Clinical trial NCT03682055
Conditions: Nasopharyngeal Carcinoma Nasopharyngeal Cancer
Keywords: Epstein-Barr Virus Nasopharyngeal Carcinoma NPC EBV EBNA1 inhibitor VK-2019 Nasopharynx cancer Nasopharynx carcinoma
Sponsor: Cullinan Therapeutics Inc.
Start date: 2019-04-04; Completion date: 2020-08-08
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
VK-2019-001 is a 1/2a trial of the oral EBNA-1 targeting agent VK-2019 in patients with EBV-positive recurrent or metastatic NPC to determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D), as well as to evaluate the PK profile of VK-2019.

Detailed description:
This is a Phase 1/2a, open-label, multicenter, first-in-human trial to evaluate the safety and tolerability, PK, PD, and preliminary efficacy of VK-2019 in patients with EBV-positive NPC.

This trial is divided into three parts: Phase 1 Dose Escalation, Phase 1 Dose Expansion, and Phase 2s Dose Expansion.

The objectives of the dose escalation part are to determine the safety, tolerability, MTD, recommended Phase 2 dose (RP2D), and to evaluate the anti-tumor activity of orally administered VK-2019 monotherapy. Additional objectives are to determine the pharmacokinetic (PK) profile of VK-2019.

VK-2019 will be dosed once daily (QD).

Arms: arm 1: VK-2019 QD in Accelerated Titration dose escalation cohorts enrolling EBV+ NPC arm 2: VK-2019 QD in Rolling Six dose escalation cohorts enrolling EBV+ NPC. arm 3: VK-2019 QD in expansion cohorts that may be opened at doses that meet pre-specified criteria for clinical and/or biological activity. arm 4: VK-2019 QD in expansion cohorts that may be opened at doses that meet pre-specified efficacy criteria in Phase 1 Dose Escalation cohorts.
Interventions: intervention 1: VK-2019
Intervention descriptions: intervention 1: EBNA1 inhibitor

Protocol documents:
Prot_000.pdf: 
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Confidential 
 
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CLINICAL STUDY PROTOCOL 
 
Protocol Title: 
Phase 1/2a open-label, multicenter clinical trial of a novel small molecule 
EBNA1 inhibitor, VK-2019, in patients with Epstein-Barr Virus positive 
nasopharyngeal cancer, with pharmacokinetic and pharmacodynamic 
correlative studies 
Product: 
VK-2019 
Protocol Number: 
VK-2019-001 
Protocol Versions: 
9.0, Amendment 9 (15 October 2019) 
IND Number: 
137265 
EudraCT Number: 
2019-001791-11 
Sponsor: 
Cullinan Apollo Corp. (Cullinan-Apollo) 
1 Main Street, Suite 520 
Cambridge, MA 02142 
USA 
+1 617-425-9200 
Protocol Chair 
A. Dimitrios Colevas, MD 
Professor of Medicine (Oncology) and, By Courtesy, of Otolaryngology  
Head and Neck Surgery 
Stanford Cancer Institute (SCI) 
Phone: +1 650-720-9707 
Fax: +1 650-498-5800 
E mail: colevas@stanford.edu  
Medical Monitor 
24/7 Medical Emergency Phone Number 
+1 (919) 674-5468 
Pharmacovigilance 
Fax: +44 (0) 208 100 5005 
Email: ICON-Safety-CentralReceipt@iconplc.com 
 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, trial staff, and applicable independent ethics committees or institutional 
review boards. The contents of this document shall not be disclosed to others without written 
authorization from Cullinan-Apollo (or its representatives). 
 
 


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SPONSOR PROTOCOL APPROVAL PAGE 
 
 
Sponsor’s Responsible Medical Officer: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Briggs Morrison, MD  
 
 
 
 
 
 
Date 
Acting Chief Medical Officer 
 


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PROTOCOL SIGNATURE PAGE 
 
The signature of the Principal Investigator below constitutes his/her agreement to comply with the 
contents of this Protocol and to conduct this study according to Good Clinical Practices (GCP) and 
applicable requirements.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
 
 
Date 
 
Principal Investigator’s Name: 
 
 
Name of Institution: 
 
 
 
 
 


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LIST OF TERMS, ACRONYMS, AND ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Transaminase (SGPT) 
ALP 
Alkaline Phosphatase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Transaminase (SGOT) 
AUC 
Area Under the Drug Concentration-Time Curve 
BCAD 
Biologically or Clinically Active Dose 
BLQ 
Below the Limit of Quantitation 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
°C 
Degrees Celsius 
Ca 
Calcium 
CBC w/ Diff 
Complete Blood Count with Differential 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cl 
Chloride 
CL 
Clearance 
Cmax  
Maximum Drug Concentration 
Cmin 
Minimum Drug Concentration 
CO2 
Carbon Dioxide 
Cr 
Creatinine 
CR 
Complete Response 
CRF 
Case Report Form 
CRO  
Contract Research Organization 
CT 
Computed tomorgraphy 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
EBNA1 
Epstein-Barr Nuclear Antigen 1 
EBV 
Epstein-Barr Virus 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EMR 
Electronic Medical Record 
EU 
European Union 
°F  
Degrees Fahrenheit 
FDA 
Food and Drug Administration (U.S.) 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
h or hr 
Hour 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
INR 
International Normalised Ratio 
IRB 
Institutional Review Board 


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K 
Potassium 
kg 
Kilogram 
L 
Liter 
m or min 
Minute 
m2 
Meter squared 
mg 
Milligram 
Mg 
Magnesium Sulfate 
mL 
Milliliter  
ms or msec 
Millisecond 
MTD 
Maximum tolerated dose 
Na 
Sodium 
NCI 
National Cancer Institute 
NPC 
Nasopharyngeal Carcinoma 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PCR 
Polymerase Chain Reaction 
PFS 
Progression Free Survival 
PD 
Progressive Disease or Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QD 
Once Daily 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
t1/2 
Half-Life 
tmax 
Time to Cmax 
T 
Temperature 
TEAEs 
Treatment Emergent Adverse Events 
ULN 
Upper Limit of Normal 
VS 
Vital Signs 
WBC 
White Blood Cells 
WOCBP 
Women of Child-Bearing Potential 
 
 
 
 
 


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 TABLE OF CONTENTS 
1 
Synopsis ........................................................................................................................................ 9 
2 
Background ................................................................................................................................ 26 
3 
Objectives of the Study .............................................................................................................. 30 
 
Phase 1 Objectives ............................................................................................................... 30 
3.1.1 Primary .............................................................................................................................. 30 
3.1.2 Secondary .......................................................................................................................... 30 
3.1.3 Exploratory ....................................................................................................................... 30 
 
Phase 2a Objectives ............................................................................................................. 30 
3.2.1 Primary .............................................................................................................................. 30 
3.2.2 Secondary .......................................................................................................................... 30 
3.2.3 Exploratory ....................................................................................................................... 30 
4 
Study Design ............................................................................................................................... 31 
 
Phase 1 Dose Escalation ...................................................................................................... 32 
 
Phase 1 Dose Expansion ...................................................................................................... 32 
 
Phase 2a Dose Expansion .................................................................................................... 32 
5 
Eligibility Criteria ...................................................................................................................... 33 
 
Inclusion Criteria ................................................................................................................. 34 
 
Exclusion Criteria ................................................................................................................ 36 
 
Age and Reproductive Status ................................................................................................ 39 
6 
Study Treatment and Conduct ................................................................................................. 40 
 
Safety Review Committee ...................................................................................................... 40 
6.1.1 During Phase 1 Dose Escalation ....................................................................................... 40 
6.1.2 During Phase 1 Dose Expansion ....................................................................................... 41 
6.1.3 During Phase 2a Dose Expansion ..................................................................................... 41 
 
Dose Escalation Procedures ................................................................................................ 41 
6.2.1 Definition of a Completed Cohort and an Evaluable Patient ............................................ 42 
6.2.2 Dose Escalation in Accelerated Titration Cohorts ............................................................ 42 
6.2.3 Dose Escalation in Rolling Six Cohorts ........................................................................... 42 
6.2.4 Intra-Patient Dose Escalation in Accelerated Titration Cohorts ....................................... 43 
6.2.5 Intra-Patient Dose Escalation in Rolling Six Cohorts ...................................................... 44 
 
Dose-limiting Toxicity .......................................................................................................... 44 
6.3.1 Dose-limiting Hematologic Toxicity ................................................................................ 44 
6.3.2 Dose-limiting Non-hematologic Toxicities ...................................................................... 44 
 
Definition of the MTD .......................................................................................................... 45 
 
Definition of a BCAD ........................................................................................................... 45 
 
Definition of the RP2D ......................................................................................................... 46 
 
Initiation of Phase 1 Expansion Cohorts .............................................................................. 46 
 
Initiation of Phase 2a Expansion Cohorts ............................................................................ 46 
 
Duration of Therapy ............................................................................................................. 46 
 Re-initiation of Therapy for Patients in Long-Term Follow-Up .......................................... 46 
 Patient Withdrawal ............................................................................................................... 47 
7 
Study Drug:  VK-2019 ............................................................................................................... 49 


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Description, Supply and Storage of Investigational Drugs .................................................. 49 
7.1.1 Classification .................................................................................................................... 49 
7.1.2 Mechanism of Action ........................................................................................................ 49 
7.1.3 Metabolism ....................................................................................................................... 49 
7.1.4 Drug interactions ............................................................................................................... 49 
7.1.5 VK-2019 capsules ............................................................................................................. 49 
7.1.6 Storage and handling ........................................................................................................ 49 
7.1.7 Side Effects ....................................................................................................................... 49 
8 
Treatment Plan .......................................................................................................................... 50 
 
Patient Enrollment and Allocation to Treatment ................................................................. 50 
 
Dosage and Administration .................................................................................................. 50 
8.2.1 Availability ....................................................................................................................... 50 
8.2.2 Preparation and Dispensing .............................................................................................. 50 
8.2.3 Administration and Accountability ................................................................................... 50 
9 
Patient Monitoring, Toxicity Management, and dose Modifications .................................... 52 
10 Concomitant Treatment ............................................................................................................ 54 
 Medication(s) or systemic treatments ................................................................................... 54 
 Concomitant Radiotherapy or Surgery ................................................................................ 54 
 Disallowed medications ........................................................................................................ 54 
11 Study Procedures and Observations ........................................................................................ 55 
 Medical and Oncology History ............................................................................................ 55 
 Physical Exam ...................................................................................................................... 55 
 Lab Assessments ................................................................................................................... 55 
 Electrocardiograms .............................................................................................................. 55 
 Tumor Assessments ............................................................................................................... 55 
 Follow-Up ............................................................................................................................. 56 
11.6.1 
Safety Follow-Up .......................................................................................................... 56 
11.6.2 
Long-Term Follow-Up .................................................................................................. 56 
12 Pharmacokinetics and Pharmacodynamics ............................................................................ 57 
 PK and Metabolite Profiling Assessments ........................................................................... 57 
12.1.1 
CSF for Analysis of VK-2019 ....................................................................................... 57 
 Effect of EBNA1 Inhibitor VK-2019 on Plasma EBV DNA .................................................. 57 
 Intra-Tumor EBNA1 Activity Inhibition by VK-2019 ........................................................... 57 
13 Adverse EventS and Serious Adverse Events ......................................................................... 59 
 Definitions of an AE ............................................................................................................. 59 
 AE Reporting ........................................................................................................................ 59 
 Reporting Period .................................................................................................................. 59 
 Definitions of an Adverse Reaction ...................................................................................... 60 
 Abnormal Test Findings ....................................................................................................... 60 
 Serious Adverse Events ......................................................................................................... 61 
 SAE Reporting Requirements ............................................................................................... 61 
 Protocol-Specified Serious Adverse Events .......................................................................... 62 
 Hospitalization ..................................................................................................................... 62 


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Severity Assessment .......................................................................................................... 63 
 
Causality Assessment ........................................................................................................ 63 
13.11.1 Suspected ....................................................................................................................... 64 
13.11.2 Unexpected .................................................................................................................... 64 
 
Exposure During Pregnancy ............................................................................................ 65 
 
Withdrawal Due to an AE ................................................................................................. 65 
 
Follow-up of AEs .............................................................................................................. 65 
14 Data Analysis/Statistical Methods ............................................................................................ 66 
 Phase 1 Endpoints ................................................................................................................ 66 
14.1.1 
Primary Endpoints ......................................................................................................... 66 
14.1.2 
Secondary Endpoints ..................................................................................................... 66 
14.1.3 
Exploratory Endpoints .................................................................................................. 66 
 Phase 2a Endpoints .............................................................................................................. 66 
14.2.1 
Primary Endpoints ......................................................................................................... 66 
14.2.2 
Secondary Endpoints ..................................................................................................... 66 
14.2.3 
Exploratory Endpoints .................................................................................................. 66 
 Sample Size Determination ................................................................................................... 67 
 Populations for Analyses ...................................................................................................... 67 
 Endpoint Analysis ................................................................................................................. 67 
14.5.1 
Analysis of Safety Endpoints ........................................................................................ 67 
14.5.2 
Analysis of Efficacy Endpoints ..................................................................................... 69 
 Patient Characteristics and Disposition .............................................................................. 69 
 Pharmacokinetic Analysis .................................................................................................... 70 
14.7.1 
Single- and Multiple-Dose VK-2019 PK Analysis ....................................................... 70 
14.7.2 
PK/PD Modeling ........................................................................................................... 71 
 Pharmacodynamic EBV DNA ............................................................................................... 71 
 Pharmacodynamic EBNA1 inhibition. ................................................................................. 71 
 
Interim Analysis ................................................................................................................ 71 
15 Study Management .................................................................................................................... 72 
 Pre-study Documentation ..................................................................................................... 72 
 Informed Consent ................................................................................................................. 72 
 Changes in the Protocol ....................................................................................................... 72 
 Handling and Documentation of Clinical Supplies .............................................................. 72 
 Case Report Forms (CRFs) .................................................................................................. 73 
 Study Monitoring .................................................................................................................. 73 
 Inspection and Retention of Records .................................................................................... 73 
 Quality Control and Quality Assurance ............................................................................... 74 
16 References ................................................................................................................................... 75 
17 Appendices .................................................................................................................................. 78 
 Appendix 1 - Performance Status Criteria ........................................................................... 78 
 Appendix 2 - Prohibited Medications During Treatment Cycle 1 and 2 .............................. 79 
 Appendix 3 - Effectiveness of family planning methods ....................................................... 80 
 


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1 
SYNOPSIS 
Study Title: 
Phase 1/2a open-label, multicenter clinical trial of a novel small 
molecule EBNA1 inhibitor, VK 2019, in patients with Epstein Barr Virus 
positive nasopharyngeal cancer, with pharmacokinetic and 
pharmacodynamic correlative studies 
Protocol Number: 
VK-2019-001 
Study Drug: 
VK-2019 
Sponsor: 
Cullinan Apollo Corp 
Hypothesis for 
Phase 1 
Plasma exposures of single agent VK-2019 associated with pre-clinical 
efficacy can be achieved in patients with NPC with less than 18% of 
patients experiencing a dose limiting toxicity (DLT). 
Hypothesis for 
Phase 2a: 
Oral administration of single agent VK-2019 at one or more doses will 
be associated with a durable overall response rate (CR+PR maintained 
for at least 6 months) of 30%. 
Objectives for 
Phase 1: 
Primary Objectives 
• To define the maximum tolerated dose (MTD) and the recommended 
Phase 2 dose (RP2D) for orally administered VK-2019 monotherapy 
in patients with recurrent or metastatic NPC. 
• To evaluate and characterize the safety profile of orally administered 
VK-2019 monotherapy in adult patients with recurrent or metastatic 
NPC. 
Secondary Objectives 
• To evaluate the anti-tumor activity of orally administered VK-2019 
monotherapy per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. 
• To characterize the PK of orally administered VK-2019 monotherapy 
in adult patients with recurrent or metastatic NPC. 
• To evaluate the anti-EBV activity by reduction of plasma EBV-DNA 
of orally administered VK-2019 monotherapy in adult patients with 
recurrent or metastatic NPC. 
Exploratory Objectives 
• To explore blood PD markers. 
• To explore PD markers such as alteration in EBV specific gene 
expression, both lytic and latent EBV genes. 
• To explore exposure-response relationships between VK-2019 
exposure and the PD endpoints (safety, efficacy, and laboratory 
correlatives). 
Objectives for 
Phase 2a: 
Primary Objectives 
• Evaluate preliminary efficacy (overall response rate [ORR], duration 
of response [DOR], disease control rate [DCR], progression free 
survival [PFS], survival rate, and overall survival [OS]) of orally 
administered VK-2019 monotherapy in adult patients with recurrent 
or metastatic NPC. 
• Confirm the safety and tolerability of orally administered VK-2019 
monotherapy in adult patients with recurrent or metastatic NPC. 
Secondary Objectives 
• To further characterize select PK parameters associated with orally 
administered VK-2019 monotherapy in adult patients with recurrent 
or metastatic NPC. 


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• Evaluate the anti-EBV activity by reduction of plasma EBV-DNA of 
orally administered VK-2019 monotherapy in adult patients with 
recurrent or metastatic NPC. 
Exploratory Objectives 
• To explore both blood and intratumoral PD markers. 
• To explore PD markers such as alteration in EBV specific gene 
expression, both lytic and latent EBV genes. 
• To explore exposure-response relationships between VK-2019 
exposure and the PD endpoints (safety, efficacy, and laboratory 
correlatives). 
Study Design: 
This is a phase 1/2a, open-label, multicenter, multi-dose, dose-escalation 
trial of VK-2019, a potent and selective inhibitor of the EBV latency 
program through its specific binding to a viral target, EBNA1.  
 
For each patient enrolled, the study will consist of at least three periods:  
Screening (up to 28 days), Treatment (comprised of 28-day dosing 
cycles), and Follow up (comprised of a safety follow-up and long-term 
follow-up for survival status).  
 
This trial is divided into three parts: Phase 1 Dose Escalation, Phase 1 
Dose Expansion, and Phase 2a Dose Expansion. One sub-study, 
collecting tumor biopsies, will be conducted during the Phase 2 
Expansion part of the trial.  
 
Phase 1 Dose Escalation 
Dose escalation in this trial will be conducted utilizing both an 
accelerated titration coupled with a “rolling six” design.  
• Dose escalation will initially proceed according to the accelerated 
titration design, enrolling one new patient per dose level.  
• Upon any instance of a VK-2019 related Grade ≥ 2 toxicity during 
Cycle 1, dose escalation will convert to the Rolling Six design in 
which a total of 3-6 patients per dose level will be enrolled.   
• Five dose escalation cohorts are planned, but additional dose 
escalation or intermediate de-escalation cohorts may be explored 
based upon emerging safety and/or PK data. 
 
Phase 1 Dose Expansion 
During dose escalation, one or more cohorts may be selected for 
expansion, enrolling up to 16 patients (inclusive of the patients already 
enrolled at the same dose during escalation) at any dose level that is 
assessed to either be the MTD or have sufficient activity to meet criteria 
as a Biologically or Clinically Active Dose (BCAD).  
 
Phase 2a Dose Expansion 
Further dose expansion in the Phase 2a part of the trial may be explored 
by utilizing a Simon 2 Stage design. Up to an additional nine patients 
may be enrolled at a particular dose if two or more objective responses 
(at least one must be confirmed) are observed at that dose in the Phase 1 
part of the trial (for a total accrual of up to 25 patients). 


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Safety Review 
Committee: 
During the trial, a Safety Review Committee (SRC) comprised of two 
external, independent oncologists, the Medical Monitor, Chief Medical 
Officer, Protocol Chairperson, Principal Investigators from each site, 
plus additional delegates (as needed), will review available safety, 
tolerability, PK, PD, efficacy, and other clinical data for the purposes of 
trial oversight and decision making as it relates to dose escalation and de-
escalation, dose selection and expansion, study termination, etc.  
Dose Escalation 
Procedures: 
The starting dose for VK-2019 is 60 mg. 
 
Each dose escalation cohort will consist of either:  
• 1 evaluable patient (Accelerated Titration cohorts), or 
• 3-6 evaluable patients (Rolling Six cohorts)  
 
To be considered evaluable, a patient will have one of the following: 
• Received 75% of doses during Cycle 1, or, 
• Received at least one dose of VK-2019 and experienced a DLT 
during Cycle 1 
 
For Accelerated Titration Cohorts 
Upon completion of an accelerated titration cohort, : 
• IF: No VK-2019 related Grade ≥ 2 AEs occur during Cycle 1; 
THEN: Dose escalation may proceed to the next accelerated titration 
cohort (no greater than a 100% dose increase) 
• IF: The patient experiences a VK-2019 related Grade ≥ 2 AE during 
Cycle 1 (not meeting the definition of a DLT); THEN: Convert the 
current cohort to the Rolling Six design and enroll an additional 2-5 
evaluable patients (3-6 total) at the same dose level 
• IF: The patient experiences a DLT; THEN: Convert to the Rolling 
Six design and enroll an additional five evaluable patients (six total) 
at the same dose level 
 
For Rolling Six Cohorts 
Upon completion of a Rolling Six cohort (a minimum of three, maximum 
of six evaluable patients),  
• IF: 0 of 3 patients experience a DLT; THEN: Dose escalation may 
proceed to the next cohort (no greater than a 50% dose increase) 
• IF: 1 of 3 patients experience a DLT; THEN: An additional three 
evaluable patients will be enrolled into the cohort at the same dose 
level 
•  IF: ≤ 1 of 6 patients experience a DLT; THEN: Dose escalation may 
proceed to the next cohort (no greater than a 50% dose increase) 
• IF: ≥ 2 patients experience a DLT; THEN: The MTD has been 
exceeded and further enrollment into that cohort will cease. Lower-
dose cohorts may then be explored until the MTD has been 
determined, including intermediate doses 
 
Intra-patient Dose Escalation in Accelerated Titration Cohorts 
After an accelerated titration cohort has been declared safe by the SRC, 
patients at lower dose levels may be considered for intra-patient dose 


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escalation if they meet the following criteria based in part on 3B design 
proposed by Simon et al: 
• Have stable disease (SD) or better after Cycle 2 (or later) 
• Experienced no VK-2019 related Grade 2 AEs during the previous 
cycle 
• Have no other safety concerns as assessed by the investigator 
The escalated dose must be agreed upon by the investigator and sponsor 
and may proceed beginning on Day 0 of the next cycle. Any patient that 
has their dose escalated will not be evaluated for DLT assessment at their 
new dose. 
 
Intra-patient Dose Escalation in Rolling Six Cohorts 
After a Rolling Six cohort has enrolled a minimum of three patients and 
has been declared safe by the SRC, patients at lower dose level may be 
considered for intra-patient dose escalation if the patient meets the 
following criteria: 
• Have stable disease (SD) or better after Cycle 2 (or later) 
• Have no safety concerns as assessed by the investigator 
 
In either situation, the escalated dose must be agreed upon by the 
investigator and sponsor and may proceed beginning on Day 0 of the 
next cycle.  
Definition of DLT: 
DLTs will be determined based on the incidence and intensity of AEs 
assessed as being at least possibly related to VK-2019 and occurring up 
to 28 days after initiation of QD VK-2019 dosing. Toxicity will be 
graded by the CTCAE v5.0.  
 
Dose-limiting Hematologic Toxicity 
• Grade 4 neutropenia > 7 days 
• Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated 
with bleeding or requiring platelet transfusion 
• Grade 3 febrile neutropenia  
• Grade 4 anemia or anemia that requires blood transfusion 
 
Dose-limiting Non-hematologic Toxicities 
• Any Grade 3 or higher non-hematology toxicity, excluding the 
following: 
o Toxicities assessed by Investigator as clearly related only to 
disease progression or intercurrent illness 
o Elevations of AST, ALT, and bilirubin, that correct to Grade 1 
within one week and do not meet any of the definitions of acute 
liver injury as listed below  
o Other asymptomatic laboratory abnormalities 
o Grade 3 fever without neutropenia that returns to Grade 1 or less 
within three days, and is not associated with hemodynamic 
compromise (including hypotension, or clinical or laboratory 
evidence of end organ perfusion impairment) 
o Grade 3 diarrhea, nausea, vomiting, or abdominal pain that 
returns to Grade 1 or baseline within three days with medical 
intervention 


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o Grade 3 pruritis or rash that returns to Grade 1 or baseline within 
seven days or baseline with medical intervention 
o Grade 3 fatigue 
o Grade 3 tumor flare (defined as pain, irritation or rash that 
localizes to sites of known or suspected tumor) 
 
A DLT will also include:  
• A laboratory finding of acute liver injury defined as: 
o Sustained (> 1 week) doubling of AST or ALT levels to no less 
than 4 x ULN, or sign of increasing functional liver impairment 
with > 2x baseline increase in total bilirubin 
o Increased AST or ALT levels above 8 x ULN 
o Suspected acute liver injury (per Hy’s law) ALT/AST > 3 x ULN 
in combination with Total Bilirubin > 2 x ULN in the absence of 
cholestatic injury (ALP < 2 x ULN). 
• Any AE resulting in a patient missing > 7 days of dosing with VK-
2019 
• Any AE not otherwise meeting the criteria or timing of a DLT as 
defined above, but is declared a DLT by the SRC  
Definition of the 
MTD: 
The MTD is defined as the highest dose level of VK-2019 at which 
fewer than two DLTs are observed in six evaluable patients treated at 
that dose. 
Definition of a 
BCAD: 
A BCAD is defined as a dose level that appears to have preliminary 
clinical or biological activity based upon the following criteria: 
o There are no safety concerns in that cohort based upon the SRC’s 
analysis of safety data. 
o The following criteria for either clinical or biological activity: 
Clinical: 
o At least one patient has experienced an objective response per 
RECIST v1.1 (i.e., a PR or CR) at that dose level. 
Biological: 
o Post-baseline plasma EBV DNA levels have declined by three 
log from baseline, or are below the lower limit of detection of the 
assay, AND 
o Plasma AUC level VK-2019 at the end of Cycle 1 is above the 
biologically active dose as defined in preclinical models (10,000 
ng*h/mL) 
Definition of the 
RP2D 
The dose of orally administered VK-2019 monotherapy that, in the 
opinion of the SRC, can be safely administered for three or more 
cycles, factoring in cumulative adverse experiences and adverse 
experiences that lead to study drug discontinuation. 
Initiation of Phase 1 
Expansion Cohorts: 
The SRC may elect to initiate a Phase 1 Dose Expansion Cohort and 
enroll additional patients at any dose level that:  
• Meets the definition of the MTD. 
• Meets the definition of a BCAD. 
The total number of patients enrolled at any one dose level during Phase 
1 (dose escalation and expansion) will not exceed 16 patients.  
 


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Based upon the above criteria, the SRC may elect to explore multiple 
dose levels as Phase 1 Expansion Cohorts (either staggered or 
concurrently).  
Initiation of Phase 
2a Expansion 
Cohorts: 
Upon completion of any Phase 1 Expansion Cohort, the SRC may elect 
to expand the cohort further, initiating a Phase 2a Dose Expansion and 
enrolling additional nine patients if the dose level meets the following: 
• Two or more patients have experienced an objective response per 
RECIST v1.1 (i.e., a PR or CR), of which at least one is a confirmed 
response. 
• There are no additional safety concerns in the cohort of existing 
patients based upon the SRC's analysis of emerging safety data. 
The total number of patients enrolled at any one dose level during all 
phases of the study will not exceed 25 patients. 
  
Based upon the above criteria, the SRC may elect to explore multiple 
dose levels as Phase 2a Expansion Cohorts (either staggered or 
concurrently). 
Study Population: 
Inclusion Criteria: 
A patient who meets all of the following inclusion criteria will be eligible 
to participate in this study: 
1. Informed consent obtained prior to any protocol mandated 
assessment. 
2. Age ≥ 18. 
3. Either loco-regionally recurrent or metastatic EBV-positive 
nasopharyngeal carcinoma not amenable to curative treatment.   
a. EBV positivity is defined as high EBV viral load in plasma 
(> 4000 genomes per µg plasma DNA) and/or biopsy tissue 
positive for EBV. 
4. Prior palliative radiation must have been completed at least 2 weeks 
prior to study Cycle 1 - Day 0. 
5. Prior anti-cancer systemic treatment must have been completed 
greater than 4 weeks prior to study Cycle 1 - Day 0. 
6. Toxicities related to prior anti-cancer therapy must have returned to 
Grade 1 or less. Peripheral neuropathy must be Grade 2 or less. 
Chronic but stable toxicities Grade > 1 (e.g., dysphasia, G tube 
dependence, etc.) may be allowed after agreement between the 
Investigator and Sponsor. 
7. For the dose expansion in Phase 1 and Phase 2a, patients must have 
RECIST v1.1 measurable disease, defined as at least one lesion that 
can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal 
lesions) as ≥ 10 mM with spiral CT scan, MRI, or calipers by clinical 
exam. 
8. ECOG performance status score of ≤ 2 at study entry. 
9. Absolute neutrophil count > 1500/µL (stable off any growth factor 
for at least 1 week prior to study drug administration). 
10. Hemoglobin > 9g/dL (transfusion to achieve this level is permitted). 
11. Platelet count > 75 x 103/ µL (transfusion to achieve this level 
is NOT permitted). 
12. Serum aspartate transaminase (AST) and serum alanine transaminase 


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(ALT) ≤ 2.5 x upper limit of normal (ULN). 
13. Total serum bilirubin ≤ 1.5 x ULN. 
14. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min 
as calculated per Cockcroft-Gault equation. 
15. Urinary protein < 2+ by dipstick.  If dipstick ≥ 2+, then a 24-hour 
urine collection can be done and the patient may enter only if urinary 
protein is < 1 g/24 hour. 
16. Sexually active patients must agree to utilize birth control method 
during treatment and for 18 weeks after the last dose of VK-2019. 
Using effective birth control methods  as defined in 
https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/co
ntraceptive_methods_508.pdf. See Appendix 3 and Section 17.3. 
17. Willingness and ability to comply with the study scheduled visits, 
treatment plans, laboratory tests and other procedures. 
Exclusion Criteria 
1. Severe or active symptomatic cardiopulmonary diseases, including 
unstable angina, congestive heart failure, or peripheral vascular 
disease within 12 months prior to study drug administration; and/or 
chronic obstructive pulmonary disease exacerbation or other 
respiratory illness requiring hospitalization within 4 weeks prior to 
study drug administration.; Patients with effectively treated 
conditions (e.g., stenting for coronary artery disease) are eligible if 
stable for at least 4 weeks prior to study drug administration. 
2. Metastatic disease with active central nervous system (CNS) 
involvement, defined as parenchymal brain involvement.  Patients 
with cranial nerve or base of skull involvement without the above are 
eligible. Patients with CNS metastases that are stable on imaging at 
least 1 month following focal treatment with radiation are eligible. 
3. Concurrent treatment with systemic cancer directed therapy including 
complementary, alternative, herbal or nutritional supplement-based 
treatments whose purpose is for anti-cancer effect. 
4. Known history of human immunodeficiency virus (HIV) unless the 
HIV-positive patient has: 
• A stable regimen of highly active anti-retroviral therapy 
(HAART)  
• No requirement for concurrent antibiotics or antifungal agents for 
the prevention of opportunistic infections  
• A CD4 count above 250 cells/mcL and an undetectable HIV viral 
load on standard PCR-based test 
5. Serious uncontrolled medical disorder or active infection which 
would, in the opinion of the Investigator, impair the ability of the 
subject to receive protocol therapy or whose control may be 
jeopardized by the complications of this therapy. 
6. Currently taking drugs that inhibit or induce OATP1B1 or OATP1B3 
within five half-lives of that agent.  Examples are included in 
Appendix 2. 
7. Have received a prior organ allograft or allogeneic bone marrow 
transplant. 
8. Current non-prescription drug or alcohol dependence. 
9. For all female patients, pregnancy or breastfeeding. 


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10. All female patients with reproductive potential must have a negative 
pregnancy test (serum or urine) prior to enrollment. 
11. Other severe acute or chronic medical or psychiatric condition or 
laboratory abnormality that may increase the risk associated with 
study participation or study drug administration, or may interfere 
with the interpretation of study results, or in the judgment of the 
investigator would make the patient inappropriate for entry into the 
study. 
12. Corrected QT by Fridericia's formula (QTcF) of > 470 ms average 
(mean) on triplicate ECG performed during Screening. 
Safety Evaluation 
Safety parameters will include AEs, serious adverse events (SAEs), 
physical examinations, ECGs, vital signs, and clinical laboratory 
evaluations. Safety and tolerability will be assessed by the incidence and 
severity of adverse events as determined by CTCAE v5. 
Efficacy Evaluation 
The antitumor activity of study treatment will be assessed according to 
RECIST v1.1 guideline. 
Pharmacokinetic 
Assessments 
PK (blood and urine) samples will be collected during this study. 
Pharmacodynamic 
Assessments 
Plasma EBV DNA samples will be collected on all patients during this 
study. Samples will be analyzed to inform changes in EBV DNA and the 
mechanism of EBNA1 inhibition.  
 
Optional tumor biopsies will be collected in the Phase 2a part of the 
study. 
Sample Size 
Determination and 
Statistical Analysis 
The number of patients to be enrolled in this trial will depend upon the 
observed safety profile and the number of dose escalations and 
expansions. However, it is estimated that up to approximately 68 patients 
will be enrolled in this trial.  
 
During the Phase 1 portion of the trial, the approximate sample size in 
the dose escalation is estimated to be 30 patients (assuming six patients 
in each of five cohorts). The approximate sample size in the Phase 1 
Dose Expansion is estimated to be 20 patients (assuming 10 additional 
patients enrolled in each of two expanded dose levels). During the Phase 
2a portion of the trial, the approximate sample size in the Phase 2a Dose 
Expansions is estimated to be 18 (assuming 9 additional patients in each 
of two expansion cohorts).  
 
The estimate for the Phase 1 and 2a expansions is based upon a Simon 
Two-Stage design at BCAD and MTD, respectively. The null hypothesis 
that the true response rate is 0.1 will be tested against a one-sided 
alternative. In the first stage (i.e., a Phase 1 Dose Expansion cohort), 16 
patients will be accrued. If there is one or fewer responses in these 16 
patients, accrual to this cohort will be stopped. Otherwise, nine 
additional patients will be accrued (i.e., a Phase 2a Dose Expansion 
cohort) for a total of 25. The null hypothesis will be rejected if five or 
more responses are observed in 25 patients. This design yields a 1-sided 
type I error rate of 10% and power of 90% when the true response rate is 
30%. This design yields a probability of 0.51 for a cohort stopping early 
if the true response rate for that cohort is 10%. 


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Detailed statistical analyses will be specified in the Statistical Analysis 
Plan (SAP). 
 


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Table 1:  Schedule of Events in Phase 1 Dose Escalation  
Assessment16 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Odd 
Cycles15 
Cycle 4 and 
Even Cycles15  
EOT 
Safety FU 
LTFU 
Within 28 days 
of C1D0 
Day 0 Day 14 
(± 1 d) 
Day 0 
(+3 d) 
Day 14 
(± 3 d) 
Day 0 
(± 3 d) 
Day 0 
(± 3 d) 
7 d (± 3 d) 
post-last dose 
28 d (± 7 d) 
post-last dose 
q12 w (± 1 w)  
post-last dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical/Oncology 
History 
X 
 
 
 
 
 
 
 
 
 
ECOG Performance 
Status1 
X 
X10 
 
 
 
 
 
X 
 
 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height & Weight3 
X 
X10 
 
X10 
 
X10 
X10 
X 
X 
 
Physical Examination4 
X 
X10 
 
X10 
 
X10 
X10 
X 
X 
 
Hematology Labs
5 
X 
X10 
X 
X10 
X 
X10 
X10 
X 
X 
 
Chemistry Labs
5 
X 
X10 
X 
X10 
X 
X10 
X10 
X 
X 
 
Urinalysis
5 
X 
X10 
 
X10 
 
X10 
X10 
X 
X 
 
Coagulation Panel5 
X 
X10 
 
X10 
 
X10 
X10 
X 
X 
 
Pregnancy Test
5 
X 
X6,10 
 
X6,10 
 
X6,10 
X6,10 
X 
X6,10 
 
Triplicate ECG
7 
X 
X 
X 
X 
 
 
 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
VK-2019
8 
 
 X 
 
 
 
PK Plasma
9 
 
X 
X 
X 
 
X (C3 only) 
 
 
 
 
Plasma EBV DNA
5 
X 
 
X 
X 
X 
X (C3 only) 
 
X 
 
 
Tumor Assessments11 
X 
 
 
 
 
X11 
 
X12 
 
X13 
Survival 
 
 
 
 
 
 
 
 
 
X14 


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Phase 1 Dose Escalation Footnotes 
1 
ECOG performance scale is available in Appendix 1. 
2 
Vital signs (VS) include blood pressure (BP), temperature (T), and heart rate (HR). See Table 4 for collection time points. 
3 
Height is required at screening only.  
4 
A full physical exam is required at screening only. All other physical exams may be symptom directed. 
5 
Lab Assessments should include: 
• 
Hematology labs: CBC with Differential 
• 
Chemistry labs: Na, K, Cl, CO2, BUN, Cr, glucose, Ca, total bili, AST, ALT, ALP, albumin, total protein, Mg 
• 
Urinalysis: pH, specific gravity, glucose, ketones, blood, protein, nitrates, leukocytes 
• 
Coagulation: PT, PTT, INR 
• 
Pregnancy labs can be performed via blood or urine 
• 
Plasma EBV DNA 
6 
Pregnancy tests on D1 of each cycle and at the Safety FU visit are only required at sites in the European Union (EU). For sites in other regions, pregnancy 
tests at these visits are only required if clinically indicated. 
7 
All ECGs must be performed in triplicate. See Table 4 for specific collection time points. 
8 
VK-2019 must be taken in the morning on an empty stomach. Patients must fast for one hour before and two hours after each dose. Study drug accountability 
will be performed at each visit. 
9 
See Table 4 for PK collection time points. PK samples will only be collected through C3D0, not beyond.  
10 
Assessments need not be repeated if performed within three days prior to the visit. 
11 
Tumor assessments must be performed using computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI). 
Assessments should include evaluation of the neck, chest, abdomen, and pelvis, Post-baseline assessments will be performed within seven days of D0 of odd 
numbered cycles (i.e., C3D0, C5D0, etc). 
12 
Tumor assessments performed within four weeks of the EOT visit need not be repeated.  
13 
Tumor assessments in LTFU are only required for patients that have discontinued for reasons other than radiographic progression of disease, and may be 
performed ± 2 weeks of the scheduled LTFU date. 
14 
Survival status may be assessed via clinic visit (either at the study site or outside facility), telephone, or videotelephony.  
15 
After completing 13 cycles of treatment (i.e., > 12 months), the Investigator and Sponsor may agree that a patient will require study visits on an every odd 
cycle basis only (i.e., C15D0, C17D0, C19D0, etc.), until more frequent visits become clinically indicated. 
16 
Visits performed out of window due to holidays, natural disasters, and similar circumstances will not be a protocol deviation. 
 
 


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Table 2:  Schedule of Events in Phase 1 Dose Expansion 
Assessment16 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Odd Cycles15 
Cycle 4 and 
Even Cycles15 
EOT 
Safety FU 
LTFU 
Within 28 days 
of C1D0 
Day 0 Day 14 
(± 1 d) 
Day 0 
(+3 d) 
Day 14 
(± 3 d) 
Day 0 
(± 3 d) 
Day 0 
(± 3 d) 
7 d (± 3 d) 
post-last dose 
28 d (± 7 d) 
post-last dose 
q12 w (± 1 w)  
post-last dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical/Oncology 
History 
X 
 
 
 
 
 
 
 
 
 
ECOG Performance 
Status1 
X 
 
 
 
 
 
 
X 
 
 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height & Weight3 
X 
X10 
 
X10 
 
X10 
X10 
X 
X 
 
Physical Examination4 
X 
X10 
 
X10 
 
X10 
X10 
X 
X 
 
Hematology Labs
5 
X 
X10 
X 
X10 
X 
X10 
X10 
X 
X 
 
Chemistry Labs
5 
X 
X10 
X 
X10 
X 
X10 
X10 
X 
X 
 
Urinalysis
5 
X 
X10 
 
X10 
 
X10 
X10 
X 
X 
 
Coagulation Panel5 
X 
X10 
 
X10 
 
X10 
X10 
X 
X 
 
Pregnancy Test
5 
X 
X6,10 
 
X6,10 
 
X6,10 
X6,10 
X 
X6,10 
 
Triplicate ECG
7 
X 
X 
X 
X 
 
 
 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
VK-2019
8 
 
X 
 
 
 
PK Plasma
9 
 
X 
X 
X 
 
X (C3 only) 
 
 
 
 
PK Urine9 
 
X 
X 
 
 
 
 
 
 
 
Plasma EBV DNA
5 
X 
 
X 
X 
X 
X (C3 only) 
 
X 
 
 
Tumor Assessments11 
X 
 
 
 
 
X11 
 
X12 
 
X13 
Survival 
 
 
 
 
 
 
 
 
 
X14 
 
 
 


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Phase 1 Dose Expansion Footnotes 
1 
ECOG performance scale is available in Appendix 1. 
2 
Vital signs (VS) include blood pressure (BP), temperature (T), and heart rate (HR). See Table 5 for collection time points. 
3 
Height is required at screening only.  
4 
A full physical exam is required at screening only. All other physical exams may be symptom directed. 
5 
Lab Assessments should include: 
• 
Hematology labs: CBC with Differential 
• 
Chemistry labs: Na, K, Cl, CO2, BUN, Cr, glucose, Ca, total bili, AST, ALT, ALP, albumin, total protein, Mg 
• 
Urinalysis: pH, specific gravity, glucose, ketones, blood, protein, nitrates, leukocytes 
• 
Coagulation: PT, PTT, INR 
• 
Pregnancy labs can be performed via blood or urine 
• 
Plasma EBV DNA 
6 
Pregnancy tests on D1 of each cycle and at the Safety FU visit are only required at sites in the EU. For sites in other regions, pregnancy tests at these visits 
are only required if clinically indicated. 
7 
All ECGs must be performed in triplicate. See Table 5 for specific collection time points. 
8 
VK-2019 must be taken in the morning on an empty stomach. Patients must fast for one hour before and two hours after each dose. Study drug accountability 
will be performed at each visit. 
9 
See Table 5 for PK collection time points. PK samples will only be collected through C3D0, not beyond. 
10 
Assessments need not be repeated if performed within three days prior to the visit. 
11 
Tumor assessments must be performed using computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI). 
Assessments should include evaluation of the neck, chest, abdomen, and pelvis, Post-baseline assessments will be performed within seven days of D0 of odd 
numbered cycles (i.e., C3D0, C5D0, etc). 
12 
Tumor assessments performed within four weeks of the EOT visit need not be repeated.  
13 
Tumor assessments in LTFU are only required for patients that have discontinued for reasons other than radiographic progression of disease, and may be 
performed ± 2 weeks of the scheduled LTFU date. 
14 
Survival status may be assessed via clinic visit (either at the study site or outside facility), telephone, or videotelephony.  
15 
After completing 13 cycles of treatment (i.e., > 12 months), the Investigator and Sponsor may agree that a patient will require study visits on an every odd 
cycle basis only (i.e., C15D0, C17D0, C19D0, etc.), until more frequent visits become clinically indicated. 
16 
Visits performed out of window due to holidays, natural disasters, and similar circumstances will not be a protocol deviation. 
 
 


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Table 3:  Schedule of Events in Phase 2a Dose Expansion 
Assessment16 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 and 
Odd Cycles15 
Cycle 4 and 
Even Cycles15  
EOT 
Safety FU 
LTFU 
Within 28 days 
of C1D0 
Day 0 Day 14 
(± 3 d) 
Day 0  
(±3 d) 
Day 0 
(± 3 d) 
Day 0 
(± 3 d) 
7 d (± 3 d) 
post-last dose 
28 d (± 7 d) 
post-last dose 
q12 w (± 1 w)  
post-last dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical/Oncology 
History 
X 
 
 
 
 
 
 
 
 
ECOG Performance 
Status1 
X 
 
 
 
 
 
X 
 
 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height & Weight3 
X 
X10 
 
X10 
X10 
X10 
X 
X 
 
Physical Examination4 
X 
X10 
 
X10 
X10 
X10 
X 
X 
 
Hematology Labs
5 
X 
X10 
X 
X10 
X10 
X10 
X 
X 
 
Chemistry Labs
5 
X 
X10 
X 
X10 
X10 
X10 
X 
X 
 
Urinalysis
5 
X 
X10 
 
X10 
X10 
X10 
X 
X 
 
Coagulation Panel5 
X 
X10 
 
X10 
X10 
X10 
X 
X 
 
Pregnancy Test
5 
X 
X6,10 
 
X6,10 
X6,10 
X6,10 
X 
X6,10 
 
ECG
7 
X 
X 
 
X 
 
 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
VK-2019
8 
 
 X 
X 
X 
X 
X 
 
 
 
PK Plasma
9 
 
X 
 
X 
X (C3 only) 
 
 
 
 
Plasma EBV DNA
5 
X 
 
 
X 
X (C3 only) 
 
X 
 
 
Optional Tumor Biopsy9 
X 
 
 
X 
 
 
 
 
 
Tumor Assessments11 
X 
 
 
 
X11 
 
X12 
 
X13 
Survival 
 
 
 
 
 
 
 
 
X14 
 
 
 


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Phase 2a Dose Expansion Footnotes 
1 
ECOG performance scale is available in Appendix 1. 
2 
Vital signs (VS) include blood pressure (BP), temperature (T), and heart rate (HR). See Table 6 for collection time points. 
3 
Height is required at screening only.  
4 
A full physical exam is required at screening only. All other physical exams may be symptom directed. 
5 
Lab Assessments should include: 
• 
Hematology labs: CBC with Differential 
• 
Chemistry labs: Na, K, Cl, CO2, BUN, Cr, glucose, Ca, total bili, AST, ALT, ALP, albumin, total protein, Mg 
• 
Urinalysis: pH, specific gravity, glucose, ketones, blood, protein, nitrates, leukocytes 
• 
Coagulation: PT, PTT, INR 
• 
Pregnancy labs can be performed via blood or urine 
• 
Plasma EBV-DNA 
6 
Pregnancy tests on D1 of each cycle and at the Safety FU visit are only required at sites in the EU. For sites in other regions, pregnancy tests at these visits 
are only required if clinically indicated. 
7 
All ECGs must be performed in triplicate. See Table 6 for specific collection time points. PK samples will only be collected through C3D0, not beyond. PD 
samples will be collected through C3D0 and at the end of treatment visit. 
8 
VK-2019 must be taken in the morning on an empty stomach. Patients must fast for one hour before and two hours after each dose. Study drug accountability 
will be performed at each visit. 
9 
See Table 6 for PK collection time points. PK samples will only be collected through C3D0, not beyond. 
10 
Assessments need not be repeated if performed within three days prior to the visit date.  
11 
Tumor assessments must be performed using computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI). 
Assessments should include evaluation of the neck, chest, abdomen, and pelvis, Post-baseline tumor assessments may be performed within seven days of D0 
of odd numbered cycles (i.e., C3D0, C5D0, etc). 
12 
Tumor assessments performed within four weeks of the EOT visit need not be repeated.  
13 
Tumor assessments in LTFU are only required for patients that have discontinued for reasons other than radiographic progression of disease, and may be 
performed ± 2 weeks of the scheduled LTFU date. 
14 
Survival status may be assessed via clinic visit (either at the study site or outside facility), telephone, or videotelephony.  
15 
After completing 13 cycles of treatment (i.e., > 12 months), the Investigator and Sponsor may agree that a patient will require study visits on an every odd 
cycle basis only (i.e., C15D0, C17D0, C19D0, etc.), until more frequent visits become clinically indicated. 
16 
Visits performed out of window due to holidays, natural disasters, and similar circumstances will not be a protocol deviation. 
 
 


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Table 4: Phase 1 Dose Escalation PK and ECG Schema  
Visit 
Timepoint 
Assessments 
PK Plasma 
ECG 
Screening 
n/a 
 
X 
C1D0 
Pre-dose (-1 hour) 
X 
X 
30 mins post-dose (± 5 
m) 
X 
 
1 h post (± 10 m)1 
X 
X 
2 h post (± 10 m) 
X 
 
3 h post (± 10 m) 
X 
 
4 h post (± 10 m) 
X 
 
6 h post (± 10 m) 
X 
 
8 h post (± 30 m) 
X 
 
24 h post (± 2 h) 
X 
 
C1D14 
Pre-dose (-1 h) 
X 
X 
1 h post (± 10 m)1 
X 
X 
C2D0 
Pre-dose (-1 h) 
X 
X 
1 h post (± 10 m)1  
X 
X 
C2D14 
Pre-dose (-1 h) 
 
 
1 h post (± 10 m)  
 
 
C3D0 
Pre-dose (-1 h) 
X 
 
1 h post (± 10 m)1 
X 
 
EOT 
n/a 
 
X 
Footnotes 
1 
For post-dose timepoints in which PK and ECGs are both collected, the ECGs should be collected first 
within the timepoint window. PK can then be drawn up to 10 minutes after the ECG collection time. 
 
Table 5: Phase 1 Dose Expansion PK and ECG Schema  
Visit 
Timepoint 
Assessments 
PK Plasma 
PK Urine 
ECG 
Screening 
n/a 
 
 
X 
C1D0 
Pre-dose (-1 hour) 
X 
X2 
X 
30 mins post-dose (± 5 
m) 
X 
 
1 h post (± 10 m)1 
X 
X 
2 h post (± 10 m) 
X 
 
3 h post (± 10 m) 
X 
 
4 h post (± 10 m) 
X 
 
6 h post (± 10 m) 
X 
 
8 h post (± 30 m) 
X 
 
24 h post (± 2 h) 
X 
X3 
 
C1D14 
Pre-dose (-1 h) 
X 
X2 
X 
30 mins post-dose (± 5 
m) 
X 
 
1 h post (± 10 m)1 
X 
X 
2 h post (± 10 m) 
X 
 
3 h post (± 10 m) 
X 
 
4 h post (± 10 m) 
X 
 
6 h post (± 10 m) 
X 
 
8 h post (± 30 m) 
X 
 


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Visit 
Timepoint 
Assessments 
PK Plasma 
PK Urine 
ECG 
24 h post (± 2 h) 
X 
X3 
 
C2D0 
Pre-dose (-1 hour) 
X 
 
X 
1 h (± 10 m)1  
X 
 
X 
C2D14 
Pre-dose (-1 hour) 
 
 
 
1 h (± 10 m)  
 
 
 
C3D0 
Pre-dose (-1 hour) 
X 
 
 
1 h (± 10 m)1 
X 
 
 
EOT 
n/a 
 
 
X 
Footnotes 
1 
For post-dose timepoints in which PK and ECGs are both collected, ECGs should be collected first within 
the timepoint window. PK can then be drawn up to 10 minutes after the ECG collection time. 
2 
Patients should empty their bladders as close to dosing as possible. Urine will then be collected until 8 
hours post-dose, with a specimen collected as close to the 8 hour time point as possible. 
3 
Urine for PK will then be collected 8 to 24 hours post-dose with a specimen collected as close to the 24 
hour time point as possible. 
 
Table 6: Phase 2a Dose Expansion PK, PD, and ECG Schema 
Visit 
Timepoint 
Assessments 
PK Plasma 
Optional Tumor Biopsy 
ECG 
Screening 
n/a 
 
X 
X 
C1D0 
Pre-dose (-1 hour) 
X 
 
X 
1 h post-dose (± 10 mins)1 
X 
 
X 
C2D0 
Pre-dose (-1 hour) 
X 
X2 
X 
1 h post (± 10 m)1  
X 
X 
C3D0 
Pre-dose (-1 hour) 
X 
 
 
1 h post (± 10 m)1 
X 
 
 
EOT 
n/a 
 
 
X 
Footnotes 
1 
For post-dose timepoints in which PK and ECGs are both collected, ECGs should be collected first within 
the timepoint window. PK can then be drawn up to 10 minutes after the ECG collection time. 
2 
The post-dose tumor biopsy may be collected ± 7 days of C2D0. 
 


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2 
BACKGROUND 
Nasopharyngeal carcinoma (NPC) arises from the epithelium of the nasopharynx.  The incidence 
and death rates from NPC worldwide are approximately 86,000 and 50,000 respectively, with an 
approximately 2 to 3-fold higher incidence in males.(1) The incidence in Southern China is about 
35/100,000 while in the US overall rates are approximately 1-2/100,000. Risk seems to migrate 
with populations, so in ethnic Asians in the US, the incidence is intermediate between these two 
rates and seems to fall in subsequent generations following migration away from regions of high 
endemic incidence. Peak incidence is in the sixth decade of life and most patients present with 
locoregional advanced disease.  
While early stage local disease is highly curable (> 90%) with radiation therapy, advanced 
locoregional disease is fatal in approximately 1/3 of all patients despite intensive chemotherapy 
and radiation treatments.(2) There are no reliable cures for patients with metastatic disease. The 
present standard systemic treatments for metastatic or locoregional recurrent disease is 
combination chemotherapy with agents such as gemcitabine and cisplatin. Such combinations 
typically are associated with response rates of 40-60% and median survivals of 20-30 months.(3)  
Evidence strongly implicates Epstein-Barr virus (EBV) as the primary etiologic agent in the 
development of NPC.(4) While most humans have evidence of EBV exposure by adolescence, the 
reason a small subset of these develop NPC is unknown. The association between EBV infection 
and NPC development is extremely strong.  Increased immunoglobulin titers against EBV, 
specifically against viral capsid antigen (VCA) of the EBV and IgA antibodies against EBV are 
highly associated with the development and presence of NPC.(5) Latent EBV infection is evident 
in virtually all cases of NPC without regard to geography or ethnicity.  Copy numbers per cancer 
cell of latent EBV are highest in the undifferentiated WHO 3 type of NPC, the form of NPC seen 
most often in Asian populations. EBV in NPC tumor cells are monoclonal, indicating that EBV 
infection likely precedes tumorigenesis. 
EBV, also known as HHV-4, is a member of the gamma human herpesvirus family.  The viral 
genome is encapsulated in an infectious particle as linear double stranded DNA approximately 
170 kb long. During latent infection, EBV DNA circularizes and replicates. It is latent infection 
that has oncogenic potential and thought to be the causative agent in NPC. Other lymphoid and 
epithelial malignancies associated with EBV include Burkitt’s lymphoma, Hodgkin’s lymphoma, 
gastric carcinoma, angiocentric T/NK lymphoma, lymphoproliferative disorders of the 
immunosuppressed, and oral hairy leukoplakia.  During latency, EBV expresses a limited set of 
viral genes that stimulate cellular proliferation and promote survival. 
Chief among the latency genes is the Epstein-Barr Nuclear Antigen 1 (EBNA1), which is 
consistently expressed in all EBV positive tumors. EBNA1 is required for the stable maintenance 
of the EBV genome in latently infected cells and provides a survival function to host-cells.(6)(7) 
EBNA1 localizes to the nucleus, binds to circularized EBV episomal DNA at a specific region 
known as the latent origin of replication (OriP).  In addition to its roles in replication, EBNA1 also 
binds to a viral region called the Family of Repeats (FR) while simultaneously binding to cellular 
genomic DNA. Thus, EBNA1 acts as a tether to promote the distribution of viral DNA to each of 
the daughter cells. EBNA1 also acts as a transcription factor for other latent EBV genes including 
EBNA2, and LMP1. 
Thus, EBNA1 plays a critical role in several processes thought to promote and maintain 
transformation and an ideal target for pharmacological inhibition. siRNA knockdown of EBNA1 


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in EBV–driven models and a dominant negative version of EBNA1 causes substantial cell death 
and inhibition of cellular growth.(8)(9)(10)(11)(12)  This EBNA1 knockout strategy appears to be 
selective for EBV transformed cells, suggesting possible selectivity to a EBNA1 targeted 
anti-cancer strategy.(13) For all of the aforementioned activities of EBNA1, the site-specific DNA 
binding function of EBNA1 is required.  
Small molecule inhibitors of the DNA binding activity of EBNA1 have been developed. The 
X-ray crystal structure of EBNA1 bound to the inhibitor VK-2019 shows that this inhibitor binds 
to a concave surface of EBNA1 critical for DNA binding. VK-2019 has nanomolar activity in 
in vitro competition assays and low micromolar activity in several cell-based assays. EBNA1 
inhibitors disrupt the interaction with viral DNA in Chromatin Immunoprecipitation (ChIP) assays 
and interfere with replication and maintenance in episomal maintenance assays.  
To assess the efficacy of EBNA1 inhibitors in vivo, a set of four unique EBV-dependent xenograft 
models were developed: One lymphoma model and three NPC models, including 2 patient-derived 
xenograft (PDX) models. The models include tumors that express varying EBV latency programs, 
all of which express EBNA1, and different mouse strains. For the PDX models, a primary 
nasopharyngeal tumor (C15) as well as a metastatic tumor line (C17) were included. 
Luciferase-positive Mutu LCL (Burkitt’s lymphoma line) were engrafted into the flanks of 
NSG-SCID mice and monitored by IVIS imaging and caliper measurements. Treatment with 
VK-2019 provided significant tumor growth inhibition (> 90%) compared to vehicle control with 
a P value < 0.0001, the null hypothesis being no effect of treatment. VK-2019 treated mice had 
significant tumor growth inhibition. VK-2019 was well tolerated with no weight loss observed. 
For the NPC models, two patient-derived tumor lines were engrafted, C15-PDX and C17-PDX 
into six to eight week old athymic nude mice, weighing 18 to 25 grams. C15-PDX was derived 
from a treatment naïve primary tumor from a patient of Moroccan decent and has been classified 
as latency program II. C17-PDX was derived from a cutaneous metastatic tumor sample that had 
previously been treated with cisplatin, bleomycin and 5-fluorouracil and is in latency program I.  
Tumor fragments of approximately 3 mM were engrafted subcutaneously. Treatment with 
10 mg/kg VK-2019 resulted in significant (> 75%) tumor growth inhibition in both the C15-PDX 
and C17-PDX. In a dose escalation experiment, significant dose response was observed with 
tumor growth inhibition of ~90% at 100 mg/kg dosed orally.  VK-2019 is well-tolerated. Twice 
daily oral administration of 100 mg/kg for > 50 days results in no weight loss, behavioral 
symptoms nor adverse findings during gross necropsy. 
To verify target engagement, i.e., that treatment with VK-2019 had an effect on latent virus—
RNA was isolated from the xenograft tumor material and performed gene expression analysis 
using the Nanostring hybridization system. Treatment with VK-2019 caused a significant decrease 
in the expression of all EBV-encoded genes—both lytic and latent genes.  This result provides 
further validation and is consistent with the hypothesis that VK-2019 treatment inhibits EBV 
replication and maintenance in latently infected cells and, thus, reduces the tumor burden of 
EBV-positive tumors. To assess selectivity, mice engrafted with EBV-positive and EBV-negative 
cell lines were treated. Treatment with 10 mg/kg VK-2019 resulted in ~70% tumor grown 
inhibition in the C666-1 (an EBV positive cell line) xenograft, whereas the same treatment 
resulted in < 10% tumor growth inhibition in A549 xenograft. 
Extensive PK analysis of VK-2019 has been performed. In rat and dog PK experiments, 
significant systemic exposure was seen with Cmax in the 25 to 50 µM range when dosed at 30 and 


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10 mg/kg, respectively. The half-life in rat (~4 hrs) and in dog (7 to 8 hrs) suggest a reasonable 
exposure may be expected in humans. In addition, significant oral bioavailability of > 50% was 
observed in both species. PK data demonstrate significant exposures at 10, 30, and 100 mg/kg/day 
in rat and dog. Using the exposures from the mouse xenograft studies (AUC = ~8600 ng*hr/mL) 
at the efficacious dose (10 mg/kg), the exposure levels from toxicity studies to ask whether a safe, 
efficacious is achievable. As will be described below, no serious adverse events were observed at 
the high dose (100 mg/kg/day) in both rats and dogs over the 28 days. At this high dose, exposure 
multiples of 80-fold and 160-fold over the efficacious exposure were calculated in rat and dog, 
respectively. This gives confidence that significant exposure in humans is achievable. 
To assess preclinical safety non-GLP Dose-limiting Toxicity (DLT), Dose Range Finding (DRF) 
studies, and GLP 28-day repeat dose toxicity studies were performed.  In single dose MTD 
studies, rats were dosed at 50, 100, 200, and 400 mg/kg and observed for clinical signs, body 
weight, and food consumption. A slight decrease in body weight gain was observed in the 
400 mg/kg group, and in 7-day repeat dose DRF study at 30 and 300 mg/kg/day. PK sampling on 
Day 1 and Day 7 were similar. At the 300 mg/kg dose level, morbidity was observed in about half 
of the rats after 3-5 days. Bioanalytical data showed that the surviving rats had > 400 μM plasma 
concentrations with a few having concentrations of ~1 mM. Averaged across all surviving rats, the 
exposure multiple was 327-fold greater than the anticipated clinical efficacious exposure.  Clinical 
pathology data indicated that the target organs were kidney and liver.  For the IND-enabling, 
28-day GLP repeat dose toxicity study in rat, 0 (control), 10, 30, and 100 mg/kg/day were dosed, 
which included toxicokinetics (TK) and 28-day recovery groups for the control and high dose 
animals. Bioanalytical evaluations of animal groups at each of the dose levels were performed. At 
all dose levels, no morbidity/mortality, no effects on body weight or food consumption, and no 
adverse clinical signs were observed. Gross necropsy uncovered a slight increase in liver weight, 
which was reversed in the recovery animals. Clinical chemistry data indicated slight, but 
significant changes in alkaline phosphatase, bilirubin, BUN, creatinine, cholesterol and total 
protein. These effects were reversible 28-days after the treatment period.  Other clinical chemistry 
or hematology effects were not observed. There were no drug-related neurobehavioral findings.  
Histopathology assessments indicated that at the high dose, mild centrilobular liver vacuolation, 
mild periportal vacuolation, minimal tubular basophilia, and mononuclear infiltration were seen.  
Bioanalytical results indicated that the exposure multiple was > 87-fold higher than the efficacious 
exposure. In dog, single dose MTD studies were carried out at concentrations of 25, 50, 75, and 
100 mg/kg. No adverse clinical signs, effects on body weight or food consumption with a single 
dose were observed. In dog 7-day repeat dose DRF studies, we dosed 10, 50, 100, and 
150 mg/kg/day. At all dose levels, no adverse clinical signs, body weight or food consumption 
changes were observed. PK data on Day 1 and Day 7 were similar.  In 28-day repeat dose toxicity 
study in dog, animals were dosed with 0 (control), 10, 30, and 100 mg/kg/day and included 
recovery groups. Morbidity/Mortality, adverse clinical signs, effects on body weight and food 
consumption were not observed at any dose levels. Clinical chemistry was normal at all dose 
levels. A slight, but significant decrease in the reticulocyte count was observed in the 
100 mg/kg/day group on Day 27 compared to the controls. In sum, preclinical safety studies 
suggest that VK-2019 will be safe at efficacious doses. 
Results from in vitro ADME experiments are not an obstacle to further development and suggest 
that VK-2019 will be safe. Aqueous solubility of > 500 µM at pH 7.4 and 9.2 was observed.  
CYP450 inhibition assays with Cyp1A2, 2D6 and 3A4 showed IC50 values of > 50 μM, the 
highest concentration that VK-2019 was tested.  No hERG binding (0%) was observed up to 


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50 μM.  Metabolic stability in human, rat and mouse liver microsomes was measured, both with 
and without cofactors.  The stability was ~100% at 60 minutes when incubated with human, rat or 
mouse liver microsomes, with and without cofactors.  In the hemolysis assay, we observed no 
hemolysis (0%) up to 500 μM.  We have run the Cerep 44 Safety Screen with 10 μM VK-2019.  
VK-2019 had no activity in all 44 receptors and enzymes ≤ 30% of positive controls at 10 μM.  
The effect of VK-2019 on OATP1B3 and PGP transporters has been characterized.  VK-2019 did 
not interact with PGP transporters, but did interact with OATP1B3, comparable to atorvastatin.  
VK-2019 did not inhibit transport of atorvastatin by OATP1B3.  In accordance with the 2012 
FDA DDI draft guidance and the decision tree, it was determined that VK-2019 falls well outside 
the parameters that would require a drug-drug interaction study. 
A specific and sensitive method to measure the progression of NPC uses real-time quantitative 
PCR to quantify cell-free circulating EBV DNA. (14)  EBV DNA in plasma is thought to originate 
from apoptotic or necrotic tumor cells. (15) EBV DNA levels have been shown to correlate with 
tumor staging, tumor burden before treatment and likelihood of tumor recurrence. (16), (17), (18)  
EBV DNA concentrations have been shown to be sensitive (> 96%) and specific (93%) in 
predicting overall survival and are possibly more accurate than the TNM staging system.  (19) 
Serum EBV DNA levels have been shown to remain consistently low or undetectable in patients 
in complete clinical remission. Interestingly, NPC patients who had an increase in plasma EBV 
DNA concentrations after achieving an undetectable level post treatment typically relapse up to 
six months after the detected rise in plasma EBV DNA levels.  These findings suggest that EBV 
DNA levels may be a reliable relapse predictor before any clinical evidence of recurrence is 
found. (20) This protocol outlines the use of EBV plasma levels as an early surrogate biomarker 
for efficacy. Tumor cell EBV copy number and viral expression will also be evaluated to 
potentially elucidate the direct mechanism of action of the EBNA inhibitor VK-2019 as EBNA1 
inhibition preclinically has been shown to cause a decrease in EBV viral gene expression. 


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3 
OBJECTIVES OF THE STUDY 
 
Phase 1 Objectives 
3.1.1 Primary 
• To define the MTD and the RP2D for orally administered VK-2019 monotherapy in patients 
with recurrent or metastatic NPC. 
• To evaluate and characterize the safety profile of single agent VK-2019 in adult patients 
with recurrent or metastatic NPC. 
3.1.2 Secondary 
• To evaluate the anti-tumor activity of single agent VK-2019 per RECIST v1.1. 
• To characterize the single-dose and steady state pharmacokinetic profile of single agent 
VK-2019 in adult patients with recurrent or metastatic NPC. 
• To evaluate the anti-EBV activity by reduction of plasma EBV-DNA of single agent 
VK-2019 in adult patients with recurrent or metastatic NPC. 
3.1.3 Exploratory 
• To explore blood PD markers. 
• To explore PD markers such as alteration in EBV specific gene expression, both lytic and 
latent EBV genes. 
• To explore exposure-response relationships between VK-2019 exposure and the PD 
endpoints (safety, efficacy, and laboratory correlatives). 
 
Phase 2a Objectives 
3.2.1 Primary 
• Evaluate preliminary efficacy (ORR, DOR, DCR, PFS, survival rate, and OS) of orally 
administered VK-2019 monotherapy in adult patients with recurrent or metastatic NPC. 
• Confirm the safety and tolerability of orally administered VK 2019 monotherapy in adult 
patients with recurrent or metastatic NPC. 
3.2.2 Secondary 
• To further characterize select PK parameters associated with orally administered VK-2019 
monotherapy in adult patients with recurrent or metastatic NPC. 
• Evaluate the anti-EBV activity by reduction of plasma EBV-DNA of orally administered 
VK-2019 monotherapy in adult patients with recurrent or metastatic NPC. 
3.2.3 Exploratory 
• To explore both blood and intratumoral PD markers. 
• To explore PD markers such as alteration in EBV specific gene expression, both lytic and 
latent EBV genes. 
• To explore exposure-response relationships between VK-2019 exposure and the PD 
endpoints (safety, efficacy, and laboratory correlatives). 
 


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4 
STUDY DESIGN 
This is a phase 1/2a, open-label, multicenter, multi-dose, dose-escalation trial of VK-2019, a potent 
and selective inhibitor of the EBV latency program through its specific binding to a viral target, 
EBNA1.  
For each patient enrolled, the study will consist of at least three periods:  Screening (up to 28 days), 
Treatment (comprised of 28-day dosing cycles), and Follow up (comprised of a safety follow-up 
and long-term follow-up for survival status).  
 
This trial is divided into three parts (Figure 1): Phase 1 Dose Escalation, Phase 1 Dose Expansion, 
and Phase 2a Dose Expansion. One sub-study, collecting tumor biopsies, will be conducted during 
the Phase 2 Expansion part of the trial.  
 
Figure 1: Study Design Schema 
   
Cohort 1 (60 mg)
Cohort 2 (TBD mg)
Cohort 3 (TBD mg)
Cohort 4 (TBD mg)
Cohort 5 (TBD mg)
Cohort X (TBD mg)
Phase 1
Dose Escalation
Escalating doses will be 
enrolled until the MTD is 
reached
Dose Expansion
Multiple dose escalation 
cohorts may be expanded 
based upon biological/clinical 
activity or at the MTD
Phase 2a
Phase 2 Expansion A
Phase 2 Expansion B
Dose Expansion
Multiple Phase 1 expansions 
may be further expanded 
into Phase 2a cohorts based 
upon efficacy
Phase 1 Expansion A
Phase 1 Expansion B
Phase 1 Expansion C
Note: Three Phase 1 and two Phase 2 dose expansions are not specifically planned. The total number of expansions 
opened will depend upon biological and clinical activity observed in the trial
1-6 Patients/Cohort
9 Patients/Cohort
16 Patients/Cohort


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Phase 1 Dose Escalation  
Dose escalation in this trial will be conducted utilizing both an accelerated titration, based in part 
upon a 3B design proposed by Simon et al (21), coupled with a “rolling six” design (22). Five dose 
escalation cohorts are planned, but additional dose escalation or intermediate de-escalation cohorts 
may be explored based upon emerging safety and/or PK data. 
By utilizing these designs it is expected to maximize accrual at pharmacologically relevant doses, 
both by potentially minimizing accrual at subtherapeutic dose levels and more efficiently 
establishing an understanding of the safety profile of VK-2019 (23).  
Dose escalation will initially proceed according to the accelerated titration design, enrolling one 
new patient per dose level. Upon any instance of a VK-2019 related Grade ≥ 2 AE during Cycle 1, 
dose escalation will convert to the Rolling Six design in which 3-6 patients per dose level will be 
enrolled.   
See Section 6.2 for dose escalation procedures. 
 
Phase 1 Dose Expansion 
During dose escalation, one or more cohorts may be selected for expansion, enrolling up to 16 
patients (inclusive of the patients already enrolled at the same dose during escalation) at any dose 
level that is assessed to either be the MTD or have sufficient activity to meet criteria as a BCAD. 
See Section 6.7 for details on initiating a Phase 1 Dose Expansion. 
 
Phase 2a Dose Expansion 
Further dose expansion in the Phase 2a part of the trial may be explored by utilizing the Simon 2 
Stage design. Up to an additional nine patients may be enrolled at a particular dose if two or more 
objective responses (at least one must be confirmed) are observed out of 16 patients at that dose in 
the Phase 1 part of the trial (for a total accrual of up to 25 patients).  
See Section 6 for details on initiating a Phase 2a Dose Expansion. 


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5 
ELIGIBILITY CRITERIA 
The inclusion and exclusion criteria for this study are provided on the Eligibility Checklist below. 
A patient must meet all of the inclusion criteria and must not meet any of the exclusion criteria to be 
eligible to participate in this study. 
The checklist may be utilized to review and confirm each patient’s eligibility prior to registration 
(unless a separate checklist is required by the institution). If used for confirmation of eligibility, the 
completed, signed, and dated checklist will be retained in the patient’s study file and the study’s 
regulatory binder.  


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Patient Eligibility Checklist 
I. 
Protocol Information  
Protocol Title: 
Phase 1-2a open-label, multicenter clinical trial of a novel small 
molecule EBNA1 inhibitor, VK-2019, in patients with Epstein-Barr 
Virus positive nasopharyngeal cancer, with pharmacokinetic and 
pharmacodynamic correlative studies 
Protocol number 
(Sponsor/Institution): VK-2019-001/  
Principal Investigator:  
II. 
Patient Information  
Patient Identifier 
(i.e., Subject Number, etc.):  
Gender  
  Male   
 Female   
III. 
Study Information  
 
Inclusion Criteria 
Prospective Study Patient Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes 
No 
Supporting 
Documentation * 
1. Informed consent obtained prior to any protocol 
mandated assessment 
 
  
2. Age ≥ 18 
 
  
3. Either loco-regionally recurrent or metastatic 
EBV-positive nasopharyngeal carcinoma not 
amenable to curative treatment.  EBV positivity is 
defined as high EBV viral load in plasma (> 4000 
genomes per µg plasma DNA) and/or biopsy tissue 
positive for EBV  
 
  
4. Prior palliative radiation must have been completed 
at least 2 weeks prior to study Cycle 1 – Day 0 
 
  
5. Prior anti-cancer systemic treatment must have been 
completed greater than 4 weeks prior to the first dose 
of VK-2019 
 
  


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Prospective Study Patient Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes 
No 
Supporting 
Documentation * 
6. Toxicities related to prior anti-cancer therapy must 
have returned to Grade 1 or less.  Peripheral 
neuropathy must be Grade 2 or less. Chronic but 
stable toxicities Grade > 1 (e.g., dysphasia, G tube 
dependence, etc.) may be allowed after agreement 
between the Investigator and Sponsor. 
 
  
7. For the dose expansion phase in Phase 1 and 
Phase 2a: Patients must have RECIST v1.1 
measurable disease, defined as at least one lesion 
that can be accurately measured in at least one 
dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions) as 
≥ 10 mM with spiral CT scan, MRI, or calipers by 
clinical exam 
 
  
8. ECOG performance status score of ≤ 2 at study 
entry.  
 
  
9. Absolute neutrophil count > 1500/µL (stable off any 
growth factor for at least 1 week of study drug 
administration) 
 
  
10. Hemoglobin > 9g/dL (transfusion to achieve this 
level is permitted) 
 
  
11. Platelet count > 75 x 103/ µL (transfusion to achieve 
this level is NOT permitted) 
 
  
12. Serum aspartate transaminase (AST) and serum 
alanine transaminase (ALT) ≤ 2.5 x upper limit of 
normal (ULN) 
 
  
13. Total serum bilirubin ≤ 1.5 x ULN 
 
  
14. Serum creatinine ≤ 1.5 x ULN or creatinine 
clearance ≥ 50 mL/min as calculated per 
Cockcroft-Gault equation 
 
  
15. Urinary protein < 2+ by dipstick.  If dipstick ≥ 2+, 
then a 24-hour urine collection can be done and the 
patient may enter only if urinary protein is < 1 g/24 
hour 
 
  


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Prospective Study Patient Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes 
No 
Supporting 
Documentation * 
16. Sexually active patients must agree to utilize birth 
control method during treatment and for 18 weeks 
after the last dose of VK-2019. Using effective birth 
control methods  as defined in 
https://www.cdc.gov/reproductivehealth/unintended
pregnancy/pdf/contraceptive_methods_508.pdf.  See 
Appendix 3 and Section 17.3 
 
  
17. Willingness and ability to comply with the study 
scheduled visits, treatment plans, laboratory tests 
and other procedures 
 
  
 
Exclusion Criteria 
Prospective Study Patient Must NOT Match  
ANY of These Exclusion Criteria  
Yes 
No 
Supporting 
Documentation * 
1. Severe or active symptomatic cardiopulmonary 
diseases, including unstable angina, congestive 
heart failure, or peripheral vascular disease within 
12 months prior to study drug administration; 
and/or chronic obstructive pulmonary disease 
exacerbation or other respiratory illness requiring 
hospitalization within 4 weeks prior to study drug 
administration. Patients with effectively treated 
conditions (eg, stenting for coronary artery 
disease) are eligible if stable for at least 4 weeks 
prior to study drug administration.  
 
  
2. Metastatic disease with active central nervous 
system (CNS) involvement, defined as 
parenchymal brain involvement. Patients with 
cranial nerve or base of skull involvement without 
the above are eligible. Patients with CNS 
metastases that are stable on imaging at least 1 
month following focal treatment with radiation are 
eligible 
 
  
3. Concurrent treatment with systemic cancer 
directed therapy including complementary, 
alternative, herbal or nutritional supplement-based 
treatments whose purpose is for anti-cancer effect 
 
  


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Prospective Study Patient Must NOT Match  
ANY of These Exclusion Criteria  
Yes 
No 
Supporting 
Documentation * 
4. Known history of human immunodeficiency virus 
(HIV) unless the HIV-positive patients has: 
• A stable regimen of highly active 
anti-retroviral therapy (HAART)  
• No requirement for concurrent antibiotics or 
antifungal agents for the prevention of 
opportunistic infections  
• A CD4 count above 250 cells/mcL and an 
undetectable HIV viral load on standard 
PCR-based test 
 
  
5. Serious uncontrolled medical disorder or active 
infection which would, in the opinion of the 
Investigator, impair the ability of the subject to 
receive protocol therapy or whose control may be 
jeopardized by the complications of this therapy 
 
   
6. Currently taking drugs that inhibit or induce 
OATP1B1 or OATP1B3 within 5 half-lives of that 
agent. Examples are included in Appendix 2. 
 
  
7. Have received a prior organ allograft or allogeneic 
bone marrow transplant. 
 
  
8. Current non-prescription drug or alcohol 
dependence 
 
  
9. For all female patients, pregnancy or breastfeeding 
 
  
10. All female patients with reproductive potential 
must have a negative pregnancy test (serum or 
urine) prior to enrollment 
 
  
11. Other severe acute or chronic medical or 
psychiatric condition or laboratory abnormality 
that may increase the risk associated with study 
participation or study drug administration, or may 
interfere with the interpretation of study results, or 
in the judgment of the investigator would make the 
patient inappropriate for entry into the study 
 
  


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Prospective Study Patient Must NOT Match  
ANY of These Exclusion Criteria  
Yes 
No 
Supporting 
Documentation * 
12. Corrected QT by Fridericia's formula (QTcF) of 
> 470 ms average (mean) on triplicate ECG 
performed during screening 
 
  
* All patient files must include supporting documentation to confirm eligibility. The method of 
confirmation can include, but is not limited to, laboratory test results, radiology test results, subject 
self-report, and medical record review.  
V. 
Statement of Eligibility  
By signing this form of this study, I verify that this subject is:  
 eligible / 
 ineligible for 
participation in the study.   
Study Coordinator Printed Name: 
Date:  
Signature: 
 
Investigator Printed Name: 
Date:  
Signature: 
 
Additional Reviewer Printed Name (if required): 
Date:  
Signature: 
 
 
 


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Age and Reproductive Status 
Sexually active patients (excluding women who are not of childbearing potential) must use 
effective methods of birth control during treatment and for up to 18 weeks after the last dose of 
VK-2019.  See Appendix 3. 
Acceptable methods of highly effective birth control include: 
• 
Condom with spermicide 
• 
Diaphragm and spermicide 
• 
Cervical cap and spermicide  
• 
Hormonal implant 
• 
Intrauterine device 
• 
Male or female surgical sterilization 
• 
Oral contraceptive pills 
Women must not be breastfeeding. 
Women of child-bearing potential (WOCBP) include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy), and who is not postmenopausal.  


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6 
STUDY TREATMENT AND CONDUCT 
 
Safety Review Committee 
During the Dose Escalation and Dose Expansion parts of this study, an SRC will review safety, 
tolerability, PK, and, if available, PD data for the purposes of oversight and decision making.  
The SRC’s membership will consist of: 
• Two external, independent oncologists (one of which will serve as SRC Co-Chair) 
• The Protocol Chairperson (who will also serve as SRC Co-Chair) 
• The sponsor Medical Monitor and/or Chief Medical Officer 
• Principal Investigators from each site 
Additional attendees including (but not limited to) the study statistician, pharmacologist, 
pharmacovigilance representatives, site staff, or sponsor representatives may be invited to 
participate on an ad hoc basis.  
More information about SRC membership and roles and responsibilities is contained in the SRC 
Charter. 
6.1.1 During Phase 1 Dose Escalation 
After completion of a dose escalation cohort, the SRC will convene to evaluate the safety, 
tolerability, PK, and, if available, PD data of VK-2019 from that cohort with the purpose of 
deciding upon the next dose level. 
Upon reviewing data from that cohort, the SRC may decide to: 
• Escalate to the next dose level 
• Convert to the rolling-six dose escalation schema 
• Enroll up to a maximum of 6 evaluable patients 
• De-escalate to either a previously explored lower dose level (up to a maximum of 6 
evaluable patients) or to an intermediate lower dose level 
• Discontinue dose escalation in the trial 
• Initiate a Phase 1 Dose Expansion Cohort  
• Consider alternative dosing frequencies or intermittent dosing schedules 
• Terminate the trial 
• Defer their decision until additional data from patients in that cohort and/or other cohorts 
becomes available 
Additionally, PK profiles for patients treated two dose levels below a dose level under consideration 
for escalation will be required by the SRC prior to starting a given dose level, e.g., Cohort 3 will 
begin only after PK information on Cohort 1 is available for review. If super-proportional PK is 
observed following the single-dose PK on C1D0, the dose of VK-2019 may be modified to account 
for the increase in exposure. If significantly less than dose proportional exposure is observed, dose 
escalation may be stopped and one of the doses with the highest exposure may be selected for 
expansion. 


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Any patient started on treatment in error, i.e., he/she failed to comply with all of the selection 
criteria, but still meets the criteria of an evaluable patient will be reviewed on a case by case basis 
by the SRC to determine if the patient should be included or excluded in the decision for dose 
escalation. 
During the dose escalation, decisions made by the SRC will be documented and provided to the 
investigators prior to dosing any new patients. 
6.1.2 During Phase 1 Dose Expansion 
Upon completion of any Phase 1 Dose Expansion Cohort in the trial, the SRC will convene to 
review accumulating safety, tolerability, pharmacokinetics, and, if available, pharmacodynamic 
data. Additionally, SRC reviews will be required at various intervals during a given expansion 
cohort. The timing and criteria for convening these reviews are described in the SRC Charter. 
Upon review of this data, the SRC may decide to: 
• Continue the trial as planned 
• Stop enrollment into a particular expansion cohort or all cohorts in the Phase 1 Dose 
Expansion part of the trial 
• De-escalate one or more of the doses being explored in the expansion 
• Initiate a Phase 2a Dose Expansion Cohort  
• Consider alternative dosing frequencies or intermittent dosing schedules 
• Terminate the trial 
• Defer their decision until additional data becomes available 
6.1.3 During Phase 2a Dose Expansion 
Upon completion of any Phase 2a Dose Expansion Cohort in the trial, the SRC will convene to 
review accumulating safety, tolerability, pharmacokinetics, and, if available, pharmacodynamic 
data. Additionally, SRC reviews will be required at various intervals during a given expansion 
cohort. The timing and criteria for convening these reviews are described in the SRC Charter. 
Upon review of this data, the SRC may decide to: 
• Continue the trial as planned 
• Stop enrollment into a particular expansion cohort or all cohorts in the Phase 2a Dose 
Expansion part of the trial 
• De-escalate one or more of the doses being explored in the expansions 
• Consider alternative dosing frequencies or intermittent dosing schedules 
• Terminate the trial 
• Defer their decision until additional data becomes available 
 
Dose Escalation Procedures 
The starting dose for VK-2019 is 60 mg QD. Sample dose escalation tables are below in Table 7, 
detailing a sample dose escalation schema based upon when escalation converts from Accelerated 
Titration to a Rolling Six design.  


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6.2.1 Definition of a Completed Cohort and an Evaluable Patient 
Each dose escalation cohort will consist of either:  
• 1 evaluable patient (Accelerated Titration cohorts), or 
• 3-6 evaluable patients (Rolling Six cohorts)  
To be considered evaluable, a patient will have and one of the following: 
• Received 75% of doses during Cycle 1, or, 
• Received at least one dose of VK-2019 and experienced a DLT during Cycle 1 
6.2.2 Dose Escalation in Accelerated Titration Cohorts 
Upon completion of an accelerated titration cohort (Figure 2),  
• IF: No VK-2019 related Grade ≥ 2 AEs occur during Cycle 1; THEN: Dose escalation 
may proceed to the next accelerated titration cohort (no greater than a 100% dose 
increase). 
• IF: The patient experiences any VK-2019 related Grade ≥ 2 AE during Cycle 1 (not 
meeting the definition of a DLT); THEN: Convert the current cohort to the Rolling Six 
design and enroll an additional 2-5 patients (3-6 total). 
• IF: The patient experiences a DLT; THEN: Convert to the Rolling Six design and enroll 
an additional five patients (six total). 
Figure 2: Accelerated Titration Dose Escalation Schema 
 
6.2.3 Dose Escalation in Rolling Six Cohorts 
Upon completion of a Rolling Six cohort (a minimum of three, maximum of six evaluable patients), 
if: 
• 0 of 3 patients experience a DLT; dose escalation may proceed to the next cohort (no 
greater than a 50% dose increase) 
1) No Gr ≥ 2 related AEs
Dose 
escalate 
by 100%
Convert to Rolling 
Six design
3) Any Gr ≥ 2 related AE 
that is not a DLT
Enroll 1 pt
Enroll an 2-5 add’l
pts @ the same 
dose level
Enroll 1 pt
4) A DLT
Convert to Rolling 
Six Design
Enroll 5 add’l pts 
@ the same dose 
level
During Cycle 1, if the patient 
experiences:


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• 1 of 3 patients experience a DLT; an additional three evaluable patients will be enrolled 
into the cohort 
• ≤ 1 of 6 patients experience a DLT; dose escalation may proceed to the next cohort (no 
greater than a 50% dose increase) 
• ≥ 2 patients experience a DLT; the MTD has been exceeded and further enrollment into 
that cohort will cease. Lower-dose cohorts may then be explored until the MTD has been 
determined, including intermediate doses. 
Table 7: Sample Dose Escalation Tables 
Dose Escalation Schema 
Target Dose / Actual Dose 
Dose Increase 
All cohorts enrolled using Accelerated 
Titration 
60 mg / 60 mg 
n/a 
120 mg / 120 mg 
100% 
240 mg / 230 mg 
100% 
460 mg / 460 mg 
100% 
920 mg / 920 mg 
100% 
Rolling-six enrollment begins at the 
60 mg cohort 
60 mg / 60 mg 
n/a 
90 mg / 90 mg 
50% 
135 mg / 120 mg 
50% 
180 mg / 180 mg 
50% 
270 mg / 260 mg 
50% 
Rolling-six enrollment begins at the 
120 mg cohort 
60 mg / 60 mg 
n/a 
120 mg / 120 mg 
100% 
180 mg / 180 mg 
50% 
270 mg / 260 mg 
50% 
390 mg / 380 mg 
50% 
Rolling-six enrollment begins at the 
230 mg cohort 
60 mg / 60 mg 
n/a 
120 mg / 120 mg 
100% 
240 mg / 230 mg 
100% 
345 mg / 320 mg 
50% 
480 mg / 460 mg 
50% 
Rolling-six enrollment begins at the 
460 mg cohort 
60 mg / 60 mg 
n/a 
120 mg / 120 mg 
100% 
240 mg / 230 mg 
100% 
460 mg / 460 mg 
100% 
690 mg / 690 mg 
50% 
Note: Sample dose levels are based upon dose escalation (target dose) and available VK-2019 
capsule strengths of 30 and 200 mg (actual dose). 
6.2.4 Intra-Patient Dose Escalation in Accelerated Titration Cohorts 
After an accelerated titration cohort has been declared safe by the SRC, patients at lower dose levels 
may be considered for intra-patient dose escalation if they meet the following criteria based in part 
on 3B design proposed by Simon et al: 
• Have stable disease (SD) or better after Cycle 2 (or later) 
• Experienced no VK-2019 related Grade 2 AEs during the previous cycle 


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• Have no other safety concerns as assessed by the investigator 
The escalated dose must be agreed upon by the investigator and sponsor and may proceed 
beginning on Day 0 of the next cycle. Any patient that has their dose escalated will not be evaluated 
for DLT assessment at their new dose. 
6.2.5 Intra-Patient Dose Escalation in Rolling Six Cohorts 
After a Rolling Six cohort has enrolled a minimum of three patients and has been declared safe by 
the SRC, patients at lower dose levels may be considered for intra-patient dose escalation if the 
patient meets the following criteria: 
• Have stable disease (SD) or better after Cycle 2 (or later) 
• Have no other safety concerns as assessed by the investigator 
The escalated dose must be agreed upon by the investigator and sponsor and may proceed 
beginning on Day 0 of the next cycle. Any patient that has their dose escalated will not be 
evaluated for DLT assessment at their new dose. 
 
Dose-limiting Toxicity 
DLTs will be determined based on the incidence and intensity of AEs assessed as being at least 
possibly related to VK-2019 and occurring up to 28 days after initiation of QD VK-2019 dosing 
on C1D0. 
6.3.1 Dose-limiting Hematologic Toxicity 
• Grade 4 neutropenia > 7 days 
• Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding or 
requiring platelet transfusion 
• Grade 3 febrile neutropenia  
• Grade 4 anemia or anemia that requires blood transfusion 
6.3.2 Dose-limiting Non-hematologic Toxicities 


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• Any Grade 3 or higher non-hematology toxicity, excluding the following: 
o Toxicities assessed by Investigator as clearly related only to disease progression 
or intercurrent illness 
o Elevations of AST, ALT, and bilirubin, that correct to Grade 1 within one week 
and do not meet any of the definitions of acute liver injury as listed below  
o Other asymptomatic laboratory abnormalities 
o Grade 3 fever without neutropenia that returns to Grade 1 or less within 3 days, 
and is not associated with hemodynamic compromise (including hypotension, or 
clinical or laboratory evidence of end organ perfusion impairment) 
o Grade 3 diarrhea, nausea, vomiting, or abdominal pain that returns to Grade 1 or 
baseline within 3 days and with medical intervention 
o Grade 3 pruritis or rash that returns to Grade 1 or baseline within 7 days or 
baseline with medical intervention 
o Grade 3 fatigue 
o Grade 3 tumor flare (defined as pain, irritation or rash that localizes to sites of 
known or suspected tumor) 
A DLT will also include: 
• A laboratory finding of acute liver injury defined as: 
o Sustained (> 1 week) doubling of AST or ALT levels to no less than 4 x ULN, or 
sign of increasing functional liver impairment with > 2x baseline increase in total 
bilirubin 
o Increased AST or ALT levels above 8xULN 
o Suspected acute liver injury (per Hy’s law) ALT/AST > 3 x ULN in combination 
with Total Bilirubin > 2 x ULN in the absence of cholestatic injury (ALP 
< 2 x ULN) and no other cause identified. 
• Any AE resulting in a patient missing < 7 days of dosing with VK-2019 
• Any AE not otherwise meeting the criteria or timing of a DLT as defined above, but is 
declared a DLT by the SRC 
 
Definition of the MTD 
The MTD is defined as the highest dose level of VK-2019 at which fewer than two DLTs are 
observed in six evaluable dose escalation patients at that dose level. 
 
Definition of a BCAD 
A BCAD is defined as any dose level that appears to have preliminary clinical or biological 
activity based upon the following criteria: 
• There are no safety concerns in that cohort based upon the SRC’s analysis of safety data. 
• The following criteria for either clinical or biological activity: 
Clinical: 


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o At least one dose escalation patient has experienced an objective response per 
RECIST v1.1 (i.e., a PR or CR) at that dose level. 
Biological: 
o Post-baseline plasma EBV DNA levels have declined by three log from baseline, 
or are below the lower limit of detection of the assay, AND, 
o Plasma AUC level VK-2019 at the end of Cycle 1 is above the biologically 
active dose as defined in preclinical models (10,000 ng*h/mL). 
 
Definition of the RP2D 
The dose of orally administered VK-2019 monotherapy that, in the opinion of the SRC, can be 
safely administered for three or more cycles, factoring in cumulative adverse experiences and 
adverse experiences that lead to study drug discontinuation. 
 
Initiation of Phase 1 Expansion Cohorts 
The SRC may elect to initiate a Phase 1 Dose Expansion Cohort and enroll additional patients at 
any dose level that:  
• Meets the definition of the MTD. 
• Meets the definition of a BCAD. 
The total number of patients enrolled at any one dose level during Phase 1 (dose escalation 
and expansion) will not exceed 16 patients.  
Based upon the above criteria, the SRC may elect to explore multiple dose levels as Phase 1 
Expansion Cohorts (either staggered or concurrently). 
 
Initiation of Phase 2a Expansion Cohorts 
Upon completion of any Phase 1 Expansion Cohort, the SRC may elect to expand the cohort 
further, initiating a Phase 2a Dose Expansion and enrolling an additional nine patients if the dose 
level meets the following: 
• Two or more patients have experienced an objective response per RECIST v1.1 (i.e., a PR or 
CR), of which at least one is a confirmed response. 
• There are no additional safety concerns in the cohort of existing patients based upon the SRC's 
analysis of emerging safety data. 
The total number of patients enrolled at any one dose level during all phases of the study will 
not exceed 25 patients.  
Based upon the above criteria, the SRC may elect to explore multiple dose levels as Phase 2a 
Expansion Cohorts (either staggered or concurrently). 
 
Duration of Therapy 
Patients may continue to receive treatment until meeting criteria for discontinuation/withdrawal, 
e.g., adverse events, disease progression, etc. as outlined in Section 6.11. 
 Re-initiation of Therapy for Patients in Long-Term Follow-Up 
Patients having discontinued treatment after achieving a confirmed CR may reinitiate study 
therapy at the time of confirmed disease progression if there is agreement between the Investigator 
and the Sponsor.  


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Patients will be required to meet eligibility criteria at the time of reinitiating study drug and will 
receive the same dose level of VK-2019 that they received prior to discontinuation. However, if 
higher dose levels of VK-2019 have been explored and deemed tolerable by the SRC, the 
Investigator and Sponsor may agree that the patient may reinitiate VK-2019 at a higher dose level. 
Patients reinitiating VK-2019 at a higher dose level will not be evaluable for a DLT.  
Patients resuming therapy in this setting will do so at the next cycle after they completed therapy 
and will be followed as specified for all patients in the study. For example, patients that 
discontinued therapy after Cycle 14 will reinitiate therapy at the beginning of Cycle 15.  
Patients that achieved a CR will not be eligible to reinitiate treatment if they:  
• Discontinued study drug due to a treatment related adverse event(s), or  
• Have completed one year of follow-up (from date of last dose of study drug) without 
evidence of disease progression.  
Additional safety and efficacy summaries will be presented for patients that reinitiated study 
therapy under these conditions. 
 Patient Withdrawal 
Patients may withdraw from the trial at any time at their own request, or they may be withdrawn at 
any time at the discretion of the investigator or sponsor for safety, behavioral, or administrative 
reasons. Patients that withdraw from treatment should be encouraged to return for the end-of-
treatment visit, complete all safety assessments, and enter long-term follow-up. If the patient 
withdraws from both treatment and follow-up, no further evaluations should be performed, and no 
additional data should be collected. The Sponsor may retain and continue to use any data collected 
before such withdrawal of consent. 
The primary reason for withdrawal must be recorded in the subject’s medical record and in the 
appropriate eCRF pages. If a subject is withdrawn for more than one reason, each reason should 
be documented in the source document and the most medically significant reason should be 
entered on the eCRF. For example, in order to best characterize the safety profile of VK-2019, 
patients that withdraw consent from treatment due to tolerability issues with VK-2019 should be 
captured in the eCRFs as having discontinued due to AE or toxicity instead of having withdrawn 
consent from treatment. 
Patients will be discontinued from treatment and begin long-term follow-up in the case of: 
• 
Disease progression or requirement for anticancer therapy not specified in the protocol. 
• 
Inter-current illness, general, or specific changes in the patient’s condition where, in the 
opinion of the Investigator, further treatment is not in the best interest of the patient. 
• 
DLT or unmanageable AE related to therapy. 
• 
Withdraw of consent from treatment. 
• 
Significant protocol violation or non-compliance with protocol. 
• 
Termination of the study by Sponsor. Note: Any patients still receiving investigational 
product at the time of study termination by the sponsor will be able to continue to receive 
VK-2019 if they are deriving clinical benefit and after agreement between the 
Investigator and sponsor. Such patients will continue to be monitored for SAEs as 


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described in Section 13. Drug Accountability information must still be collected until all 
patients have completed treatment. 
Patients will be withdrawn from study (long-term follow-up) in the case of: 
• 
Withdrawal of consent from follow-up. 
• 
Patient lost to follow-up. 
• 
Death. 
• 
Termination of study by Sponsor. 
 
 


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7 
STUDY DRUG:  VK-2019 
 
  Description, Supply and Storage of Investigational Drugs 
7.1.1 Classification 
VK-2019 is an anti-viral compound being tested for its effect on cancer. 
7.1.2 Mechanism of Action 
VK-2019 binds to EBNA1 and inhibits EBNA1 DNA binding activity.  
7.1.3 Metabolism 
Two VK-2019 metabolites were observed when incubated with liver microsomes:  A hydroxylated 
form and a glucouronidation form. These forms are likely the major routes of clearance of 
VK-2019.  
7.1.4 Drug interactions 
Drug interaction studies with VK-2019 have not been conducted.  The following information is 
based on results from in vitro studies with VK-2019.  All concomitant medications must be 
recorded and approved by the sponsor at study entry and up to the end of Cycle 2. 
VK-2019 did not inhibit CYP450 1A2, 2D6 or 3A4 in vitro.  IC50 values were greater than 50 µM, 
the highest concentration that was tested.  In addition, VK-2019 did not induce the mRNA 
expression of drug-metabolizing CYP450 1A2, 2B6 and 3A4 in primary human hepatocytes from 
3 different donors. Therefore, the interaction of VK-2019 with metabolism of drugs through these 
P450 subtypes appears unlikely at clinical concentrations.  In cell assay, VK-2019 was classified 
as a substrate of OATP1B3 transporter at low concentration, but not at high concentrations.  The 
influx rate of atorvastatin was increased in the presence of VK-2019, suggesting that OATP1B3 
mRNA expression was induced. It is not known how the administration of VK-2019 will affect the 
absorption of drugs that are transported by OATP1B3, for example, atorvastatin. See Appendix 2 
for details regarding disallowed medications. 
7.1.5 VK-2019 capsules 
VK-2019 will be provided in capsules containing either 30 mg or 200 mg VK-2019.  
7.1.6 Storage and handling 
VK-2019 is formulated in capsules, in 30 mg and 200 mg per capsule formulations. The capsules 
are packaged in High-Density Polyethylene (HDPE) bottles, with protection from moisture and 
should be handled with care.  
The site Investigator must ensure that all investigational drug supplies are stored in a locked, safe 
area at room temperature (15-25°C) with access limited to authorized study staff.  Investigational 
drug supplies should not be repackaged in any way.  
Once patients are given study treatment, they will be asked to store them away from moisture at 
room temperature. 
7.1.7 Side Effects 
Information on pre-clinical toxicity and updated adverse event information if available are 
presented in the Investigational Drug Brochure. 


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8 
TREATMENT PLAN 
 
Patient Enrollment and Allocation to Treatment 
Each patient will provide informed consent prior to any study related assessments. In some cases, 
procedures performed as standard of care prior to signing consent may be allowed as assessments 
of a patient’s eligibility, e.g., scans performed on a patient’s prior treatment regimen serving as 
baseline scans for this study so long as they will be within the 28-day screening window. 
Upon determination that the patient meets all eligibility criteria, the Investigator or designee will 
enroll the patient according to the procedures described by the Sponsor. Each enrolled patient will 
be assigned a unique subject number by the Sponsor or its designee.  
Recruitment into the study will be conducted in a controlled manner. No patient will be enrolled 
without prior authorization from the Sponsor to ensure adherence with the study design. If a 
patient withdraws from the study, then the subject number cannot be reused, even in cases where 
the patient has withdrawn prior to receiving a dose of VK-2019. Dose level assignment will be 
controlled by the Sponsor. The Investigator and/or designee will receive from the Sponsor 
confirmation of enrollment along with the assigned dose level. Sponsor will notify the other 
sites of slot allocation and will inform sites about the available slots, next possible enrollment 
dates after SRC review, etc. 
Potential patients will NOT receive study drug until the entire enrollment process has been 
completed. 
 
Dosage and Administration 
8.2.1 Availability 
Upon activation, study centers will receive a supply of VK-2019.  Re-supplies of VK-2019 will be 
made at regular intervals during the course of the study based upon need. The Sponsor should be 
contacted for any issues related to drug supplies.  
8.2.2 Preparation and Dispensing 
VK-2019 will be provided in HDPE bottles containing either 30 mg or 200 mg capsules with 
protection from moisture. Patients should be given sufficient supply to last until their next study 
visit or for an entire cycle, depending upon institutional policy and study team discretion. 
VK-2019 must be handled and administered with care. Patients should be instructed to keep their 
medication bottles provided at room temperature in a dry and safe place and not transfer it to any 
other containers. 
8.2.3 Administration and Accountability 
Site personnel must ensure that patients clearly understand the directions for self-medication. 
Patients should record daily administration of each study drug in their patient diaries. If a patient 
misses a dose, they must be instructed not to “make it up” or double the dose on the next day.  
Patient diaries and pill counts by research staff at least once each cycle will be used to determine 
actual dosing. 
If a patient vomits any time after taking a dose, they must be instructed not to “make it up,” but to 
resume subsequent doses the next day as prescribed. 


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On PK days (Tables 4-6), VK-2019 will be administered during the clinic visit to optimally control 
for PK times relative to dosing. On all other days, patients will be instructed to self-administer 
VK-2019 in the morning on an empty stomach with a glass of water at approximately the same time 
each day. Patients must fast for one hour before and two hours after each dose.  
Patients will be instructed to swallow VK-2019 capsules whole and not to chew them prior to 
swallowing. No capsule should be ingested if it is broken, cracked, or otherwise not intact. When a 
patient is required to ingest more than six capsules per daily dose and the patient reports 
difficulties doing so, it is allowable to take the dose in split doses during the morning hours.  
Medication errors are reportable irrespective of the presence of an associated AE/SAE, including: 
• Medication errors involving patient exposure to the product, 
• Potential medication errors or uses outside of what is foreseen in the protocol that do or do 
not involve the participating subject. 
Whether or not the medication error is accompanied by an AE, as determined by the investigator, 
the medication error and, if applicable, any associated AEs are to be captured on an AE CRF page. 


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9 
PATIENT MONITORING, TOXICITY MANAGEMENT, AND DOSE 
MODIFICATIONS 
Each patient will be assessed for the development of any toxicity as outlined in Section 13. Dose 
adjustments will be made according to the system showing the greatest degree of toxicity. The 
table below outlines parameters for dose holds, dose reductions, resuming dosing, and study drug 
discontinuance for AEs assessed to be at least possibly related to VK-2019. 
Table 8: Toxicity Management and Dose Modifications for VK-2019 
Adverse Event  
Action with VK-2019 and Toxicity Management 
All Grade 1 AEs  
Continue VK-2019 at the same dose level. Manage with 
supportive therapy at the Investigator’s judgment. 
All Grade 2 AEs 
Continue VK-2019 at the same dose level. Manage with 
supportive therapy at the Investigator’s judgment. 
All Grade ≥ 3 AEs (unless 
otherwise noted below) 
Hold VK-2019 and administer supportive therapy as 
required in accordance with local practice/guidelines. 
If AE resolves to Grade ≤ 2 within 21 days, VK-2019 may 
be restarted at the same dose (unless meeting criteria for a 
DLT) or a lower dose pending discussion between the 
investigator and Sponsor. 
If AE does not resolve to Grade ≤ 2 after 21 days, 
permanently discontinue VK-2019 and observe the patient 
until the AE is resolved. 
Grade ≥ 2 diarrhea 
Manage with Loperamide (4mg at first onset, followed by 
2mg every 2-4 hours (or with each loose bowel movement) 
until diarrhea free for 12 hours (maximum daily dose: 16 
mg/24 hours). If loperamide is ineffective, consider adding 
Lomotil (5 mg, four times a day), or tincture of opium (15-
20 drops orally every 4 hours), or octreotide (150 to 300 
mcg SQ twice daily). Modifications to this regimen can be 
made per local standard practice. 
Grade ≥ 3 diarrhea 
Hold VK-2019 and manage as above until resolves to Grade 
≤ 2. 
If diarrhea resolves to Grade ≤ 2 within 21 days, VK-2019 
may be restarted at the same dose (unless meeting criteria 
for a DLT) or a lower dose pending discussion between the 
investigator and Sponsor. 
If diarrhea does not resolve to Grade ≤ 2 after 21 days, 
permanently discontinue VK-2019 and observe the 
patient until the AE is resolved. 


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Adverse Event  
Action with VK-2019 and Toxicity Management 
Nausea/vomiting, all grades 
Standard antiemetics for the treatment of nausea and/or 
vomiting may be used. If it has been demonstrated that  
there is significant emetogenic potential based on individual 
and cumulative AE data, prophylactic anti-emetics may be 
used using ASCO guidelines. 
Grade ≥ 3 nausea/vomiting 
Hold VK-2019 and initiate antiemetic medication until 
resolves to Grade ≤ 2. 
If nausea and/or vomiting resolves to Grade ≤ 2 within 21 
days, VK-2019 may be restarted at the same dose (unless 
meeting criteria for a DLT) or a lower dose pending 
discussion between the investigator and Sponsor. 
If nausea and/or vomiting does not resolve to Grade ≤ 2 
after 21 days, permanently discontinue VK-2019 and 
observe the patient until the AE is resolved. 
Grade ≥ 3 mean QTcF 
elongation 
Hold VK-2019 and perform regular ECGs (with repeat in 24 
hours or less, then as clinically indicated) until resolution to 
Grade ≤ 1 or baseline.  
If QTc prolongation does not resolve to Grade ≤ 1 or 
baseline within 21 days, permanently discontinue VK-2019. 
Recurrence of the same Grade 
≥ 3 AE 
Hold VK-2019 and restart at one dose level lower if AE 
resolves to Grade ≤ 2 within 21 days.  
If recurring AE does not resolve to Grade ≤ 2 after 21 days, 
permanently discontinue VK-2019 and observe the patient 
until the AE is resolved. 
 
 


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10 CONCOMITANT TREATMENT 
 Medication(s) or systemic treatments 
All concomitant medications shall be recorded on case report forms. 
No systemic anti-cancer treatment is permitted concurrently with VK-2019, including 
complementary, alternative, herbal, or nutritional supplement-based treatments whose purpose is 
for anti-cancer effect. Supportive agents such as bisphosphonates, denosumab, and RANKL 
inhibitors are permitted. 
 Concomitant Radiotherapy or Surgery 
Focal treatment with either surgery or radiation for non-target lesions to alleviate discomfort is 
permitted after discussion with the study sponsor. For non-emergent, elective major surgical 
procedures, the investigational agent should be held one week before and one week after the 
procedure. G-tube placement or placement of indwelling catheters are not considered major 
surgical procedures. 
 Disallowed medications 
In vitro studies have indicated that VK-2019 is a substrate for OATP1B1 and OATP1B3.   
Dosing of VK-2019 in combination with OATP1B1 or OATP1B3 substrates or inhibitors are not 
permitted during the first two cycles of treatment with VK-2019. See Appendix 2 for a list of 
restricted medications. Use of OATP1B1 or OATP1B3 substrates or inhibitors after Cycle 2 
should be done in consultation with the Sponsor. 
It is not known how the administration of VK-2019 will affect the absorption of drugs that are 
transported by OATP1B3, e.g., atorvastatin, and concomitant use of these drugs should be done 
with caution. 
 


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11 STUDY PROCEDURES AND OBSERVATIONS 
See Tables 1-6 for a complete schedule and descriptions of protocol specified procedures and 
evaluations. 
 Medical and Oncology History 
A detailed medical history will be taken at Screening, including significant, relevant medical history 
within the past 5 years and all cancer related history, including treatment, surgical, and radiation 
history.  
 Physical Exam 
Body systems assessed during physical exams should be performed per institutional practice 
 Lab Assessments 
Table 9:  Assessments by Type and Visit 
Lab Type 
Assessment 
Visits 
Hematology 
CBC with Differential 
All visits (excluding LTFU) 
Chemistry 
Na, K, Cl, CO2, BUN, Cr, 
glucose, Ca, total bili, AST, ALT, 
ALP, albumin, total protein, Mg 
All visits (excluding LTFU) 
Urinalysis 
pH, specific gravity, glucose, 
ketones, blood, protein, nitrates, 
leukocytes 
Screening, D1 of each cycle, 
EOT, and Safety FU 
Coagulation 
PT, PTT, INR 
Screening, D1 of each cycle, 
EOT, and Safety FU 
Pregnancy 
Blood or urine 
EU only: 
Screening, D1 of each cycle, 
EOT, and Safety FU 
All other regions: 
Screening and EOT 
EBV DNA 
EBV DNA in plasma 
Screening, C2D0, C2D0, and 
EOT 
 
 Electrocardiograms  
ECGs using a 12-lead tracing will be collected in triplicate (i.e. three 10-second tracings 
approximately 1 minute apart) and should be performed in the supine position unless collecting 
them in this position is not feasible. A machine with the capacity to calculate standard intervals 
automatically should be used. At each time point, heart rate and PR, R-R, QRS, and QT intervals 
will be calculated.  
 Tumor Assessments 
Response and progression in this study will be evaluated using RECIST 1.1 and its definitions of 
evaluable lesions, response, measurable disease, target lesions, non-target lesions. Tumor 
assessments must be performed using computed tomography (CT), positron emission tomography 
(PET)/CT, or magnetic resonance imaging (MRI). Assessments should include evaluation of the 
neck, chest, abdomen, and pelvis, however, on a case-by-case basis the investigator and Medical 


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Monitor may agree to limit scan volume for a given patient (e.g., due to concern over radiation 
exposure). 
The same modality used at baseline should be used throughout the study. 
 Follow-Up 
11.6.1 Safety Follow-Up 
A safety follow-up visit will be conducted at least 28 days (± 7 days) after the patient’s last dose 
of study drug. 
11.6.2 Long-Term Follow-Up 
All patients that discontinue study treatment will be followed for:  
• 
Survival: Via clinic visit (either at the study site or outside facility), telephone, or 
videotelephony until a) death, b) withdrawal of consent, c) they are lost to follow-up, d) the 
Sponsor notifies sites that survival follow-up is no longer required, or e) termination of study 
by the Sponsor, and 
• 
Assessment of treatment-related SAEs until resolution to baseline or Grade ≤ 1.  
Patients discontinuing treatment due to reasons other than radiographic disease progression will 
have their tumor assessed (using the same modality that was used during study treatment) every 12 
weeks (± 14 days) for up to 2 years after the last treatment visit, or until a) they have progressive 
disease, b) they start a new therapy for their cancer, b) death, c) withdrawal of consent, d) they are 
lost to follow-up, e) the Sponsor notifies sites that tumor assessment is no longer required during 
long-term follow-up, or f) termination of study by the Sponsor.  
 


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12 PHARMACOKINETICS AND PHARMACODYNAMICS 
 PK and Metabolite Profiling Assessments 
Specific visits and timepoints for each PK blood and urine collection are specified in Tables 3-6. 
See the lab manual for PK collection, processing, and shipping instructions. The PK assessments 
during Cycle 1 may be repeated if the PK sampling is missed for any reason or if the PK data 
collected are deemed non-evaluable. 
Timing of sampling may be modified administratively based upon emerging PK data, but the 
number of samples will not increase. 
PK samples used for the determination of VK-2019 concentrations and its metabolites will be 
analyzed by a central laboratory on behalf of the Sponsor, using an appropriate bioanalytical 
method. Full details of the analytical method used will be described in a separate bioanalytical 
report. 
PK samples may be subjected to additional analyses by the Sponsor in order to further investigate 
the presence and/or identity of additional drug metabolites. 
12.1.1 CSF for Analysis of VK-2019 
If a patient undergoes a lumbar puncture while on trial as part of standard of care medical 
evaluation (i.e., not required per protocol), if possible, an additional sample of CSF should be 
collected for exploratory analysis of VK-2019 concentrations. If feasible, an unscheduled plasma 
PK sample should also be collected at approximately the same time. See the lab manual for CSF 
collection, processing, and shipping instructions. 
 Effect of EBNA1 Inhibitor VK-2019 on Plasma EBV DNA 
Specific visits and timepoints for each plasma EBV DNA collection are specified in Tables 4-6. 
Plasma EBV DNA sample analysis will be performed by each participating institution’s clinical 
lab.  
Analysis of plasma EBV DNA will explore whether VK-2019 has any impact of NPC EBV DNA 
shedding into the bloodstream at time points prior to the standard of practice clinical and imaging 
analyses for tumor response.(24) It is possible that early changes in plasma EBV DNA in this 
setting may provide early hints of activity in an individual patient relative to conventional tumor 
response evaluations.  It is also possible that early plasma EBV DNA alterations in initial cohorts 
of patients may reveal evidence of an impact of VK-2019 at lower dose levels than the usual 
clinical parameters used for evaluation of anti-cancer effect and therefore may provide evidence as 
a biomarker for activity in an accelerated time frame. (25) A harmonized assay for plasma EBV 
DNA testing will be utilized in this study and analysis will be performed at a central lab on behalf 
of the Sponsor. 
 Intra-Tumor EBNA1 Activity Inhibition by VK-2019 
During the Phase 2a Dose Expansion, patients may elect to provide biopsies for EBNA1 activity 
alteration associated with VK-2019 administration. Using biopsied material before and after 
treatment from selected patients, DNA will be isolated and quantitative PCR (qPCR) performed on 
collected tissue. Using validated EBV specific primers, GAPDH control primers, and the Namalwa 
cell line (which has 2 EBV copies/cell), EBV genome copy number will be assessed on per cell 
basis.  In addition, RNA will be isolated from biopsied material and Nanostring gene expression 
analysis of viral and cellular genes will be performed. The PanCancer Pathways panel will be used, 


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supplemented with 30 EBV viral genes to assess which pathways are affected by EBNA1 
inhibition. These studies will help to establish proof-of-mechanism of EBNA1 inhibitors for the 
treatment of EBV-positive NPC. 
Biopsy samples may be subjected to additional analyses by the Sponsor in order to further 
investigate the presence and/or identity of additional biomarkers and/or mechanisms of activity. 
 
 


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13 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 Definitions of an AE 
An AE (also known as an adverse experience) is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related.  More 
specifically, an AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any judgment 
about causality. Laboratory values that the investigator determines to be not clinically significant 
should not be considered as AE. Additionally, an adverse event can arise from any use of the drug 
(e.g., off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose. 
For all AEs, the investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to the sponsor or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the AE.  
The investigator is required to assess causality.  Follow-up by the investigator may be required 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator and the 
sponsor concurs with that assessment. 
Any AE assessed by the investigator and/or Sponsor to be serious will be reported by the sponsor 
as an SAE.  To assist in the determination of case seriousness further information may be 
requested from the investigator to provide clarity and understanding of the event in the context of 
the clinical trial. 
 AE Reporting 
All observed or volunteered adverse events regardless of suspected causal relationship to the 
investigational product will be reported as described in the following sections.  For each mandated 
AE evaluation, there may be an AE query form developed to actively query patients and to 
document high priority AEs for collection, based upon preclinical AE data and emerging AE data 
as the study continues. 
All documentation of AEs should include the following elements, further discussed below: 
• 
AE term using the CTCAE v5.0 
• 
AE severity grading using the CTCAE v5.0 
• 
AE seriousness per the below guidance 
• 
AE attribution (causality) per the below guidance 
• 
AE expectedness for all AEs attributed to the investigational agent 
 Reporting Period 
For AEs (including SAEs), the active reporting period to the sponsor or its designated 
representative begins from the time the patient provides informed consent, which is obtained prior 
to the patient’s participation in the study, i.e., prior to undergoing any study-related procedure 
and/or receiving investigational product, until either a) 28 calendar days after the last 
administration of the investigational product, or b) initiation of a new anti-cancer therapy.  Should 
an investigator be made aware of any SAE considered at least possibly related to study drug 
occurring any time after the active reporting period, it must be promptly reported. 


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Worsening of signs and symptoms of the malignancy under study should be reported as AEs in the 
appropriate section of the CRF.  Disease progression assessed by measurement of malignant 
lesions on radiographs or other methods should not be reported as adverse events. 
 Definitions of an Adverse Reaction 
An adverse reaction is defined as any AE caused by the use of a drug. Adverse reactions are a 
subset of all suspected adverse reactions, for which there is reason to conclude that the drug 
caused the event. Examples of adverse reactions include but are not limited to: 
• 
Abnormal test findings; 
• 
Clinically significant symptoms and signs; 
• 
Changes in physical examination findings; 
• 
Hypersensitivity; 
• 
Drug abuse; 
• 
Drug dependency. 
Additionally, they may include the signs or symptoms resulting from: 
• 
Drug overdose; 
• 
Drug withdrawal; 
• 
Drug misuse; 
• 
Drug interactions; 
• 
Exposure during pregnancy; 
• 
Exposure via breastfeeding; 
• 
Medication error. 
 Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be considered 
clinically significant and therefore reported as an AE are as follows: 
• 
Test result is associated with accompanying symptoms, and/or 
• 
Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
• 
Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant drug 
treatment or other therapy, and/or 
• 
Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 


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 Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that: 
• 
Results in death; 
• 
Is life-threatening (immediate risk of death); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity (substantial disruption of 
the ability to conduct normal life functions); 
• 
Results in congenital anomaly/birth defect. 
• 
Other serious (important medical event) 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  
Progression of the malignancy under study is an AE but should not be reported as an SAE unless 
the outcome is fatal or meets other SAE criteria AND occurs within the reporting period defined 
in Section 13.3. In these situations, every effort should be made to report the signs and symptoms 
of progression as the event(s) meeting criteria as an SAE unless otherwise not feasible. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or result 
in death or hospitalization. However, if it is determined that the event may jeopardize the patient 
or may require intervention to prevent one of the other AE outcomes, the important medical event 
should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
 SAE Reporting Requirements 
If an SAE occurs, the sponsor is to be notified within 24 hours of the site investigator or other site 
personnel become aware of the event, using the sponsor’s forms and routes pre-specified in the 
protocol procedures manual. 
In particular, if the SAE is fatal or life-threatening and meets other reporting requirements, 
notification to the sponsor must be made immediately, irrespective of the extent of AE 
information. This timeframe also applies to additional new information (follow-up) on previously 
forwarded SAE reports as well as to the initial and follow-up reporting of exposure during 
pregnancy and exposure via breastfeeding cases. 
For all SAEs, the investigator is obligated to pursue and provide information to the sponsor in 
accordance with the timeframes for reporting specified above. In addition, an investigator may be 
requested by the sponsor to obtain specific additional follow-up information in an expedited 
fashion. In general, this will include a description of the adverse event in sufficient detail to allow 
for a complete medical assessment of the case and independent determination of possible 
causality. 
Information on other possible causes of the event, such as concomitant medication and illnesses 
must be provided. In the case of a patient death, a summary of available autopsy findings must be 
submitted as soon as possible to the sponsor or its designated representative. 


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 Protocol-Specified Serious Adverse Events 
The following expected SAEs will be reported by the investigator as described in previous 
sections, and will be handled as SAEs in the safety database but will not be reported individually 
in an expedited manner to regulatory authorities because they are anticipated to occur in the study 
population: 
• 
Infections or complications from central lines or feeding tubes. 
• 
AEs related to loco-regional or metastatic extension of the disease including central 
nervous system involvement of disease. 
 Hospitalization 
Adverse events associated with hospitalization or prolongations of hospitalization are considered 
serious.  Any initial admission (even if less than 24 hours) to a healthcare facility meets these 
criteria.  Admission also includes transfer within the hospital to an acute/intensive care unit (e.g., 
from the psychiatric wing to a medical floor, medical floor to a coronary care unit, neurological 
floor to a tuberculosis unit): 
Hospitalization does not include the following: 
• 
Rehabilitation facilities; 
• 
Hospice facilities; 
• 
Respite care (e.g., caregiver relief); 
• 
Skilled nursing facilities; 
• 
Nursing homes; 
• 
Emergency room visit that does not result in admission; 
• 
Same day surgeries (as outpatient/same day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical adverse 
event is not in itself a serious adverse event.  Examples include: 
• 
Admission for treatment of a preexisting condition not associated with the development 
of a new adverse event or with a worsening of the preexisting condition (e.g., for work-up 
of persistent pre-treatment lab abnormality); 
• 
Social admission (e.g., patient has no place to sleep); 
• 
Administrative admission (e.g., for yearly physical exam); 
• 
Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol); 
• 
Optional admission not associated with a precipitating clinical adverse event (e.g., for 
elective cosmetic surgery); 
• 
Hospitalization for observation without a medical AE; 
• 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient; 
• 
Admission exclusively for the administration of blood products. 


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Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs.  However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE.  For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE. 
 Severity Assessment 
If required on the adverse event case report forms, the investigator will use the definitions of 
Severity in accordance with CTCAE Version 5.0 to describe the maximum intensity of the adverse 
event.  If the event is serious, the CTCAE grade reported in the adverse event CRF must be 
consistent with the description of CTCAE grade included in the narrative section of the serious 
adverse event report. Event-specific CTCAE grading must be used if available; otherwise the 
general grading system below should be applied.  
Table 10:  CTCAE v5.0 general grading system for adverse events.  See the CTCAE v5.0 for 
AE specific grading. 
Grade 
Clinical Description of Severity 
0 
No change from normal or reference range (This grade is not included in Version 
4.0 document but may be used in certain circumstances.) 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living.* 
3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care Activities 
of Daily Living.** 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Note the distinction between severity and the seriousness of an adverse event.  A severe event is 
not necessarily a serious event.  For example, a headache may be severe (interferes significantly 
with patient’s usual function) but would not be classified as serious unless it met one of the criteria 
for serious adverse events, listed above. 
 Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and non-serious); 
the investigator must record the causal relationship in the CRF, as appropriate, and report such an 
assessment in accordance with the serious adverse reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE.  If the investigator does 


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not know whether or not investigational product caused the event, then the event will be handled 
as “related to investigational product” for IND or other regulatory authority reporting purposes, as 
defined by the sponsor (see Section on Reporting Requirements).  If the investigator’s causality 
assessment is “unknown but not related to investigational product,” this should be clearly 
documented on study records and the SAE report. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse event reporting 
requirements, if applicable. 
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered onto CRFs as either related or unrelated 
to the investigational agent.  All AEs judged to be possibly, probably or definitely related to the 
investigational agent should be assigned the “related” designation. The Investigator will also 
assign attribution for study procedures.   
13.11.1Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  For the purposes of IND safety reporting and 
reporting to other regulatory authorities, “reasonable possibility” indicates that there is evidence to 
suggest a causal relationship between the drug and the adverse event.  A suspected adverse 
reaction implies a lesser degree of certainty about causality than an adverse reaction. 
13.11.2Unexpected 
An AE or suspected adverse reaction is considered unexpected if it is not listed in the IB or 
package insert(s) or is not listed at the specificity or severity that has been observed, or, if an IB is 
not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug but are not specifically mentioned as 
occurring with the particular drug under investigation. 
Except as specified in Section 13.10, AEs that would be anticipated to occur as part of the disease 
process are considered unexpected for the purposes of regulatory authority reporting because they 
would not be listed in the IB.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally not 
be listed as a suspected adverse reaction in the IB. 
Some AEs are listed in the IB as occurring with the same class of drugs, or as anticipated from the 
pharmacological properties of the drug, even though they have not been observed with the drug 
under investigation.  Such events would be considered unexpected until they have been observed 
with the drug under investigation.  For example, although angioedema is anticipated to occur in 
some patients exposed to drugs in the ACE inhibitor class and angioedema would be described in 
the IB as a class effect, the first case of angioedema observed with the drug under investigation 
should be considered unexpected for reporting purposes. 


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 Exposure During Pregnancy 
The definition of exposure during pregnancy (also referred to as in utero) is met if: 
• 
A female becomes, or is found to be, pregnant either while receiving or being exposed to 
(e.g., due to treatment or environmental exposure) or after discontinuing or having been 
directly exposed to the investigational product; 
• 
A male has been exposed to the investigational product prior to or around the time of 
conception and/or is exposed during his partner’s pregnancy. 
If any study patient or study patient’s partner becomes or is found to be pregnant during the study 
patient’s treatment with the investigational product, the investigator must submit this information 
to the sponsor.  In addition, the investigator must submit information regarding environmental 
exposure to the sponsor.  This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the exposure.  The information submitted should include the 
anticipated date of delivery.  The investigator will follow the pregnancy until completion or until 
pregnancy termination.  Further follow-up of birth outcomes will be handled on a case-by-case 
basis. 
 Withdrawal Due to an AE 
Withdrawal due to AE should be distinguished from withdrawal due to insufficient response, 
according to the definition of adverse event noted earlier and recorded on the appropriate adverse 
event CRF page. 
When a patient withdraws due to an SAE, the SAE must be reported in accordance with the 
reporting requirements defined below. 
 Follow-up of AEs 
All adverse events will be followed with appropriate medical management until resolved.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 


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14 DATA ANALYSIS/STATISTICAL METHODS 
As the primary purpose of this study is to evaluate and characterize the safety profile of single 
agent VK-2019, and evaluate preliminary efficacy, no confirmatory inferential analyses are 
planned. Descriptive statistics (such as means, medians, standard deviations and ranges for 
continuous data and percentages for categorical data) will be used to summarize patient 
characteristics, treatment administration/compliance, efficacy, and safety, pharmacodynamic and 
pharmacokinetic parameters. Data will also be displayed graphically where appropriate. 
 Phase 1 Endpoints 
14.1.1 Primary Endpoints 
• 
The frequency, severity, and duration of AEs and DLTs, AEs leading to discontinuation. 
and AEs leading to death. 
14.1.2 Secondary Endpoints 
• 
The rate and severity of treatment emergent AEs at the MTD and BCAD. 
• 
Single dose and steady state plasma pharmacokinetic parameters of VK-2019. 
• 
Incidence of safety laboratory assessment abnormalities 
• 
Incidence of abnormalities in vital signs or other clinical safety assessments 
• 
ORR, DOR, and Disease control rate (DCR) per RECIST v1.1  
• 
Rate of partial or complete plasma EBV-DNA antiviral response during treatment 
(assessed as 3xlog10 reduction or a drop below the lower limit of detection of the assay 
[LLOD], respectively).  
14.1.3 Exploratory Endpoints 
• 
Exploratory analysis of relationships among PK, PD and clinical activity in order to 
preliminarily define BCAD. 
 Phase 2a Endpoints 
14.2.1 Primary Endpoints 
• 
The durable ORR rate as well as ORR, DOR, DCR-6, DCR-12, PFS, rate of survival, and 
OS per RECIST v1.1. 
14.2.2 Secondary Endpoints 
• 
The rate and severity of treatment emergent AEs at the MTD, BCAD, and RP2D. 
• 
Rate of partial or complete plasma EBV-DNA antiviral response during treatment 
(assessed as 3xlog10 reduction or a drop below the lower limit of detection of the assay 
[LLOD], respectively).  
• 
Plasma PK parameters of VK-2019. 
14.2.3 Exploratory Endpoints 
• 
Exploratory PD assay for EBER in situ hybridization levels in baseline and on treatment 
tumor biopsies in a limited number of patients at RP2D.  


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 Sample Size Determination 
The number of patients in the dose escalation phase is estimated to be 30 patients (assuming six 
patients will be dosed in each of five cohorts).  The number of patients in the Phase 1 Dose 
Expansion and Phase 2a Dose Expansion is based on a Simon 2-stage design as described below. 
The approximate sample size in the Phase 1 Dose Expansion is estimated to be 20 patients 
(assuming 10 additional patients in each of two expanded dose levels). During the Phase 2a 
portion of the trial, the approximate sample size in the Phase 2a Dose Expansions is estimated to 
be 18 (assuming 9 patients in each of two expansion cohorts).  In total, it is estimated that up to 
approximately 68 patients will be dosed in this trial.  
The number of patients for the Phase 1 and 2a expansions is based upon a Simon Two-Stage 
design at BCAD and MTD, respectively. The null hypothesis that the true response rate is 0.1 will 
be tested against a one-sided alternative. In the first stage (i.e., a Phase 1 Dose Expansion cohort), 
a total of 16 patients will be accrued. If there is one or fewer responses in these 16 patients, 
accrual to this cohort will be stopped. Otherwise, 9 additional patients will be accrued (i.e., a 
Phase 2a Dose Expansion cohort) for a total of 25. The null hypothesis will be rejected if five or 
more responses are observed in 25 patients. This design yields a 1-sided type I error rate of 10% 
and power of 90% when the true response rate is 30%. This design yields a probability of 0.51 for 
a cohort stopping early if the true response rate for that cohort is 10%.The sample size in the dose 
escalation phase is not based on statistical considerations, but rather depends on the number of 
observed toxicities; up to 6 subjects are expected to be treated after the accelerated titration design 
has ended at each conventional escalation cohort dose prior to the expansion cohort at MTD.  
 Populations for Analyses 
• All Enrolled Subjects: All subjects who sign informed consent form and were confirmed 
eligible and assigned to a treatment cohort. 
• All Treated Subjects: All subjects who receive at least one dose of VK-2019. 
• PK Subjects: All subjects who receive at least one dose of study medication and have 
available VK-2019 plasma concentration data. 
• Response Evaluable Subjects: All treated subjects with measurable disease at baseline 
and one of the following: 1) at least one post-dose tumor assessment, 2) discontinuation 
prior to the first efficacy assessment due to clinical disease progression or toxicity or 
3) death either on treatment or within 28 days of last VK-2019 dose. 
• EBV DNA Subjects: All subjects who receive at least one dose of study medication and 
have available biomarker data. 
 Endpoint Analysis 
14.5.1 Analysis of Safety Endpoints 
Safety objectives in this study will be assessed using the following endpoints in the All Treated 
population: 
• Incidence of adverse events, SAEs, adverse events meeting protocol-defined DLT 
criteria, severe adverse events, adverse events leading to study treatment or study 
discontinuation, and adverse events resulting in death.  


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• Incidence of clinical laboratory test abnormalities including hematology and serum 
chemistry abnormalities assessed at protocol designated time points 
• Changes in vital signs relative to baseline include blood pressure and heart rate measured 
at protocol designated time points 
Adverse Events 
All adverse events will be listed, including the verbatim description and MedDRA preferred term 
and system organ class (SOC).  
Treatment emergent adverse events (TEAEs) are defined as those occurring after the first dose of 
study treatment. 
TEAEs will be summarized by SOC and by preferred term. The incidence of TEAEs will be based 
on the numbers and percentages of patients with events and number of events. TEAEs will be 
further summarized by severity (according to NCI CTCAE Version 5.0) and relationship to study 
treatment.  
An overall summary of adverse event incidence will also be presented by dose level to include the 
number and percentage of patients with at least one: TEAE, treatment related TEAE, Grade 3 to 
Grade 5 TEAE, death, SAE, treatment related SAE, DLT, TEAE leading to study treatment 
discontinuation, TEAE leading to dose modifications (e.g. dose reduction) and TEAE leading to 
study discontinuation. 
TEAE data will be presented across all cycles and for each cycle.  The denominator for each cycle 
will be the number of patients available at the start of the cycle who received at least 1 dose of 
study drug for that cycle.  
Individual patient listings will be prepared for all AE data.  Listing of the first cycle DLTs for each 
cohort within each phase will be provided.  
Laboratory Safety Tests 
Severity grading, using NCI CTCAE Version 5.0, will be assigned to laboratory safety values 
where applicable. Laboratory results in reported units and standard international units will be 
listed, including high and low flags, NCI CTCAE grades where applicable, the corresponding 
normal range and clinical significance. 
Laboratory safety tests summaries will be based on results in SI units. Absolute and change from 
baseline results will be summarized using descriptive statistics.  
Treatment emergent out of range results with the corresponding NCI CTCAE grade, normal 
ranges, baseline results and clinical significance will be separately listed. Shift tables will be used 
to show changes from baseline at each timepoint and the worst change in CTCAE grade for each 
patient.   
Vital Signs and 12-lead ECGs 
Absolute and change from baseline vital sign and 12-lead ECG results will be summarized using 
descriptive statistics. QT analysis intervals will be corrected for heart rate using the Fridericia 
correction (QTcF). Study conclusions will be based on the most appropriate correction method for 
the analysis. The effect of VK 2019 concentration on QTcF will be explored after dosing and will 
be baseline corrected for each patient. 


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14.5.2 Analysis of Efficacy Endpoints 
The Response Evaluable population will be used for all efficacy endpoints with the exception of 
OS and rate of survival which will use the All Treated population. 
The following endpoints will be summarized by dose level and across the Phase 1 and 2a Dose 
Expansions cohorts for selected doses. 
Durable ORR: 
The number and percentage of patients who achieve either a complete 
or partial response that is maintained for at least 6 months. 
ORR:  
The number and percentage of patients whose best overall response 
(BOR) is either a complete response (CR) or partial response (PR).  
To qualify as a responder a patient must have a complete or partial 
visit response confirmed by a second scan performed at least 4 weeks 
after the criteria for response are first met. 
DOR:  
Duration of response (applicable only to patients whose BOR is CR or 
PR) is defined as the time interval between the date of the earliest 
qualifying response (complete response or partial response) and the 
date of disease progression or death for any cause, whichever occurs 
earlier.  
DCR-6 and DCR-12:  
The number and percentage of patients who either achieve a best 
response of either complete response, partial response confirmed by a 
second scan performed at least 4 weeks later or have stable disease 6 
and 12 months after dosing respectively 
PFS: 
Defined as the interval between the day of the first dose of study 
treatment to the first documentation of disease progression or death, 
whichever occurs earlier.   Censoring rules will be defined in the 
Statistical Analysis Plan. 
OS: 
Defined as the interval between the day of the first dose of study 
treatment until the date of death because of any cause. Patients who 
discontinue the study will be censored at the date of their final study 
visit. 
OS-6 and OS-12:  
Kaplan-Meier estimates of the proportion of patients alive at 6 and 12 
month after the first dose of study treatment respectively using the OS 
endpoint. 
The number and percentage of patients with Durable ORR, ORR, DCR-6 and DCR-12 will be 
summarized together with exact 95% confidence intervals using a binomial distribution. A 
Kaplan-Meier method will be used to summarize PFS and OS, from which median values will be 
presented if reached. Additionally, a Kaplan-Meier method will be used to estimate OS-6 and OS-
12.  
 Patient Characteristics and Disposition 
All enrolled patients who receive at least one dose of any study medication will be included in the 
listings and summaries of demographic characteristics, study drug administration and disposition. 


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Demographic characteristics such as patient age, gender, height, weight, ethnicity, prior therapy, 
medications, medical history, ECOG performance status and signs and symptoms will be 
tabulated. 
An accounting of the study patients will be tabulated.  Patients not meeting the eligibility criteria 
will be identified.  Patients not completing the study will be listed along with the reason for their 
premature discontinuation.  Reasons for premature discontinuation will be summarized. 
Study drug administration will be described in terms of the total number of cycles administered, 
the median (range) of cycles administered, dose intensity, and reasons for deviations from planned 
therapy. 
All medications received during the treatment period will be considered as concomitant 
medications; patients who received concomitant medications will be listed. 
 Pharmacokinetic Analysis 
14.7.1 Single- and Multiple-Dose VK-2019 PK Analysis 
The PK concentration population is defined as all enrolled patients treated who have at least one 
concentration evaluation. The PK parameter analysis population is defined as all enrolled patients 
treated who have at least one of the PK parameters of interest. 
Standard plasma pharmacokinetic parameters including the maximum plasma concentration 
(Cmax), time to maximum plasma concentration (Tmax), and area under the plasma concentration 
versus time curve (AUC) for VK-2019 and metabolites will be estimated using 
non-compartmental analysis. If data permit or if considered appropriate, minimum plasma 
concentration (Cmin), area under the plasma concentration versus time curve to infinity (AUCinf) 
terminal elimination half-life (t1/2), oral plasma clearance (CL/F), apparent volume of distribution 
(Vd/F), accumulation ratio (Rac) will be estimated. If data permit renal clearance (CLR), 
cumulative amount recovered unchanged in the urine up to 24 hours post-dose (AE24), and 
cumulative amount recovered unchanged in the urine up to 24 hours post-dose expressed as a 
fraction of administered dose (AE24%) will be also estimated. In the event of improper urine 
collection, the cumulative amount recovered unchanged in the urine up to 8 hours post dose (AE8) 
will be explored. The relative systemic exposure to VK-2019 for the metabolites will also be 
assessed based on AUC.  Descriptive statistics will be provided for these PK parameters in tabular 
form (N, mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV) by 
dose, cycle, and day. 
For VK-2019 concentrations, individual values and descriptive statistics (N, mean, SD, CV, 
median, minimum, maximum, geometric mean and its associated CV) will be presented by dose, 
cycle, day of assessment, and nominal time in tabular form.  Individual patient and median 
profiles of the concentration-time data will be plotted by dose, cycle, and day using nominal times.  
Median profiles will be presented on both linear-linear and log-linear scales. 
Dose normalized VK-2019 AUC and Cmax will be plotted against dose (using a logarithmic 
scale) by cycle and day. These plots will include individual patient values and the geometric 
means for each dose. The observed accumulation ratio for VK-2019 and the linearity ratio will be 
summarized descriptively. The means and 90% confidence intervals (CIs) obtained from the 
model will be back-transformed to provide means and 90% CI for the accumulation and linearity 
ratios for each dose. 


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The attainment of steady-state for VK-2019 will be assessed by visual inspection of the pre-dose 
concentrations on Cycle 1 Day 14 and Cycle 2 Day 0. 
14.7.2 PK/PD Modeling 
Pharmacokinetic/pharmacodynamic modeling may be attempted to investigate any causal 
relationship between VK-2019 exposure and biomarkers or significant safety endpoints. The 
results of these analyses, if performed, may be reported separately. 
 Pharmacodynamic EBV DNA  
Summaries of change from baseline to treatment to post-treatment levels of cell-free plasma EBV 
DNA will be provided, as appropriate. Individual values and descriptive statistics (N, mean, SD, 
minimum, maximum, geometric mean and its associated CV) will be presented by dose and cycle 
in tabular form.  The rate of partial response (a reduction by 3xlog10 or more) or complete 
response (reduction below the LLOD of the assay) will be computed as well.  
 Pharmacodynamic EBNA1 inhibition. 
Using biopsied material before and after treatment from selected patients, DNA will be isolated 
and quantitative PCR (qPCR) will be performed. Using validated EBV specific primers, GAPDH 
control primers, and the Namalwa cell line (which has 2 EBV copies/cell), EBV genome copy 
number per cell will be assessed. In addition, RNA will be isolated from biopsied material and 
Nanostring gene expression analysis of viral and cellular genes will be performed. A PanCancer 
Pathways panel will be used, supplemented with 30 EBV viral genes to assess which pathways are 
affected by EBNA1 inhibition.  These studies will allow us to establish proof-of-mechanism of 
EBNA1 inhibitors for the treatment of EBV-positive NPC. Individual values and descriptive 
statistics (N, mean, SD, minimum, maximum, geometric mean and its associated CV) will be 
presented in tabular form. 
 Interim Analysis 
For each dose level expanded, an interim analysis of efficacy will be performed after 16 
patients have been dosed. If one or fewer patients have a BOR of CR or PR (not necessarily 
confirmed 4 weeks later) accrual to this cohort will be stopped.   


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15 STUDY MANAGEMENT 
 Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigators will have written and dated approval from the 
Institutional Review Boards for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol related 
procedures are performed on any subjects. 
The clinical investigation will not begin until either FDA has determined that the study under the 
IND is allowed to proceed.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
 Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants must 
sign the IRB/IEC-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
Documentation of participant signature may be made by facsimile copy or other electronic 
transmission such as electronic photograph of signed consent document.  A high-resolution scan 
or photograph of a signed consent is considered adequate documentation.  The original signed 
copy of the consent (or scanned/ photographic copy thereof) document must be retained in the 
medical record or research file. 
 Changes in the Protocol 
Once the protocol has been approved by the IRB/IEC, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be approved by each site’s 
IRB/IEC prior to implementation at that site. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB/IEC approval.  In this circumstance, however, the 
Investigator must then notify the IRB/IEC at each site in writing within five (5) working days after 
implementation.  The study sponsor and the study team will be responsible for updating any 
participating sites. 
 Handling and Documentation of Clinical Supplies 
The Principal Investigator and each participating site will maintain complete records showing the 
receipt, dispensation, return, or other disposition of all investigational drugs.  The date, quantity 
and batch or code number of the drug, and the identification of patients to whom study drug has 
been dispensed by patient number and initials will be included.   


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The Investigators shall not make the investigational drug available to any individuals other than to 
qualified study patients.  Furthermore, the investigators will not allow the investigational drug to 
be used in any manner other than that specified in this protocol. 
 Case Report Forms (CRFs) 
The Principal Investigator at each site and/or his/her designee, will prepare and maintain adequate 
and accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into the clinical trial database via 
standardized CRFs (paper or secure electronic) in accordance with the study calendar. The 
investigator’s designee at each site will complete the CRFs as soon as possible upon completion of 
the study visit. 
The information collected on CRFs shall be consistent with the original source documents.  Source 
documents will be found in the patient’s medical records maintained by site personnel.  In 
accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs at their site.  Each site PI will 
approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate. 
All source documentation and data will be available for review/monitoring by the sponsor and 
regulatory agencies.  A high-resolution scan or photograph of signed CRFs is considered adequate 
documentation and the official EMR is considered adequate primary source documentation. Not 
all EMR source documentation need be reproduced within separate clinical trials study materials 
in paper form.  Storage of locked PDF documents is an acceptable alternative to paper copies of 
protocol related documents, including consent forms and data from the EMR.  
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the database 
will be locked.  Any changes to the data entered into the CRFs after that time can only be made by 
joint written agreement among the PI, the Trial Statistician, and the Sponsor. 
 Study Monitoring  
During the course of the trial, a monitor appointed by the Sponsor will make site visits to review 
protocol compliance, compare CRFs and individual patient’s medical records, assess drug 
accountability, and ensure that the trial is being conducted according to pertinent regulatory 
requirements. CRF entries will be verified with source documentation. The review of medical 
records will be performed in a manner to ensure that patient confidentiality is maintained. 
 Inspection and Retention of Records 
Cullinan Apollo or a Cullinan Apollo representative, a regulatory authority, an IRB or IEC may 
visit the clinical site to perform audits or inspections, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 
guidelines of the International Conference on Harmonization, and any applicable regulatory 
requirements. Direct access to source data will be required for these audits and inspections; they 
will be carried out giving due consideration to data protection and medical confidentiality. The PI 


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or designee is responsible for providing necessary support at all times. The PI or designee should 
contact Cullinan or designee immediately if contacted by a regulatory agency about an inspection. 
According to ICH guidelines, the PI must maintain all documentation relating to the study for a 
period of 2 years after the last marketing application approval and until there are no pending or 
contemplated marketing applications in an ICH region or for at least 2 years following the 
discontinuation of clinical development of the investigational product. These documents should be 
retained for a longer period if required by applicable legal requirements. 
 Quality Control and Quality Assurance 
The Sponsor or designee will conduct a site visit to verify the qualifications of each PI and 
designee, inspect the site facilities, and inform the PI of responsibilities and the procedures for 
ensuring adequate and correct documentation.  
The CRFs for each patient will be checked against source documents at the clinical site by the 
monitor (Source Data Verification [SDV]).  
In the case of electronic CRFs, the site monitor can also review CRFs remotely at any time during 
the trial and generate queries for site resolution prior to the site monitoring visit.  
Instances of missing or uninterpretable data will be queried by the site monitor for site resolution.  
The data management plan, to be developed during the initiation of the trial, will include 
specifications for consistency and plausibility checks on data. CRF completion guidelines will also 
be developed and include data entry instructions for the site. Queries raised during data 
management review of SDV data will be generated for site resolution with the PI or designee. The 
site will either update the CRF if original data is incorrect or will provide a confirmation that the 
data is correct. Data Management can also review data and generate queries prior to SDV to 
expedite data clean-up. The site can then update the CRF if needed and the site monitor will verify 
the update during SDV.  


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16 REFERENCES 
1. 
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Lee AW, Lau WH, Tung SY, Chua DT, Chappell R, Xu L, Siu L, Sze WM, Leung TW, 
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JT, Hong Kong Nasopharyngeal Cancer Study G.  Preliminary results of a randomized study 
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Wu S, Lian Y, Yang Q, Zhao C.  Gemcitabine plus cisplatin versus fluorouracil plus 
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10.1016/S0140-6736(16)31388-5.  PubMed PMID:  27567279. 
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Raghupathy R, Hui EP, Chan AT.  Epstein-Barr virus as a paradigm in nasopharyngeal 
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Henle G, Henle W.  Epstein-Barr virus-specific IgA serum antibodies as an outstanding 
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Frappier L.  EBNA1.  Current topics in microbiology and immunology.  2015;391:3-34.  
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Mohammad R, Kumita W, Mizuguchi H, Hayakawa T, Nakamura H, Taguchi T, Wakiguchi 
H, Imai S.  Eradication of Epstein-Barr virus episome and associated inhibition of infected 
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Yin Q, Flemington EK.  siRNAs against the Epstein Barr virus latency replication factor, 
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11. 
Yasuda A, Noguchi K, Minoshima M, Kashiwazaki G, Kanda T, Katayama K, Mitsuhashi J, 
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Noh KW, Park J, Kang MS.  Targeted disruption of EBNA1 in EBV-infected cells 
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14. 
Chan KC, Lo YM.  Circulating EBV DNA as a tumor marker for nasopharyngeal 
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Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, Knippers R.  DNA 
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Lo YM, Chan LY, Chan AT, Leung SF, Lo KW, Zhang J, Lee JC, Hjelm NM, Johnson PJ, 
Huang DP.  Quantitative and temporal correlation between circulating cell-free Epstein-Barr 
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1999;59(21):5452-5.  PubMed PMID:  10554016. 
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Lo YM, Chan AT, Chan LY, Leung SF, Lam CW, Huang DP, Johnson PJ.  Molecular 
prognostication of nasopharyngeal carcinoma by quantitative analysis of circulating 
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20. 
Lin JC, Jan JS, Hsu CY, Jiang RS, Wang WY.  Outpatient weekly neoadjuvant 
chemotherapy followed by radiotherapy for advanced nasopharyngeal carcinoma:  high 
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Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC.  Accelerated 
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22. 
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of 
pediatric phase I trials: the rolling six design. J Clin Oncol. 2008;26(2):190–19. PubMed 
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23. 
Horstmann E, McCabe MS, Grochow L, Yamamoto S, Rubinstein L, Budd T, Shoemaker D, 
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24. 
Kim KY, Le QT, Yom SS, Pinsky BA, Bratman SV, Ng RH, El Mubarak HS, Chan KC, 
Sander M, Conley BA.  Current State of PCR-Based Epstein-Barr Virus DNA Testing for 
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10.1093/jnci/djx007.  PubMed PMID:  28376165. 
25. 
Le QT, Zhang Q, Cao H, Cheng AJ, Pinsky BA, Hong RL, Chang JT, Wang CW, Tsao KC, 
Lo YD, Lee N, Ang KK, Chan AT, Chan KC.  An international collaboration to harmonize 
the quantitative plasma Epstein-Barr virus DNA assay for future biomarker-guided trials in 
nasopharyngeal carcinoma.  Clin Cancer Res.  2013;19(8):2208-15.  Epub 2013/03/06.  doi:  
10.1158/1078-0432.CCR-12-3702.  PubMed PMID:  23459720; PMCID:  PMC3630245. 
 
 
 


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17 APPENDICES 
 Appendix 1 - Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance without 
restriction 
100 
Normal, no complaints, no evidence of 
disease 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work) 
80 
Normal activity with effort; some signs 
or symptoms of disease 
 
70 
 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs 
50 
Requires considerable assistance and 
frequent medical care 
 
3 
 
In bed > 50% of the time 
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden Completely 
disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
 
 
 
 


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Version 9.0, 15-October-2019 
Confidential 
 
Page 79 of 81 
 Appendix 2 - Prohibited Medications During Treatment Cycle 1 and 2 
 
Aosetron: 
lotronex 
Bosentan: 
Tracleer  
Candesartan: 
Atacand  
Celecoxib: 
Celebrex 
Diclofnac: 
Volaren 
Dronabinol: 
Marinol 
Flubiprofen: 
Ansaid 
Fluvastatin: 
Lescol  
Glimepiride: 
Amaryl  
Ibuprofen: 
Advil, Motrin  
Indomethacin: Indocin  
Irbesartan: 
Avapro 
Losartan: 
Cozaar 
Meloxicam: 
Mobic  
Montelukast: 
Singulair  
Naproxen: 
Aleve 
Nateglinide: 
Starlix Phenobarbital  
Phenytoin: 
Dilantin 
Piroxicam: 
Feldene  
Rosiglitazone: Avandia  
Rosuvastatin: 
Crestor Sulfmethoxazole Tolbutamide 
Torsemide: 
Demadex 
Valsartan: 
Diovan 
Warfarin: 
Coumadin 
 
NOTE:  This list contains common drugs and is not all-inclusive. The study team should check a 
frequently-updated medical reference for a list of drugs to avoid or minimize use of OATP1B3 substrate 
prohibited medications.  
 
 


Cullinan Apollo Corp  
 
 
 
 
 
Protocol VK-2019-001  
 
 
 
 
 
Version 9.0, 15-October-2019 
Confidential 
 
Page 80 of 81 
 Appendix 3 - Effectiveness of family planning methods 
 
https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/contraceptive_methods_508.pdf 


Cullinan Apollo Corp  
 
 
 
 
 
Protocol VK-2019-001  
 
 
 
 
 
Version 9.0, 15-October-2019 
Confidential 
 
Page 81 of 81 
 

SAP_001.pdf: 
ABBREVIATED STATISTICAL ANALYSIS PLAN 
 
 
PHASE 1/2A OPEN-LABEL, MULTICENTER CLINICAL TRIAL OF A NOVEL SMALL 
MOLECULE EBNA1 INHIBITOR, VK-2019, IN PATIENTS WITH EPSTEIN-BARR 
VIRUS POSITIVE NASOPHARYNGEAL CANCER, WITH PHARMACOKINETIC AND 
PHARMACODYNAMIC CORRELATIVE STUDIES 
 
 
 
SAP Version 1.0 
FINAL 
Date: 12November2020 
 
for 
 
Protocol No. VK-2019-001 
 
 
Submitted to: 
Cullinan-Apollo Corp. 
1 Main Street, Suite 520 
Cambridge, MA 02142 
USA 
+1 617-425-9200 
 
 
 
 
Prepared by: 
ICON Clinical Research, LLC 
 
 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
2 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
BCAD 
Biologically or Clinically Active Dose 
BOR 
Best Overall Response 
CI 
Confidence Interval 
CR 
Complete Response 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
EBNA1 
Epstein-Barr Nuclear Antigen 1 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
h or hr 
Hour 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
Mg 
Milligram 
MTD 
Maximum tolerated dose 
NPC 
Nasopharyngeal Carcinoma 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PCR 
Polymerase Chain Reaction 
PFS 
Progression Free Survival 
PD 
Progressive Disease or Pharmacodynamics 
PK 
Pharmacokinetics 
PR 
Partial Response 
QD 
Once Daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
TEAEs 
Treatment Emergent Adverse Events 
 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
3 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
1 BACKGROUND ........................................................................................................................5 
2 STUDY DESCRIPTION ............................................................................................................5 
2.1 
Study Design .................................................................................................................5 
2.1.1 
Phase 1 Dose Escalation .....................................................................................6 
2.1.2 
Phase 1 Dose Expansion .....................................................................................7 
2.1.3 
Phase 2a Dose Expansion ...................................................................................7 
2.2 
Treatment Assignment ..................................................................................................7 
2.2.1 
Definition of a Completed Cohort and an Evaluable Patient .............................7 
2.2.2 
Dose Escalation in Accelerated Titration Cohorts .............................................7 
2.2.3 
Dose Escalation in Rolling Six Cohorts ..............................................................8 
2.2.4 
Intra-Patient Dose Escalation in Accelerated Titration Cohorts .......................9 
2.2.5 
Intra-Patient Dose Escalation in Rolling Six Cohorts ......................................10 
2.3 
Blinding and Unblinding ............................................................................................10 
2.4 
Protocol Amendments ................................................................................................10 
3 OBJECTIVES ...........................................................................................................................10 
3.1 
Primary .......................................................................................................................10 
3.2 
Secondary ...................................................................................................................11 
3.3 
Exploratory .................................................................................................................11 
4 ENDPOINTS ............................................................................................................................12 
4.1 
Primary Endpoints ......................................................................................................12 
4.2 
Secondary Endpoints ..................................................................................................12 
4.3 
Exploratory Endpoints ................................................................................................13 
5 SAMPLE SIZE AND POWER .................................................................................................13 
6 STUDY PERIODS, DOSAGE AND ADMINISTRATION ....................................................14 
6.1 
Study Periods ..............................................................................................................14 
6.1.1 
Safety Follow-Up ..............................................................................................14 
6.1.2 
Long-Term Follow-Up ......................................................................................14 
6.2 
Dosage and Administration ........................................................................................14 
7 STATISTICAL ANALYSES ...................................................................................................15 
7.1 
General Methods .........................................................................................................15 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
4 
7.2 
Handling of Dropouts or Missing Data ......................................................................15 
7.2.1 
Handling of Incomplete Dates for Adverse Events ...........................................15 
7.2.2 
Handling Missing or Partial Prior and Concomitant Medication Dates .........16 
7.3 
Study Population .........................................................................................................16 
7.4 
Subject Accountability ................................................................................................17 
7.5 
Protocol Deviation Reporting .....................................................................................17 
7.6 
Demographics Characteristics ....................................................................................17 
7.7 
Medical and Surgical History .....................................................................................17 
7.8 
Prior and Concomitant Medications ...........................................................................17 
7.9 
Extent of Exposure .....................................................................................................18 
7.10 
Analysis of Pharmacokinetic Data ..............................................................................18 
7.11 
Pharmacodynamic EBV DNA ....................................................................................19 
7.12 
Pharmacodynamic EBNA1 inhibition ........................................................................19 
7.13 
Efficacy .......................................................................................................................19 
7.14 
Safety ..........................................................................................................................19 
7.14.1 
Adverse Events ..................................................................................................19 
7.14.2 
Clinical Laboratory Assessments ......................................................................20 
7.14.3 
Vital Signs .........................................................................................................20 
7.14.4 
Electrocardiograms ..........................................................................................20 
7.14.5 
Physical Examinations ......................................................................................21 
7.14.6 
ECOG ................................................................................................................21 
7.14.7 
Pregnancy Testing .............................................................................................21 
7.15 
Interim Analysis ..........................................................................................................21 
7.16 
General Conventions for Tables, Listings and Figures ..............................................22 
8 DOCUMENT HISTORY ..........................................................................................................23 
9 REFERENCES ..........................................................................................................................24 
 
 
 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
5 
 
1 
BACKGROUND 
This is a phase 1/2a, open label, multicenter, multi dose, dose escalation trial of VK-2019, a potent 
and selective inhibitor of the EBV latency program through its specific binding to a viral target, 
EBNA1, in patients with Epstein Barr Virus positive nasopharyngeal cancer, with pharmacokinetic 
(PK), and pharmacodynamics (PD) correlative studies. 
This statistical analysis plan (SAP) is for the abbreviated CSR of study VK-2019-001 and is based 
on the approved clinical study protocol, 15 October 2019, Version 9.0, Amendment 9.  
The purpose of this document is to provide details about the statistical analysis methods for the 
VK-2019-001 protocol “Phase 1/2a open label, multicenter clinical trial of a novel small molecule 
EBNA1 inhibitor, VK-2019, in patients with Epstein Barr Virus positive nasopharyngeal cancer, 
with pharmacokinetic and pharmacodynamic correlative studies”. 
For background of study refer to Protocol Section 2 Background. 
 
2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is a phase 1/2a, open label, multicenter, multi dose, dose escalation trial of VK-2019, a potent 
and selective inhibitor of the EBV latency program through its specific binding to a viral target, 
EBNA1.  
For each patient enrolled, the study will consist of at least three periods:  Screening (up to 28 days), 
Treatment (comprised of 28-day dosing cycles), and Follow up (comprised of a safety follow-up 
and long-term follow-up for survival status).  
This trial is divided into three parts (Figure 1): Phase 1 Dose Escalation, Phase 1 Dose Expansion, 
and Phase 2a Dose Expansion. One sub-study, collecting tumor biopsies, will be conducted during 
the Phase 2 Expansion part of the trial.  
 
 
 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
6 
Figure 1: Study Design Schema 
 
2.1.1 Phase 1 Dose Escalation  
Dose escalation in this trial will be conducted utilizing both an accelerated titration, based in part 
upon a 3B design proposed by Simon et al (1), coupled with a “rolling six” design (2).  Five dose 
escalation cohorts are planned, but additional dose escalation or intermediate de-escalation cohorts 
may be explored based upon emerging safety and/or PK data. 
By utilizing these designs it is expected to maximize accrual at pharmacologically relevant doses, 
both by potentially minimizing accrual at subtherapeutic dose levels and more efficiently 
establishing an understanding of the safety profile of VK-2019 (3).  
Cohort 1 (60 mg)
Cohort 2 (TBD mg)
Cohort 3 (TBD mg)
Cohort 4 (TBD mg)
Cohort 5 (TBD mg)
Cohort X (TBD mg)
Phase 1
Dose Escalation
Escalating doses will be 
enrolled until the MTD is 
reached
Dose Expansion
Multiple dose escalation 
cohorts may be expanded 
based upon biological/clinical 
activity or at the MTD
Phase 2a
Phase 2 Expansion A
Phase 2 Expansion B
Dose Expansion
Multiple Phase 1 expansions 
may be further expanded 
into Phase 2a cohorts based 
upon efficacy
Phase 1 Expansion A
Phase 1 Expansion B
Phase 1 Expansion C
Note: Three Phase 1 and two Phase 2 dose expansions are not specifically planned. The total number of expansions 
opened will depend upon biological and clinical activity observed in the trial
1-6 Patients/Cohort
9 Patients/Cohort
16 Patients/Cohort


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
7 
Dose escalation will initially proceed according to the accelerated titration design, enrolling one 
new patient per dose level. Upon any instance of a VK-2019 related Grade ≥ 2 AE during Cycle 1, 
dose escalation will convert to the Rolling Six design in which 3-6 patients per dose level will be 
enrolled. 
2.1.2 Phase 1 Dose Expansion 
During dose escalation, one or more cohorts may be selected for expansion, enrolling up to 16 
patients (inclusive of the patients already enrolled at the same dose during escalation) at any dose 
level that is assessed to either be the MTD or have sufficient activity to meet criteria as a BCAD.  
2.1.3 Phase 2a Dose Expansion 
Further dose expansion in the Phase 2a part of the trial may be explored by utilizing the Simon 2 
Stage design. Up to an additional nine patients may be enrolled at a particular dose if two or more 
objective responses (at least one must be confirmed) are observed out of 16 patients at that dose in 
the Phase 1 part of the trial (for a total accrual of up to 25 patients). See Protocol Section 6 for 
details on initiating a Phase 2a Dose Expansion. 
2.2 
Treatment Assignment 
The starting dose for VK-2019 is 60 mg QD. Sample dose escalation tables are below in Table 1, 
detailing a sample dose escalation schema based upon when escalation converts from Accelerated 
Titration to a Rolling Six design.  
2.2.1 Definition of a Completed Cohort and an Evaluable Patient 
Each dose escalation cohort will consist of either:  
• 
1 evaluable patient (Accelerated Titration cohorts), or 
• 
3-6 evaluable patients (Rolling Six cohorts)  
To be considered evaluable, a patient will have and one of the following: 
• 
Received 75% of doses during Cycle 1, or, 
• 
Received at least one dose of VK-2019 and experienced a DLT during Cycle 1 
2.2.2 Dose Escalation in Accelerated Titration Cohorts 
Upon completion of an accelerated titration cohort (Figure 2): 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
8 
• 
IF: No VK-2019 related Grade ≥ 2 AEs occur during Cycle 1; THEN: Dose escalation 
may proceed to the next accelerated titration cohort (no greater than a 100% dose 
increase). 
• 
IF: The patient experiences any VK-2019 related Grade ≥ 2 AE during Cycle 1 (not 
meeting the definition of a DLT); THEN: Convert the current cohort to the Rolling Six 
design, and enroll an additional 2-5 patients (3-6 total).  
• 
IF: The patient experiences a DLT;THEN: Convert to the Rolling Six design and enroll 
an additional five patients (six total).  
Figure 2: Accelerated Titration Dose Escalation Schema 
  
 
2.2.3 Dose Escalation in Rolling Six Cohorts 
Upon completion of a Rolling Six cohort (a minimum of three, maximum of six evaluable 
patients), if: 
• 
0 of 3 patients experience a DLT; dose escalation may proceed to the next cohort (no 
greater than a 50% dose increase) 
• 
1 of 3 patients experience a DLT; an additional three evaluable patients will be enrolled 
into the cohort  
• 
≤1 of 6 patients experience a DLT; dose escalation may proceed to the next cohort (no 
greater than a 50% dose increase) 
1) No Gr ≥ 2 related AEs
Dose 
escalate 
by 100%
Convert to Rolling 
Six design
3) Any Gr ≥ 2 related AE 
that is not a DLT
Enroll 1 pt
Enroll an 2-5 add’l
pts @ the same 
dose level
Enroll 1 pt
4) A DLT
Convert to Rolling 
Six Design
Enroll 5 add’l pts 
@ the same dose 
level
During Cycle 1, if the patient 
experiences:


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
9 
• 
≥ 2 patients experience a DLT; the MTD has been exceeded and further enrollment into 
that cohort will cease. Lower-dose cohorts may then be explored until the MTD has 
been determined, including intermediate doses. 
Table 1: Sample Dose Escalation Tables 
Dose Escalation Schema 
Target Dose / Actual Dose 
Dose Increase 
All cohorts enrolled using Accelerated 
Titration 
60 mg / 60 mg 
n/a 
120 mg / 120 mg 
100% 
240 mg / 230 mg 
100% 
460 mg / 460 mg 
100% 
920 mg / 920 mg 
100% 
Rolling-six enrollment begins at the 
60 mg cohort 
60 mg / 60 mg 
n/a 
90 mg / 90 mg 
50% 
135 mg / 120 mg 
50% 
180 mg / 180 mg 
50% 
270 mg / 260 mg 
50% 
Rolling-six enrollment begins at the 
120 mg cohort 
60 mg / 60 mg 
n/a 
120 mg / 120 mg 
100% 
180 mg / 180 mg 
50% 
270 mg / 260 mg 
50% 
390 mg / 380 mg 
50% 
Rolling-six enrollment begins at the 
230 mg cohort 
60 mg / 60 mg 
n/a 
120 mg / 120 mg 
100% 
240 mg / 230 mg 
100% 
345 mg / 320 mg 
50% 
480 mg / 460 mg 
50% 
Rolling-six enrollment begins at the 
460 mg cohort 
60 mg / 60 mg 
n/a 
120 mg / 120 mg 
100% 
240 mg / 230 mg 
100% 
460 mg / 460 mg 
100% 
690 mg / 690 mg 
50% 
Note: Sample dose levels are based upon dose escalation (target dose) and available VK-2019 
capsule strengths of 30 and 200 mg (actual dose). 
2.2.4 Intra-Patient Dose Escalation in Accelerated Titration Cohorts 
After an accelerated titration cohort has been declared safety by the SRC, patients at lower dose 
levels may be considered for intra-patient dose escalation if they meet the following criteria based 
in part on 3B design proposed by Simon et al: 
• 
Have stable disease (SD) or better after Cycle 2 (or later) 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
10 
• 
Experienced no VK-2019 related Grade 2 AEs during the previous cycle 
• 
Have no other safety concerns as assessed by the inverstigator 
The escalated dose must be agreed upon by the investigator and sponsor and may proceed 
beginning on Day 0 of the next cycle. Any patient that has their dose escalated will not be evaluated 
for DLT assessment at their new dose. 
2.2.5 Intra-Patient Dose Escalation in Rolling Six Cohorts 
After a Rolling Six cohort has enrolled a minimum of three patients and has been declared safe by 
the SRC, patients at lower dose levels may be considered for intra-patient dose escalation if the 
patient meets the following criteria: 
• 
Have stable disease (SD) or better after Cycle 2 (or later) 
• 
Have no other safety concerns as assessed by the investigator 
The escalated dose must be agreed upon by the investigator and sponsor and may proceed 
beginning on Day 0 of the next cycle. Any patient that has their dose escalated will not be evaluated 
for DLT assessment at their new dose. 
2.3 
Blinding and Unblinding 
This is an open-label study and there will be no blinding of subjects’ treatment during this study. 
2.4 
Protocol Amendments 
 This analysis plan reflects revised protocol version 09, amendment 9, and dated 15-OCTOBER-
2019.  
 
3 
OBJECTIVES 
3.1 
Primary  
Phase 1: 
• 
To define the MTD and the RP2D for orally administered VK-2019 monotherapy in 
patients with recurrent or metastatic NPC. 
• 
To evaluate and characterize the safety profile of single agent VK-2019 in adult patients 
with recurrent or metastatic NPC. 
Phase 2a:  


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
11 
• 
Evaluate preliminary efficacy (ORR, DOR, DCR, PFS, survival rate, and OS) of orally 
administered VK-2019 monotherapy in adult patients with recurrent or metastatic NPC. 
• 
Confirm the safety and tolerability of orally administered VK-2019 monotherapy in adult 
patients with recurrent or metastatic NPC. 
3.2 
Secondary 
Phase 1:  
• 
To evaluate the anti tumor activity of single agent VK-2019 per RECIST v1.1. 
• 
To characterize the single dose and steady state pharmacokinetic profile of single agent 
VK-2019 in adult patients with recurrent or metastatic NPC. 
• 
To evaluate the anti-EBV activity by reduction of plasma EBV-DNA of single agent VK-
2019 in adult patients with recurrent or metastatic NPC. 
Phase 2a:  
• 
To further characterize select PK parameters associated with orally administered VK-2019 
monotherapy in adult patients with recurrent or metastatic NPC. 
• 
Evaluate the anti EBV activity by reduction of plasma EBV DNA of orally administered 
VK 2019 monotherapy in adult patients with recurrent or metastatic NPC. 
3.3 
Exploratory 
Phase 1:   
• 
To explore blood PD markers. 
• 
To explore PD markers such as alteration in EBV specific gene expression, both lytic and 
latent EBV genes. 
• 
To explore exposure response relationships between VK 2019 exposure and the PD 
endpoints (safety, efficacy, and laboratory correlatives). 
Phase 2a: 
• 
To explore both blood and intratumoral PD markers. 
• 
To explore PD markers such as alteration in EBV specific gene expression, both lytic and 
latent EBV genes. 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
12 
• 
To explore exposure response relationships between VK 2019 exposure and the PD 
endpoints (safety, efficacy, and laboratory correlatives). 
 
4 
ENDPOINTS 
4.1 
Primary Endpoints 
Phase 1: 
• 
The frequency, severity, and duration of AEs and DLTs, AEs leading to discontinuation. 
and AEs leading to death. 
Phase 2a:  
• 
The durable ORR rate as well as ORR, DOR, DCR-6, DCR-12, PFS, rate of survival, and 
OS per RECIST v1.1. 
4.2 
Secondary Endpoints 
Phase 1: 
• 
The rate and severity of treatment emergent AEs at the MTD and BCAD. 
• 
Single dose and steady state plasma pharmacokinetic parameters of VK 2019. 
• 
Incidence of safety laboratory assessment abnormalities 
• 
Incidence of abnormalities in vital signs or other clinical safety assessments 
• 
ORR, DOR, and Disease control rate (DCR) per RECIST v1.1  
• 
Rate of partial or complete plasma EBV DNA antiviral response during treatment 
(assessed as 3xlog10 reduction or a drop below the lower limit of detection of the assay 
[LLOD], respectively).  
Phase 2a:  
• 
The rate and severity of treatment emergent AEs at the MTD, BCAD, and RP2D. 
• 
Rate of partial or complete plasma EBV DNA antiviral response during treatment 
(assessed as 3xlog10 reduction or a drop below the lower limit of detection of the assay 
[LLOD], respectively).  
• 
Plasma PK parameters of VK-2019. 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
13 
4.3 
Exploratory Endpoints 
Phase 1: 
• 
Exploratory analysis of relationships among PK, PD and clinical activity in order to 
preliminarily define BCAD. 
Phase 2a:  
• 
Exploratory PD assay for EBER in situ hybridization levels in baseline and on treatment 
tumor biopsies in a limited number of patients at RP2D.  
 
5 
SAMPLE SIZE AND POWER 
The number of patients in the dose escalation phase is estimated to be 30 patients (assuming six 
patients will be dosed in each of five cohorts). The number of patients in the Phase 1 Dose 
Expansion and Phase 2a Dose Expansion is based on a Simon 2-stage design as described below. 
The approximate sample size in the Phase 1 Dose Expansion is estimated to be 20 patients 
(assuming 10 additional patients in each of two expanded dose levels). During the Phase 2a portion 
of the trial, the approximate sample size in the Phase 2a Dose Expansions is estimated to be 18 
(assuming 9 patients in each of two expansion cohorts). In total, it is estimated that up to 
approximately 68 patients will be dosed in this trial.  
The number of patients for the Phase 1 and 2a expansions is based upon a Simon Two-Stage design 
at BCAD and MTD, respectively. The null hypothesis that the true response rate is 0.1 will be 
tested against a one-sided alternative. In the first stage (i.e., a Phase 1 Dose Expansion cohort), a 
total of 16 patients will be accrued. If there is one or fewer responses in these 16 patients, accrual 
to this cohort will be stopped. Otherwise, 9 additional patients will be accrued (i.e., a Phase 2a 
Dose Expansion cohort) for a total of 25. The null hypothesis will be rejected if five or more 
responses are observed in 25 patients. This design yields a 1-sided type I error rate of 10% and 
power of 90% when the true response rate is 30%. This design yields a probability of 0.51 for a 
cohort stopping early if the true response rate for that cohort is 10%.The sample size in the dose 
escalation phase is not based on statistical considerations, but rather depends on the number of 
observed toxicities; up to 6 subjects are expected to be treated after the accelerated titration design 
has ended at each conventional escalation cohort dose prior to the expansion cohort at MTD.  
 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
14 
6 
STUDY PERIODS, DOSAGE AND ADMINISTRATION 
6.1 
Study Periods 
For each patient enrolled, the study will consist of at least three periods:  Screening (up to 28 days), 
Treatment (comprised of 28-day dosing cycles), and Follow up (comprised of a safety follow-up 
and long-term follow-up for survival status).  
6.1.1 Safety Follow-Up 
A safety follow up visit will be conducted at least 28 days (± 7 days) after the patient’s last dose 
of study drug. 
6.1.2 Long-Term Follow-Up 
All patients that discontinue study treatment will be followed for:  
• 
Survival: Via clinic visit (either at the study site or outside facility), telephone, or 
videotelephony until a) death, b) withdrawal of consent, c) they are lost to follow-up, d) 
the Sponsor notifies sites that survival follow-up is no longer required, or e) termination 
of study by the Sponsor, and 
• 
Assessment of treatment-related SAEs until resolution to baseline or Grade ≤1.  
Patients discontinuing treatment due to reasons other than radiographic disease progression will 
have their tumor assessed (using the same modality that was used during study treatment) every 
12 weeks (± 14 days) for up to 2 years after the last treatment visit, or until a) they have progressive 
disease, b) they start a new therapy for their cancer, b) death, c) withdrawal of consent, d) they are 
lost to follow-up, e) the Sponsor notifies sites that tumor assessment is no longer required during 
long-term follow-up, or f) termination of study by the Sponsor. 
6.2 
Dosage and Administration 
The number of patients in the dose escalation phase is estimated to be 30 patients (assuming six 
patients will be dosed in each of five cohorts).  The starting dose for VK-2019 is 60 mg QD. 
Sample dose escalation tables are in Table 1, detailing a sample dose escalation schema based 
upon when escalation converts from Accelerated Titration to a Rolling Six design. 
VK-2019 will be provided in HDPE bottles containing either 30 mg or 200 mg capsules with 
protection from moisture. Patients should be given sufficient supply to last until their next study 
visit or for an entire cycle, depending upon institutional policy and study team discretion. 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
15 
Site personnel must ensure that patients clearly understand the directions for self medication. 
Patients should record daily administration of each study drug in their patient diaries. If a patient 
misses a dose, they must be instructed not to “make it up” or double the dose on the next day.  
Patient diaries and pill counts by research staff at least once each cycle will be used to determine 
actual dosing. 
If a patient vomits any time after taking a dose, they must be instructed not to “make it up,” but to 
resume subsequent doses the next day as prescribed. 
7 
STATISTICAL ANALYSES 
7.1 
General Methods 
The statistical analysis will be conducted following the principles specified in the International 
Conference on Harmonisation (ICH) Topic E9 Statistical Principles for Clinical Trials 
(CPMP/ICH/363/96). 
All statistical tabulations and analyses will be done using SAS®, Version 9.4 or higher.  
Unless otherwise noted, continuous variables will be summarized using number of non-missing 
observations (n), arithmetic mean (mean), standard deviation (SD), median, minimum, and 
maximum; categorical variables will be summarized using the frequency count and the percentage 
of subjects in each category.  
In the data listings, study day relative to first dose of study drug may be presented. Study day 
relative to first dose will be calculated as: event date – first dose date in the study (+ 1 if event date 
≥ first dose date in the study). 
When appropriate, baseline is defined as the last non-missing result with a collection date-time 
less than the date-time of the first dose of study medication. If time is missing, unless otherwise 
specified, baseline is the last non-missing result prior to or equal to the date of first dose of study 
drug. 
7.2 
Handling of Dropouts or Missing Data 
7.2.1 Handling of Incomplete Dates for Adverse Events 
Imputation rules for missing or partial AE start date are defined as follows. 
If only day of AE start date is missing, - if the start date has month and year but day is missing, 
the first day of the month will be imputed. If this date is earlier than the first dose date, then the 


Abbreviated Statistical Analysis Plan 
VK-2019-001 
 
 
 
16 
first dose date will be used instead. If this date is later than the stop date (possibly imputed), then 
the stop date will be used instead. 
If day and month of AE start date are missing - if the start date has year but day and month are 
missing, the first of January will be imputed. If this date is earlier than the first dose date, then the 
first dose date will be used instead. If this date is later than the stop date (possibly imputed), then 
the stop date will be used instead. 
If the year of AE start date is missing or AE start date is completely missing, then Data 
Management will query site with no imputation and compare the full (or partial) AE end date to 
the first dose date. If the AE end date is before the first dose date, then the AE should be considered 
a pre-treatment AE. Otherwise, the AE will be considered a TEAE. 
7.2.2 Handling Missing or Partial Prior and Concomitant Medication Dates 
For a missing or partial medication start date, if only Day is missing, the first day of the month 
will be assumed. If day and month are both missing, the first day of the year will be assumed. If 
day, month and year are all missing, the date before the first dose date will be assumed. 
For a missing or partial medication stop date, if only day is missing, the last day of the month will 
be assumed. If day and month are both missing, the last day of the year will be assumed. If day, 
month and year are all missing, ‘continuing’ status to stop date will be assigned. 
7.3 
Study Population 
• 
All Enrolled Population:  All subjects who sign informed consent form and were 
confirmed eligible and assigned to a treatment cohort. 
• 
All Treated Population (Safety Population):  All subjects who receive at least one dose of 
VK-2019. All Treated Population will be used for the summaries of demographics, 
baseline characteristics, prior therapy, prior history, and safety. 
• 
PK Population:  All subjects who receive at least one dose of study medication and have 
available VK-2019 plasma concentration data. 
• 
Response Evaluable Population:  All treated subjects with measurable disease at baseline 
and one of the following: 1) at least one post-dose tumor assessment, 2) discontinuation 
prior to the first efficacy assessment due to clinical disease progression or toxicity or 3) 
death either on treatment or within 28 days of last VK-2019 dose. 


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• 
EBV DNA Population:  All subjects who receive at least one dose of study medication 
and have available biomarker data. 
7.4 
Subject Accountability 
Summaries of analysis populations and subject disposition will be presented by cohort and will 
contain the following information: 
• 
Number of subjects enrolled 
• 
Number and percent of subjects who were dosed 
• 
Number and percent of subjects who discontinued early from the study and reason for 
early discontinuation 
• 
Number and percent of subjects who discontinued treatment and reason for 
discontinuation 
• 
Number and percent of subjects in the All Treated Population, Response Evaluable 
Population and EBV DNA Population 
• 
Number and percent of subjects entered in safety and long term follow-up  
This table will be based on All Enrolled Population. 
Subject disposition listing will be provided for All Enrolled Population. 
7.5 
Protocol Deviation Reporting 
No TLF’s will be provided for abbreviated CSR.  
7.6 
Demographics Characteristics 
A listing will be provided for demographics characteristics for All Treated Population, including 
patient age, sex, race, ethnicity, height and weight at baseline, etc.,    
7.7 
Medical and Surgical History 
Medical and surgical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, Version 23.0 or later) and listed for All Treated Subjects by SOC and PT.  
7.8 
Prior and Concomitant Medications  
Prior medications are defined as those medications that started and stopped prior to the first dose 
of study drug. Concomitant medications are defined as all medications received during the 


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treatment period, that is, those medications with a start date on or after the first dose of study drug 
(inclusive) and before last dose of study drug (inclusive), or started prior to the first dose of study 
drug and were continued after the first dose of study drug.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODDE – global March 20 B3 version) and classified according to anatomical 
therapeutic chemical code levels. Prior and concomitant medication data will be listed by ATC 
classifications level and preferred term for All Treated Population. 
7.9 
Extent of Exposure 
The extent of exposure will be characterized according to the duration of exposure, the total 
number of cycles administered and the median (range) of cycles administered. Descriptive 
statistics of cumulative dose and dose intensity will also be presented for All Treated Population. 
A listing will also be provided.  
7.10 Analysis of Pharmacokinetic Data 
The PK concentration population is defined as all enrolled patients treated who have at least one 
concentration evaluation. The PK parameter analysis population is defined as all enrolled patients 
treated who have at least one of the PK parameters of interest. 
Standard plasma pharmacokinetic parameters including the maximum plasma concentration (Cmax) 
and area under the plasma concentration versus time curve (AUC) for VK-2019 will be estimated 
using non-compartmental analysis. If data permit or if considered appropriate, terminal elimination 
half-life (t1/2) will be estimated. Descriptive statistics will be provided for these PK parameters in 
tabular form (N, mean, SD, CV, median, minimum, maximum, geometric mean and its associated 
CV) by dose, cycle, and day. 
Individual patient and median profiles of the concentration-time data will be plotted by dose, cycle, 
and day using nominal times.  Median profiles will be presented on both linear-linear and log-linear 
scales.  
Graphs of PK concentration over time and tables of PK parameters will be provided by Cullinan. 
 


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7.11 Pharmacodynamic EBV DNA  
A line graph for mean +/- SD of change from baseline for EBV DNA will be provided by visit for 
all post baseline visits (C1D14, C2D0, C2D14, C3D0) for Phase 1 Dose Escalation. EBV DNA 
population will be used to generate this graph.  
7.12 Pharmacodynamic EBNA1 inhibition 
No TLF’s will be provided for abbreviated CSR as no biopsies were collected. 
7.13 Efficacy  
The number and percentage of patients for best overall response (BOR) will be provided. The 
number and percentage of patients with ORR will also be summarized together with exact 95% 
confidence intervals (CI) using a binomial distribution for Response Evaluable Population. 
The endpoint objective response rate (ORR) is defined as the number and percentage of patients 
whose best overall response is either a complete response (CR) or partial response (PR).  To qualify 
as a responder, a patient must have a complete or partial visit response confirmed by a second scan 
performed at least 4 weeks after the criteria for response are first met. A by subject listing will also 
be provided for Overall Response. 
7.14 Safety 
Safety objectives in this study will be assessed using the following endpoints in the All Treated 
population: 
• 
Incidence of adverse events, SAEs, adverse events meeting protocol-defined DLT criteria, 
severe adverse events, adverse events leading to study treatment or study discontinuation, 
and adverse events resulting in death.  
• 
Incidence of clinical laboratory test abnormalities including hematology and serum 
chemistry abnormalities assessed at protocol designated time points 
• 
Changes in vital signs relative to baseline include blood pressure and heart rate measured 
at protocol designated time points 
7.14.1 Adverse Events 
Adverse events will be listed, including the verbatim description and MedDRA preferred term and 
system organ class (SOC).  


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Treatment emergent adverse events (TEAEs) are defined as those starts or severity becomes worse 
after the first dose of study treatment. 
TEAE leading to study treatment discontinuation and death will be summarized by SOC, by 
preferred term and by maximum CTCAE grade (according to NCI CTCAE Version 5.0). The 
incidence of TEAEs will be based on the numbers and percentages of patients with events and 
number of events. In addition summary of DLT will also be provided for first cycle.  
TEAE data will be presented across all cycles and for each cycle. The denominator for each cycle 
will be the number of patients available at the start of the cycle who received at least 1 dose of 
study drug for that cycle.  
Individual patient listings will be prepared for AE leading to  study treatment discontinuation and 
death.  Listing of the first cycle DLTs for each cohort will be provided. 
7.14.2 Clinical Laboratory Assessments 
Severity grading, using NCI CTCAE Version 5.0, will be assigned to laboratory safety values 
where applicable. Laboratory results in reported units and standard international units will be 
listed, including high and low flags, NCI CTCAE grades where applicable, the corresponding 
normal range and clinical significance. 
Laboratory safety tests summaries will be based on results in SI units. Absolute and change from 
baseline results at each scheduled visit will be summarized using descriptive statistics.  
7.14.3 Vital Signs 
For vital sign parameters of heart rate, blood pressure (systolic and diastolic), temperature, height 
(baseline only), weight and BMI, the actual value and change from baseline for the maximum 
value, minimum value, and last available assessment will be summarized with descriptive 
statistics.  
Vital signs data will be listed by subject at each scheduled visit.    
7.14.4 Electrocardiograms 
Absolute and change from baseline 12-lead ECG results will be summarized using descriptive 
statistics. QT analysis intervals will be corrected for heart rate using the Fridericia correction 
(QTcF). Study conclusions will be based on the most appropriate correction method for the 


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analysis. The effect of VK-2019 concentration on QTcF will be explored after dosing and will be 
baseline corrected for each patient. 
Individual ECG data will be listed. 
7.14.5 Physical Examinations 
 A by subject listing will be presented. 
7.14.6 ECOG 
No TLF’s will be provided for abbreviated CSR.  
7.14.7 Pregnancy Testing  
No TLF’s will be provided for abbreviated CSR.   
7.15 Interim Analysis 
No TLF’s will be provided for abbreviated CSR.  
 
 


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7.16 General Conventions for Tables, Listings and Figures  
Tables and listings will be presented in landscape mode with minimum of 3/4” bound edge margin 
and 3/8” other margins on 8.5” x 11” paper. 
Times new roman font size of no less than 8 point will be used for tables and listings. 
A source line will be included on the bottom of each page of all tables and listings. It will contain 
the SAS code program name and the run date and time. 
Each variable is recorded to a specific number of decimal places. If the raw data is presented with 
varying precision, then the least precise value will be considered as the data precision. 
For summary tables, unless otherwise specified, the number of decimal places provided in the SAS 
output will be based on the accuracy of the least accurate value in the raw data as follows: 
 
• n 
integer 
• Arithmetic mean 
1 decimal place more than the least accurate number in the raw data 
• SD 
2 decimal places more than the least accurate number in the raw data 
• Median 
1 decimal place more than the least accurate number in the raw data 
• Minimum 
same number of decimal places as raw data 
• Maximum 
same number of decimal places as raw data 
 
 


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8 
DOCUMENT HISTORY 
Table 8-1: 
Document History 
Version 
Author 
Summary of Changes 
1.0 
Wenjun Xin 
Original version 
 
 
 


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9 
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DOI: 10.1200/JCO.2007.12.7712. PMID: 18182661. 
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D, Emanuel EJ, Grady C.  Risks and benefits of phase 1 oncology trials, 1991 through 
2002. The New England journal of medicine. 2005; 352 (9): 895-904. Epub 2005/03/05.  
doi: 10.1056/NEJMsa042220. PubMed PMID: 15745980.