Receiving concomitant drugs that are inhibitors of P-glycoprotein (P-gp) and/or 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). 


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22. Psychiatric illness/social situations/substance abuse disorder that would interfere with 
compliance with study requirements. 
23. Has a prior or ongoing clinically significant illness such as New York Heart Association 
Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable 
arrhythmias, or unstable angina, or pulmonary disease, 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 compliance with the protocol, or is not in the 
best interest of the patient to participate. 
24. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening visit through 6 months after 
the last dose of nanatinostat. 
5. 
STUDY TREATMENT PRODUCT INFORMATION 
For this study, the term “study treatment” refers to the combination of nanatinostat 
and valganciclovir, except for those patients enrolled into Cohort 3a (nanatinostat monotherapy 
for the first 6 weeks). 
5.1. 
Nanatinostat 
5.1.1. 
Dosage Form and Composition 
Nanatinostat is available as 10 mg tablets. Instructions for requesting and receiving nanatinostat 
from the Sponsor will be included in the Pharmacy Manual. Nanatinostat will be dosed on a flat 
scale of mg/day. 
Nanatinostat film coated immediate-release (IR) 10 mg tablets consist of the active nanatinostat 
(VRx-3996), and inactive excipients (ie, mannitol, microcrystalline cellulose, croscarmellose 
sodium, sodium stearyl fumarate, and coating material).  
All inactive ingredients in the drug product meet compendial requirements of the United States 
Pharmacopeia (USP) 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 15 to 30ºC (59 to 86ºF). Once the bottle seal is broken, 
bottles should be stored tightly capped. 
5.1.3. 
Nanatinostat Administration 
All patients will receive nanatinostat 20 mg orally once daily on Days 1 to 4 per week (ie, 4 days 
on, 3 days off). Patients will continue dosing in 28-day cycles until discontinuation as described 
in Section 7.2.3. 
There are no special dietary restrictions or requirements associated with nanatinostat, however 
valganciclovir absorption is affected by food and it should be taken with food (see Section 5.2.2 


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for additional clarification). Valganciclovir and nanatinostat should be taken at the same time 
following a light meal.  
On study visit days requiring PK trough levels, patients will be asked to consume one can of 
Ensure® or equivalent or consume a light breakfast in place of consuming an Ensure® equivalent 
prior to dosing in order to avoid taking study drugs on an empty stomach (see Section 5.3). 
See Section 5.5.2 for medications to be used with caution with nanatinostat. 
5.2. 
Valganciclovir 
Valganciclovir is available as 450 mg tablets. Valganciclovir tablets will be provided to the 
investigational sites by Viracta. Instructions for requesting and receiving valganciclovir will be 
included in the Pharmacy Manual. Valganciclovir tablets must not be broken or crushed. 
Valganciclovir tablets consist of the active valganciclovir hydrochloride, and inactive excipients 
(ie, microcrystalline cellulose, povidone K-30, crospovidone, magnesium stearate or stearic acid 
and coating material). 
5.2.1. 
Valganciclovir Study Drug Storage 
Valganciclovir should be stored at controlled room temperature (20 to 25ºC, 68 to 77ºF) in a 
secure location. Excursions are permitted to 15 to 30ºC (59 to 86ºF). Once the bottle seal is 
broken, bottles should be stored tightly capped.  
5.2.2. 
Valganciclovir Administration 
The daily dose of valganciclovir for patients ≥17 years of age is 900 mg orally (continuous 
treatment) in combination with nanatinostat. Patients with a CrCl 50-59 mL/min at study entry 
will receive valganciclovir 450 mg orally once daily as per Table 4. Patients will continue to 
receive nanatinostat plus valganciclovir in 28-day cycles until discontinuation as described in 
Section 7.2.3. 
The daily dose of valganciclovir for patients ≤16 years of age is based on body surface area 
(BSA) and CrCl derived from a modified Schwartz formula, and is calculated using the equation 
below: 
                         Adolescent dose (mg) = 7 x BSA x Schwartz Creatinine Clearance 
 
Note: k value is 0.55 (boys <13 years and girls <16 years) or 0.7 (boys aged 13 to 16 years). 
 
Patients should be monitored for serum creatinine levels regularly, consider changes in height 
and body weight, and adapt the valganciclovir dose as appropriate. Valganciclovir tablet dose is 


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determined based on the calculated valganciclovir dose in mg and available tablet strength (450 
mg) ±10% range of the tablet strength. For example, if the calculated dose exceeds 900 mg, a 
maximum dose of 900 mg should be administered. If the calculated dose is between 900 mg and 
810 mg, a 900 mg dose (two 450 mg tablets) should be taken. If the calculated dose is between 
809 mg and 405 mg, 450 mg dose (one 450 mg tablet) should be taken. 
Adequate hydration should be maintained for all patients. For patients who develop an elevated 
creatinine while on study, their dose of valganciclovir should be adjusted (see Section 5.4.1). 
In patients who are unable to tolerate oral dosing of valganciclovir, the Investigator will have 
the option of administering ganciclovir intravenously (IV) at 5 mg/kg QD. In patients who are 
receiving a dose of valganciclovir less than 900 mg orally once daily, the dose of ganciclovir will 
be reduced accordingly using the ratio of 900 mg valganciclovir to 5 mg/kg ganciclovir. 
Valganciclovir absorption is affected by food. Therefore, 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 
during the study must be accurately recorded in the eCRFs. 
5.3. 
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® or equivalent, prior to the dose of study drugs (within 30 minutes) on days 
with pre- and post-dose PK assessments as outlined in Section 7.3.3. Note that valganciclovir 
and nanatinostat should be taken at the same time, including on Cycle 1 Day 1. 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® equivalent and should start the meal 30 minutes 
before administration of valganciclovir and nanatinostat. 
See Section 5.5.3 for medications to be used with caution with valganciclovir. 
5.4. 
Dose Modifications of Nanatinostat and Valganciclovir 
For patients who do not tolerate the protocol-specified dosing schedule, or develop toxicities, 
dose adjustments are permitted to allow the patient to continue study treatment. Dose 
adjustments, except for valganciclovir adjustments based on renal function (Section 5.4.1) 
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. Requirements for dose modifications and criteria for resumption of 
dosing are presented in Table 3. 
Table 3: 
Dose Modification Guidelines for Study Treatment-Related Toxicity 
NCI CTCAE v5.0 
Toxicity Grade 
Action to be Taken with Study Drugs 
Grade 4 neutropenia 
(ANC <0.5 × 109/L) 
 Interrupt nanatinostat/valganciclovir dosing. 
 Resume nanatinostat/valganciclovir at the same doses when 
ANC ≥1.0 × 109/L. 


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NCI CTCAE v5.0 
Toxicity Grade 
Action to be Taken with Study Drugs 
 If the grade 4 neutropenia lasts more than 7 days or recurs, then reduce 
valganciclovir to 450 mg orally daily. If the reduced dose is tolerated for 
≥4 weeks, then the valganciclovir dose may be increased to 900 mg 
daily. 
 Use of growth factors (G-CSF, GM-CSF) is permitted as per the ASCO 
2015 clinical practice guidelines (Smith 2015). 
Grade 3 neutropenia 
(ANC 0.5 – <1.0 × 109/L) 
 If persistent (>7 days) then interrupt nanatinostat/valganciclovir dosing. 
Resume nanatinostat/valganciclovir at the same doses when 
ANC ≥1.0 × 109/L. If recurs and persists >7 days, then consider reducing 
valganciclovir to 450 mg orally daily. 
 Use of growth factors (G-CSF, GM-CSF) is permitted as per the ASCO 
2015 clinical practice guidelines (Smith 2015). 
Grade 4 thrombocytopenia 
(Platelet count <25 × 109/L) 
 Interrupt nanatinostat/valganciclovir dosing. 
 If thrombocytopenia resolves to ≤Grade 2 (>50 × 109/L), then restart 
both drugs. 
 If recurs, then consider reducing valganciclovir to 450 mg orally daily. 
Grade 3 anemia 
(Hemoglobin <8.0 g/dL) 
 Interrupt nanatinostat/valganciclovir dosing. 
 If anemia resolves to ≤Grade 2 (≥8.0 g/dL), then restart both drugs. 
 If recurs, then consider reducing valganciclovir to 450 mg orally daily.  
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) 
 Interrupt nanatinostat/valganciclovir dosing. 
 Resume nanatinostat/valganciclovir at the same doses when 
ANC ≥1.0 × 109/L. 
 Use of growth factors (G-CSF, GM-CSF) is permitted as per the ASCO 
2015 clinical practice guidelines (Smith 2015). 
QTc prolongation 
For QTc interval >450 msec and ≤480 msec: Check magnesium and 
potassium levels and correct any abnormalities. If possible, stop any 
medications that may prolong the QTc interval. Continue 
nanatinostat/valganciclovir at the same dose. 
For QTc interval >480 msec and <500 msec: Check magnesium and 
potassium levels and correct any abnormalities. If possible, stop any 
medications that may prolong the QTc interval. Decrease nanatinostat to 
10 mg once daily, days 1 to 4/7 for the remainder of the cycle. 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 10 mg once daily, days 1–4/7. 
For QTc interval >500 msec: Check magnesium and potassium levels 
and correct any abnormalities. Interrupt nanatinostat/valganciclovir dosing 
and stop any medications that may prolong the QTc interval. If the QTc 
interval improves to ≤470 msec just prior to the start of the next cycle, 
resume nanatinostat/valganciclovir at the initial dose. If no other cause of 
QTc prolongation is identified, reduce dose of nanatinostat to 10 mg once 
daily, days 1-4/7. 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 or clinically significant laboratory 
abnormalities: Discontinue nanatinostat/valganciclovir dosing. 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 Viracta.  


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NCI CTCAE v5.0 
Toxicity Grade 
Action to be Taken with Study Drugs 
Grade 3 non-hematologic AE or clinically significant laboratory 
abnormalities: withhold dose until toxicity resolves to ≤Grade 1 and resume 
nanatinostat/valganciclovir at the same dose. 
Abbreviations: ANC = absolute neutrophil count; 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.  
 
Patients should be monitored approximately twice weekly for 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 6.1). If the dose interruption extends beyond 
the end of the cycle, the subsequent cycle will not begin until dosing has resumed. If the dose is 
held for more than 14 days, the Investigator should consult with the 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 should be considered. Re-escalation of study drug dose may only 
be performed after approval by Medical Monitor. 
5.4.1. 
Dose Modifications for Patients with Renal Impairment 
Patients ≥17 years of age who develop an elevated creatinine while on study should have their 
creatinine clearance (CrCl) recalculated and dose of valganciclovir adjusted per Table 4. 
An estimated CrCl 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 4, 
the Investigator should discuss the amount of dose reduction with the Medical Monitor. 


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Table 4: 
Valganciclovir Dosing for Patients with Renal Impairment 
Creatinine Clearance (mL/minute) 
Valganciclovir Dose 
≥60 
900 mg once daily 
40–59 
450 mg once daily 
25–39 
450 mg every 2 days 
10–24 
450 mg twice weekly 
<10 (on hemodialysis) 
Not recommended (discuss with Medical Monitor) 
Source: Valcyte USPI 2021(Genentech 2021) and SmPC 2018 (Roche 2018) 
Note: Patients ≥17 years of age receiving hemodialysis (CrCl less than 10 mL/min) cannot use valganciclovir 
tablets because the daily dose of valganciclovir tablets required for these patients is less than 450 mg. In this case 
the Investigator will have the option of administering ganciclovir IV at 5 mg/kg QD, after discussion with the 
Study Medical Monitor. 
Patients 12 to 16 years of age who develop an elevated creatinine while on study should have 
their CrCl recalculated (by a modified Schwartz formula per Section 5.2.2) and dose of 
valganciclovir adjusted based on body surface area (BSA). 
5.4.2. 
Missed or Vomited Doses 
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, but within 8 hours of the missed dose. If more 
than 8 hours or an entire day has passed, the normal dosing schedule will be resumed the 
following day without a change in the daily dose or schedule. 
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 
scheduled dose. No replacement dose should be given. If the situation persists, the site should 
consult the Medical Monitor. 
5.5. 
Prior and Concomitant Medications 
Prior and concomitant medications include all vitamins, vaccinations, herbal remedies and 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 and valganciclovir. Patients are not allowed to participate 
concurrently in any other therapeutic study. 
5.5.1. 
Permitted Concomitant Medications 
During the time on study treatment, 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 (see Section 5.5.4). 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. 


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5.5.1.1. 
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 3). The American Society of Clinical Oncology (ASCO) clinical 
practice guidelines should be followed (Smith 2015). Hematopoietic growth factors may not be 
used to allow for patient eligibility at screening. 
5.5.2. 
Concomitant Therapy Requiring Caution and/or Action 
5.5.2.1. 
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-lymphoma 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. 
5.5.2.2. 
Proton-Pump Inhibitors 
The effect of gastric pH on nanatinostat absorption is not known. Proton-pump inhibitors and H2 
antagonists should be excluded from patient use if possible. If they must be given, then do not 
administer proton-pump inhibitors, H2 antagonists, or antacids within 2 hours prior or within 
4 hours post-nanatinostat administration. 
5.5.2.3. 
Concomitant Therapies to be Used with Caution with Nanatinostat 
A study with recombinant human cytochrome P450 isoforms (CYP450) suggests that 
nanatinostat is a direct inhibitor of CYP3A4 isoform. In vitro studies indicated that nanatinostat 
is not metabolized by or induces the 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 11). Please refer to the IB for a detailed description. 
Select antiretroviral therapies (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 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 12). 


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5.5.3. 
Concomitant Therapies to be Used with Caution with Valganciclovir 
Drug-drug interaction studies with ganciclovir/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. 
5.5.4. 
Prohibited Medications 
The following medications/therapies are prohibited during the study 
 Other investigational and antineoplastic therapies, including anti-CD20 agents 
 Prednisone >10 mg per day (or equivalent) 
 Live vaccines  
 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. 
5.6. 
Patient Numbering & Treatment Assignment 
5.6.1. 
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.). 
5.6.2. 
Treatment Assignment (Including Randomization) 
Patients will be enrolled into each cohort based on their primary lymphoma diagnosis to receive 
the combination nanatinostat plus valganciclovir with exception of Cohort 3a. 
The first 20 patients enrolled with PTCL in Cohort 3 will be randomized 1:1 to either Cohort 3a 
(nanatinostat monotherapy) or Cohort 3b (nanatinostat plus valganciclovir). Randomization will 
occur at the time of drug dispensation for Cycle 1 Day 1. Following a disease response 


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assessment at 6 weeks, patients in Cohort 3a with a CR or PR will continue nanatinostat 
monotherapy. Those in Cohort 3a with stable disease at 6 weeks or disease progression at any 
time will be offered the option to cross over to combination therapy for the remainder of the 
study, provided they qualify per hematology, chemistry, no sign of CNS disease progression, and 
ECOG parameters (see Section 4.1.1).  
5.6.3. 
Treatment Blinding 
This is an open-label study; therefore, treatment assignments will not be blinded. 
5.7. 
Study Drug Preparation and Dispensation 
5.7.1. 
Study Drug Packaging and Labelling 
The study drugs 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) 
and Section 5.2 (valganciclovir). 
5.7.2. 
Drug Supply and Storage 
Drug supply and storage is described in Section 5.1 (nanatinostat) and Section 5.2 
(valganciclovir). Additional information is provided in the Pharmacy Manual. 
5.7.3. 
Study Drug Compliance and Accountability 
5.7.3.1. 
Study Drug Compliance 
Patient compliance with 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 document at each patient visit. 
Paper diaries will be utilized to record doses and collect tablet counts. 
5.7.3.2. 
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 
dates, quantity, lot numbers, and use by patients. Drug accountability will be reviewed during 
monitoring visits and at the completion of the study. 
5.7.4. 
Study Drug Handling and Disposal 
Upon completion of the study, all remaining study drugs at the sites will be accounted for and 
returned to the Sponsor, or their designee, via a traceable method (UPS, FedEx, etc.) or disposed 
following institution’s Standard Operating Procedures (SOPs), if instructed by the Sponsor. 
 


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6. 
SCHEDULE OF EVENTS 
The Schedule of Events provided in Section 6.1 lists all the on-study assessments and the visit 
dates when they are to be performed. Every effort should be made to follow the schedule 
outlined in the Schedule of Events. Allowed visit windows are specified as follows: 
a. Screening assessments per the Schedule of Events must occur within 28 days (14 days for 
laboratory assessments, urinalysis, and pregnancy test) of Cycle 1 Day 1. 
b. Vital signs, ECOG performance status, and physical exam should be performed within 
28 days of start of study drug (Cycle 1 Day 1). Required laboratory assessments should 
be performed within 14 days of the start of study drug (Cycle 1 Day 1). 
c. Radiologic assessments must be performed as indicated in Section 6.1. A visit window of 
±7 days is allowed. Radiological assessments should stay on schedule even if there are 
dose holds. 
d. For all other visits, a general ±3-day window is permitted on assessments; the disease 
assessments window is ±7 days. 
 
 


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6.1. 
Schedule of Events Tables 
Table 5: 
Visit/Evaluation Schedule 
 
Screeninga 
Cycle 1 (±3 days) 
Cycle 2 
(±3 days) 
Cycles 3+ 
(±3 days) 
EOT 
Safety 
Follow-upb 
(±3 days) 
Long-Term 
Follow-up 
(±7 days) 
Day(s) of Cyclec -28 to -1 -14 to -1
1 
8 
15 
22 
   4 
15 
1 (or 
4 in 
Cycle
6) 
15 
+14 Days 
After Last 
Dose 
+28 Days 
After Last 
Dose 
Without
PD (q12 
weeks) 
With PD
(q6 
months)
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 
 
 
FFPE tumor specimend 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Weight 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Height  
X 
 
Xw 
 
 
 
Xw 
 
Xw 
 
 
 
 
 
ECOG performance status 
X  
 
X 
 
 
 
X 
 
X  
 
X 
 
 
 
Vital signse  
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chemistryg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Creatinine clearance 
(Cockcroft-Gault estimation)h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Screeninga 
Cycle 1 (±3 days) 
Cycle 2 
(±3 days) 
Cycles 3+ 
(±3 days) 
EOT 
Safety 
Follow-upb 
(±3 days) 
Long-Term 
Follow-up 
(±7 days) 
Day(s) of Cyclec -28 to -1 -14 to -1
1 
8 
15 
22 
   4 
15 
1 (or 
4 in 
Cycle
6) 
15 
+14 Days 
After Last 
Dose 
+28 Days 
After Last 
Dose 
Without
PD (q12 
weeks) 
With PD
(q6 
months)
Serum immunoglobulinsi 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Coagulationf 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine pregnancy testk
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Xq12wks for 
6 mos 
Xq12wks for 
6 mos 
Disease assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT with contrast (or MRI) of 
brain  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
18FDG-PET/CTl 
X 
 
 
 
 
 
 
 
XWks 
8, 16 
 
 
 
 
 
CT with contrast (or MRI) of 
neck, chest, abdomen, 
and pelvism 
X 
 
 
 
 
 
 
 
XWks 
8, 16, 24 
+ q12wks
 
X 
 
Xq12wks 
 
Bone marrow biopsyn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGo 
X 
 
[X] 
 
 
 
 
 
 
 
X 
 
 
 
Adverse events  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CMV, HHV-6, HHV-8, HIV 
levelsp 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
EBV DNA levelsp 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling (Stage 1)q 
 
 
 
 
 
 
[X]q 
 
[X]q 
 
 
 
 
 
 


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Screeninga 
Cycle 1 (±3 days) 
Cycle 2 
(±3 days) 
Cycles 3+ 
(±3 days) 
EOT 
Safety 
Follow-upb 
(±3 days) 
Long-Term 
Follow-up 
(±7 days) 
Day(s) of Cyclec -28 to -1 -14 to -1
1 
8 
15 
22 
   4 
15 
1 (or 
4 in 
Cycle
6) 
15 
+14 Days 
After Last 
Dose 
+28 Days 
After Last 
Dose 
Without
PD (q12 
weeks) 
With PD
(q6 
months)
PK sampling (Stage 2)q 
 
 
 
 
 
 
Xq 
 
 
 
 
 
 
 
Biomarkersr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunophenotype 
and function, and mutation 
analysiss 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Histone acetylationt 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
On-study biopsy/fine needle 
aspirate (optional with disease 
progression or relapse)u 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Nanatinostat/valganciclovir 
dispensing/return 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Anti-lymphoma therapies 
since discontinuation of study 
treatment and responsev 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Survival assessmentv 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: 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; HHV = human herpesvirus; HIV = human immunodeficiency virus; mo = 
month; MRI = magnetic resonance imaging; PD = progressive disease; 18FDG-PET = fluorodeoxyglucose positron emission tomography; PK = pharmacokinetic; q = once; wk = 
week. 
Note: Brackets (“[X]”) indicate procedures performed in Stage 1 only. 
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 14 days of 
Cycle 1 Day 1. 
b. Safety Follow-up – Visit must be conducted in-person. 
c. Visit windows – There is a ±3-day window allowable for each clinic visit. The End of Treatment visit must be completed within 14 days after the last dose. 
The Safety Follow-up visit has a +3-day allowable window, and Long-term Follow-up has a ±7-day allowable window. For disease assessments, a ±7-day 
window is allowable (not applicable during Screening). 
d. Formalin-Fixed Paraffin-Embedded (FFPE) tumor specimen – 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 15 unstained slides of a representative tumor specimen 


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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. 
A recent biopsy is ideal, but if not available, an archival biopsy may be submitted, provided the tumor specimen meets the criteria described in Section 7.1.5. 
The specimen must be representative of the current disease (eg, for patients who have relapsed, the biopsy specimen should have been taken after the most 
recent relapse). Details will be discussed in the separate Pathology Manual. 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. 
e. Vital signs – Vital signs include heart rate, blood pressure, and temperature. For patients requiring serial PK draws and ECGs, vital signs should be collected 
following ECGs and prior to the PK blood draw at pre-dose and 1, 2, and 4 hours post-dose on Cycle 2 Day4 (ECG and vital signs are not performed at the 6-
hour post-dose PK draw). At time points requiring ECGs, vital signs, and PK blood draws, assessments should be performed in as short of a timeframe as 
possible and in this order: ECG, vital signs, then blood draw. 
f. Hematology and coagulation – Hematology includes complete blood count to include white blood cells (WBCs) with differential, red blood cells (RBCs), 
hemoglobin (Hgb), hematocrit, platelets, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH). Coagulation includes prothrombin 
time (PT) or International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT). 
g. Chemistry – Chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, phosphate, magnesium, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, total protein, albumin, uric acid, lactate 
dehydrogenase (LDH), and serum amylase. 
h. Creatinine clearance (Cockcroft-Gault estimation) – The Cockcroft-Gault formula will be used to calculate estimated creatinine clearance (CrCl): 
 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 5.4.1 for patients who develop creatinine elevations/impaired renal function while 
on study. 
i. Serum immunoglobulins – Samples will be collected to evaluate serum immunoglobulins including quantitative levels of IgA, IgE, IgG and IgM. Samples 
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 the EOT visit. 
j. 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 patient positive for HCV Ab will be evaluated by qPCR). 
k. Pregnancy testing – Pregnancy testing is only required for females of childbearing potential. Serum test must be performed during screening. Serum or urine 
tests are to be performed at the beginning of each cycle, the EOT visit, the 28-day Safety Follow-up visit, and every 12 weeks for 6 months following the last 
dose of study drug. 
l. 
18FDG-PET/CT – Scans will be performed at Screening, Week 8, Week 16 (±7 days), and subsequently for evaluation of a possible CR or PR. Diagnostic 
contrast-enhanced CT scans obtained as part of a PET/CT scan may be used in lieu of dedicated CT scans. 
m. CT with contrast (or MRI) of neck, chest, abdomen, and pelvis – A diagnostic contrast-enhanced CT (or MRI, if CT contraindicated) will be conducted 
at Screening, Week 8, and Week 16, Week 24 then every 12 weeks until relapse or disease progression (Week 36, 48, 60, etc.), ±7 days. MRI may be 
performed only if CT with contrast is contraindicated in the opinion of the Investigator or if frequent CT scans are not allowed according to local IRB/IEC. 
The same imaging modality used at screening must be used for all response evaluations throughout the study to ensure consistency across the different time 
points for each patient. A scan to confirm an unconfirmed PR or unconfirmed CR ≥4 weeks later may also be performed. 
For patients who discontinue due to relapse/progression, the EOT visit 18FDG-PET/CT and/or CT with contrast is not needed if the last scan was within 
4 weeks of the EOT visit. 


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n. Bone marrow biopsy – A recent bone marrow biopsy, conducted within 12 weeks of Cycle 1 Day 1, is acceptable as the screening biopsy (if the biopsy is 
available for review by central pathology). If no such recent bone marrow biopsy is available, then re-biopsy will be required prior to enrollment except as 
noted in Section 7.1.7.2. During the study, a repeat bone marrow biopsy is required only for patients who have attained a complete response (CR) and had 
bone marrow involvement at screening. The bone marrow biopsy should be performed within 28 days after the criteria for radiological CR have been met. 
For patients with Hodgkin lymphoma and DLBCL, a baseline bone marrow biopsy is not necessary if the PET/CT demonstrates bone disease. 
o. 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. For patients enrolled in Stage 1, ECGs will be performed in triplicate as follows: 2 ECGs will be performed pre-dose within 1 hour of dosing at 
least 15 minutes apart. Post-dose ECGs will be performed prior to and as close as possible to PK blood draws at 1, 2, and 4 hours post-dose on Cycle 2 Day 4. 
An additional triplicate ECG will be obtained at screening, Day 46 (Cohort 3a only) visit, and EOT. Detailed instructions on ECGs are provided in 
Section 7.3.2.8 and in the separate ECG Manual. 
p. EBV, CMV, HHV-6, HHV-8, HIV levels – Plasma samples will be collected to investigate circulating EBV, HHV-8, HHV-6, CMV, and HIV (HIV+ 
patients only). EBV levels will be utilized for both safety and biomarker analyses, and will continue every 12 weeks during Long-term Follow-up until 
disease progression or the start of new lymphoma treatment. Only EBV levels will be measured at Screening. 
q. PK sample collection – During Stage 1 of the study PK will be collected on Cycle 2 Day 4 and Cycle 6 Day 4 from Cohorts 1, 2, 3b, 4, 5, 6, and 7 at pre-
dose and 1, 2, 4, and 6 hours post-dose (±15 minutes). For patients in Cohort 3a, PK will be conducted at Cycle 2 Day 4 of the monotherapy and repeated on 
Cycle 2 Day 4 and Cycle 6 Day 4 of the combination therapy for patients that cross over. 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. During Stage 2 of the study sparse 
PK sampling will be conducted at selected sites. Sparse sampling will occur at Cycle 2 Day 4. Patients will be assigned one of 3 sampling schedules: 
 
Pre-dose and 4 hours post-dose (±15 minutes) 
 
0.5 and 2 hours post-dose (±15 minutes) 
 
1 and 6 hours post-dose (±15 minutes) 
r. Exploratory biomarkers – Blood draws for exploratory biomarkers should be taken prior to the patient taking study medication on that day. 
s. Immunophenotype and immune function, and mutation analysis – Peripheral blood mononuclear cells (PBMCs) and plasma 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 the EOT visit. Cycle 1 Day 1 pre-dose sample may be collected during 
screening within 14 days of Cycle 1 Day 1. 
t. Histone acetylation – PBMCs for histone acetylation will be collect pre-dose and at 3 hours (±15 minutes) post-dose on Cycle 1 Day 1. 
u. On-study biopsy – FFPE tumor specimens collected during the study as standard of care should be provided to the central pathology laboratory, along with a 
frozen tissue specimen, if available. For patients with disease progression on study, a frozen and an FFPE tumor specimen will be provided to the central 
pathology laboratory. 
v. Subsequent anti-lymphoma therapies and response – Patients will be contacted by telephone or e-mail for assessment of additional therapy, response 
status, and survival following the Safety Follow-up assessment. 
w. Height – Height measurements should be obtained for all patients at Screening. Post-baseline height measurements should be obtained for patients 12 to 17 
years of age. 
 


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Table 6: 
Visit/Evaluation Schedule for Cohort 3a (Nanatinostat Monotherapy), 
Days 1-43 
 
Nanatinostat Monotherapy Cycle  
 
Day(s) of Cycle c
1 
15 
29 
431,2,3 
 
Enrollment/Randomization  
X 
 
 
 
Responders continue monotherapy (Table 5; Cycle 3, Day 1) 
Non-responders cross -over to combination treatment (Table 5; Cycle 1, Day 1) 
Prior and concomitant medications 
X 
X 
X 
X 
Physical examination 
X 
 
X 
 
Weight 
X 
 
X 
 
ECOG performance status 
X 
 
X 
X 
Vital signse  
X 
 
X 
X 
Laboratory assessments 
 
 
 
 
Hematologyf 
X 
X 
X 
X 
Chemistryg 
X 
X 
X 
X 
Creatinine clearance (Cockcroft-Gault estimation)h 
 
 
 
X 
Serum immunoglobulinsi 
X 
 
 
X 
Coagulationf 
 
 
 
X 
Urinalysis  
 
 
 
X 
Serum or urine pregnancy testk 
X 
 
X 
X 
Disease assessments 
 
 
 
 
18FDG-PET/CT4 
 
 
 
X 
CT with contrast (or MRI) of neck, chest, abdomen, 
and pelvis4 
 
 
 
X 
Safety assessments 
 
 
 
 
12-lead ECGo 
X 
 
 
X 
Adverse events  
X 
X 
X 
X 
CMV, HHV-6, HHV-8, HIV levelsp 
X 
X 
X 
X 
EBV DNA levelsp 
X 
X 
X 
X 
Pharmacokinetics 
 
 
 
 
PK samplingq 
X 
 
 
 
Biomarkersr 
 
 
 
 
Immunophenotype and functions 
X 
 
 
 
Histone acetylationt 
X 
 
 
 
On-study biopsy/fine needle aspirate (optional with 
disease progression or relapse)u 
 
 
X 
 
Nanatinostat dispensing/return 
X 
 
X 
 
 
Abbreviations and lettered footnotes are defined in Table 5. Numbered footnotes are defined below. 
1. If a patient has stable or progressive disease AND qualifies to continue (safety laboratory assessments, no sign 
of CNS disease progression, and ECOG status) at the Day 43 visit (or progressive disease prior to Day 43), the 
patient may switch to the combination therapy. Crossover to combination therapy must occur within 7 days of 
the disease assessment. The Day 43 visit (considered the end of monotherapy visit for these patients) and the 
Cycle 1 Day 1 visit for combination therapy may be combined into a single visit. Patients must complete the 


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Day 43 Monotherapy Disease Assessment and qualify prior to beginning the Cycle 1 Day 1 of the 
nanatinostat/valganciclovir combination therapy. 
2. If a patient discontinues monotherapy prior to the Day 43 disease assessment for reasons other than disease 
progression the patient will follow the EOT, Safety Follow-up, and Long-term Follow-up procedures outlined 
in Table 5.  
3. If patient has a response (complete or partial response) to nanatinostat monotherapy at the Day 43 disease 
response assessment, the patient will continue monotherapy treatment, restarting assessments at Day 57 
(Cycle 3, Day 1). Visits will continue every 14 days as described in Table 5. 
4. 
18FDG-PET/CT and CT with contrast (or MRI) of neck, chest, abdomen, and pelvis – 18FDG-PET/CT and 
CT with contrast (or MRI, if CT with contrast is contraindicated) will be conducted at Week 6 ± 7 days. 
Patients continuing on monotherapy will have 18FDG-PET/CT and CT with contrast conducted at Week 14 and 
Week 22, ±7 days. Subsequent contrast-enhanced CTs (or MRI, if CT contraindicated) will be performed at 
Week 34 then every 12 weeks until relapse or disease progression (Week 46, 58, 70, etc.), ±7 days. MRI may 
be performed only if CT with contrast is contraindicated in the opinion of the Investigator or if frequent CT 
scans are not allowed according to local IRB/IEC. The same imaging modality used at screening must be used 
throughout the study for each patient. 
7. 
Enrollment and Study Procedures 
7.1. 
Screening Period 
Selected screening procedures are highlighted below. For the additional screening assessments to 
be performed, please see the Schedule of Events provided in Section 6.1. 
7.1.1. 
Informed Consent 
Written informed consent in a language fully comprehensible to the prospective patient and/or 
designee will be obtained prior to performing any study-related procedures. A copy of the signed 
informed consent form (ICF) will be provided to the patient and/or designee. The Investigator 
will retain all original versions of signed ICFs. 
After ICF signature, 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 (See 
Section 7.3.4.3).  
Rescreening of patients is only allowed once per patient if the patient was not registered as 
entering the treatment phase before (ie, 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. 
7.1.2. 
Demographic Information 
Demographic information will be collected at the Screening visit. Standard demography 
parameters include age, gender, and race/ethnicity (recorded in accordance with local 
regulations). 


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7.1.3. 
Physical Examinations 
Physical examinations will be performed as specified in the Schedule of Events (Section 6.1). 
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. 
7.1.4. 
Medical History 
All lymphoma-related history over the patient’s lifetime should be recorded, including: 
 Lymphoma diagnosis 
 Prior lymphoma therapies and dates 
 Responses to prior lymphoma therapies (including stem cell transplantation, 
radiotherapy, CAR-T cell or other adaptive T-cell therapies, surgery, etc.) 
 Whether patient was refractory to their most recent prior therapy 
The non-lymphoma-related medical history should include any ongoing medical conditions 
and symptoms and should also include the toxicity grade. 
7.1.5. 
Tumor Specimen 
A FFPE tumor block is preferred; if a tissue block is not available, at least 15 unstained slides or 
freshly cut serial sections (3−5 μm in thickness), preferably with an accompanying block punch 
will be accepted. A representative tumor specimen or lymph node meeting the following criteria 
must be available at the time of screening and submitted to the central pathology laboratory 
within 8 weeks after Cycle 1 Day 1: 
 For patients with ENKTL, AITL, PTLD, and HIV-L: Tumor specimen is preferably 
≤1 year old. For tumor specimens >1 year old, please consult the Medical Monitor to 
discuss eligibility. 
 For patients with all other lymphoma subtypes: Tumor specimen is preferably 
≤6 months old. For tumor specimens >6 months old, please consult the Medical Monitor 
to discuss eligibility. 
The specimen must be representative of the current disease (eg, for patients who have relapsed, 
the biopsy specimen should have been taken after the most recent relapse).  
The process for submitting archived tissue or fresh tissue biopsy as FFPE tissue specimens and 
procedures for central pathology review is provided in a separate Pathology Manual. 
7.1.6. 
Central Review of EBV Status and Verification of Lymphoma Subtype 
All enrolled patients will have tumor tissue from a representative biopsy reviewed centrally 
for confirmation of EBV-positive lymphoma. In situ hybridization for EBV encoded RNA 
(EBER-ISH) and/or immunohistochemistry for LMP-1 will be performed. The central pathology 
lab slides and local pathology report will be reviewed regarding morphology and ancillary test 
results to confirm the diagnosis. Appropriate pathology review and/or immunophenotyping will 
be conducted to confirm the diagnosis. 


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For clinical trial sites with capability, digital images of slides utilized in local diagnosis, 
subclassification, and EBV status with controls, will be submitted to the central pathology 
laboratory. 
Patients enrolled based on local pathology results will not be removed from the study if the 
central pathology lab shows a different result (eg, patient is EBV+ based on local pathology 
and EBV– on central review). 
7.1.7. 
Baseline Disease Assessments 
7.1.7.1. 
18FDG-PET/CT and CT with Contrast 
Any imaging assessments already completed during the regular work-up of the patient within 
28 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. 
An 18FDG-PET/CT and a diagnostic contrast-enhanced CT (or MRI if a CT with contrast is 
contraindicated) of the neck, chest, abdomen, and pelvis is required to confirm measurable 
disease (one target lesion) greater than 1.5 cm in diameter or at least one extranodal lesion 
greater than 1.0 cm in both long and short diameter. All evaluable or measurable disease must be 
documented at baseline/screening and re-assessed at each subsequent tumor evaluation. 
18FDG-PET/CT scans in conjunction with diagnostic contrast-enhanced CT scans will be 
obtained in this study. Diagnostic contrast-enhanced CT scans obtained as part of a PET/CT scan 
may be used in lieu of a dedicated CT scan. Patients may have extranodal disease that is 
inadequately imaged by CT scan. MRI may be preferred in these cases. The same imaging 
modality used for lymphoma evaluation at screening must be used for all response evaluations 
throughout the study to ensure consistency across the different time points for each patient. 
7.1.7.2. 
Bone Marrow Biopsy 
For patients with HL and DLBCL, a baseline bone marrow biopsy is not necessary if the 
PET/CT demonstrates bone disease. 
Patients with HL and DLBCL are only required to have a baseline bone marrow biopsy if 
clinically indicated (eg, cytopenias are present and the screening PET/CT scan does not indicate 
bone/bone marrow involvement). 
For all other patients, a baseline bone marrow biopsy is required at screening. 
If a bone marrow biopsy was performed within 12 weeks prior to Cycle 1 Day 1 and is available, 
it may be used as the screening biopsy. Bone marrow biopsy samples must be submitted to 
central pathology within 8 weeks after Cycle 1 Day 1. 
The process for submitting tissue to the central pathology laboratory is provided in a separate 
Laboratory Manual. 
7.1.8. 
Eligibility Determination and Patient Registration 
Investigative sites will submit patient registration materials for Medical Monitor approval prior 
to the enrollment of the patient in the trial. Details on this process will be included in the Study 
Manual. 


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Once all screening procedures are complete, an eligibility checklist must be completed by the 
Investigator or designee and provided to the Medical Monitor for review. Eligibility will be 
reviewed and approved by the Sponsor Chief Medical Officer (CMO) or designee 
(eg, Medical Monitor) prior to patient enrollment. 
7.1.8.1. 
Screen Failures 
Patients who have provided informed consent or assent 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. 
7.2. 
Treatment Period 
Patients will be treated with nanatinostat and valganciclovir until discontinuation of study 
treatment as described in Section 7.2.3. 
7.2.1. 
Treatment Cycles 
For Cohorts 1, 2, 3b, 4, 5, 6, and 7, patients will receive nanatinostat/valganciclovir 
(nanatinostat 20 mg orally once daily on Days 1 to 4 per week and valganciclovir 900 mg orally 
once daily) continuously for 28-day treatment cycles. During treatment Cycle 1, visits will occur 
on Days 1, 8, 15, and 22. Starting at Cycle 2, visits will occur on Days 1 and 15. Each scheduled 
clinic visit has an allowable ±3-day window. Visit windows are not applicable to dosing. Should 
a visit occur during the ± 3-day window, patients will be instructed to continue following the 4 
days on, 3 days off dosing cycle for nanatinostat. 
For Cohort 3a, the PTCL patients randomized to monotherapy will begin with 6 weeks of 
nanatinostat monotherapy (20 mg orally once daily on Days 1 to 4 per week) with visits on 
Days 1, 15, 29, and 43. Each scheduled clinic visit has an allowable ±3-day window. If a patient 
has stable or progressive disease at the Day 43 visit, the patient will be offered the option to 
switch to nanatinostat/valganciclovir combination and follow the 28-day treatment cycles as 
described above. Patients must complete the End of Monotherapy Disease assessment and 
qualify (labs, no sign of CNS disease progression, ECOG) prior to beginning Cycle 1 Day 1 of 
the nanatinostat/valganciclovir combination therapy. If a patient has a response (complete or 
partial response) to nanatinostat monotherapy at the Day 43 visit, the patient will continue 
monotherapy treatment. 
7.2.2. 
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. 
7.2.3. 
Discontinuation of Study Treatment 
Patients will continue on study until disease progression, unacceptable toxicity, withdrawal of 
consent by the patient, patient is lost to follow-up, death, or discontinuation from the study due 
to any other reason (eg, Sponsor terminates the study). 


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Patients may voluntarily discontinue from study treatment at any time and for any reason. In this 
case, the Investigator must make every effort to determine the primary reason for the decision 
and record this information in the eCRF. 
When 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 and yet agree to 
continued follow-up of associated clinical outcome information in which case this information 
would be collected and maintained in the clinical trial database. 
The Investigator may discontinue study treatment for a given patient if he/she is of the opinion 
that continuation of therapy would be detrimental to the patient’s well-being. 
For patients that discontinue treatment without relapse/disease progression, follow the CT scan 
assessment schedule until disease progression, start of new anti-lymphoma therapy, or end of 
study (see Table 5). 
Patients may be withdrawn from the study if any of the following occur: 
 Adverse event 
 Progressive disease or relapse 
 Lost to follow-up 
 Physician decision 
 Pregnancy 
 Withdrawal of consent 
 Death 
 Study terminated by Sponsor 
 Any protocol deviation where continuing participation in the study would result 
in a significant risk to the patient’s safety 
7.2.4. 
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 minimum, all patients who 
discontinue study treatment, including those who refuse to return for a final visit, will be 
contacted for safety evaluations during the 28 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 
Section 6.1. 
7.2.5. 
Safety Follow-up Visit 
The Safety Follow-up visit will occur approximately 28 days following the final administration 
of nanatinostat/valganciclovir. The Safety Follow-up visit has an allowable ±3-day window. 


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If a patient withdraws consent after the EOT visit but prior to the 28-day safety evaluation, safety 
data should be collected on the patient up to the date of consent withdrawal. 
Adverse events will be assessed (contact by phone is permitted) until 28 days following the last 
dose of study drug. In addition to AEs, all concomitant medications given to a patient as a result 
of an AE during this period will be recorded on the Prior and Concomitant medication eCRF 
page. All new anti-lymphoma therapies given to a patient within 28 days after the last dose of 
study drug must be recorded in the eCRF. 
7.2.6. 
Long-term Follow-up Visits 
Patients who discontinue treatment for reasons other than disease progression will start 
Long-term Follow-up visits every 12 weeks (±7 days) following the EOT visit. Scans performed 
during the Follow-up period should be performed on the same schedule with the same imaging 
modality as previously used. Tumor and EBV DNA level assessments will continue as part of the 
Long-term Follow-up visits until disease progression or start of new anti-lymphoma therapy. 
At disease progression/relapse or the start of new anti-lymphoma therapy, patients will be 
contacted (eg, telephone, e-mail) at least every 6 months (±7 days) following the previous 
Long-term Follow-up assessment for a description of subsequent anti-lymphoma therapy given, 
response to subsequent therapies, and survival, unless they withdraw consent. 
Long-term Follow-up visits will continue until all patients have either withdrawn consent, died, 
become lost to follow-up, completed 3 years of follow-up, or the trial is terminated by the 
Sponsor. 
7.2.7. 
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. 
7.3. 
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 Section 6.1. A central laboratory 
will be used for the analysis of hematology and chemistry. Clinical decisions and dose 
modifications during the study can be based on local laboratory results. 
7.3.1. 
Efficacy Assessments 
7.3.1.1. 
Baseline Evaluation 
The following radiologic assessments are to be performed in the screening period 
(within 28 days prior to the start of treatment): 
1. A brain CT or MRI to rule out CNS involvement with lymphoma. 
2. 18FDG-PET/CT and diagnostic CT with contrast or MRI from base of skull to mid-thigh 
(including other known sites of disease) to establish disease status at baseline. A 
diagnostic contrast enhanced CT scan obtained as part of a PET/CT scan may be used in 
lieu of dedicated CT scans. 


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7.3.1.2. 
Tumor Response Assessments 
Disease response assessments will be made every 8 weeks until 24 weeks, and then every 
12 weeks for the remainder of the study, according to the revised response criteria for malignant 
lymphoma based on the IWG-NHL guidelines (Cheson 2007). A scan to confirm an unconfirmed 
PR or unconfirmed CR ≥4 weeks later may also be performed. 
18FDG-PET/CT scans in conjunction with diagnostic contrast-enhanced CT scans (or MRI if a 
CT with contrast is contraindicated) will be obtained in this study at baseline, and for the 8-week 
and 16-week tumor assessments. Diagnostic contrast enhanced CT scans obtained as part of a 
PET/CT scan may be used in lieu of dedicated CT scans. 
Subsequent evaluations will be by CT with contrast (without PET) or MRI only. Patients with 
FDG-avid lymphoma at baseline may have an 18FDG-PET/CT performed to evaluate a possible 
CR or PR after Week 16 (unless prohibited by local practice) and may use a diagnostic contrast-
enhanced CT for follow-up once a complete metabolic response is obtained. 18FDG-PET/CT 
scans may also be obtained per investigator discretion (eg, in instances where extranodal disease 
may be inadequately imaged by contrast-enhanced CT), and responses recorded in the eCRF. 
MRI may be substituted only if i) CT is contraindicated as assessed by the Investigator, ii) if 
frequent CT scanning is not permitted by the local Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), or iii) in the case of extranodal disease that is inadequately imaged by 
CT scan.  
At all times during the study, suspected disease progression based on clinical findings must be 
confirmed by imaging as soon as possible (and before initiating non-protocol specified anti-
lymphoma therapy). 
Efficacy will be evaluated in terms of ORR, DOR, PFS, OS, TTP, and TTNLT. ORR will be 
used to move from Stage 1 to Stage 2. The responses will be assessed by both the Investigator 
(for management of the patient) and the IRC (for the primary and secondary endpoints). 
Investigator-determined response assessments at each assessment time point will be entered onto 
the appropriate eCRF. 
All CT or MRI 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 patient. The scans will be performed: 
 Every 8 weeks (±1 week) until 24 weeks 
 Every 12 weeks (±1 week) for the remainder of the study 
 At the EOT visit (unless the previous scan was within 4 weeks of the EOT visit) 
 A scan to confirm an unconfirmed PR or unconfirmed CR ≥4 weeks later may also be 
performed. 
If local regulatory authorities mandate less frequent imaging, the minimum frequency must be 
every 12 weeks.  
All patients will be followed for disease progression (ie, PD) or relapse using the schedule 
described in the Schedule of Events provided in Section 6.1. This includes patients who 
discontinue the protocol-specified treatments or the study early for any reason without 
documented evidence of PD or relapse. 


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Protocol-defined efficacy endpoints except OS and TTNLT will be assessed by an IRC. 
The IRC review includes central radiology and clinical review. Since the study endpoint is ORR 
based on PET/CT (first 2 disease response assessments) and thereafter CT with contrast, disease 
progression will typically be based on CT scans. In limited instances where disease progression 
is evident only by assessments other than CT, CT scans must still be provided along with the 
non-CT documentation of disease progression. 
The radiologic assessments (18FDG-PET/CT, CT with contrast, or MRI) are considered the 
primary method of response assessment. Any additional assessments – clinical assessments, 
bone marrow biopsy assessments, etc. are considered confirmatory. 
Repeat bone marrow biopsies will be performed to confirm CR only for patients with bone 
marrow involvement reported at baseline. 
Patients who relapse or progress will continue to be followed for OS, TTNLT, all subsequent 
anti-lymphoma therapy, and response, including disease progression/relapse to subsequent 
lymphoma therapy. 
Disease assessment data including actual scan data and radiology reports will be submitted to the 
Sponsor as it becomes available for evaluation by a central radiology reader. 
7.3.2. 
Safety and Tolerability Assessments 
Adverse events will be assessed, and concomitant medications, procedures, and hospitalizations 
will be recorded from the signing of the ICF until 28 days post-last dose of study treatment. 
All 12-lead ECGs will be conducted in triplicate. Average corrected QT interval using 
Fridericia’s method (QTcF) is to be calculated to confirm eligibility. For patients enrolled in any 
Stage 1 cohort, ECGs will be performed in triplicate, as described in Section 7.3.2.8. ECG 
tracings will be provided to a central laboratory, instructions are provided in the ECG Manual. 
Viral levels [EBV, CMV, HHV-6, HHV-8, and HIV (for HIV+ patients only)] will be monitored 
for viral reactivation.  
Tolerability will be assessed by the incidence of AEs leading to dose modifications or study drug 
discontinuation. 
7.3.2.1. 
Physical Examination 
The physical examination including ECOG performance status (see Section 7.3.2.4) should be 
repeated at the beginning of each cycle, at treatment discontinuation, and any additional times 
deemed necessary by the Investigator. 
7.3.2.2. 
Vital Signs 
Vital signs (temperature, blood pressure, and heart rate) will be obtained at the Screening visit 
(Day -28 to Day -1), on Day 1 of each cycle (Day 4 of Cycles 2 and 6), and at the EOT visit. 
Vital signs should 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, collect vital signs once 
(prior to dosing of study drugs, if administered in clinic). 
Investigators are to report any clinically significant abnormal findings as AEs. 


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7.3.2.3. 
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 (Day 4 of Cycles 2 and 6) and at the EOT 
visit. Height should additionally be measured in patients 12 to 17 years of age on Day 1 of each 
cycle (Day 4 of Cycles 2 and 6). 
7.3.2.4. 
ECOG Performance Status 
The ECOG performance status will be assessed according to Table 7 (Oken 1982). 
ECOG performance status will be assessed at screening (Day -28 to Day -1), on Day 1 of each 
cycle (Day 4 of Cycles 2 and 6), and the EOT visit. 
Table 7: 
ECOG Performance Status 
Grade 
ECOG Performance 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 
7.3.2.5. 
Laboratory Evaluations 
7.3.2.6. 
Clinical Laboratory (Safety) Testing 
Laboratory tests will be collected and analyzed in an accredited central or local/site laboratory 
in accordance with quality standards. 
A central laboratory will be used for the analysis of hematology and chemistry. Clinical 
decisions and dose modifications during the study can be based on local laboratory results. 
Hematology, serum chemistry, urinalysis, serology, and other parameters to be tested are listed 
in Table 8 and will be performed per the Schedule of Events provided in Section 6.1. In addition, 
the investigative sites will provide archived or newly obtained tumor samples at baseline and 
optionally at the time of relapse. 


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Table 8: 
Clinical Laboratory Tests 
Laboratory 
Test Category 
Specific Laboratory Tests 
Hematology 
WBCs with differential (neutrophils, monocytes, eosinophils, lymphocytes, basophils), RBCs, 
Hgb, hematocrit, platelets, MCV, MCH 
Coagulation 
PT or INR, activated partial thromboplastin time (aPTT) 
Serum 
Chemistry 
Aspartate aminotransferase (AST [SGOT]) 
Lactate dehydrogenase (LDH) 
Alanine aminotransferase (ALT [SGPT]) 
Bicarbonate 
Alkaline phosphatase (ALP) 
Blood urea nitrogen (BUN) 
Albumin 
Creatinine 
Total bilirubin 
Glucose 
Sodium 
Chloride 
Potassium 
Calcium 
Magnesium 
Phosphate 
Total protein 
Uric acid 
Amylase 
 
Urinalysis a 
Macroscopic panel (dipstick) 
Serology 
Hepatitis B virus (HBV) surface antigen (Ag) 
HBV DNA PCR a, b 
HBV core and surface antibody (Ab) 
Hepatitis C virus (HCV) Ab a, c 
EBV, CMV, HHV-6, HHV-8 levels 
 
Pregnancy a 
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. 
Abbreviations: CMV = cytomegalovirus; Hgb = hemoglobin; HHV-6 = human herpesvirus-6; HHV-8 = human herpesvirus-8; 
INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; 
PCR = polymerase chain reaction; PT = prothrombin time; RBC = red blood cell; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cell. 
a. Collected and analyzed in an accredited local/site laboratory in accordance with quality standards. 
b. HBV DNA PCR only for patients with positive HBV core Ab or surface Ag. 
c. Any patient positive for HCV Ab will be evaluated by quantitative polymerase chain reaction (qPCR). 
7.3.2.7. 
Pregnancy Testing 
Pregnancy testing is only required for females of childbearing potential. Serum test must be 
performed during screening. Serum or urine tests are to be performed at the beginning of each 
cycle (Day 4 of Cycles 2 and 6), the EOT visit, the 28-day Safety Follow-up visit, and every 12 
weeks for up to 6 months post-last dose of study drugs. 
7.3.2.8. 
Cardiac Assessments: Electrocardiograms (ECGs) 
Triplicate ECGs should be obtained in close succession from the first ECG to the third ECG. For 
each sampling time point, 3 standard resting 12-lead ECGs will be obtained in close succession 
and no more than 2 minutes apart (4 minutes total for 3 ECGs). 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 


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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 on days that include PK sample collection (Stage 1), two triplicate 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 
Cmax (1 and 2 hours) and 4 hours. If possible, patients should not consume additional food 
between dosing and the last ECG time point. 
For days with no scheduled PK sample collections, the ECG may be performed at any time 
during the clinic visit, or 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 ECG 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. 
7.3.3. 
Pharmacokinetics 
The PK parameters of nanatinostat and its metabolites and ganciclovir (primary active hydrolytic 
product of valganciclovir) will be evaluated for patients enrolled in Stage 1, and sparse sampling 
will be collected during the Stage 2 part of the study at selected sites. The scheduled time points 
are outlined in the Schedule of Events in Section 6.1. Pharmacokinetic parameters to be 
evaluated include time to maximum plasma concentration (tmax), maximum plasma concentration 
(Cmax), area under the plasma concentration-time curve (AUC) for patients in the PK substudy. 
Details for collection, shipment, and storage are provided in the Laboratory Manual. 
7.3.4. 
Biomarker Assessments 
7.3.4.1. 
Rationale for Biomarker Assessments 
The exploratory biomarker analyses outlined in this study are intended to foster an understanding 
of how baseline expression of certain biomarkers may impact efficacy, as well as to evaluate the 
effect of combination therapy with nanatinostat and valganciclovir on pharmacodynamic markers 
of activity, such as plasma EBV DNA levels, and correlation with clinical efficacy. Potential 
predictive markers will be studied to identify patients with optimal responses to nanatinostat plus 
valganciclovir. The impact of study drug administration on B-cell-/T-cell/NK cell/myeloid cell 
populations will be evaluated over time. The specific study procedures to be conducted for each 
patient enrolled in the study are presented in the Schedule of Events in Section 6.1. Cells and 
plasma from peripheral blood, or tumor tissue (lymph nodes), will be sent to a central laboratory 
selected by the study sponsor for analysis of viral DNA levels, and gene expression, phenotypic 
alterations in B-cells/T-cells/NK cells/myeloid cells and mutation profile and stored for up to 15 
years after the study is completed for this purpose. After the duration of the storage, samples will 
be destroyed. 


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Details on the collection procedure and timing for each procedure will be provided in the 
Laboratory Manual. The sample collection information must be entered on the appropriate 
sample collection log eCRF page(s) and requisition form(s). 
Table 9: 
Biomarker Sample Collection Plan 
Sample Type 
Visit/Time Point 
Analyses 
Purpose 
Archival FFPE 
tumor sample 
 
Screening 
 IHC: PD-1, PD-L1 and other 
immune checkpoint molecules 
 Tumor-infiltrating lymphocyte 
(TIL) counts (CD3, CD4, CD8) 
 TP53, MYC, BCL2, etc. 
 EBV-associated genes/proteins: 
EBER, BZLF-1/ZTA, LMP-1, 
BGLF-4/PK, BXLF-1/TK, 
BRLF-1/Rta, etc. 
 RNA expression of selected 
immunological/cancer-related 
genes 
Identify possible 
predictive markers 
Tumor biopsy 
(optional) 
At relapse or with disease 
progression 
EBER, LMP-1, TIL counts, PD-L1 
and other immune checkpoint 
molecules; markers related to 
resistance 
Identify potential 
resistance markers 
Plasma 
 Screening 
 Cycle 1 Day 1, Cycle 1 
Day 15, then monthly 
 Every 3 months in 
follow-up 
 EBV DNA levels (EBV viral 
load by q-PCR) 
 Tumor-associated mutation 
profiling 
Pharmacodynamic effect 
(on and off treatment) 
PBMC 
(whole blood) 
 Screening 
 Every 3 months 
 Histone H3 acetylation (prior to 
and 3 hours post-nanatinostat 
administration, Cycle 1 Day 1 
only) 
 RNA expression of selected 
immunological genes 
 Flow cytometry/IF for immune 
cell markers 
 Flow cytometry for 
identification of circulating 
lymphoma cells and RNAseq 
Pharmacodynamic effect 
(on treatment) 
Abbreviations: EBER = Epstein-Barr encoded RNA; EBV = Epstein-Barr virus; FFPE = formalin-fixed paraffin-embedded; 
IHC = immunohistochemistry; LMP-1 = latent membrane protein 1; PBMC = peripheral blood mononuclear cell; PD-
1 = programmed cell death-1; PD-L1 = programmed death-ligand 1; qPCR = quantitative polymerase chain reaction.  
7.3.4.2. 
Pharmacodynamic Assessments in Blood 
For pharmacodynamic assessments in blood/plasma, collection of pre- and on-treatment samples 
as indicated in the Schedule of Events provided in Section 6.1 is mandatory for all patients. 


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7.3.4.3. 
Additional Biomarker Assessments 
Once protocol defined exploratory testing (Section 7.3.4.1) is complete and the patient agrees, 
any remaining biomarker samples (tumor, blood) and residual PK samples may be further 
analyzed to address pertinent scientific questions related to EBV+ lymphomas. 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. 
An overdose, accidental or intentional, associated with an AE, or abuse, withdrawal, sensitivity, 
or toxicity to an investigational product should be reported as an AE.  Overdoses with or without 
an associated AE will be recorded on the dosing eCRF. All patients will be monitored for AEs 
during the study and continue until 28 days after the last dose of study drugs or until a new 
anticancer treatment is started, whichever occurs first.  
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.  
Assessments may include monitoring any or all of the following parameters: the patient’s clinical 
symptoms, laboratory, pathological, radiological, or surgical findings, physical examination 
findings, or other appropriate tests and procedures. 
All AEs will be recorded by the Investigator from the time the patient signs the informed 
consent. Adverse events and serious adverse events (SAE) will be recorded on the Adverse 
Events eCRF and in the patient’s source documents. All SAEs must be reported to ICON Drug 
Safety 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.  
Pre-existing conditions are not considered AEs unless the condition worsens by at least one 
grade following the start of administration of the study drugs. 
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, 


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whichever is first. Death is an outcome of an adverse event and not an adverse event in and of 
itself. All reports of death should include an adverse event term for the cause of death (if 
known).  
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 term for standard adverse event reporting, and if applicable, serious adverse 
event reporting. Death due to disease progression should only be reported in the clinical database 
on the designated eCRF.  
8.1.1. 
Laboratory Test Abnormalities 
An abnormal laboratory value is considered to be 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 
(see 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 was 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: 
 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 


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 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 SAEs 
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 e-mail the report to: 
ICON Pharmacovigilance e-mail at CHOSafety@iconplc.com  (North/South America) or 
MHG Safety@iconplc.com (Europe, Asia, Pacific)  
or 
Fax to +888-772-6919 (North/South America) or +44 1792 525 720 (Europe, Asia, 
Pacific) 
The Investigator should discuss with the Medical Monitor any SAEs for which the issue of 
seriousness is unclear or questioned. Contact information for the Medical Monitor is: 
Table 10: 
ICON Medical Monitoring Support Center 
Region 
Phone  
Fax 
E-mail 
North America (NA) 
+1 866 326 5053 (toll-free) 
+1 434 951 4082 (direct) 
+1 800 280 7035 (toll-
free) 
+1 913 307 5751 (direct) 
NAVAL1@iconplc.com 
 
Europe, Asia Pacific & 
Africa (EAPA) 
+ 49 621 878 2850 
+ 44 203 365 6752 
Serious adverse events 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. 
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. 
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. 


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8.4. 
Relationship to Study Drugs 
The Investigator will use his/her best medical judgment to determine the relationship of an AE 
to one or both study drugs. 
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 the purpose of regulatory reporting, the Sponsor will determine the expectedness of events 
suspected of being related to the study drugs based on the IB. 
For countries within the European Economic Area (EEA), 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, 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). 
For the purpose of regulatory reporting in the EEA, the Sponsor will determine the expectedness 
of events suspected of being related to valganciclovir based on the Reference Safety Information 
(RSI) as included in the IB. 
Disease progression or relapse, death related to disease progression or relapse (in the absence of 
serious study drug-related events), and serious events due to the relapse of the studied indication 
will not be subject to expedited reporting by the Sponsor to regulatory authorities. 


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8.6. 
Reporting Adverse Events 
Any AEs which occur following signing of the informed consent up to and including 28 days 
after the last dose of study drugs or until the start of subsequent anticancer therapy, whichever 
occurs first, will be recorded.  
Unanticipated problems that require reporting to IRB might include: 
 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. Positive urine 
pregnancy 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 ICON 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. 
The Investigator will follow the female patient until completion of the pregnancy and must notify 
ICON 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 was abnormal (eg, spontaneous or therapeutic abortion), 
the Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets 


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any of the serious criteria, it must be reported as an SAE to ICON Drug Safety within 24 hours 
of the Investigator’s knowledge of the event using the SAE Report Form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects 
is related to the in utero exposure to the study treatment should also be reported to ICON 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 the IRB/IEC’s requirements. 
8.7.2. 
Male Patients 
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. 
Of note, valganciclovir may cause temporary or permanent inhibition of spermatogenesis. The 
Sponsor recommends that the Investigator provide advice to patients regarding the conservation 
of sperm prior to treatment with valganciclovir. 
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. 
All overdoses, whether accidental or intentional, should be recorded in the eCRF. All AEs 
associated with an overdose should be captured on the Adverse Events eCRF.  If an overdose 
occurs 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 serious 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 trial. 
The investigational site is responsible for ensuring 24-hour emergency availability. 
All cases of emergency must immediately be reported to the medical expert and to the clinical 
project manager and will be noted in the eCRF. 
8.10. 
Unanticipated Problems 
An AE observed during the conduct of a study should be considered an unanticipated problem 
involving risk to human subjects and reported to the IRB/IEC, only if it was unexpected, serious, 
and would have implications for the conduct of the study (eg, requiring a significant, and usually 


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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 the following criteria could be 
reported by the Investigator to the IRB/IEC as an unanticipated problem: 
 Unexpected given: 
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 was 
previously known or recognized. 


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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 in patients with EBV+ relapsed/refractory 
lymphoma following prior systemic therapy(ies) with no available standard therapies as per the 
eligibility criteria.  
All data will be summarized by EBV+ lymphoma subtype and overall subtypes. In addition, 
sub-cohorts of PTCL patients randomized to monotherapy versus those randomized to 
combination therapy will be summarized separately. 
9.2. 
Statistical and Analytical Plans 
A statistical analysis plan will present the detailed statistical methods and analyses for this study. 
9.3. 
Definition of Analysis Populations 
The following 4 populations will be used in the analysis: 
1. Intent-to-Treat (ITT) population: All patients who are enrolled into the trial, regardless of 
whether they received study treatment or not. 
The ITT population will be used for the primary efficacy analysis. Patients will be analyzed 
according to their disease/cohort. If a patient has no post-baseline tumor assessment for 
efficacy, they will be counted as a treatment failure in this population analysis. 
2. Modified ITT (mITT) population: All enrolled patients who have received at least one 
dose of study medication, met all eligibility criteria, and have at least one post-baseline tumor 
assessment for efficacy. 
The efficacy analysis will also be performed on the mITT population as supportive evidence 
and/or sensitivity analyses. Patients will be analyzed according to their cohort and overall. 
3. Safety population: All patients who have received at least one dose of study medication will 
be summarized for safety based on cohort and overall. 
4. PK population: All patients with PK assessments. 
9.4. 
Sample Size and Power Considerations 
This multinational, multicenter study will employ a Simon’s 2-stage design to allow 
termination of enrollment into cohorts where treatment appears futile (Simon 1989). 
The decision to transition from Stage 1 to Stage 2 is dependent on the assumption of ORR: 
ORR ≤10% (poor response); ORR ≥35% (good response). The sample size estimation uses 
1-sided alpha = 0.05 and targets statistical power = 85%.  
Using the Simon’s 2-stage design approach, the null hypothesis that the true response rate is 10% 
will be tested against a one-sided alternative. In the first stage, up to 10 patients will be accrued 
in each cohort. If there are 1 or fewer responses, the cohort will be discontinued. If the cohort 
fails to enroll any patients within 1 year from the enrollment of the first patient, the cohort will 


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be considered for termination of enrollment. Otherwise, if at least 2 patients in a cohort respond, 
additional patients will be accrued for a total of 21 in the cohort. The null hypothesis that the true 
response rate is 10% will be rejected in each cohort where 5 or more responses are observed in 
21 patients. This design yields a type I error rate of 0.0440 and power of 86.2% within each 
cohort where the true response rate is 35%. 
If 10 patients of a given lymphoma subtype are enrolled into Cohort 7, then the Simon’s decision 
criteria will be applied to determine whether or not to add patients in Stage 2 for that subtype. If 
none of the subtypes represented in Cohort 7 enrolls at least 10 patients, efficacy data collected 
on those patients will be listed, but not summarized by group. All patients will be summarized 
for safety, regardless of the decision to discontinue enrollment into any cohort. 
If at the end of Stage 2 there are at least 7 responders observed in the initial 21 patients in any 
cohort (ORR ≥33.3%), enrollment will be expanded to include up to 120 additional patients in 
that cohort (N=141), with the possibility of performing an interim analysis in that cohort to be 
described in the statistical analysis plan. The maximum sample size estimated for the expanded 
cohort is dependent on the assumption of ORR ≥35% with the lower bound of its 95% CI 
excluding ORR 25%.  
9.5. 
Baseline Characteristics and Patient Disposition 
Demographic and baseline (last non-missing observation prior to treatment) disease 
characteristics will be summarized by treatment group for the ITT, mITT, and Safety 
populations. Patients’ age, height, weight, and continuous baseline characteristics will be 
summarized using descriptive statistics (N, mean, standard deviation, median, minimum, 
maximum), while age group, gender, ethnicity, histology, and other categorical variables will 
be provided using frequency tabulations (count, percent) by treatment group. Medical history 
data (coded by Medical Dictionary for Regulatory Activities [MedDRA] dictionary) will be 
summarized using frequency tabulations by treatment group, System Organ Class 
and Preferred Term for the ITT, mITT, and Safety populations. 
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 ITT population. 
Corresponding patient listings will be provided as well. 
9.6. 
Efficacy Analysis 
All efficacy analyses will be performed on the ITT population. Key efficacy analyses will be 
performed on the mITT population as supportive evidence and to assess robustness of efficacy 
findings. 
9.6.1. 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is ORR assessed by an IRC. Disease response assessments will be 
made every 8 weeks until 24 weeks, and then every 12 weeks for the remainder of the study, 
according to the revised response criteria for malignant lymphoma based on the IWG-NHL 


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guidelines (Cheson 2007). A scan to confirm an unconfirmed PR or unconfirmed CR ≥4 weeks 
later may also be performed. 
18FDG-PET/CT scans in conjunction with diagnostic contrast-enhanced CT scans (or MRI if a 
CT with contrast is contraindicated) will be performed at baseline, and for the 8-week and 
16-week tumor assessments. Diagnostic contrast enhanced CT scans obtained as part of a 
PET/CT scan may be used in lieu of dedicated CT scans. 
Subsequent evaluations will be by CT with contrast (without PET) or MRI only. Patients with 
FDG-avid lymphoma at baseline may have an 18FDG-PET/CT performed to evaluate a possible 
CR or PR after Week 16 (unless prohibited by local practice) and may use a diagnostic contrast-
enhanced CT for follow-up once a complete metabolic response is obtained. 18FDG-PET/CT 
scans may also be obtained per investigator discretion (eg, in instances where extranodal disease 
may be inadequately imaged by contrast-enhanced CT). Efficacy will be evaluated in terms of 
ORR, DOR, PFS, OS, TTP, and TTNLT. ORR will be used to move from Stage 1 to Stage 2. 
ORR is defined as the proportion of patients who achieve a confirmed CR or PR as determined 
by an IRC. 
Patients will be analyzed according to their cohort/lymphoma subtype. The number 
and percentage of patients with a CR or PR after initiation of treatment will be summarized 
overall and by cohort. Ninety-five percent (95%) confidence intervals (Cis) around the ORR 
(CR + PR) will be calculated using the Clopper-Pearson method. 
For patients who achieve CR/PR, the duration of response (DOR), defined as time from date of 
first observed complete or partial response to the date of disease progression, death due to any 
cause, or last adequate (radiographic) response assessment, will be estimated using the Kaplan-
Meier method. Any patient who does not need new anti-lymphoma treatment, experiences 
disease progression, or death will be censored at the last non-missing assessment. Patients 
initiating new anti-cancer therapy will be censored at the last adequate disease assessment prior 
to the start of therapy. 
Overall survival will be estimated using the Kaplan-Meier method and will include all enrolled 
patients. Patients still alive will be censored at the last non-missing assessment. The 95% CI 
around the OS rate at 12 months will be presented. Analyses of other time-to-event efficacy 
endpoints (DOR, TTP, PFS, and TTNLT) will be analyzed in a similar manner. 
9.6.2. 
Secondary Efficacy Endpoints Analysis 
Secondary efficacy endpoints will include OS, DOR, PFS, and TTNLT. 
 
Duration of response (DOR): defined as the interval from date of first observed CR or PR 
to the date of disease progression, death due to any cause, or last adequate (radiographic) 
response assessment. 
 
Time to next anti-lymphoma treatment (TTNLT): defined as the interval from the start of 
study drug treatment to date of next anti-lymphoma treatment (including chemotherapy, 
radiotherapy, radioimmunotherapy or immunotherapy). 
 
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, 


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whichever occurs first. Responding patients and patients who are lost to follow-up will be 
censored at their last tumor assessment date. 
 
Overall survival (OS): defined as the interval from the start of study drug treatment 
to date of death, for any reason. 
For time-to-event type of endpoints (OS, DOR, PFS, TTNLT), Kaplan-Meier estimates will be 
provided.  
9.6.3. 
Exploratory Endpoints 
All exploratory endpoints will be summarized by cohort and overall. Future analysis of these 
endpoints will be described in a separate analysis plan. 
9.7. 
Safety Analysis 
Safety analysis will be based on all patients in the Safety population and will be summarized 
overall, by cohort, and by any other relevant subgroup, such as randomization to monotherapy. 
Study medication exposure will be summarized for each patient and tabulated by cohort 
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 cohort. Tabulations and listings of values for 
vital signs and laboratory safety evaluations will be presented. 
Adverse events will be coded according to MedDRA and classified using the NCI CTCAE 
Version 5.0. The incidence rates of AEs will be tabulated by System Organ Class and Preferred 
Term. Subsets of AEs to be summarized include serious AEs (SAEs), events of all CTCAE grade 
severities, suspected 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 cohort, 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 selected 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 cohort. 
9.8. 
Interim Analysis 
Aside from the Stage 1 analysis specified by the Simon’s decision criteria for proceeding to 
Stage 2, an interim analysis may be conducted during the Expansion phase. Further details will 
be provided in the statistical analysis plan. 


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10. 
STUDY COMMITTEES 
10.1. 
Study Steering Committee 
An SSC will be responsible for assisting the Sponsor with i) management of the overall 
stewardship of the study according to the protocol, and ii) to recommend and approve any 
modifications needed upon request of the Sponsor (eg, assisting the Sponsor with review of any 
study amendments, interpretation of data, presentation and publication of study results). The SSC 
will be composed of 4 to 5 Investigators and the Sponsor’s medical expert for the study. Other 
specialists may be invited to participate as members of the SSC at any time if additional 
expertise is desired. 
10.2. 
Independent Review Committee 
An IRC will be established to provide an independent review of radiographic and pertinent 
clinical data to provide expert interpretation of changes in tumor status and response assessment. 
The IRC will include an independent board-certified radiologist and an independent board-
certified hematologist/oncologist, and will be managed by the contracted imaging provider, 
Clario (Philadelphia, PA USA). The review of radiographic and clinical data by the IRC will be 
performed on an ongoing basis. The specifics of Clario’s processes and reading methods will be 
described in an IRC charter developed by Clario in conjunction with the study Sponsor. 
11. 
STUDY ADMINISTRATION 
11.1. 
Regulatory and Ethical Consideration 
11.1.1. 
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: 
 US Code of Federal Regulations (CFR) applicable to clinical studies: 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 
11.1.2. 
Ethics Review 
Each participating institution must provide for the review and approval of this protocol and the 
associated informed consent documents prior to the initiating the study and on an annual basis 
and approve any recruitment material by an appropriate IRB or IEC. 
Protocol amendments require review and approval by the applicable IRB/IEC prior to 
implementation. 
Changes to the ICF will be submitted to the appropriate IRB/IEC for review and approval. 


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At the time of any protocol amendment or change to the informed consent document, 
an assessment will be made regarding the need for re-consenting existing patients. 
Additional materials may be provided to the appropriate IRB or IEC per local regulations. 
11.1.3. 
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. Assent must be obtained for adolescent patients <18 years old, and a parent/guardian 
must provide written consent. 
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. 
11.1.4. 
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 
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 
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11.1.5. 
Use of Research Samples and Data 
The Sponsor will be responsible for all stored samples generated during this study and the types 
of analyses to be done on the sample. 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. Samples will be stored 
via pseudonymization. Samples will be labeled with a code that only the study team can link to a 
patient. Patients’ identities will not be revealed to the laboratory(ies) where samples will be 
stored or analyzed. 
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 
any biological specimens left over from study-specified assessments stored and used for future 
research. However, withdrawal of consent with regard to 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. 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. 
11.2. 
Data Handling and Recordkeeping 
11.2.1. 
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 CRF Manual. Clinical data will be entered directly from 
the source documents. 
11.2.2. 
Retention of Records 
This study is conducted under an Investigational New Drug (IND) application with the FDA; 
therefore, ICH GCP guidelines apply. 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 


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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. 
11.2.3. 
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 with regard 
to 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. 
 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. 
11.2.4. 
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 


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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 Good Clinical Practice (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. 
11.2.5. 
Quality Control and Quality Assurance 
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. 
11.3. 
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. 
In the event that the Sponsor elects to terminate or suspend this study prior to completion, it will 
discuss the feasibility of continued administration of nanatinostat/valganciclovir with each 
participating Investigator for those patients that appear to be benefitting from 
nanatinostat/valganciclovir. 
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. 
11.4. 
Use of Study Information and Publication 
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). 
Upon study completion and finalization of the study report, the results of this study will be 
submitted for publication. Data derived from the study are the exclusive property of the Sponsor. 
The results of the study may be published or presented by the Investigator(s) following review 
and agreement by the Sponsor. 


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retrospective analysis. Lancet Oncol. 2016;17(3):389-400. 
38. Ahn HK, Kim SJ, Hwang DW, Ko YH, Tang T, Lim ST, et al. Gemcitabine alone and/or 
containing chemotherapy is efficient in refractory or relapsed NK/T-cell lymphoma. Invest 
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39. Jeong SH, Song HN, Park JS, Yang DH, Koh Y, Yoon SS, et al. Allogeneic Stem Cell 
Transplantation for Patients with Natural Killer/T Cell Lymphoid Malignancy: A 
Multicenter Analysis Comparing Upfront and Salvage Transplantation. Biol Blood Marrow 
Transplant. 2018;24(12):2471-8. 
40. Li X, Cheng Y, Zhang M, Yan J, Li L, Fu X, et al. Activity of pembrolizumab in 
relapsed/refractory NK/T-cell lymphoma. J Hematol Oncol. 2018;11(1):15. 
41. Kim SJ, Lim JQ, Laurensia Y, Cho J, Yoon SE, Lee JY, et al. Avelumab for the treatment 
of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study. 
Blood. 2020;136(24):2754-63. 
42. Diepstra A, van Imhoff GW, Schaapveld M, Karim-Kos H, van den Berg A, Vellenga E, et 
al. Latent Epstein-Barr virus infection of tumor cells in classical Hodgkin's lymphoma 
predicts adverse outcome in older adult patients. J Clin Oncol. 2009;27(23):3815-21. 
43. Ansell SM. Hodgkin lymphoma: 2018 update on diagnosis, risk-stratification, and 
management. Am J Hematol. 2018;93(5):704-15. 
44. Straus DJ, Długosz-Danecka M, Connors JM, Alekseev S, Illés Á, Picardi M, et al. 
Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma 
(ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. 
Lancet Haematol. 2021;8(6):e410-e21. 
45. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Hodgkin 
Lymphoma. Version 2.2022 - April 10, 2022. Plymouth Meeting, PA: National 
Comprehensive Cancer Network; 2022. 


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46. Karantanos T, Politikos I, Boussiotis VA. Advances in the pathophysiology and treatment 
of relapsed/refractory Hodgkin's lymphoma with an emphasis on targeted therapies and 
transplantation strategies. Blood Lymphat Cancer. 2017;7:37-52. 
47. Dierickx D, Habermann TM. Post-Transplantation Lymphoproliferative Disorders in 
Adults. N Engl J Med. 2018;378(6):549-62. 
48. Trappe RU, Dierickx D, Zimmermann H, Morschhauser F, Mollee P, Zaucha JM, et al. 
Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant 
Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-
CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial. J Clin 
Oncol. 2017;35(5):536-43. 
49. Sanz J, Storek J, Socié G, Thirumalai D, Guzman-Beccera N, Xun P, et al. Abstract 1454. 
Presented at: ASH Annual Meeting and Exposition; December 11–14, 2021; Atlanta. 
Clinical Outcomes of Patients with Epstein–Barr Virus-Driven Post-Transplant 
Lymphoproliferative Disease Following Hematopoietic Stem Cell Transplantation Who 
Fail Rituximab:A Multinational, Retrospective Chart Review Study. Blood. 
2021;138(Suppl 1):1454. 
50. Dharnidharka VR, Green M, Webber SA, and Trappe RU, (Editors). Post-Transplant 
Lymphoproliferative Disorders. 2 ed. Springer Nature Switzerland AG 20212021 12 
February 2021. 
51. Socié G, Pigneux A, Herbaux C, Chauvet P, Xu H, Thirumalai D, et al. Clinical Outcomes 
of EBV+ PTLD Patients Following HCT Who Fail Rituximab: A Retrospective Chart 
Review Study from France (Atara Bio Poster). 2020. 
52. Zimmermann H, Trappe RU. Therapeutic options in post-transplant lymphoproliferative 
disorders. Ther Adv Hematol. 2011;2(6):393-407. 
53. Swerdlow S, Campo E, Harris N, Jaffa E, Pileri S, Stein H, et al. WHO Classification of 
Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). Lyon: 
International Agency for Research on Cancer; 2017. 
54. Carbone A, Tirelli U, Gloghini A, Volpe R, Boiocchi M. Human immunodeficiency virus-
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Epstein-Barr viral latent gene expression. J Clin Oncol. 1993;11(9):1674-81. 
55. Shindiapina P, Ahmed EH, Mozhenkova A, Abebe T, Baiocchi RA. Immunology of EBV-
Related Lymphoproliferative Disease in HIV-Positive Individuals. Front Oncol. 
2020;10:1723. 
56. Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA. Hodgkin lymphoma 
and immunodeficiency in persons with HIV/AIDS. Blood. 2006;108(12):3786-91. 
57. Mbulaiteye SM, Pullarkat ST, Nathwani BN, Weiss LM, Rao N, Emmanuel B, et al. 
Epstein-Barr virus patterns in US Burkitt lymphoma tumors from the SEER residual tissue 
repository during 1979-2009. Apmis. 2014;122(1):5-15. 
58. Grulich AE, Vajdic CM. The epidemiology of cancers in human immunodeficiency virus 
infection and after organ transplantation. Semin Oncol. 2015;42(2):247-57. 
59. Dunleavy K, Wilson WH. How I treat HIV-associated lymphoma. Blood. 
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60. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): B-Cell 
Lymphomas. Version 1.2022 - March 2, 2022. Plymouth Meeting, PA: National 
Comprehensive Cancer Network; 2022. 
61. Banerji U, van Doorn L, Papadatos-Pastos D, Kristeleit R, Debnam P, Tall M, et al. A 
phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I 
selective histone deacetylase inhibitor in refractory solid tumors. Clin Cancer Res. 
2012;18(9):2687-94. 
62. Ghosh SK, Forman LW, Akinsheye I, Perrine SP, Faller DV. Short, discontinuous 
exposure to butyrate effectively sensitizes latently EBV-infected lymphoma cells to 
nucleoside analogue antiviral agents. Blood Cells Mol Dis. 2007;38(1):57-65. 
63. Hui KF, Cheung AK, Choi CK, Yeung PL, Middeldorp JM, Lung ML, et al. Inhibition of 
class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle 
and mediates enhanced cell death with ganciclovir. Int J Cancer. 2016;138(1):125-36. 
64. Beckers T, Burkhardt C, Wieland H, Gimmnich P, Ciossek T, Maier T, et al. Distinct 
pharmacological properties of second generation HDAC inhibitors with the benzamide or 
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65. Moffat D, Patel S, Day F, Belfield A, Donald A, Rowlands M, et al. Discovery of 2-(6-
{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-
carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor. J 
Med Chem. 2010;53(24):8663-78. 
66. Kim SJ, Kim JH, Ki CS, Ko YH, Kim JS, Kim WS. Epstein-Barr virus reactivation in 
extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious 
adverse event in a pilot study with romidepsin. Ann Oncol. 2016;27(3):508-13. 
67. Ritchie D, Piekarz RL, Blombery P, Karai LJ, Pittaluga S, Jaffe ES, et al. Reactivation of 
DNA viruses in association with histone deacetylase inhibitor therapy: a case series report. 
Haematologica. 2009;94(11):1618-22. 
68. Celgene. ISTODAX® (romidepsin) Prescribing Information (07/2021). 2021. 
69. Gryder BE, Sodji QH, Oyelere AK. Targeted cancer therapy: giving histone deacetylase 
inhibitors all they need to succeed. Future Med Chem. 2012;4(4):505-24. 
70. Porcu P, Haverkos B, Alpdogan O, Baiocchi R, Brammer J, Feldman T, et al. Oral 
nanatinostat (Nstat) and valganciclovir (VGCV) in patients with recurrent Epstein-Barr 
virus (EBV)-positive lymphomas: initial phase 2 results (Abstract 1154).  62nd American 
Society of Hematology (ASH) Annual Meeting and Exposition; Dec 05, 2020; Virtual 
Meeting.2020. 
71. Haverkos BM, Alpdogan O, Baiocchi R, Brammer JE, Feldman TA, Capra M, et al. 
Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-
Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 
Study. Blood. 2021;138(1):623. 
72. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. 
Recommendations for the Use of WBC Growth Factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33(28):3199-212. 
73. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55. 


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13. 
APPENDICES 


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APPENDIX 1. CONCOMITANT THERAPIES TO BE USED WITH 
CAUTION WITH NANATINOSTAT 
Table 11: 
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 
 Note: This list is not exhaustive of all substrates. For more information, discuss with your research pharmacist.  
Table 12: 
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 
 Note: This list is not exhaustive of all inhibitors. For more information, discuss with your research pharmacist.  
 


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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 
Monitor 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 
Abbreviation: CBC = complete blood count. 
a Includes, but is not limited to, adefovir, adriamycin, dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, 
tacrolimus, tenofovir, trimethoprim/sulfamethoxazole, vinblastine, vincristine, and zidovudine. 
Adapted from VALCYTE® USPI 2021 (Genentech 2021).
 


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APPENDIX 3. RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA 
 
Table 13: Response Definitions for Clinical Trials 
 
Source: (Cheson 2007). 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Viracta Therapeutics, Inc. 
Study VT3996-202 (NAVAL-1) 
Protocol Title: 
An Open-Label, Phase 2 Trial of Nanatinostat in Combination 
with Valganciclovir in Patients with Epstein-Barr Virus-Positive 
(EBV+) Relapsed/Refractory Lymphomas (NAVAL-1) 
Protocol Version 
and Date: 
Amendment 5.0: Version 6.0, 19 October 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, 09 October 2024 
(NCT05011058)


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STATISTICAL ANALYSIS PLAN APPROVAL 
Sponsor: 
Viracta Therapeutics, Inc. 
Clinical Protocol Number: VT3996-202 (NAVAL-1) 
Protocol Title: 
An Open-Label, Phase 2 Trial of Nanatinostat in 
Combination with Valganciclovir in Patients with 
Epstein-Barr Virus-Positive (EBV+) 
Relapsed/Refractory Lymphomas (NAVAL-1) 
Document File and Name: 
Viracta_VT3996-202_SAP_v1.0_2024-10-09.pdf 
Document Version and 
Effective Date: 
Version 1.0; 09 October 2024 
Approved By: 
Darrel P. Cohen, MD, PhD 
Chief Medical Officer 
Viracta Therapeutics, Inc. 
Sarah Parisi 
Associate Director, Biostatistics 
Emanate Biostats, Inc. 
(NCT05011058)


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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 Objective ................................................................................. 8 
2.2 
Secondary Study Objectives ............................................................................ 8 
2.3 
Exploratory Study Objectives ......................................................................... 9 
3. 
INVESTIGATIONAL PLAN ................................................................................ 9 
3.1 
Overall Study Design ...................................................................................... 9 
3.2 
Schedule of Assessments .............................................................................. 12 
3.3 
Treatments ..................................................................................................... 12 
3.3.1 
Treatments Administered ....................................................................... 12 
3.3.2 
Method of Assigning Patients to Cohorts .............................................. 13 
3.4 
Efficacy and Safety Variables ....................................................................... 14 
3.4.1 
Efficacy Variables .................................................................................. 14 
3.4.2 
Safety Variables ..................................................................................... 16 
3.4.3 
Pharmacokinetic Variables .................................................................... 18 
3.5 
Data Quality Assurance ................................................................................. 18 
4. 
STATISTICAL METHODS ................................................................................ 19 
4.1 
General Methodology .................................................................................... 19 
4.1.1 
Reporting Conventions .......................................................................... 19 
4.1.2 
Summarization by Visit ......................................................................... 20 
4.1.3 
Data Handling Rules .............................................................................. 20 
4.1.4 
Baseline Value ....................................................................................... 20 
4.1.5 
Standard Calculations ............................................................................ 20 
4.2 
Analysis Sets ................................................................................................. 21 
4.3 
Study Patients ................................................................................................ 21 
4.3.1 
Disposition of Patients ........................................................................... 21 
4.3.2 
Protocol Deviations ................................................................................ 22 
4.4 
Demographic and Other Baseline Characteristics ......................................... 22 
4.5 
Efficacy Evaluation ....................................................................................... 23 
4.5.1 
Datasets Analyzed .................................................................................. 23 
4.5.2 
Measurements of Treatment Compliance .............................................. 23 


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4.5.3 
Primary Efficacy Endpoint Analysis Methods ...................................... 24 
4.5.4 
Secondary Endpoint Analysis Methods ................................................. 24 
4.5.5 
Additional Efficacy Endpoint Analysis Methods .................................. 24 
4.5.6 
Statistical/Analytical Issues ................................................................... 25 
4.5.7 
Plasma Concentrations ........................................................................... 27 
4.5.8 
Pharmacokinetic Analysis ...................................................................... 27 
4.6 
Safety Evaluation .......................................................................................... 27 
4.6.1 
Extent of Exposure ................................................................................. 28 
4.6.2 
Adverse Events ...................................................................................... 28 
4.6.3 
Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events 30 
4.6.4 
Clinical Laboratory Evaluation .............................................................. 31 
4.6.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 32 
4.7 
Determination of Sample Size ....................................................................... 33 
4.8 
Changes in the Conduct of the Study or Planned Analyses .......................... 35 
5. 
REFERENCE LIST ............................................................................................. 36 
 
 
 


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TABLE OF TABLES 
Table 1 
List of Abbreviations ................................................................................... 6 
Table 2 
Valganciclovir Dosing for Patients with Renal Impairment ..................... 13 
Table 3 
Censoring Conventions for Progression-Free Survival, Time to 
Progression, and Duration of Response ....................................................................... 25 
 
TABLE OF FIGURES 
Figure 1 
Study Design.............................................................................................. 10 
  
 
 


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ABBREVIATIONS 
Table 1 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AITL 
angioimmunoblastic T-cell lymphoma 
ALT 
aminotransferase, alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC  
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CI 
confidence interval 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete response 
CRR 
complete response rate 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug-induced liver injury 
EBV+ 
Epstein-Barr Virus-Positive 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
ENKTL 
extranodal NK/T-cell lymphoma 
EOT 
End of Treatment 
FDG 
fluorodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded 
DLBCL 
diffuse large B-cell lymphoma 
DOR 
duration of response 
HDAC 
histone deacetylase 
HIV 
human immunodeficiency virus 
HL 
Hodgkin lymphoma 
ICH 
International Council for Harmonisation 
IPD 
important protocol deviation 
IRC 
Independent Review Committee 
IWG 
International Working Group 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NHL 
non-Hodgkin lymphoma 
OS 
overall survival 
PD-1 
programmed cell death-1 


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Abbreviation 
Definition 
PD-L1 
programmed cell death-ligand 1 
PET 
positron emission tomograph 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PTCL 
peripheral T-cell lymphoma 
PTLD 
post-transplant lymphoproliferative disorder 
NCI 
National Cancer Institute 
NOS 
not otherwise specified 
ORR 
Objective Response Rate 
Q1 
1st quartile (25th percentile) 
Q3 
3rd quartile (75th percentile) 
QTcF 
corrected QT interval using Fridericia’s method 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SI 
Système International 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocyte 
TTNLT 
time to next anti-lymphoma treatment 
TTP 
time to progression 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
VGCV 
valganciclovir 
 
 


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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 presentations of data analyses proposed for 
Viracta Therapeutics-sponsored Study VT3996-202 (An Open-Label, Phase 2 Trial of 
Nanatinostat in Combination with Valganciclovir in Patients with Epstein-Barr Virus-
Positive [EBV+] Relapsed/Refractory Lymphomas [NAVAL-1]). 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) 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).  
This SAP will be finalized prior to any formal interim or final data analyses and before 
database lock to provide comprehensive details of the data analyses to be presented in 
the Clinical Study Report (CSR). For the purpose of the data analyses, this SAP will 
supersede the study protocol-specified analysis plan. 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 Objective 
The primary objective of this study is to evaluate the anti-tumor activity of the 
combination treatment of nanatinostat with valganciclovir (VGCV) based on objective 
tumor response rates. 
2.2 
Secondary Study Objectives 
The secondary objectives of this study are to: 
• Determine the duration of tumor control; 
• Determine survival outcomes; 
• Describe the safety profile of the combination treatment of nanatinostat and 
VGCV;  
• Generate pharmacokinetic (PK) data with the intended commercial dose and 
administration of nanatinostat. 
 
 


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2.3 
Exploratory Study Objectives 
The exploratory objectives of this study are to: 
• Explore correlation of baseline PD-L1 expression and other immune checkpoint 
molecules with outcome; 
• Evaluate potential biomarkers of activity of combination therapy; 
• Identify potential resistance markers to therapy. 
3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
This is an open-label, multicenter, multinational single-arm, Phase 2 basket design 
study utilizing Simon’s 2-stage design options for discontinuing enrollment into each 
cohort where treatment appears to be futile. The study will include 7 cohorts of patients 
with the following EBV+ relapsed/refractory lymphomas: 
• Cohort 1: EBV+ diffuse large B-cell lymphoma, not otherwise specified 
(DLBCL, NOS) 
• Cohort 2: Extranodal NK/T-cell lymphoma (ENKTL) 
• Cohort 3: Peripheral T-cell lymphoma (PTCL), including PTCL-NOS and 
angioimmunoblastic T-cell lymphoma (AITL) 
o Cohort 3a: Nanatinostat monotherapy 
o Cohort 3b: Nanatinostat + valganciclovir 
• Cohort 4: Hodgkin lymphoma (HL) 
• Cohort 5: Post-transplant lymphoproliferative disorder (PTLD)  
• Cohort 6: Lymphomas associated with human immunodeficiency virus 
(HIV) infection (HIV-L): Plasmablastic, Burkitt, Hodgkin, and DLBCL 
• Cohort 7: EBV+ lymphomas other than Cohorts 1, 3, 4, 5, and 6 above 
(Cohort 7 will not enroll patients in France). 
A study schema is shown in the figure below: 
 
 


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Figure 1 
Study Design 
 
The purpose of this study is to determine the efficacy of the combination treatment of 
nanatinostat with valganciclovir in patients with relapsed/refractory EBV+ lymphomas. 
At screening, the patient will provide a signed informed consent form prior to any 
study-related activities. A recent formalin-fixed paraffin-embedded (FFPE) specimen 
must be available for retrospective central review of diagnosis. FFPE tissue blocks are 
preferred; if a tissue block is not available, at least 15 unstained slides or freshly cut 
serial sections (3−5 μm in thickness), preferably with an accompanying block punch 
will be accepted. Collection and shipment of this formalin-fixed paraffin-embedded 
tumor sample 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 verification of lymphoma subtype. Additional 
screening evaluations must be performed within 28 days or 14 days before treatment 
start as defined in the Schedule of Events. Patient eligibility will be confirmed once all 
screening procedures are completed. 
The method of assigning patients to individual cohorts is described in detail in Section 
3.3.2. It is estimated that up to 486 patients in Cohorts 1 to 6 may be enrolled for 
combination therapy, of which approximately 60 would be enrolled in Stage 1 and 66 
would be enrolled in Stage 2, and up to 360 would be enrolled into the post-Stage 2 
expansion cohorts. Additional patients (n=10) with PTCL will be enrolled in Cohort 3a 
for nanatinostat monotherapy, and patients with lymphoma subtypes other than those 
assigned to Cohorts 1, 3, 4, 5, and 6 may be enrolled into Cohort 7 (with the exception 
of France). 
If 10 patients of a given lymphoma subtype are enrolled into Cohort 7, then the Simon’s 
decision criteria will be applied to determine whether or not to add patients in Stage 2 
for that subtype. If none of the subtypes represented in Cohort 7 enrolls at least 10 
patients, efficacy data collected on those patients will be listed but not summarized by 
group.  
Enrolled patients will receive treatment until disease progression (per Investigator 
assessment), unacceptable toxicity, withdrawal of consent, Investigator’s discretion, 
death, initiation of new antineoplastic therapy, discontinuation from the study for any 


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reason, or study termination by the Sponsor. All antineoplastic therapies given after the 
last dose of study drug (and time to next therapy) will be recorded in the electronic case 
report form (eCRF) (unless the patient withdraws consent or is lost to follow-up). 
Patients will be followed for survival regardless of treatment discontinuation reason 
(except if consent is withdrawn or patient is lost to follow-up). 
Study treatment will start on Cycle 1 Day 1. Patients enrolled in Cohorts 1 to 7 (with 
the exception of Cohort 3a), and patients crossed over from Cohort 3a will receive 
intermittent dosing of nanatinostat and continuous valganciclovir in 28-day cycles. 
Nanatinostat and valganciclovir will be taken at the same time following a light meal. 
During treatment Cycle 1, visits will occur on Days 1, 8, 15, and 22. Starting at Cycle 
2, visits will occur on Days 1 and 15. Each scheduled clinic visit has an allowable ±3-
day window. 
For Cohort 3a, the PTCL patients randomized to monotherapy will begin with 6 weeks 
of nanatinostat monotherapy (20 mg orally once daily on Days 1 to 4 per week) with 
visits on Days 1, 15, 29, and 43. Each scheduled clinic visit has an allowable ±3-day 
window.  
If a Cohort 3a patient has stable disease at the Day 43 visit (or progressive disease at 
any time), the patient will be offered the option to cross over to combination 
nanatinostat/valganciclovir therapy and follow the 28-day treatment cycles as described 
above. Patients must complete the End of Monotherapy Disease assessment and qualify 
(labs, no sign of central nervous system [CNS] disease progression, Eastern 
Cooperative Oncology Group [ECOG]) prior to beginning Cycle 1 Day 1 of the 
nanatinostat/valganciclovir combination therapy. If a patient has a response (complete 
or partial response) to nanatinostat monotherapy at the Day 43 visit, the patient will 
continue monotherapy treatment. 
For patients enrolled in Cohorts 1 to 7 (with the exception of Cohort 3a prior to potential 
crossover to combination therapy), disease response assessments will be made every 8 
weeks until 24 weeks, and then every 12 weeks for the remainder of the study, 
according to the revised response criteria for malignant lymphoma based on the 
International Working Group (IWG) guidelines (Cheson 2007). A scan to confirm an 
unconfirmed partial response (PR) or unconfirmed complete response (CR) ≥4 weeks 
later may also be performed. Responses will be assessed by both the Investigator and 
an Independent Review Committee (IRC). 
The safety and tolerability of study drug treatments will be evaluated by means of 
adverse event (AE) reports (incidence, causality, and severity), ECOG performance 
status, physical examinations, 12-lead electrocardiograms (ECGs), and laboratory 
safety evaluations. Laboratory abnormalities and AE severity will be graded according 
to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0. 
Upon discontinuation of the protocol-specified treatments, patients will enter the 
Follow-up period. All patients will be followed for AEs for 28 days after the last dose 
of study drug (permanent discontinuation) and complete the Safety Follow-up visit as 
described in Section 7.2.5 of the clinical study protocol, except if the patient is lost to 
follow-up or withdraws consent. The PK parameters of nanatinostat and its metabolites 


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and ganciclovir (primary active hydrolytic product of valganciclovir) will be evaluated 
for patients enrolled in Stage 1 and sparse sampling will be collected during the Stage 
2 part of the study at selected sites. 
In the Long-term Follow-up period, patients will be followed as described in Section 
7.2.6 of the clinical study protocol (or more frequently if a survival update is required 
for safety or regulatory reasons) for disease progression, overall survival [OS], 
subsequent anti-lymphoma therapies, and response (best overall responses and disease 
progression date) to subsequent lymphoma therapies. Survival information can be 
obtained by phone calls, clinic visits, or public records, such as government census or 
death records, until the patient is lost to follow-up, death, or withdraws consent. 
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 (SD) 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 drugs on an individual basis (e.g., by 
separate protocol or post-trial access plan) with Sponsor approval. 
Because of the open-label single-arm trial design elements, each cohort will be 
monitored individually for safety and efficacy. Therefore, each cohort may advance 
from Stage 1 to Stage 2 and complete Stage 2 at different rates. The decision to expand 
enrollment beyond Stage 2 will also occur independently for each cohort. However, a 
study-wide analysis of efficacy and safety over all cohorts will be performed once either 
all cohorts have completed assessments of response at the end of Stage 2 and those with 
responses have been followed for up to 3 years, or the study is prematurely terminated 
by the Sponsor. 
3.2 
Schedule of Assessments 
For the complete schedule of assessments, refer to Section 6.1 of the clinical study 
protocol. 
3.3 
Treatments 
3.3.1 Treatments Administered 
Nanatinostat is a selective histone deacetylase (HDAC) Class I inhibitor with activity 
against HDAC1, HDAC2, and HDAC3. Valganciclovir (VALCYTE®) is an oral 
prodrug of ganciclovir. The antiviral activity of valganciclovir is based on the 
generation of ganciclovir-triphosphate, which is a competitive substrate for the 
cytomegalovirus (CMV) DNA polymerase. 
Patients enrolled in Cohorts 1 to 7 (with the exception of Cohort 3a), and patients 
crossed over from Cohort 3a, will receive intermittent dosing of nanatinostat and 
continuous valganciclovir in 28-day cycles as follows: 
• Nanatinostat 20 mg orally once daily on Days 1 to 4 per week (i.e., 4 days 
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• Valganciclovir 900 mg orally once daily, except patients with creatinine 
clearance 50-59 mL/min at study entry will receive valganciclovir 450 mg 
orally once daily as described in Table 2 below. 
Table 2 
Valganciclovir Dosing for Patients with Renal Impairment 
Creatinine Clearance 
(mL/minute) 
Valganciclovir Dose 
≥60 
900 mg once daily 
40-59 
450 mg once daily 
25-39 
450 mg every 2 days 
10-24 
450 mg twice weekly 
<10 (on hemodialysis) 
Not recommended (discuss with Medical 
Monitor) 
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, but within 8 hours of the 
missed dose. If more than 8 hours or an entire day has passed, the normal dosing 
schedule will be resumed the following day without a change in the daily dose or 
schedule. 
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 scheduled dose. No replacement dose should be given. If the situation 
persists, the site should consult the Medical Monitor. 
3.3.2 Method of Assigning Patients to Cohorts 
Patients will be enrolled utilizing Simon’s 2-stage design options for discontinuing 
enrollment into each cohort where treatment appears to be futile. In Stage 1, 6 cohorts 
(Cohorts 1, 2, 3b, 4, 5, and 6) will enroll up to 10 patients each. Patients will be enrolled 
into each cohort based on their primary lymphoma diagnosis to receive the combination 
nanatinostat plus valganciclovir with exception of Cohort 3a. 
The first 20 patients enrolled with PTCL in Cohort 3 will be randomized 1:1 to either 
Cohort 3a (nanatinostat monotherapy) or Cohort 3b (nanatinostat plus valganciclovir). 
Randomization will occur at the time of drug dispensation for Cycle 1 Day 1. Following 
a disease response assessment at 6 weeks, patients in Cohort 3a with a CR or PR will 
continue nanatinostat monotherapy. Those in Cohort 3a with stable disease at 6 weeks 
or disease progression at any time will be offered the option to cross over to receive 
combination therapy for the remainder of the study, provided they qualify per 
hematology, chemistry, no sign of CNS disease progression, and ECOG performance 
status parameters. 
All cohorts that have a response in 2 or more patients in Stage 1 will expand enrollment 
by 11 patients in Stage 2, for a total of 21 patients in each cohort (Figure 2). If ≥7 
responses are observed in the initial 21 patients in any cohort, then enrollment will be 
expanded to include up to 120 additional patients in that cohort (N=141), with an 
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subpopulation (see Section 4.7 for sample size details). Data from a total of 40 patients 
who have been followed for at least 6 months or permanently discontinued study 
treatment will be used for this interim analysis. If the interim efficacy analysis outcome 
is positive (see Section 4.5.6.3 for details of this interim efficacy analysis), then the 
final analysis would still be conducted for all second-line EBV+ lymphoma patients and 
the entire cohort. Cohort 3a will not enroll beyond the initial 10 patients, regardless of 
the number of responders in Stage 1. See Section 4.7 for details. 
Cohort 7 will be closed to enrollment when all other cohorts are closed, or sooner at the 
discretion of the Sponsor, regardless of the number of patients recruited at that time and 
will not be subject to the decision criteria of the Simon’s 2-stage design. 
3.4 
Efficacy and Safety Variables 
3.4.1 Efficacy Variables 
3.4.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the objective response rate (ORR) as assessed by an 
IRC. The ORR is defined as the proportion of patients who achieve a complete response 
CR or PR using the 2007 International Working Group (IWG) NHL criteria (Cheson 
2007). The investigator will also use the 2007 IWG for assessment of disease 
progression/relapse and for any clinical decisions requiring assessment of disease 
progression/relapse. The IRC review includes central radiology and clinical review. 
The radiologic assessments (fluorodeoxyglucose-positron emission tomograph [FDG-
PET]/computed tomography [CT], CT with contrast, or magnetic resonance imaging 
[MRI]) are considered the primary method of response assessment. Any additional 
assessments (e.g., clinical assessments, bone marrow biopsy assessments, etc.) are 
considered confirmatory. 
FDG-PET/CT scans in conjunction with diagnostic contrast-enhanced CT scans (or 
MRI if a CT with contrast is contraindicated) will be performed at baseline, and for the 
8-week and 16-week tumor assessments. For Cohort 3a only, scans are performed at 
the 6-week tumor assessment instead of the 8-week tumor assessment to determine if 
patients may cross over to receive combination therapy. For patients who do cross over 
to receive combination therapy, subsequent scans will occur at the 8-week and 16-week 
visits, consistent with Cohort 3b. Patients continuing on nanatinostat monotherapy will 
have subsequent scans at the 14-week and 22-week tumor assessments. Diagnostic 
contrast-enhanced CT scans obtained as part of a PET/CT scan may be used in lieu of 
dedicated CT scans. 
Subsequent evaluations will be performed by CT with contrast (without PET) or MRI 
only. Patients with FDG-avid lymphoma at baseline may have an FDG-PET/CT 
performed to evaluate a possible CR or PR after Week 16 (unless prohibited by local 
practice) and may use a diagnostic contrast-enhanced CT for follow-up once a complete 
metabolic response is obtained. FDG-PET/CT scans may also be obtained per 
investigator discretion (e.g., in instances where extranodal disease may be inadequately 
imaged by contrast-enhanced CT scan). 


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Responses will also be assessed by the investigator for management of the patient. 
Investigator-determined response assessments at each assessment time point will be 
recorded on the appropriate eCRF.  
3.4.1.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
• Complete response rate (CRR) – defined as the proportion of patients who 
achieve a CR using the 2007 IWG NHL criteria (Cheson 2007) per IRC review, 
as well as per Investigator assessment. 
• 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 IWG criteria. TTR will 
be determined for response assessments per IRC review as well as by 
investigator. 
• Duration of response (DOR) – defined as the interval from the date of first 
documented CR or PR per IWG criteria to the date of disease progression, death 
due to any cause, or last adequate (radiographic) response assessment. Dates of 
disease progression and censoring will be determined as described in Section 
4.5.6.2. Duration of response will be determined for response assessments per 
IRC review as well as by investigator. 
• Duration of complete response (DOCR) – defined as the interval from the date 
of first documented CR per IWG criteria to the date of disease progression, 
death due to any cause, or last adequate (radiographic) response assessment. 
Dates of disease progression and censoring will be determined as described in 
Section 4.5.6.2. Duration of complete response will be determined for response 
assessments per IRC review as well as by investigator. 
• Time to next anti-lymphoma treatment (TTNLT) – defined as the interval from 
the start of study drug treatment to the date of next anti-lymphoma treatment 
(including 
chemotherapy, 
radiotherapy, 
radioimmunotherapy, 
or 
immunotherapy). Patients who do not receive subsequent anti-lymphoma 
treatment will be censored at the date of their last non-missing disease 
assessment prior to the start of therapy. 
• Progression-free survival (PFS) – defined as the interval from the start of study 
drug treatment to the date of first documented disease progression, initiation of 
new antineoplastic therapy, or death from any cause, whichever occurs first. 
Dates of disease progression and censoring will be determined as described in 
Section 4.5.6.2. 
• Time to progression (TTP) – defined as the interval from the start of study drug 
treatment to the date of disease progression. Patients whose disease does not 
progress will be censored at the date of their last tumor assessment. 
• Overall survival (OS) – defined as the interval from the start of study drug 
treatment to the date of death, for any reason. Patients without documentation 


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of death at the time of analysis will be censored at the date the patient was last 
known to be alive. 
3.4.1.3 
Exploratory Efficacy Endpoints 
The following will be used to explore the correlation of baseline programmed cell 
death-1 (PD-1) expression and other immune checkpoint molecules with outcome: 
• Expression of programmed cell death-ligand 1 (PD-L1) and other immune 
checkpoint molecules in tumor 
• Tumor-infiltrating lymphocyte (TIL) counts (e.g., CD3, CD4, CD8) 
• EBV-associated genes/proteins (e.g., EBER, BZLF-1/ZTA, LMP-1, BGLF- 
4/PK, BXLF-1/TK, BRLF-1Rta) 
In addition, the following potential biomarkers of activity will be evaluated for the 
combination therapy: histone H3 acetylation, plasma EBV DNA levels, ribonucleic 
acid (RNA) expression of selected immunological genes, and flow cytometry/IF/IHC 
for immune cell markers.  
EBER, LMP-1, TIL counts, PD-L1, and other immune checkpoint molecules will be 
evaluated to identify potential resistance markers to therapy. 
3.4.2 Safety Variables 
Safety assessments consist of monitoring and recording all AEs, regular laboratory 
evaluation for hematology, blood chemistry, coagulation and urinalysis, periodic 
measurement of vital signs, ECGs, performance status, and physical examinations. 
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 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 (i.e., any clinically significant adverse change in 
the frequency or intensity of a pre-existing condition) will be considered an AE. A 
diagnosis or syndrome will be recorded on the Adverse Events eCRF rather than the 
individual signs or symptoms of the diagnosis or syndrome. 
An overdose, accidental or intentional, associated with an AE, or abuse, withdrawal, 
sensitivity, or toxicity to an investigational product should be reported as an AE. 
Overdoses with or without an associated AE will be recorded on the dosing eCRF. All 
patients will be monitored for AEs during the study and continue until 28 days after the 
last dose of study drugs or until a new anticancer treatment is started, whichever occurs.  


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Pre-existing conditions are not considered AEs unless the condition worsens by at least 
one grade following the start of administration of the study drugs. 
3.4.2.2 
Laboratory Parameters 
Clinical laboratory evaluations will follow those outlined in the clinical study protocol 
and will be performed using a central or local laboratory. Evaluations include 
hematology, chemistry, urinalysis, coagulation, and pregnancy tests (for women of 
childbearing-potential only). Specific parameters to be collected are listed below: 
• Hematology (blood): Complete blood count with differential to include white 
blood cells and differential, red blood cells, hemoglobin, hematocrit, platelets, 
mean corpuscular hemoglobin, mean corpuscular volume 
• Chemistry (blood): Sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose, calcium, phosphate, magnesium, aspartate 
aminotransferase (AST), aminotransferase, alanine aminotransferase (ALT), 
total bilirubin, alkaline phosphatase, total protein, albumin, uric acid, lactate 
dehydrogenase (LDH), and serum amylase 
• Coagulation (blood): prothrombin time, partial thromboplastin time, and 
international normalized ratio 
• Urinalysis (urine): color (appearance), glucose, bilirubin, ketones, specific 
gravity, blood pH, protein, urobilinogen, nitrite, leukocyte esterase 
3.4.2.3 
Other Safety Variables 
Electrocardiograms 
Electrocardiograms will be performed as outlined in the clinical study protocol. 
Triplicate ECGs should be obtained in close succession from the first ECG to the third 
ECG. For each sampling time point, 3 standard resting 12-lead ECGs will be obtained 
in close succession and no more than 2 minutes apart (4 minutes total for 3 ECGs). 
Average corrected QT interval using Fridericia’s method (QTcF) will be calculated to 
confirm eligibility. 
When performed on days that include PK sample collection (Stage 1), two triplicate 
ECGs will be performed post-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 Cmax (1 and 2 hours) and 4 hours.  
For days with no scheduled PK sample collections, the ECG may be performed at any 
time during the clinic visit, or when clinically indicated, irrespective of the time of study 
drug dosing. All ECGs will be independently reviewed by a central laboratory. 
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. 


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Vital Signs 
Vital signs (temperature, blood pressure, and heart rate) will be obtained at the 
Screening visit (Day -28 to Day -1), on Day 1 of each cycle (Day 4 of Cycles 2 and 6), 
and at the End of Treatment (EOT) visit. 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, collect vital signs once (prior to dosing of study 
drugs, if administered in clinic). 
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 (Day 4 of Cycles 2 and 6) and at the 
EOT visit. Height should additionally be measured in patients 12 to 17 years of age on 
Day 1 of each cycle (Day 4 of Cycles 2 and 6). 
Physical Examinations and Performance Scales 
Physical examinations will be performed at the screening visit only; symptom-directed 
physical examinations will be conducted at each visit through Safety Follow-up as 
outlined in the clinical study protocol. Performance status will be measured by ECOG 
performance status assessments and will be regularly evaluated as outlined in the 
clinical study protocol.  
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. 
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. 
 
 


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4. STATISTICAL METHODS 
4.1 
General Methodology 
Data will be analyzed by Emanate biostatistics personnel. Statistical analyses will be 
reported in the form of 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 Simon 2-stage and post-Stage 2 expansion parts of the study will be analyzed 
separately. For safety analyses only, all patients who receive combination therapy over 
the course of the study will also be analyzed separately. 
Tables and figures will be summarized by cohort within each part. A more detailed 
description for how these data will be presented for each type of analysis (e.g., safety, 
efficacy, etc.) is provided in subsequent sections herein. 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, cohort, patient number, and assessment or event 
date. The cohort 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, the denominator to determine the percentage of patients in each 
category will be based on the number of patients with available data. 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., SD, SE) 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. 


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No formal statistical analysis will be performed to compare cohorts. No formal type-1 
error adjustment will be performed at the interim analysis or at the final analysis. 
Descriptive statistics will be tabulated by cohort 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 will be summarized 
separately and this summary will be labeled as “End of Treatment” in the analysis. 
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 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 the first dose of study drug. 
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 reference 
date of interest (e.g., date of first dose of study drug); or 
o Later date – earlier date, if the earlier date is prior to the reference date 
of interest. 


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• 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. 
• Second-Line EBV+ Lymphoma: Relapsed or refractory disease following 1 
prior systemic therapy (regimen). Inclusion in this subgroup will be determined 
using data collected for line of therapy on the Anti-Cancer Therapy Regimen 
eCRF. 
4.2 
Analysis Sets 
The analysis sets are defined as follows:  
• Intent-to-Treat Analysis Set: All patients who are enrolled into the trial, 
regardless of whether they received study treatment or not. 
• Modified Intent-to-Treat Analysis Set: All enrolled patients who have received 
at least one dose of study medication with a confirmed diagnosis of lymphoma 
subtype by central pathology review. The primary efficacy analysis will be 
performed in the Modified Intent-to-Treat Analysis Set per FDA guidance and 
historical precedent.  
• Efficacy-Evaluable Analysis Set: All enrolled patients who have received at 
least one dose of study medication, met all eligibility criteria, and have at least 
one adequate (radiographic) post-baseline tumor assessment. 
• Safety Analysis Set: Patients who have received at least one dose of study 
medication will be summarized for safety by cohort and over all patients 
combined. 
4.3 
Study Patients 
4.3.1 Disposition of Patients 
Patient disposition will be summarized for all enrolled patients (i.e., the Intent-to-Treat 
Analysis Set) by cohort and over all patients combined within each part of the study 
(Simon 2-Stage, Expansion). Summaries will include the number and percentage of 
patients in each analysis set, completing the study, and discontinuing the study early by 
the primary reason for discontinuation.  


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For the post-Stage 2 expansion phase of the study, disposition will also be summarized 
for the subgroup of patients in the Intent-to-Treat Analysis Set with second-line EBV+ 
lymphoma as defined in Section 4.1.5. 
The number and percentage of screen failures within each part will be presented by 
screen failure reason, based on the total number of patients screened. 
4.3.2 Protocol Deviations 
Important Protocol Deviations (IPDs) will be summarized by cohort and over all 
patients combined for the Intent-to-Treat Analysis Set within each part of the study 
(Simon 2-Stage, Expansion). Important Protocol Deviations are identified by the 
Sponsor and are defined in the ICH guideline Structure and Content of Clinical Study 
Reports – Questions and Answers (E3[R1], 2013) as a subset of protocol deviations that 
might significantly affect the completeness, accuracy, and/or reliability of the study 
data or that might significantly affect a patient’s rights, safety, or well-being.  
For the post-Stage 2 expansion phase of the study, disposition will also be summarized 
for the subgroup of patients in the Intent-to-Treat Analysis Set with second-line EBV+ 
lymphoma as defined in Section 4.1.5. All IPDs will be determined and appropriately 
categorized prior to database lock. The number and percentage of patients with any 
IPDs as well as the number and percentage of patients with IPDs within each category 
will be presented.  
4.4 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristic variables will be summarized by cohort and 
over all patients combined within each part of the study (Simon 2-Stage, Expansion) 
for the Modified Intent-to-Treat, Safety, and Efficacy Evaluable Analysis Sets. 
Demographic and baseline characteristic variable summaries may also be repeated for 
the Intent-to-Treat Analysis Set if meaningfully different than the Modified Intent-to-
Treat Analysis Set. 
For the post-Stage 2 expansion phase of the study, demographic and baseline 
characteristics will also be summarized in the Modified Intent-to-Treat Analysis Set for 
the subgroup of patients with second-line EBV+ lymphoma as defined in Section 4.1, 
maintaining the option of repeating summaries of demographics and baseline 
characteristics for the Intent-to-Treat Analysis Set if meaningfully different than the 
Modified Intent-to-Treat Analysis Set. This subgroup will also be used for the primary 
interim analyses. 
Demographic variables include age, sex, ethnicity, and race. Age as collected in the 
EDC 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 medical history, ECOG performance status, height, 
weight, and body mass index (BMI), lymphoma subtype by central review, time from 
initial diagnosis, stage of disease at study entry, presence or absence of bone marrow 
involvement, number and types of prior systemic therapies (and prior local therapies) 
for lymphoma, and plasma EBV DNA level. Body mass index will be calculated as: 
weight (kg) / [height (cm) / 100]2.  


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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 26.0). 
Frequency counts and percentages to summarize patients reporting abnormal medical 
history by system organ class will be presented. 
For lymphoma medical history, pathological diagnosis, the number of prior systemic 
therapies, presence or absence of bone marrow involvement, best response achieved 
with the most recent treatment regimen, stage at study entry, whether or not patient is 
or refractory to last therapy received prior to entering the study, number of prior 
autologous or allogeneic stem cell transplants, and whether or not the patient has 
exhausted all available therapies in the opinion of the investigator will be summarized 
with the number and percentage of patients in each category. The time since the date of 
original lymphoma primary diagnosis will be summarized using descriptive statistics. 
All other lymphoma medical history will be included in patient data listings.  
4.5 
Efficacy Evaluation 
For the Simon 2-stage part of the study, since Cohort 3 (PTCL) patients are initially 
randomized to monotherapy or combination therapy, their data will be summarized as 
follows: patients randomized to monotherapy, patients who start on monotherapy and 
then cross over to combination therapy, and patients randomized to combination 
therapy. 
For the post-Stage 2 expansion part of the study, patients with second-line EBV+ 
lymphoma will also be analyzed separately, and the primary efficacy analyses will be 
performed in this patient subgroup at the interim analysis (see Section 4.5.6.3 for details 
of this interim efficacy analysis) and at the final analysis. 
4.5.1 Datasets Analyzed 
Efficacy summaries will be produced as described in Section 4.2. Efficacy summaries 
will be repeated for the Efficacy Evaluable Analysis Set as supportive evidence and to 
assess the robustness of efficacy findings. Efficacy summaries may also be repeated for 
the Intent-to-Treat Analysis Set if meaningfully different than the Modified Intent-to-
Treat Analysis Set. A data listing of patients excluded from the Intent-to-Treat, 
Modified Intent-to-Treat, and Efficacy Evaluable Analysis Sets, 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 dispensed, multiplied 
by 100.  
The total number of tablets taken will be determined as the number of tablets dispensed 
minus the total number of tablets returned. The expected number of tablets received 
will be determined as the number of tablets dispensed.  


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Dosing compliance will be summarized using descriptive statistics, for each cohort 
based on the Safety Analysis Set. The number and percentages of patients who are 
<80% compliant and ≥80% compliant within each cohort will be summarized. 
Treatment compliance will also be included in a by-patient data listing.  
4.5.3 Primary Efficacy Endpoint Analysis Methods 
The primary efficacy endpoint is ORR assessed by an IRC.  
Patients will be analyzed according to their cohort/lymphoma subtype. For Cohort 3a 
patients who cross over from monotherapy to receive combination therapy, the CT/PET 
scan immediately preceding their first dose of combination therapy will be used for 
their baseline tumor assessment (and not the scan performed at the screening visit).  
The number and percentage of patients with a CR or PR after initiation of treatment 
will be summarized by cohort. Ninety-five percent (95%) confidence intervals (CIs) 
around the ORR (CR + PR) will be calculated using the Clopper-Pearson method. For 
patients with measurable disease, a swimmer plot of each patient’s overall tumor 
response assessments during study participation and patient deaths (for those patients 
who have died) will be presented by cohort. 
4.5.4 Secondary Endpoint Analysis Methods 
The ORR per investigator assessment, CRR per IRC review, and CRR per investigator 
assessment will be summarized using the same methods as described for the primary 
efficacy endpoint.  
Time to response, DOR, DOCR, TTNLT, TTP, PFS, and OS will be summarized in 
days using Kaplan-Meier (KM) methodology. The number of patients who experienced 
the event of interest and the number of patients censored will be presented; as will KM 
product limit estimates of the median 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 for DOR, PFS, and OS over time will be generated and all derived 
efficacy measures will also be provided in a separate listing.  
For Cohort 3a patients who crossover to receive combination therapy, DOR and DOCR 
will only be applicable after crossover given the requirement that patients only cross 
over from monotherapy to combination therapy after stable disease at the Day 43 visit 
(or progressive disease at any time). 
4.5.5 Additional Efficacy Endpoint Analysis Methods 
Each patient’s EBV viral load will be plotted over time by cohort and displayed on 
logarithmic scales. 
Additional exploratory endpoints will be described in a separate analysis plan. 


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4.5.6 Statistical/Analytical Issues 
4.5.6.1 
Adjustments for Covariates 
There are no planned applications of covariate adjustments; all statistical results are 
descriptive in nature. 
4.5.6.2 
Handling of Dropouts or Missing Data 
Overall response is 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. Progression-free survival and DOR will be 
right-censored for patients who meet one of the following conditions: 1) non-protocol 
systemic anti-cancer treatment started before documentation of disease progression or 
death, 2) death or disease progression after more than one missed disease assessment 
visit, or 3) alive and does not have documentation of disease progression before a data 
analysis cutoff date. These conventions are based on the FDA Guidance for Industry, 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2018) and 
Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and 
Biologics (2015). The analyses of PFS and DOR will be right-censored according to 
the conventions described in the table below. 
Table 3 
Censoring Conventions for Progression-Free Survival, Time to 
Progression, and Duration of Response 
Situation 
Date of Progression for 
Censoring 
Outcome 
No baseline tumor assessments 
Randomization (if applicable) or 
enrollment 
Censored 
New anti-cancer therapy started 
before documentation of PD or 
death 
Date of last disease assessment 
prior to start of new anti-cancer 
therapy 
Censored* 
Death or 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 
Death or PD between planned 
disease assessments 
Date of death or first disease 
assessment showing PD, 
whichever occurs first 
Progressed 


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Situation 
Date of Progression for 
Censoring 
Outcome 
Death before first disease 
assessment 
Date of death 
Progressed 
*PFS, TTP, DOR will additionally be analyzed without censoring for hematopoietic stem cell transplant 
4.5.6.3 
Interim Analyses and Data Monitoring 
In addition to the Stage 1 analysis specified by Simon’s decision criteria for proceeding 
to Stage 2, a formal interim analysis will be performed for a post-Stage 2 expanded 
lymphoma subtype cohort overall and for patients with second-line EBV+ lymphoma. 
A total of 40 second-line EBV+ lymphoma patients who have been followed for at least 
6 months or permanently discontinued study treatment, will be used for the interim 
analysis. For these interim analyses, the observed ORR by IRC will be evaluated along 
with the 95% confidence interval. Other secondary endpoints will be evaluated with 
descriptive statistics such as both point and interval estimates.  
The final efficacy analysis will be performed as planned with a total 120 patients with 
relapsed or refractory EBV+ lymphoma patients enrolled in the post-Stage 2 expansion 
phase of the study, which are anticipated to include approximately 50-60 patients with 
second-line EBV+ lymphoma. The final analysis will be performed when all patients, 
including those with second-line EBV+ lymphoma have been followed for at least 6 
months or permanently discontinued study treatment. If at least 26 responses are 
observed for an ORR ≥65% (95% CI: 79%, 48%) at interim analysis of 40 patients with 
second-line EBV+ lymphoma, then overwhelming efficacy would be declared to 
potentially support accelerated NDA submission after these patients are followed for at 
least 6 months for DOR and other secondary endpoints. This magnitude of treatment 
effect at the interim analysis would exclude an approximately 47% ORR with 95% 
confidence. Of note, enrollment into any post-Stage 2 expansion cohort would continue 
to complete the planned enrollment of 120 patients for the final analysis independent 
of the interim analysis outcome. 
4.5.6.4 
Multicenter Studies 
This is a multicenter study, with approximately 80 sites expected to participate. 
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.  
4.5.6.5 
Multiple Comparisons/Multiplicity 
There will be no adjustments for multiple comparisons in the efficacy analysis for this 
study. Results are descriptive in nature, and no statistical hypothesis testing is planned. 
There will be no adjustments for multiple comparisons in the efficacy analysis for this 
study.  


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4.5.6.6 
Use of an “Efficacy Subset” of Patients 
The primary efficacy analysis will be performed in the Modified Intent-to-Treat 
Analysis Set; the Intent-to-Treat and Efficacy Evaluable Analysis Sets will be utilized 
as sensitivity analyses.  
4.5.6.7 
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. 
4.5.6.8 
Examination of Subgroups 
The primary efficacy endpoint may be summarized by various 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, 1, and 2), number of prior 
systemic therapies (1 line and 2+ lines), stage of disease at study entry (Stages 1-2 and 
Stages 3-4), gender, and race. Summaries by subgroup will only be produced if there 
are at least 6 patients in the category of interest. 
For the post-Stage 2 expansion part of the study, all efficacy analyses will also be 
summarized in the Modified Intent-to-Treat and Efficacy Evaluable Analysis Sets for 
the subgroup of patients with second-line EBV+ lymphoma as defined in Section 4.1. 
Additional subgroup analyses may be performed post-hoc, as appropriate. 
4.5.7 Plasma Concentrations 
Plasma concentration measurements will be summarized in a separate report and is 
outside the scope of this SAP. 
4.5.8 Pharmacokinetic Analysis 
Pharmacokinetic analysis 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 Set as defined in Section 4.2 
to include all patients who receive at least one dose of study drug. Patients who do not 
complete the study, for whatever reason, will have all available data up until the time 
of study discontinuation included in the safety analysis.  
For the Simon 2-stage part of the study, since Cohort 3 (PTCL) patients are initially 
randomized to monotherapy or combination therapy, their data will be summarized as 
follows for occurrence-based analyses: patients randomized to monotherapy, patients 
who start on monotherapy and then cross over to combination therapy, and patients 
randomized to combination therapy. For analyses presented by study visit, their data 
will be summarized as randomized. 
In addition, all patients who receive combination therapy at any point on study (to 
include Cohort 3a patients who cross over from monotherapy to combination therapy 


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during the Simon 2-stage part of the study) will be summarized across both parts of the 
study separately by cohort and also overall. 
4.6.1 Extent of Exposure 
Extent of exposure to both study treatments will be summarized. The duration of 
exposure 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 (mg) will be summarized using descriptive statistics. 
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 cohort and over all patients 
combined. 
Specific to Cohort 3a, for patients who cross over to receive combination therapy, 
events that occur during the monotherapy period will be counted in the Cohort 3a 
monotherapy subcohort only. Events that occur after the end of monotherapy but prior 
to the first date of treatment within the combination period will also be counted in the 
Cohort 3a monotherapy subcohort only. Events occurring after the start of combination 
therapy will be counted in the Cohort 3a crossover subcohort only.  
Events reported with a partial onset date (e.g., month and year are reported but the day 
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 26.0.  
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 serious adverse 
events (SAEs) and patient incidence of treatment-emergent SAEs 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 Set) by MedDRA preferred term; 


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• Patient incidence of TEAEs by 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 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 the most frequently occurring TEAEs related to 
nanatinostat (i.e., related TEAEs occurring in ≥ 10% of the Safety Analysis Set) 
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 
Set) 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 Set) by MedDRA preferred term; 
• Patient incidence of TEAEs leading to dose interruption of nanatinostat by 
MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs leading to dose interruption of valganciclovir by 
MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs leading to dose interruption of nanatinostat or 
valganciclovir 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 dose reduction of 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 related to nanatinostat leading to discontinuation of 
study drug by MedDRA system organ class and preferred term; 


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• 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 
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 TEAEs leading to death by MedDRA system organ class 
and preferred term. 
Select AE summaries will also be repeated for different age subgroups (<65 years old, 
≥65 years old). Separate AE summaries may also be repeated for adolescents 12-17 
years old if there are at least 5 patients enrolled for this age group. Selected AE 
summaries may be repeated in terms of exposure-adjusted rates in 100 patient-years.  
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 CTCAE 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 study drug; 
events considered not related are those reported as “Unrelated” to 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, cohort, 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 also be 
listed by patient, to include the primary cause of death. Serious AEs and other 
significant AEs, including those that led to study withdrawal, dosing interruption, or 
dose reduction of either study drug, will be provided in separate patient data listings. 


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4.6.4 Clinical Laboratory Evaluation 
All descriptive summaries of laboratory test results will be based on data analyzed by 
the central or local laboratories 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. By-patient data listings of laboratory test abnormalities Grade 
≥3 will also be provided. In addition, normal ranges provided by the central or local 
laboratories will be presented in a separate listing. 
Clinical laboratory measurements, including serum chemistry, hematology, and 
coagulation will be summarized by study phase and cohort. 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.  
The cumulative number and percentage of patients with liver function test abnormalities 
meeting drug-induced liver injury (DILI) criteria will be summarized by cohort. 
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 will be calculated as [(140 - age) × weight 
(kg)] / [72 ×serum creatinine (mg/dL)]. For females, the creatinine clearance in mL/min 
will be 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 cohort 
and over all patients combined. 
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 cohort. 
Where applicable, hematology and chemistry results for selected 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 criteria for a grade includes a quantitative component and a clinical 
intervention component, the clinical intervention component will be ignored where it 
cannot be programmatically addressed using available data and only the quantitative 
portion of the criteria will be considered. 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 


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summarized as a category. Laboratory parameters that include multiple sets of criteria 
for each direction (e.g., 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 for 12-lead ECG interval parameters will be presented for 
observed values and changes from baseline at each visit where parameters were 
scheduled to be collected. All ECGs will be performed in triplicate, and the mean of 
these triplicate measurements at each time point will be used for summarization. 
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 cohort. 
Prolonged QTcF will be summarized as QTcF 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 cohort. 
Clinically significant abnormalities occurring at any point in the study post-baseline 
will be presented in patient data listings. 
4.6.5.3 
Physical Examination 
Results of physical examinations will be presented in patient data listings by patient, 
study visit, and body system. Any findings during symptom-directed exams will be 
reported as AEs. 


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4.6.5.4 
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. 
4.6.5.5 
Viral Levels 
Viral levels [EBV, CMV, HHV-6, HHV-8, and HIV (for HIV+ patients only)] will be 
monitored for viral reactivation. Results will be presented in patient data listings only. 
4.6.5.6 
Prior and Concomitant Medications  
Medications will be coded using the World Health Organization Drug Dictionary 
Enhanced (WHODDE), version March 1, 2023. Medications entered on the eCRF will 
be mapped to Anatomical Therapeutic Chemical (ATC) drug class (level 4) and drug 
name. 
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 28 days after 
the last dose of study medication. 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 
This multinational, multicenter study will employ a Simon’s optimal 2-stage design to 
allow termination of enrollment into cohorts where treatment appears futile (Simon 
1989). The decision to transition from Stage 1 to Stage 2 is dependent on the assumption 
of ORR: ORR ≤10% (poor response); ORR ≥35% (good response). The sample size 
estimation uses 1-sided alpha = 0.05 and targets statistical power = 85%. 
Using the Simon’s 2-stage design approach, the null hypothesis that the true response 
rate is 10% will be tested against a one-sided alternative. In the first stage, up to 10 
patients will be accrued in each cohort. If there are 1 or fewer responses, the cohort will 


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be discontinued. If the cohort fails to enroll any patients within 1 year from the 
enrollment of the first patient, the cohort will be considered for termination of 
enrollment. Otherwise, if at least 2 patients in a cohort respond, additional patients will 
be accrued for a total of 21 in the cohort. The null hypothesis that the true response rate 
is 10% will be rejected in each cohort where 5 or more responses are observed in 21 
patients. This design yields a type I error rate of 0.0440 and power of 86.2% within 
each cohort where the true response rate is 35%. 
If 10 patients of a given lymphoma subtype are enrolled into Cohort 7, then the Simon’s 
decision criteria will be applied to determine whether or not to add patients in Stage 2 
for that subtype. If none of the subtypes represented in Cohort 7 enrolls at least 10 
patients, efficacy data collected on those patients will be listed, but not summarized by 
group. All patients will be summarized for safety, regardless of the decision to 
discontinue enrollment into any cohort. 
If at the end of Stage 2 there are at least 7 responders observed in the initial 21 patients 
in any cohort (ORR ≥33.3%), enrollment will be expanded to include up to 120 
additional patients in that cohort (N=141), with an interim analysis in that cohort to be 
performed as described in Section 4.5.6.3. Simon’s Stage 2 estimate was ORR=33.3% 
for the PTCL cohort. Using Clopper-Pearson Exact confidence interval approach, the 
sample size for a 95% CI that would exclude 25% if the ORR was 33.3% was N=120. 
Using ORR=35%, the minimum sample size is estimated to be N=85. 
A formal interim analysis will be performed for each post-Stage 2 expanded lymphoma 
subtype cohort in patients with second-line EBV+ lymphoma when a total of 40 second-
line EBV+ lymphoma patients have been followed for at least 6 months or permanently 
discontinued study treatment. The rationale for selecting 40 patients at the interim 
analysis is provided in Table 4 below using the Clopper-Pearson binomial confidence 
intervals of the proportion (Clopper 1934). 
Table 4 
Sample Sizes for the Interim and Final Analyses of Patients with 
Second-Line EBV+ Lymphoma 
Sample Size 
Observed Rate 
95% CI 
Control Rate 
 
40 
42.5% 
(59%, 27%) 
25% 
52.5% 
(68%, 36%) 
35% 
65% 
(79%, 48%) 
45% 
 
50 
40% 
(55%, 26%) 
25% 
50% 
(64%, 36%) 
35% 
62% 
(75%, 47%) 
45% 
 
60 
38% 
(52%, 26%) 
25% 
48% 
(61%, 35%) 
35% 


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Sample Size 
Observed Rate 
95% CI 
Control Rate 
60% 
(72%, 46%) 
45% 
If the observed effect is 52.5% (i.e., 21 responders out of 40 patients) at the interim 
analysis, then the 95% CI will exclude an ORR effect size of 35%. For these interim 
analyses, the observed ORR by IRC will be evaluated along with 95% CI. Other 
secondary endpoints will be evaluated with descriptive statistics such as both point and 
interval estimates.  
The final efficacy analysis will be performed as planned with total 120 patients in the 
expansion stage of the study. Approximately 50-60 patients with second-line EBV+ 
lymphoma are anticipated to be enrolled at the time of the final analyses. The final 
analyses will be performed when all patients, including second-line EBV+ lymphoma 
patients, have been followed for at least 6 months or permanently discontinued study 
treatment. 
4.8 
Changes in the Conduct of the Study or Planned Analyses 
The following changes were made to planned analyses identified during the 
development of this SAP, relative to the descriptions provided within the clinical study 
protocol amendment 5, dated 19 October 2023: 
The protocol states that the Intent-to-Treat population will be used for the primary 
efficacy analysis. This SAP substitutes the following analysis sets as defined in Section 
4.2 above for efficacy analyses, preserving the opportunity to repeat efficacy summaries 
for the Intent-to-Treat Analysis Set if meaningfully different than the Modified Intent-
to-Treat Analysis Set: 
• Modified Intent-to-Treat Analysis Set 
• Efficacy-Evaluable Analysis Set 
Addition of the following secondary efficacy endpoints as defined in Section 3.4.1.2 
above: 
• Complete response rate 
• Duration of complete response 
• Time to response  
 
 
 


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