Conditions: Solid Tumor Metastatic Bladder Cancer
Keywords: oncology tumor metastatic bladder
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 127
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the maximum tolerated dose of RX-3117 in subjects with advanced or metastatic solid tumors (Phase 1). The purpose of the Phase 2 portion is to estimate anti-tumor activity in subjects with advanced malignancies (relapsed or refractory pancreatic or advanced bladder cancer).

Detailed description:
This is a dose-finding, open-label, single agent study of RX-3117. Once the maximum tolerated dose is identified additional subjects will be treated in a dose expansion followed by a 2-stage Phase 2 study. Subjects will be treated for up to 8 cycles of therapy. A cycle will be 4 weeks. RX-3117 dosing will be 3 times each week for 3 weeks follow by 1 week off treatment. All subjects will be followed for at least 30 days after the last dose of RX-3117.

Arms:
arm 1: All subjects will receive RX-3117.

Interventions: intervention 1: RX-3117
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
Note:  There is no separate Statistical Analysis Plan (SAP) document to include  with 
this protocol. The previous sponsor and responsible party that conducted this study, 
Rexahn Pharmaceuticals, did not provide a SAP for this study to the current sponsor 
and responsible party, Processa Pharmaceuticals. An abbreviated clinical study report, 
not a full clinical study report, was generated at study completion.  Section 10 of this 
protocol (pages 75-88) includes the statistical analysis details for this study. 


Protocol Number:  RX-3117-P1-01 
Product:  RX-3117 
19 February 2016 
Amendment 04 
CONFIDENTIAL 
Page 1 of 108
A Phase1, Open-Label, Dose-Ranging, Safety and Pharmacokinetic Study 
to Determine the Maximum Tolerated Dose of RX-3117 Administered Orally 
as a Single-Agent to Subjects with Advanced Malignancies 
Rexahn Protocol Number RX-3117-P1-01 
Clinical Study Sponsor: 
Rexahn Pharmaceuticals, Inc 
15245 Shady Grove Road, Suite 455 
Rockville, MD 20850 USA 
Telephone (240) 268-5300 
Fax (240) 268-5310 
Key Sponsor Contacts: 
Christine Peterson, Ph.D. 
Rexahn Pharmaceuticals, Inc 
15245 Shady Grove Road, Suite 455 
Rockville, MD 20850 USA 
Telephone (240) 268-5300 x 320 
Fax (240) 268-5310 
Kathy Tran 
Rexahn Pharmaceuticals, Inc 
15245 Shady Grove Road, Suite 455 
Rockville, MD 20850 USA 
Telephone (240) 268-5300 x 365 
Fax (240) 268-5310 
Date:  Original 
07 November 2013 
Amendment 01 
27 December 2013 
Amendment 02 
17 October 2014 
Amendment 03 
06 August 2015 
Amendment 04 
19 February 2016 
Confidentiality Notice 
This document contains confidential information of Rexahn Pharmaceuticals Inc 
(Rexahn). 
This document must not be disclosed to anyone other than the study staff and members 
of the institutional review board.   
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Rexahn. 
If you have questions regarding how this document may be used or shared, call Rexahn 
(1-240-268-5300).  For all other study-related questions, continue to contact the Key 
Sponsor Contacts. 
NCT02030067


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 2 of 108 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase1, Open-Label, Dose-Ranging, Safety 
and Pharmacokinetic Study to Determine the Maximum Tolerated Dose of RX-3117 
Administered Orally as a Single-Agent to Subjects with Advanced Malignancies, dated 
19 February 2016, and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice and applicable regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
before study initiation, during the study if there are changes that affect my financial 
disclosure status, and after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Rexahn Pharmaceuticals Inc.  
 
 
 
Signature 
 
 
Name of Principal Investigator 
 
Date (DD Month YYYY) 
I, Christine Peterson, as representative of Rexahn, agree to the provisions described in 
this protocol. 
 
 
 
Signature 
 
 
Christine Peterson 
 Rexahn Pharmaceuticals Inc. 
 
Date (DD Month YYYY) 


Protocol Number:  RX-3117-P1-01 
Product:  RX-3117 
19 February 2016 
Amendment 04 
CONFIDENTIAL 
Page 3 of 108
Protocol Synopsis 
Title:  A Phase1, Open-Label, Dose-Ranging, Safety and Pharmacokinetic Study to Determine 
the Maximum Tolerated Dose of RX-3117 Administered Orally as a Single-Agent to Subjects with 
Advanced Malignancies 
Study Phase:  Phase 1/2 
Indication:  Advanced Malignancies 
Phase 1 Objectives: 
Primary Objectives: 
To evaluate the safety and tolerability of escalating RX-
3117doses and multiple schedules in subjects with advanced or 
metastatic solid tumors 
To determine the maximum tolerated dose of RX-3117 when 
administered orally to subjects with advanced solid tumors 
Secondary Objectives: 
To determine the pharmacokinetic profile of RX-3117 
To evaluate the antitumor activity of RX-3117 
To evaluate the potential for QT interval prolongation due to 
RX-3117 
Exploratory Objective: 
To investigate predictive and pharmacodynamic blood or tumor 
biomarkers suggested from nonclinical studies/literatures which 
may be predictive of a response or resistance to RX-3117 
treatment   
Phase 2 Objectives: 
Primary Objective: 
To estimate the antitumor activity of RX-3117 in subjects with 
advanced malignancies (relapsed or refractory pancreatic or 
advanced  bladder cancer) 
Secondary Objective 
To assess additional measures of antitumor activity 
To characterize the safety profile associated with RX-3117 
To evaluate population pharmacokinetics using a limited 
sampling 
Exploratory Objectives: 
To investigate the effect of RX-3117 on potential biomarkers in 
blood or tumor samples 
To evaluate the change in tumor burden response 
Phase 1 Endpoints: 
Primary Endpoints: 
Overall safety profile characterized by the type, frequency, 
severity, timing of onset, duration and relationship to study 
therapy of any adverse events, or abnormalities of laboratory 
tests or electrocardiograms (ECGs) 
Enumeration and description of any dose limiting toxicities 
(DLTs) that occur during Cycle 1, serious adverse events, or 
adverse events leading to discontinuation of study treatment. 
Secondary Endpoints 
Pharmacokinetic parameters (e.g., time to maximum observed 


Protocol Number:  RX-3117-P1-01 
Product:  RX-3117 
19 February 2016 
Amendment 04 
CONFIDENTIAL 
Page 4 of 108
concentration [Tmax], maximum observed plasma concentration 
[Cmax], trough concentration [Ctrough], area under the 
concentration-time curve [AUC]) 
Indices of anti-tumor activity (e.g., overall response rate [ORR], 
time to response [TTR], duration of response [DOR], and 
progression-free survival [PFS]) during treatment. 
Exploratory Endpoints 
Baseline biomarker expression/concentration, including (but not 
limited to) concentrative nucleoside transporter (CNT) 2; 
equilibrative nucleoside transporter (ENT) 1; uridine-cytidine 
kinase (UCK) 1 and 2; DNA methyltransferase (DNMT) 1, 3a 
and 3b; and ribonucleotide reductases (RRM) 1 and 2 and RX-
3117 incorporation into DNA/RNA. 
Phase 2 Endpoints: 
Primary Endpoint 
Progression free survival rate and/or objective clinical response 
rate 
Secondary Endpoints 
Time to progression, overall response rate and duration of 
response 
Adverse events, serious adverse events, assessments of 
clinical laboratory values, and vital sign measurements 
Pharmacokinetic profile 
Exploratory Endpoints 
Biochemical levels of drug targets in tumor and blood samples 
Changes in tumor burden 
Study Design: 
This will be a Phase 1 multicenter, dose- and schedule-finding, 
open-label, single-agent study of RX-3117 administered orally 
to subjects with advanced or metastatic solid tumors followed 
by a 2-stage Phase 2 study design.  Subjects will be treated for 
up to 8 cycles of therapy.  In the Phase 1 portion of the study 
subjects with any advanced solid tumor malignancies will be 
enrolled. During the Phase 1 portion of the study, the maximum 
tolerated dose (MTD) or a recommended phase 2 dose (RP2D) 
and schedule will be determined and the pharmacokinetics of 
RX-3117 characterized in eligible subjects.  In the Dose 
Expansion, subjects will be enrolled in 1 of 3 diagnosis groups: 
relapsed or refractory pancreatic, colorectal or advanced 
bladder cancers.  In the Phase 2 portion, subjects will be 
enrolled in 1 of 2 diagnosis groups: relapsed or refractory 
pancreatic or advanced bladder cancers.  The Dose Expansion 
and Phase 2 portion will use the dose and schedule identified in 
the Phase 1.  The Phase 2 portion will follows a 2-stage design. 
An interim analysis will be conducted when 10 response 
evaluable subjects in each tumor indication are enrolled and 
have had the opportunity to complete a minimum of 4 cycles of 
therapy or have discontinued therapy due to progressive 
disease. In the second stage of the Phase 2, enrollment for a 
disease group will proceed if responses are observed within the 
first 10 response-evaluable subjects enrolled in that disease 
group. Approximately 40 additional subjects will be enrolled in 
each of the disease indications.  Subjects will be treated for up 
to 8 cycles of therapy. 
Sample Size:  Number of planned subjects is approximately 152 subjects (40 subjects in the 
Phase 1, depending upon the number of dose levels needed to identify the maximum tolerated 


Protocol Number:  RX-3117-P1-01 
Product:  RX-3117 
19 February 2016 
Amendment 04 
CONFIDENTIAL 
Page 5 of 108
dose (MTD), 12 subjects in the Dose Expansion, 20 subjects in Stage 1 of the Phase 2 and 80 
subjects in Stage 2 of the Phase 2). 
Duration:  The study will consist of a screening period (up to 14 days; [up to 21 days for tumor 
imaging]), up to eight 28-day treatment cycles, an end-of-treatment visit, and a follow up visit 
approximately 30 days after the last dose of RX-3117. Subject participation is anticipated to be 
approximately 10 months.  Additional cycles of therapy may be provided following discussions 
with the investigator, sponsor and medical monitor.  Subjects may remain on study treatment until 
the earliest of disease progression, an intolerable RX-3117-related toxicity, withdrawal of consent, 
pregnancy, substantial noncompliance with study procedures, principal investigator judgment that 
it is in the best interest of the subject to stop treatment, or study discontinuation. 
Summary of Subject Eligibility Criteria:  
Inclusion Criteria 
Disease Related 

Confirmed histologic or cytologic evidence of metastatic or locally advanced solid
neoplasm that has failed to respond to standard therapy, progressed despite standard
therapy or for which standard therapy does not exist. There is no limit on the number of
prior treatment regimens (Phase 1).

Confirmed histologic or cytologic evidence of metastatic pancreatic, colorectal or
advanced bladder cancers that failed to respond to standard therapy, progressed despite
standard therapy or for which standard therapy does not exist. There is no limit on the
number of prior treatment regimens (Phase 1 Dose Expansion)

Confirmed histologic or cytologic evidence of metastatic pancreatic or advanced bladder
cancers that failed to respond to standard therapy, progressed despite standard therapy
or for which standard therapy does not exist. There is no limit on the number of prior
treatment regimens (Phase 2)

Measurable or evaluable disease using Response Evaluation Criteria in Solid Tumors
(RECIST) v 1.1.

Life expectancy of at least 3 months

ECOG performance status 0, 1 or 2 (Phase 1)

ECOG performance status 0 or 1 (Phase 2)

Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy,
systemic corticosteroids, or investigational therapy) for the treatment of cancer within
2 weeks before planned start of study therapy.

All acute toxic effects of any prior antitumor therapy resolved to Grade  1 before the
start of study therapy (with the exception of alopecia [Grade 1 or 2 permitted], or
neurotoxicity [Grade 1 or 2 permitted], or anemia [Grade 2 permitted])
Demographic 

Males or females who are 18 years or older

Able to swallow capsules
Laboratory 

Hemoglobin ≥ 9.0 g/dL

Absolute neutrophil count ≥ 1.5 x 109/L

Platelet count ≥ 100 x 109/L

Serum creatinine ≤ 1.5 times the upper limit of normal OR 24-hour measured urine
creatinine clearance ≥ 50 mL/min for subjects with serum creatinine levels > 1.5 times the
upper limit of normal

Serum bilirubin ≤ 1.5 times the upper limit of normal OR ≤ 3 times the upper limit of
normal in the presence of known liver metastases


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 6 of 108 
 
Aspartate aminotransferase (AST; SGOT) and alanine amino transferase (ALT; SGPT) 
≤ 2.5 times the upper limit of normal OR ≤ 5 times the upper limit of normal in the 
presence of known liver metastases 
 
Alkaline phosphatase ≤ 2.5 times the upper limit of normal OR ≤ 5 times the upper limit of 
normal in the presence of known liver or bone metastases 
 
Prothrombin time (PT) < 1.2 times the upper limit of normal unless receiving therapeutic 
anticoagulation, International normalized ratio (INR) up to 3-4 times the upper limit of 
normal if on therapeutic anticoagulation and partial thromboplastin time (PTT) < 1.2 times 
the upper limit of normal unless receiving therapeutic anticoagulation. 
 
For women of childbearing potential: Negative serum pregnancy test during screening 
and negative serum or urine pregnancy test at start of study therapy (Cycle1 Day 1). 
 
Reproductive 
 
For female subjects of childbearing potential, willingness to abstain from heterosexual 
intercourse or use a protocol-recommended method of contraception from the screening 
visit throughout the study treatment period and for 30 days following the last dose of 
study drug.  
 
For fertile male subjects having intercourse with females of childbearing potential, 
willingness to abstain from heterosexual intercourse or use a protocol-recommended 
method of contraception from the start of study therapy throughout the study treatment 
period and for 30 days following the last dose of study drug and to refrain from sperm 
donation from the start of study treatment throughout the study treatment period and for 
30 days following the last dose of study drug.  
 
Ethical 
 
In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current disease status, medical condition, and the 
potential benefits and risks of alternative treatments for the subject’s cancer. 
 
Before any study-specific procedure, the appropriate written informed consent must be 
obtained 
 
Exclusion Criteria 
Disease Related 
 
Primary brain tumors or clinical evidence of active brain metastasis 
 
Medications 
 
Systemic corticosteroid use within 7 days before planned start of study therapy 
 
General 
 
Active infection requiring parenteral or oral antibiotics within 2 weeks before planned start 
of study therapy 
 
Uncontrolled diabetes as assessed by the investigator  
 
Second malignancy other than curatively resected basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, in situ carcinoma of the cervix, or other cancers 
treated with curative intent and no known active disease within 3 years before planned 
start of study therapy 
 
QTcF interval greater than 470 msec, with a known history of QTcF prolongation, is 
taking medications known to prolong QTcF, or has history of torsade de pointes. 
 
Documented history of hepatitis B, hepatitis C or human immunodeficiency virus 
 
History of any other concurrent conditions that could preclude the subject’s participation 
in the study, pose an undue medical hazard, or interfere with the interpretation of the 
study results, including, but not limited to, subjects with congestive heart failure (New 
York Heart Association [NYHA] Class III or IV), cardiac arrhythmia, or acute coronary 
syndromes within 6 months before planned start of study therapy 
 
History of prior allogeneic bone marrow progenitor cell or solid organ transplantation. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 7 of 108 
 
Any other medical, psychiatric, or social condition, which in the opinion of the 
investigator, would preclude participation in the study, pose an undue medical hazard, 
interfere with the conduct of the study, or interfere with interpretation of the study results 
 
Pregnant, planning a pregnancy or breast feeding during the study 
 
Concurrent participation in another therapeutic clinical trial 
 
Has any disorder that may interfere with drug absorption, distribution, metabolism, or 
excretion (including gastrointestinal surgery, bariatric surgery)  
 
Has known hypersensitivity to prior gemcitabine, azacytidine or cytosine arabinoside 
exposure  
 
Unwilling or unable to comply with study requirements or planned unavailability for follow-
up assessments. 
 
Investigational Product Dosage and Administration:    
RX-3117 will be provided as 30-mg, 100-mg, 200-mg and 500-mg capsules.  The capsules will 
consist of hydroxypropylmethyl cellulose and be packaged in a high-density polyethylene (HDPE) 
bottle with a child-resistant closure and an induction seal.  Subjects will take RX-3117 3 times per 
week (i.e., preferably on a Monday, Wednesday and Friday), 5 times per week (i.e., for 5 
consecutive days followed by 2 days off), or daily for 7 days for 3 weeks followed by 1 week of 
rest, in each 28-day cycle.    
Subjects will be fasting for 8 hours, the dose will be taken with 4-8 ounces of water, and a light 
meal will be permitted approximately 1 hour later.  During Cycle 1 subjects will be dispensed 
doses of RX-3117 each week and during cycles 2 to 8 doses will be dispensed at the start of 
each cycle. 
The starting dose will be 30 mg/day.  The dose escalation will begin with an accelerated design 
(Simon et al., 1997) in single subjects.  After the occurrence of a single ≥ Grade 2 adverse event 
that is considered related to RX-3117, the study will transition to a standard 3 + 3 design using a 
modified Fibonacci sequence.  Doses will be rounded to accommodate available dose strengths.  
Additional doses and schedules may be recommended by the review committee which includes 
investigators, medical monitor and sponsor. 
 
Control Group:  There will be no control group. 
 
Key Screening Procedures:  (key procedures, see Section 7.2 for a complete list): 
 
Review of inclusion and exclusion criteria 
 
Medical history including histology report confirming diagnosis of solid tumor 
malignancies, concomitant medications/treatment(s) including cancer therapies 
 
Resting vital signs: pulse, respiration, temperature, blood pressure and pulse oximetry 
 
Physical examination including height and weight 
 
Performance status assessment (i.e., ECOG) 
 
Laboratory tests 
 
12-lead electrocardiogram 
 
Tumor imaging assessment 
 
Key Treatment Procedures (key procedures, see Section 7.3 for a complete list): 
 
Collection of archival tumor tissue if available 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 8 of 108 
 
Collection of tumor biopsy for biomarker (optional) 
 
Collection of pretreatment blood biomarkers  
 
Recording of adverse events and concomitant medications 
 
Resting vital signs and weight 
 
ECOG performance status  
 
Laboratory tests 
 
12-lead electrocardiogram in Cycle 1 
 
Pharmacokinetic sampling  
 
Tumor imaging assessments once per cycle for Cycles 1 through 4 and after every 2 
cycles of treatment, thereafter 
 
Collection of blood biomarkers at the time of tumor assessment 
 
Safety Parameters:  Adverse events will be coded using the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA, Version 15.1) and will be graded using the 
Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03).  The CTCAE will also 
be used to grade abnormalities in vital signs, laboratory assessments that include serum 
chemistry, hematology, coagulation and urinalysis and electrocardiograms (Phase 1). 
 
Statistical Considerations:   
Analysis Methods:  
In the Phase 1 portion and the Dose Expansion the statistical methods will be descriptive in 
nature.  Appropriate data analysis sets will be defined. The full-analysis set will include data from 
all subjects who receive  1 dose of study therapy; other data sets (responding and evaluable 
data sets) will be defined in a separate statistical analysis plan and will include data from subjects 
who have sufficient baseline and on-study measurements to provide interpretable results for 
specific parameters of interest.  
Subject characteristics and study results will be described and summarized by RX-3117 dose 
level, schedule and overall for the relevant analysis sets.  
Based on the full-analysis set, information regarding study treatment administration, study drug 
compliance, and safety variables will be described and summarized.  Using data from the 
relevant evaluable data sets, RX-3117 plasma concentrations, pharmacokinetic parameters, and 
pharmacodynamic markers will also be described and summarized.  Calculated pharmacokinetic 
parameters will be derived using non-compartmental methods. 
For endpoints related to tumor assessment, analyses will be done based on the full-analysis, 
responding, or evaluable data sets, as appropriate.  Continuous and categorical variables will be 
summarized.  Changes from baseline in categorical variables and changes from baseline in 
continuous endpoints will be analyzed using appropriate methods.  Time-to-event endpoints will 
be summarized using Kaplan-Meier methods. 
The Phase 2 portion of the study will follow a 2-stage design (Simon, 1989). An interim analysis 
will be conducted when 10 response-evaluable subjects, treated with the recommended phase 2 
dose (RP2D) of RX-3117, in each tumor indication are enrolled and have had the opportunity to 
complete a minimum of 4 cycles of therapy or have discontinued therapy due to progressive 
disease (PD). The critical value for evaluation of each tumor type to proceed to the second stage 
of the Phase 2 is 2 in 10 subjects (20%) measured by a benefit in PFS (stable disease for at least 
4 months) or 1 subject with an objective clinical response (partial or complete response) 
supported by acceptable safety and tolerability reviewed through the conduct of the study by the 
investigators, medical monitor and sponsor.. In the second stage of the Phase 2 objective clinical 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 9 of 108 
response rate and PFS will be further evaluated, in 40 additional subjects within each of the 
disease groups that continue beyond the first stage.   
 
Sample Size Calculation: 
In this dose-escalation Phase 1 trial designed to determine an MTD for RX-3117, the sample size 
for the study is not based on a formal statistical hypothesis but will be determined based on 
observed number of first-cycle DLTs at each dose level and schedule.  The planned accelerated 
design followed by a sequential 3+3 dose-escalation is consistent with usual oncologic paradigms 
for dose ranging and schedule finding.  The intent is to limit the number of subjects who are 
exposed to excessively toxic doses of a drug in a Phase 1 evaluation of an anticancer agent.  The 
trial will use the standard National Cancer Institute (NCI) definition of MTD (starting dose 
associated with DLT in < 33.3% of subjects during the first cycle of therapy).  The dose group 
size and dose-escalation rules establish a low probability of increasing the dose if the true rate of 
DLT is high while there is a high likelihood of escalating or proceeding to the next stage of the 
study if the true underlying proportion of DLT is low.  Once the recommended phase 2 dose or 
MTD and schedule is identified approximately 12 subjects will be treated in the Dose Expansion. 
The maximum number of subjects needed for Phase 2 is approximately 100 (50 per tumor 
indication).  An estimated 20 subjects (10 per indication) will be enrolled in the first stage of the 
Phase 2 at the recommended dose from the Phase 1.  The Dose Expansion subjects who have 
measurable disease at baseline and at least 1 post-baseline response assessment may be 
considered as part of the first stage of the Phase 2.  
A formal statistical analysis plan will be developed and finalized before database lock. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 10 of 108 
Study Glossary 
Abbreviation 
Definition 
ANC 
Absolute neutrophil count 
AUC 
Area under the plasma concentration time curve 
AUC0-t 
area under the plasma concentration-time curve from the time of dosing to the 
last measurable concentration 
AUC0– 
area under the plasma concentration-time curve from time 0 to the end of the 
dosing interval 
AUC0-∞  
area under the plasma drug concentration-time curve from 0 to time 
extrapolated to infinity 
AUC0-last 
area under the plasma drug concentration-time curve from 0 to time of the last 
quantifiable concentration 
Cmax 
Maximum observed plasma concentration 
CYP 
Cytochrome P450 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of Response 
ECG 
Electrocardiography, electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
GLP 
Good Laboratory Practice 
HED 
Human equivalent dose 
IC50 
Half maximum inhibitory concentration 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenously 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
Overall Response Rate 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTcF 
Corrected QT interval using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
RNA 
Ribonucleic Acid 
SD 
Stable disease 
Tmax 
Time to maximum observed plasma concentration 
TTR 
Time to response 
UCK 
Uridine-cytidine kinase 
ULN 
Upper limit of normal 
Vz 
Volume of distribution 
 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 11 of 108 
 
Study Definitions 
 
Baseline Value 
The “baseline value” is the value measured before first 
administration of study specified treatment.  For 
variables/assessments not scheduled to be performed on study day 
1 or that are missing at baseline, the baseline value is the value 
from the screening period measured closest to study day 1. 
Duration of Response 
The time from the date of first documentation of a response to the 
first documented progressive disease. 
End of Study  
This visit is planned for approximately 30 days after a subject 
discontinues investigational product administration. 
Investigational Product 
RX-3117 
On-Study Death 
Any death that occurs after receiving protocol directed therapy 
through 30 days after the last dose of investigational product.  The 
cause of any on-study death will be reported as a serious adverse 
event.  
Overall Response Rate 
The number of complete responders and partial responders in the 
response evaluable population 
Progression Free 
Survival 
The time from the date of first study drug administration to the date 
of documented progressive disease or death due to any cause, 
whichever occurs first. The progression-free survival rate will also 
be measured. It is defined as the proportion of subjects with stable 
disease for at least 4 months. 
Safety Follow-up  
This period is planned for approximately 30 days after a subject 
discontinues investigational product administration. 
Screen Failure 
A subject who signs an informed consent but does not qualify to be 
enrolled into the study. 
Screening Period 
The period that occurs between the signing of the informed consent 
and day of enrollment (14 day maximum). 
Study Day 1 
The day that the first dose of investigational product is 
administered.   
Study Start 
Occurs when the first subject has been enrolled. 
Treatment emergent 
adverse event 
An adverse event that occurs following the first administration of 
study specified treatment. 
Time to Progression 
The time from the date of first study drug administration to the date 
of documented progression 
Time to Response 
The interval from the start of study treatment to the first 
documentation of CR or PR or other measure of response 
 


Protocol Number:  RX-3117-P1-01 
Product:  RX-3117 
19 February 2016 
Amendment 04 
CONFIDENTIAL 
Page 12 of 108
Table of Contents 
Page 
Investigator Agreement ................................................................................................... 2 
Protocol Synopsis ............................................................................................................ 5 
Study Glossary ................................................................................................................ 7 
1.
OBJECTIVES ....................................................................................................... 17 
1.1 
Phase 1 Primary ........................................................................................ 17 
1.2 
Phase 1 Secondary ................................................................................... 17 
1.3 
Phase 1 Exploratory .................................................................................. 17 
1.4 
Phase 2 Primary ........................................................................................ 17 
1.5 
Phase 2 Secondary ................................................................................... 17 
1.6 
Phase 2 Exploratory .................................................................................. 17 
2.
BACKGROUND AND RATIONALE ...................................................................... 18 
2.1 
Disease ..................................................................................................... 18 
2.2 
Cytidine Analogs in the Therapy of Cancer ............................................... 18 
2.2.1 
RX-3117 Structure ..................................................................... 20 
2.2.2 
Mechanism of Action and Nonclinical Pharmacology 
Studies ...................................................................................... 20 
2.2.3 
Nonclinical Safety Pharmacology Studies.................................. 21 
2.2.4 
Nonclinical Pharmacokinetic and Drug Metabolism 
Studies ...................................................................................... 22 
2.2.5 
Nonclinical Toxicology Studies .................................................. 25 
2.2.6 
Exploratory Clinical Study .......................................................... 27 
2.3 
Selection of Starting Dose ......................................................................... 28 
2.4 
Dosing Frequency Rationale ..................................................................... 30 
3.
EXPERIMENTAL PLAN ........................................................................................ 30 
3.1 
Study Design ............................................................................................. 30 
3.2 
Number of Centers .................................................................................... 32 
3.3 
Number of Subjects ................................................................................... 32 
3.4 
Estimated Study Duration .......................................................................... 32 
3.4.1 
Study Duration for Participants .................................................. 32 
3.4.2 
End of Study .............................................................................. 32 
4.
SUBJECT ELIGIBILITY ........................................................................................ 32 
4.1 
Screening Log ........................................................................................... 33 
4.2 
Inclusion Criteria ....................................................................................... 33 
4.3 
Exclusion Criteria ...................................................................................... 35 
5.
SUBJECT ENROLLMENT .................................................................................... 36 
5.1 
Subject Recruitment .................................................................................. 36 
5.2 
Subject Registration, Enrollment and Treatment Assignment .................... 36 


Protocol Number:  RX-3117-P1-01 
Product:  RX-3117 
19 February 2016 
Amendment 04 
CONFIDENTIAL 
Page 13 of 108
5.3 
Subject Enrollment and Treatment Assignment ......................................... 37 
5.4 
Subject Replacement ................................................................................ 37 
6.
TREATMENT PROCEDURES .............................................................................. 37 
6.1 
Study Drug Administration ......................................................................... 37 
6.1.1 
Dosing Schedule ....................................................................... 37 
6.1.2 
Dose Administration .................................................................. 38 
6.2 
Dose Escalation and Stopping Rules ........................................................ 38 
6.3 
Determination of MTD and Recommended Phase 2 Starting 
Dose ......................................................................................................... 41 
6.4 
Definitions of Dose-Limiting Toxicity .......................................................... 42 
6.5 
Delayed, Missed and Vomited Doses ........................................................ 42 
6.6 
Dosage Modifications ................................................................................ 43 
6.6.1 
Dose Modifications During a Cycle ............................................ 43 
6.6.2 
Dose Modifications at the Beginning of the Next Cycle .............. 43 
6.6.3 
Dose Re-Escalation ................................................................... 44 
6.7 
Discontinuation of Study Treatment ........................................................... 44 
6.8 
Concomitant and Supportive Therapy ....................................................... 46 
6.8.1 
Analgesics ................................................................................. 46 
6.8.2 
Antibiotics .................................................................................. 46 
6.8.3 
Anticancer or Experimental Systemic Therapies Other 
than Investigational Treatments ................................................. 47 
6.8.4 
Antidiarrheals ............................................................................ 47 
6.8.5 
Antiemetics ................................................................................ 48 
6.8.6 
Contraception ............................................................................ 48 
6.8.7 
Corticosteroids .......................................................................... 49 
6.8.8 
Diet ............................................................................................ 49 
6.8.9 
Drugs with Potential for Interactions with RX-3117 .................... 50 
6.8.10 
Erythropoietin and Granulocyte Colony-Stimulating 
Factors ...................................................................................... 50 
6.8.11 
Immunization ............................................................................. 51 
6.8.12 
Radiation Therapy ..................................................................... 51 
6.8.13 
Surgery or Other Invasive Procedures ....................................... 51 
6.8.14 
Transfusions .............................................................................. 52 
7.
STUDY PROCEDURES ....................................................................................... 52 
7.1 
General Study Procedures ........................................................................ 52 
7.2 
Screening Procedures ............................................................................... 52 
7.3 
Treatment Period – Cycle 1 Day 1 ............................................................. 53 
7.3.1 
Pre-dosing Assessments ........................................................... 53 
7.3.1 
Post-dosing Assessments – Cycle 1 Day 1 ............................... 54 
7.4 
Treatment Period – Cycle 1 Day 8 ............................................................. 55 
7.5 
Treatment Period – Cycle 1 Day 15 ........................................................... 56 
7.5.1 
Pre-dosing Assessments ........................................................... 56 


Protocol Number:  RX-3117-P1-01 
Product:  RX-3117 
19 February 2016 
Amendment 04 
CONFIDENTIAL 
Page 14 of 108
7.5.2 
Post-dosing Assessments – Cycle 1 Day 15 ............................. 57 
7.6 
Treatment Period – Cycle 1 Day 22 ........................................................... 57 
7.7 
Treatment Period – Cycles 2 - 8 ................................................................ 58 
7.8 
Treatment Period – ≥ Cycles 9 .................................................................. 59 
7.9 
End of Treatment Visit or Early Termination .............................................. 60 
7.9.1 
RX-3117 Dosing ........................................................................ 60 
7.10 
Safety Follow-Up Visit ............................................................................... 61 
7.11 
Unscheduled Visit(s) ................................................................................. 61 
7.12 
Tumor measurements ............................................................................... 62 
8.
OTHER ASSESSMENT(S) ................................................................................... 62 
8.1 
Predictive and Pharmacodynamic Biomarker ............................................ 62 
8.2 
Sample Storage and Destruction ............................................................... 63 
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 64 
9.1 
Definitions ................................................................................................. 64 
9.1.1 
Adverse Events ......................................................................... 64 
9.1.2 
Serious Adverse Events ............................................................ 65 
9.2 
Other Events Requiring Rapid Reporting ................................................... 66 
9.2.1 
Eliciting Adverse Event Information ........................................... 67 
9.3 
Reporting Procedures for All Adverse Events ............................................ 67 
9.4 
Grading of the Severity of an Adverse Event ............................................. 68 
9.5 
Describing Adverse Event Relationship to Study Drug and Study 
Procedures ................................................................................................ 69 
9.6 
Adverse Event Reporting Requirements .................................................... 69 
9.6.1 
Site Reporting Requirements ..................................................... 69 
9.6.2 
Study Sponsor Reporting Requirements.................................... 71 
9.7 
Special Situation Reporting Requirements ................................................ 72 
9.7.1 
Definitions of Special Situations ................................................ 72 
9.7.2 
Pregnancy ................................................................................. 73 
9.7.3 
Instructions for Reporting Special Situations ............................. 74 
10.
STATISTICAL CONSIDERATIONS ...................................................................... 75 
10.1 
Study Endpoints ........................................................................................ 75 
10.1.1 
Primary Endpoints – Phase 1 .................................................... 75 
10.1.2 
Secondary Endpoints – Phase 1 ............................................... 75 
10.1.3 
Exploratory Endpoints ............................................................... 76 
10.1.4 
Primary endpoint – Phase 2 ...................................................... 76 
10.1.5 
Secondary endpoints – Phase 2 ................................................ 76 
10.1.6 
Exploratory endpoints – Phase 2 ............................................... 77 
10.2 
Analysis Conventions ................................................................................ 77 
10.2.1 
Analysis Sets ............................................................................. 77 
10.3 
Sample Size Considerations ..................................................................... 77 
10.4 
Randomization and Stratification ............................................................... 78 


Protocol Number:  RX-3117-P1-01 
Product:  RX-3117 
19 February 2016 
Amendment 04 
CONFIDENTIAL 
Page 15 of 108
10.5 
Interim Analysis and Early Stopping Guidelines ........................................ 78 
10.5.1 
Data Handling Conventions ....................................................... 79 
10.6 
Analysis Plan ............................................................................................. 81 
10.6.1 
Subject Disposition and Baseline Characteristics ...................... 81 
10.6.2 
Exposure and Safety Analyses .................................................. 82 
10.6.3 
Efficacy Analyses ...................................................................... 86 
10.6.4 
Other Analyses .......................................................................... 87 
10.7 
Statistical Basis for the Dose Escalation Paradigm.................................... 87 
10.8 
Timing of Analyses .................................................................................... 88 
10.8.1 
Interim Analyses ........................................................................ 88 
10.8.2 
Final Analysis ............................................................................ 88 
11.
INVESTIGATIONAL PRODUCT ........................................................................... 89 
11.1 
RX-3117 .................................................................................................... 89 
11.2 
Packaging and Labelling ........................................................................... 89 
11.3 
Storage and Handling ................................................................................ 89 
11.4 
Source ....................................................................................................... 89 
11.5 
Dispensing ................................................................................................ 89 
11.6 
Procedures for Monitoring Subject Compliance ......................................... 90 
11.7 
Drug Accountability ................................................................................... 90 
11.8 
Overdose Precautions ............................................................................... 91 
11.9 
Inadvertent Exposure and Spill Precautions .............................................. 92 
12.
REGULATORY OBLIGATIONS ............................................................................ 92 
12.1 
Informed Consent ...................................................................................... 92 
12.2 
Institutional Review Board ......................................................................... 93 
12.3 
Prestudy Documentation Requirements .................................................... 93 
12.4 
Subject Confidentiality ............................................................................... 94 
12.5 
Investigator Signatory Obligations ............................................................. 94 
13.
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 95 
13.1 
Protocol Amendments and Study Termination ........................................... 95 
13.2 
Study Documentation and Archive ............................................................ 95 
13.3 
Study Monitoring and Data Collection........................................................ 96 
13.4 
Language .................................................................................................. 97 
13.5 
Publication Policy ...................................................................................... 97 
13.6 
Compensation ........................................................................................... 98 
14.
REFERENCES ..................................................................................................... 99 
15.
APPENDICES .................................................................................................... 101 
List of Appendices 
Appendix A.  Schedule of Assessments ...................................................................... 101 
Appendix B.  Analytes ................................................................................................. 104 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 16 of 108 
Appendix C.  Response Evaluation Criteria in Solid Tumors ........................................ 105 
 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 17 of 108 
1. 
OBJECTIVES 
1.1 Phase 1 Primary  
 
To evaluate the safety and tolerability of escalating RX-3117 doses and multiple 
schedules in subjects with advanced or metastatic solid tumors 
 
To determine the maximum tolerated dose (MTD) of RX-3117 when administered 
orally to subjects with advanced solid tumors  
1.2 Phase 1 Secondary  
 
To determine the pharmacokinetic profile of RX-3117  
 
To evaluate the anti-tumor activity of RX-3117  
 
To evaluate the potential for QT interval prolongation due to RX-3117 
1.3 Phase 1 Exploratory   
 
To investigate predictive and pharmacodynamic blood or tumor biomarkers 
suggested from nonclinical studies/literatures which may be predictive of 
response or resistance to RX-3117 treatment 
1.4 Phase 2 Primary  
 
To estimate the antitumor activity of RX-3117 in subjects with advanced 
malignancies (relapsed or refractory pancreatic or advanced  bladder cancer) 
1.5 Phase 2 Secondary  
 
To assess additional measures of antitumor activity 
 
To characterize the safety profile associated with RX-3117 
 
To evaluate population pharmacokinetics using a limited sampling 
1.6 Phase 2 Exploratory 
 
To investigate the effect of RX-3117 on potential biomarkers in blood or tumor 
samples  
 
To evaluate changes in tumor burden response 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 18 of 108 
2. 
BACKGROUND AND RATIONALE 
2.1 Disease  
According to the latest statistics (American Cancer Society, 2013), cancer causes 
around 7.6 million deaths worldwide each year.  Deaths from cancer are projected to 
continue rising to an estimated 21.4 million worldwide in 2030 (American Cancer 
Society, 2011). 
For patients presenting with confined local-regional cancer, the development of systemic 
therapies as adjuvants to primary surgery or irradiation have substantially improved 
outcomes by delaying recurrence of disease.  However, for patients who present with 
large primary tumors or metastases or who develop recurrent metastatic disease, cancer 
becomes a life-threatening disorder.  Therapy for patients with advanced cancer has 
focused on the sequential use of systemic treatments to impede the disease progression 
that leads to disabling symptoms and death.  Depending upon the tumor type, hormonal 
therapies, therapeutic monoclonal antibodies, or tyrosine kinase receptor inhibitors may 
be employed, and most commonly, cytotoxic chemotherapy in various sequences and 
combinations is administered.  
The development of newer agents in the past 2 decades illustrates that it is still possible 
to improve outcomes by offering more efficacious, less toxic, and more convenient 
therapies to patients with cancer.  However, for patients with metastatic disease, the 
acquisition of drug resistance results in less activity with each successive type of 
treatment, leading to a decrease in the quality and the duration of tumor response with 
each subsequent therapy.  Survival rates for patients with metastatic cancer remain poor 
because tumor progression leads to death in the majority of patients.  Consequently, 
new therapies with alternative mechanisms of action are needed to offer additional 
treatment options for patients with advanced cancer. 
2.2 
Cytidine Analogs in the Therapy of Cancer 
Cytidine analogs have been widely used as antivirals and for the treatment of various 
types of cancer, both hematologic as well as solid tumors.  These agents include 
cytarabine, 5-azacytidine, 5-aza-2’deoxycytidine (decitabine) and gemcitabine.  
Among these, gemcitabine is the most broadly used anticancer agent.  Initially 
developed as an antiviral agent, gemcitabine (2’,2’-difluoro-2’-deoxycytidine) is 
structurally similar to cytarabine differing due to a fluorine substitution at position 2’ of 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 19 of 108 
the furanose ring. Gemcitabine is a prodrug that requires cellular uptake and intracellular 
phosphorylation.  Within the cell, gemcitabine is phosphorylated to gemcitabine 
monophosphate (dFdCMP) by deoxycytidine kinase which ultimately is converted to 
either the di- or triphosphate forms (gemcitabine diphosphate [dFdCDP] and 
gemcitabine triphosphate [dFdCTP]; Heinemann et al 1992). 
Gemcitabine appears to have several intracellular targets.  Much of its anticancer 
properties, however, involve inhibition of deoxyribonucleic acid (DNA) synthesis (Gandhi 
and Plunkett 1990, Heinemann et al 1990, Hertel et al, 1990).  Gemcitabine diphosphate 
is an inhibitor of DNA polymerase (Gandhi and Plunkett 1990) and is also physically 
incorporated into DNA which can lead to termination of chain elongation (Huang et al 
1991). The nonterminal positioning of dFdCTP in DNA prevents detection and repair of 
that sequence by repair enzymes, which ultimately induces apoptosis (Gandhi and 
Plunkett 1990, Schy et al 1993).  A metabolite of gemcitabine, which is most likely 
dFdCTP, can also incorporate into ribonucleic acid (RNA) (Ruiz van Haperen et al 
1993).  Other activities associated with gemcitabine metabolites include inhibition of 
cytidine triphosphate synthetase (CTP synthetase) and inhibition of deoxycytidylate 
deaminase (dCMP deaminase) by dFdCTP (Heinemann et al 1992).  Gemcitabine can 
also affect topoisomerase I, which suggests that induction of topoisomerase I mediated 
DNA break formation can contribute to the cytotoxic potential of this drug (Pourquier et al 
2002). 
Initial Phase 2 studies with gemcitabine as a single-agent (800 mg/m2 weekly for 3 
weeks) demonstrated an overall response rate (ORR) in chemotherapy-naive patients 
with metastatic adenocarcinoma of the pancreas in the range of 6% to 11% (Carmichael 
et al 1996, Casper et al 1994).  Despite this low objective response rate, clinical benefit 
was derived. In the Phase 2 study that led to Food and Drug Administration (FDA) 
approval, clinical benefit was defined as improvement in pain, performance status, or 
weight without deterioration in any other factors (Rothenberg et al 1996).  Clinical benefit 
was reported at 27% as compared to the objective response rate of 11% in 126 patients. 
In addition to its indication in metastatic pancreatic cancer (Burris, III et al 1997), 
gemcitabine is used in combination treatment in non-small cell lung cancer (Sandler et al 
2000), bladder cancer (von der Maase et al 2000), breast cancer (Albain et al 2004), 
ovarian cancer, mesothelioma, and head/neck cancers (Mini et al 2006). 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 20 of 108 
Despite the clinical value of gemcitabine, drug resistance is common, which may be due 
to the loss of transporters and kinases responsible for the first phosphorylation step.  
2.2.1 
RX-3117 Structure 
RX-3117 is a small-molecule, cyclopentyl pyrimidyl nucleoside being developed by 
Rexahn Pharmaceuticals, Inc. RX-3117 was synthesized as a new oral antimetabolite 
with the potential to overcome gemcitabine resistance and offer a favorable 
pharmacologic profile. Its chemical name is 4-amino-1-[(1S,4R,5S)-2-fluoro-4,5-
dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl]pyrimidin-2-one. The RX-3117 
monohydrate drug substance is a white to yellow crystalline solid. The molecular weight 
is 257.22 daltons for the anhydrous form and 275.24 daltons for the monohydrate form. 
Its molecular formula is C10H12N3O4F•H2O. 
2.2.2 
Mechanism of Action and Nonclinical Pharmacology Studies 
The mechanism of action of RX-3117 has been investigated extensively. RX-3117 is an 
antimetabolite that mimics the building blocks of DNA or ribonucleic acid (RNA).  
Antimetabolites are incorporated into DNA or RNA of cells, where they interfere with cell 
division. RX-3117 is activated by uridine-cytidine kinase (UCK), and thus differs from 
gemcitabine, which is activated by deoxycytidine kinase.  In addition, gemcitabine is 
inactivated by cytidine deaminase at a fast rate, whereas RX-3117 is inactivated by 
cytidine deaminase at a slow rate, thus allowing higher cellular concentrations of 
RX-3117 to enhance its anticancer activity.  
In vitro mechanism studies characterized the effects of RX-3117 on cell cycle, apoptosis, 
and further elucidated its mode of action. Cell-cycle analysis by flow cytometry 
demonstrated that RX-3117 inhibited the cell cycle in G1 phase and also induced 
programmed cell death (apoptosis). The sensitivity of RX-3117 to a variety of 
antimetabolite-resistant cell lines was tested, and it was shown that RX-3117 was 
effective in wild-type cells as well as cells with acquired antimetabolite resistance. 
RX-3117 showed a variable resistance pattern in the cell lines tested, with a marked 
cross-resistance for the intrinsically gemcitabine-sensitive A2780 and gemcitabine-
resistant AG6000 ovarian cancers, a moderate cross-resistance for CCRF-CEM acute 
lymphoblastic T-cell leukemia cells, and an enhanced sensitivity for gemcitabine-
resistant SW1573/G non-small cell lung cancer cells. The effect of RX-3117 on DNA and 
RNA was evaluated; the majority of cell lines investigated showed a concentration-


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 21 of 108 
dependent inhibition of DNA and RNA synthesis after exposure to RX-3117, and 
RX-3117 showed inhibition of DNA synthesis more than RNA synthesis in most cell 
lines. Moreover, RX-3117 inhibited the proliferation of a variety of cancer cell lines of 
different origins, including bladder, bone, brain, breast, cervical, colon, liver, lung, 
muscle, ovary, pancreas, prostate, renal, and skin.  
Deoxyribonucleic acid methyltransferase 1 (DNMT1) is responsible for the methylation of 
cytosine residues on newly synthesized DNA and also regulates and maintains 
methylation patterns. DNMT1 is often overexpressed in cancer cells, potentially resulting 
in aberrant methylation patterns that can further cancer progression. It has been shown 
that RX-3117 mediates the down-regulation of DNMT1 protein expression with no effect 
on DNMT1 messenger RNA (mRNA) levels. While the basis for this activity of RX-3117 
on DNMT1 is unclear, this additional action of RX-3117 could contribute to its anti-
cancer activity. 
In vivo studies in nude mice evaluated the effects of RX-3117 on tumor 
proliferation/growth.  RX-3117 displayed antitumor activity in nude mice implanted with 
human tumors (COLO 205 colorectal adenocarcinoma, HCT116 colorectal carcinoma, 
MV-522 and A549 non-small cell lung carcinomas, H460 large-cell lung carcinoma, H69 
small-cell lung cancer, Caki-1 renal carcinoma, CTG-0298 and Mia PaCa-2 pancreatic 
carcinomas, and OVCAR3 ovarian carcinoma). 
The efficacy of RX-3117 in subcutaneous xenograft models (Colo-205, H460, H69 and 
CaSki models), which are moderately sensitive or resistant to gemcitabine, indicates that 
RX-3117 may have the potential to be used for the treatment of tumors that do not 
respond to gemcitabine or have become resistant to gemcitabine. 
In vitro cross-species myelotoxicity data showed a myelotoxic effect on human and 
monkey bone marrow, a potential cytotoxic effect on mouse bone marrow, while non-
significant myelotoxicity was observed on canine and rat bone marrow. 
2.2.3 
Nonclinical Safety Pharmacology Studies 
Safety pharmacology studies by the oral route evaluated potential functional effects of 
RX-3117 on the cardiovascular system, respiratory system, and central nervous system. 
Effects on the central nervous system and the cardiovascular system were also 
evaluated as part of the 28-day oral repeated dose toxicity study in dogs.  In vitro, 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 22 of 108 
RX-3117 displayed no human ether-a-go-go-related gene (hERG) potassium channel 
inhibition, no cardiac cytotoxicity, and had no effect on spontaneous beating in Cor.At® 
pure embryonic stem cell derived cardiomyocytes.  In vivo, RX-3117 did not elicit any 
changes in blood pressure parameters, electrocardiography (ECG) parameters, or heart 
rate in dogs. RX-3117 had no significant effects on respiratory parameters in mice. In 
addition, RX-3117 had no effects on the central or autonomic nervous systems, or on 
peripheral motor and sensory systems in both mice and dogs. Finally, RX-3117 had no 
effects on electroencephalography activity following an intravenous (IV) dose of 
100 mg/kg in monkeys. 
Further nonclinical safety pharmacology information can be found in the RX-3117 
Investigator’s Brochure. 
2.2.4 
Nonclinical Pharmacokinetic and Drug Metabolism Studies 
The pharmacokinetic properties of RX-3117 were investigated in mice, dogs, and 
monkeys in conjunction with toxicity studies, as well as in separate pharmacokinetic 
studies.  
Pharmacokinetic studies indicate that RX-3117 is orally bioavailable in mice and dogs, in 
contrast to gemcitabine, which can only be administered by the IV route only. RX-3117 is 
only poorly orally bioavailable in monkeys.  For all species investigated in which the drug 
was orally bioavailable, RX-3117 displayed generally biphasic plasma profiles, with fast 
absorption and a relatively fast initial distribution phase followed by a slower terminal 
phase.  Nonclinical pharmacokinetic parameters characterize a longer terminal 
elimination half-life (t½) of RX-3117 than that of gemcitabine.  Following repeated 
administration, although plasma concentrations were detectable before the last dose, the 
extent of RX-3117 accumulation was minimal, with similar exposure parameters on the 
first and last days of administration.  No sex-related differences of pharmacokinetic 
parameters were observed in any of the species tested. 
In CD-1 mice, RX-3117 displayed dose-dependent pharmacokinetics upon oral 
administration, with subproportional increase in exposure across dose levels of 100, 
300, and 1000 mg/kg.  The absorption of RX-3117 following oral administration was fast, 
resulting in an early time to maximum observed plasma concentration (Tmax) (0.75-1 hour 
postdose).  Oral bioavailability was determined to be 74%.  The t½ values ranged from 3 
to 10.3 hours. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 23 of 108 
In Beagle dogs, linear pharmacokinetic properties were evident following both IV and 
oral administration, at the dose ranges of 100 to 400 mg/kg and 30 to 300 mg/kg, 
respectively.  The absorption of RX-3117 was fast, resulting in an early Tmax (0.25 hour 
postdose).  Administration of 10 mg/kg RX-3117 hydrate in hydroxypropylmethyl-
cellulose capsules, with and without Avicel PH-102 as excipient, did not significantly 
affect absorption of RX-3117 in female dogs relative to solution; although Tmax was 
slightly delayed (0.5-1 hour postdose), relative exposure was the same.  Oral 
bioavailability was determined to be greater than 100%.  The t½ values ranged from 3 to 
5.35 to 39 hours following oral administration and 3.25 to 4.7 hours following IV 
administration. 
The pharmacokinetic properties of RX-3117 were investigated in male Cynomolgus 
monkeys following a single bolus IV administration dose of 2.5 mg/kg (not conducted 
under Good Laboratory Practice [non-GLP] study), or an IV infusion for 6 minutes at 100 
to 300 mg/kg.  Monkeys were dosed via IV administration since RX-3117 displayed poor 
oral bioavailability (11%) in monkeys.  Analysis of RX-3117 after IV infusion showed that 
increasing the dose from 2.5 to 35 mg/kg resulted in a supraproportional increase in 
exposure (greater than twice the expected value), suggesting nonlinear 
pharmacokinetics.  However, IV administration of RX-3117 between the dose range of 
35 to 300 mg/kg displayed linear kinetics.  RX-3117 was rapidly eliminated and showed 
moderate systemic clearance (CL) and volume of distribution (Vz) after low- and 
moderate-dose IV administration. The t½ values ranged from 1.28 to 11.25 hours. 
RX-3117 showed low permeability (< 5×10-6 cm/sec) in Caco-2 cells in both the A-B and 
B-A directions, and seems to be actively transported from the gastrointestinal tract into 
the blood, as well as from the blood into tissues, possibly by human equilibrative 
nucleoside transporter (hENT). 
RX-3117 was tested for plasma protein binding in vitro, in mouse, rat, dog, monkey, and 
human plasma, at concentrations of 1 to 500 μM.  No measurable percentage of protein 
binding was observed in any of the species and concentrations examined. 
Early nonclinical pharmacokinetic and toxicokinetic investigations in dogs and monkeys 
characterized the plasma deaminated metabolite profile of RX-3117.  Deamination of 
RX-3117 was faster in monkeys than in dogs (Tmax= 2.5 and 5 hours).  Relative plasma 
exposure for the deaminated metabolite was higher in monkeys than in dogs (area under 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 24 of 108 
the plasma drug concentration-time curve from 0 to time of the last quantifiable 
concentration [AUC0-last] of metabolite and AUC from 0 to time extrapolated to infinity 
[AUC0-∞] of RX-3117 were 56% and 30% in monkeys and dogs, respectively), and the 
observed elimination of the metabolite was slower than the elimination of the drug for 
both species.  Due to its longer t½, the deaminated metabolite exposure following 
repeated administration equaled or exceeded RX-3117 exposure.  In monkeys, the ratio 
of AUC0-last of metabolite to AUC0-last of the parent drug was 197% and 93%, respectively, 
after 5 daily IV administrations of 35 mg/kg RX-3117 and 4 doses of 150 mg/kg 
administered IV twice weekly.  In dogs, accumulation of the metabolite was less 
pronounced, with an increase of the exposure ratio to around 50% upon repeated 
administration. 
Interspecies comparison of the in vitro metabolism of RX-3117 in mouse, rat, dog, 
monkey, and human liver microsomes revealed that RX-3117 does not undergo 
cytochrome P450 (CYP)-mediated metabolism in any of these species.  RX-3117 
metabolism was further investigated in human transformed cell lines.  It was shown that 
RX-3117 was not phosphorylated by deoxycytidine kinase, but by UCK, into an active 
nucleotide form (mono-, bi-, or triphosphorylated RX-3117) and further incorporated into 
both RNA and DNA.  It was also shown that RX-3117 deamination was cytidine 
deaminase -mediated, although its extent and rate are relatively very low. 
RX-3117 excretion was studied using 300 mg/kg of 3H-RX-3117 orally administered to 
mice.  RX-3117 excretion was relatively rapid with about 80% of the radioactivity 
eliminated during the first 24 hours.  Total recovery following 1 week was 94%, with 48% 
of dose radioactivity excreted in the urine and 46% in the feces. 
When tested in vitro in human liver microsomes, RX-3117 at 0.1 to 100 μM did not cause 
direct or time-dependent inhibition of any of the CYP enzymes tested, namely CYP1A2, 
CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5. 
When tested in vitro in human transporter-transfected polarized cell monolayer/vesicles, 
RX-3117 did not inhibit any of the transporters studied, namely organic anion transporter 
(OAT)1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, breast cancer resistance protein, 
P-glycoprotein, and bile salt export pump, at clinically relevant concentrations (up to 
5 mM). The effect of RX-3117 on CYP induction has not yet been evaluated. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 25 of 108 
2.2.5 
Nonclinical Toxicology Studies 
In mice, a single oral administration of RX-3117 at doses up to 1000 mg/kg did not 
induce toxicity signs on the day of treatment or during a 14-day recovery period, at any 
of the doses tested.  Following daily oral administration of RX-3117 at 180/100 
mg/kg/day (male/female mice), 60 and 30 mg/kg/day (both male and female mice) for up 
to 28 days, mortality occurred at the high dose in male and female mice (180 and 100 
mg/kg, respectively) and in the mid-dose female mice (60 mg/kg).  Consequently, dosing 
of the high-dose groups was terminated early.  Clinical signs were observed mainly in 
high-dose groups and included hunched posture, piloerection, decreased activity, 
lethargy, tremors, semi-closed eyes, and cold to touch.  Clinical signs mostly appeared 
just prior to the death or unscheduled sacrifice of the animals.  Marked reductions in 
body weight and food consumption were observed in high-dose groups and to a lesser 
extent in mid-dose groups with complete recovery at the end of the recovery period.  
Hematology investigations showed anemia, thrombocytosis, and leukopenia to be dose 
dependent, with partial recovery at the end of the recovery period. In clinical chemistry, 
reductions in glucose, and elevated globulin and creatine kinase levels were seen.  At 
necropsy, atrophy was seen in the thymus, lymph nodes, spleen, and bone marrow.  
Histopathologic examinations revealed reductions in the normally present 
intracytoplasmic glycogen contents and single-cell necrosis in the liver, sporadic cases 
of vacuolation of the epithelium lining the kidney tubules, moderate inflammation of the 
intestinal mucosa associated with atrophy of the villi, and sporadic presence of ulcers in 
the cecum and atrophy of the ovary corpora lutea.  Partial recovery was seen at the end 
of the recovery period.  The dose of 60 mg/kg/day was considered as the severely toxic 
dose (STD). 
In a non-GLP study in mice in which RX-3117 was given orally 3 times a week at 500, 
1000, and 1500 mg/kg for a total of 5 administrations, a similar picture of toxicity 
appeared, yet at much higher doses as compared with the daily dosing regimen.  
Mortality occurred in the mid- and the high-dose groups (1000 and 1500 mg/kg, 
respectively).  Clinical signs were observed in the mid- and high-dose groups and 
included piloerection, hunched posture and decreased activity.  Reduction in body 
weights and food consumption were mainly observed in high-dose groups.  Hematologic 
changes included significant reductions in reticulocytes and anemia, thrombosis, and 
leukopenia to be dose dependent. The dose of 500 mg/kg/day was considered to be the 
maximum tolerated dose (MTD) in this study. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 26 of 108 
In dogs, the main effects following a single oral administration of RX-3117 at doses up to 
300 mg/kg were bone marrow toxicity, consisting of significant changes in hematologic 
parameters, and reductions in weights of the thymus and male sexual glands in mid- 
(100 mg/kg) and high-dose (300 mg/kg) groups.  Following daily oral administration of 
RX-3117 for up to 28 days at doses of 1, 2.5, and 5 mg/kg, isolated episodes of emesis 
and liquid feces, along with reductions in body weight and food consumption, were seen 
in high-dose groups.  Hematologic changes were noted in high-dose groups, consisting 
of decreases in erythrocytes, hemoglobin, hematocrit, reticulocytes, and leucocytes and 
elevations in platelets, which were fully recoverable by the end of the recovery period. At 
necropsy, thymus weights were reduced in high-dose groups and mid-dose female dogs, 
with complete recovery in 3 of 4 animals.  Thymus atrophy was noted at histopathologic 
examinations in 1 male dog given the high dose.  The changes seen in the thymus were 
potentially secondary, related to stress-associated with the administration of high dose. 
No changes were observed in weights or histopathology of male sexual glands.  The 
dose of 5 mg/kg/day was determined as the highest nonseverely toxic dose (HNSTD) 
while the dose of 2.5 mg/kg/day was determined as the no-observed-adverse-effect level 
(NOAEL). 
In a non-GLP study in dogs in which RX-3117 was given orally at doses of 15 and 
30 mg/kg 3 times per week for a total of 6 administrations, abnormal feces were 
observed in the high-dose group but no significant reductions in body weight and food 
consumption were seen in either dose group.  Hematologic changes included reductions 
in neutrophils, lymphocytes, monocytes, and basophils in both dose groups with full 
recovery 5 days after the last dose.  Overall, the toxicity profile of RX-3117 in this study 
was similar to that observed during the 28-day repeated dose toxicity study, yet toxic 
effects were observed at higher doses in the thrice-weekly dosing regimen.  The dose of 
30 mg/kg/day was considered to be the MTD in this study. 
Intravenous administration of high doses of RX-3117 in dogs and monkeys was 
associated with marked central nervous system toxicity, which was not observed in any 
of the tested species following dosing by the oral route.  In dogs, a single IV dose of 400 
mg/kg induced tremors of the head and convulsions 10 hours postdose.  No such signs 
were noted in dogs following a single oral administration of RX-3117 at up to 300 mg/kg, 
or after 28-days repeated oral administration at doses up to 5 mg/kg/day.  In monkeys, a 
single IV dose of 300 mg/kg induced convulsions, tremors, and behavioral disturbances 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 27 of 108 
(disorientation, incoordination, and falling over), which were observed 8 hours postdose, 
while a single IV dose of 200 mg/kg or repeated twice weekly doses of 150 mg/kg (given 
4 times) were associated with dilated pupils, ataxia, and tremors.  Daily IV doses of 
35 mg/kg in monkeys (given for 5 consecutive days) were not associated with any signs 
of central nervous system toxicity. 
RX-3117 was tested in a dedicated electroencephalography study in monkeys, in order 
to set safe doses and exposure levels based on electroencephalography measurements.  
Following a single IV dose of 100 mg/kg, no effects were noted on 
electroencephalographic activity and no clinical or electrophysiologic findings suggesting 
proconvulsant or seizure liability were observed.  Exposure levels measured at this safe 
dose of 100 mg/kg IV were: 200428 ng/mL and 206670 ng/mL (mean maximum 
observed plasma concentration measured [Cmax] in male and female monkeys, 
respectively) and 119,811 ng•hr/mL and 13439 ng•hr/mL (mean AUC from the time of 
dosing to the last measurable concentration, [AUC0-t] in male and female monkeys, 
respectively). 
RX-3117 was not mutagenic in the Ames in vitro reverse mutation assay using 5 strains 
of bacteria.  However, RX-3117 was mutagenic to mammalian cells, when tested in the 
mouse lymphoma cell assay. 
No studies on reproductive toxicity and carcinogenicity with RX-3117 have been 
performed. 
2.2.6 
Exploratory Clinical Study 
RX-3117 was evaluated in an exploratory pharmacokinetic study of a single oral dose 
(50 or 100 mg) or a single IV dose (20 mg) of RX-3117 performed at 2 centers in 
Hungary.  Subjects had advanced solid tumor and had not received any chemotherapy 
for 2 weeks prior to receiving the study drug. 
The primary study objective was to determine the absolute oral bioavailability of 
RX-3117 from a single dose administered to subjects with solid tumors.  The secondary 
objectives were to evaluate the safety and tolerability of a single dose of RX-3117 
administered either orally or IV and to evaluate dose proportionality of 2 single dose 
levels of RX-3117 administered orally.  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 28 of 108 
Nine subjects (3 subjects in each group [50 mg oral dose, 100 mg oral dose, or 20 mg IV 
dose]) were administered study drug in this first-in-human, sub-therapeutic, single-dose 
study.  Study drug was administered either orally or IV to the subject in the clinical 
setting.  The in-patient observation period was from Study Day 1 through Study Day 3.  
After administering the appropriate single dose of RX-3117, blood samples were 
collected at specific times throughout a 48-hour period.  A safety follow-up assessment 
was performed on Study Day 7.  No efficacy or pharmacodynamic endpoints were 
assessed.  Pharmacokinetic and safety results were assessed. Information on 
concomitant medications was collected. 
No subjects were withdrawn from the study for any reason and all subjects completed 
the study.  All 9 subjects were included in the safety and pharmacokinetic analyses. 
Following oral administration, RX-3117 exposure parameters for the 50-mg and 100-mg 
dose levels were not markedly different.  For the respective 50- and 100-mg doses, the 
mean Tmax was 2.16 and 2.49 hours, the mean Cmax was 303 ng/mL and 311 ng/mL, the 
mean AUC0-∞ was 2440 ng•h/mL and 2986 ng•h/mL, and mean t½ values were 14 hours 
and 21 hours (with the concentration-time profiles after the peak showing an initial 
distribution phase followed by a slower terminal elimination phase).  After a single IV 
bolus administration of 20 mg RX-3117, plasma concentrations declined rapidly, 
resulting in a multiphasic profile with a rapid initial decline followed by a slow terminal 
elimination phase, with mean t½ of 21 hours.  The calculated absolute oral bioavailability 
(F), based on non-crossover data, was 55.7% for the 50-mg dose and 33.4% for the 
100-mg dose.  The mean Vz calculated was 345 L.  
No adverse events, treatment-emergent adverse events, deaths, or other serious 
adverse events were reported.  No significant findings resulted from assessments of 
clinical laboratory test results, vital sign measurements, ECG, or physical examination 
findings.  No safety issues (including cardiac toxicity) were reported although it should 
be noted that data were only collected on Days 1 through 3 and Day 7 after the study 
drug administration. 
2.3 
Selection of Starting Dose 
The starting dosage of RX-3117 selected for this study is 30 mg/day administered in 
repeated 4-week cycles comprising administration of the drug 3 times per weekly for 
3 weeks with a 1-week hiatus.  This starting dosage selection is based on the results of 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 29 of 108 
28-day toxicology studies in both mice and dogs and is in compliance with the 
International Conference on Harmonisation (ICH) S9 guideline.  
Repeated oral dose toxicity studies with RX-3117 were conducted up to 28 days in mice 
and dogs followed by recovery periods of up to 28 days.  Dosages evaluated in mice 
were 180/100 mg/kg/day (male/female mice), 60 mg/kg/day and 30 mg/kg/day (both 
male and female mice), which were converted into human equivalent doses (HED) of 
540/300 mg/m2, 180 mg/m2, and 90 mg/m2, respectively.  Dosages evaluated in dogs 
were 1, 2.5, and 5 mg/kg/day with HEDs of 20 mg/m2, 50 mg/m2, and 100 mg/m2, 
respectively. 
Using data from rodents, the initial starting dose in humans is calculated as 1/10 of the 
HED that produces severe toxicity in 10% of the animals (STD10).  The STD10 in mice 
was determined to be 60 mg/kg, which is converted to an HED of 180 mg/m2; with 
application of the 1/10 safety factor, the starting dose in humans would be 18 mg/m2.  
For an adult (60 kg) with an average body surface area of 1.6 m2, this calculates to a 
dose of 28.8 mg/subject.  
Using data from nonrodents, the initial starting dose is calculated as 1/6 of the human 
equivalent of the HNSTD.  In the case of RX-3117, the HED is calculated according to 
body surface comparison as described by Senderowicz (2010).  Thus, the STD10 of 5 
mg/kg in dogs is converted to a HED of 100 mg/m2; with application of the 1/6 safety 
factor, the starting dose based on this species is 16.7 mg/m2.  For an adult (60 kg) with 
an average body surface area of 1.6 m2, this calculates to a dose of 26.7 mg/subject. 
Therefore, the human starting doses of RX-3117 calculated from 28-day toxicity studies 
in mice and dogs are comparable, at 28.8 or 26.7 mg/subject, respectively.  Thus an 
appropriate starting dose is 30 mg. 
Based on preliminary xenograft modeling in the most sensitive tumor cell line to date, 
renal cell (Caki-1), 3 times/week dosing was effective (see RX-3117 Investigator’s 
Brochure).  Considering toxicity data from nude mice and beagle dogs, clinical 
administration of repeated therapy cycles comprising drug administration 3 times per 
week weekly for 3 weeks with a 1-week hiatus appears appropriate to induce tumor cell 
killing but permit recovery from myelosuppression.  However, there are other studies in 
dogs in which once daily dosing for 5 days was given.  Additional studies may suggest 
daily dosing for 5 days with a 2-day hiatus over a 2-week period with a 2-week period of 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 30 of 108 
no drug for a total 28-day cycle. If the planned treatment schedule is not fully feasible, 
the study design may be amended to evaluate alternate treatment schedules.  
2.4 Dosing Frequency Rationale 
Three times per week dosing up to 4500 mg was originally planned for this study.  
However, following treatment with 1000 to 2000 mg, RX-3117 levels in the blood began 
to plateau.  Based upon this finding more frequent dosing at lower doses is 
recommended. 
To predict the potential exposures resulting from variable doses and schedules, a 
simulated population PK model was created and then validated with the clinical 
pharmacokinetic data collected in the current study at 3 times per week dosing 
administration (doses 30 to 2000 mg 3 times per week). At each dose level, 500 
simulated profiles were generated using the RX-3117 population PK model. At most 
dose levels, the clinically measured concentration profiles were generally within the 
middle 90% of the simulated profiles and often were close to the median concentration 
line, thereby providing a positive visual predictive check of the model. Using the 
population PK model, potential RX-3117 plasma exposures were predicted for proposed 
5 and 7 times per week dosing schedules. In the revised dosing schedule (Table 2), the 
total weekly doses, total weekly exposures (AUCs), and total cycle doses are initially 
planned not to exceed doses administered previously on a 3 times per week dosing 
schedule (Table 1).  
3. 
EXPERIMENTAL PLAN 
3.1 Study Design 
This is a Phase 1, multicenter, open-label, single-agent study of RX-3117 administered 
orally to subjects with advanced or metastatic solid tumors, with a dose expansion at the 
MTD or recommended Phase 2 dose and schedule followed by a 2-stage (Simon, 1989) 
Phase 2 study design in subjects with relapse/refractory pancreatic cancer or advanced  
bladder cancer.  The study consists of a screening period (up to 14 days; up to 21 days 
for tumor imaging assessments), repeated 28-day treatment cycles for up to 8 cycles, an 
end-of-treatment visit, and a follow-up visit approximately 30 days after the last dose of 
RX-3117.  Additional cycles of therapy may be provided following discussions with the 
investigator, sponsor and medical monitor. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 31 of 108 
The drug will be administered orally in repeated 4-week cycles comprising administration 
of the drug 3 times per weekly, 5 times per week, or daily (e.g., 7 days per week) for 
3 weeks with a 1-week hiatus.  These dosing regimens and schedules are supported by 
non-clinical toxicology studies performed in the mouse and dog, clinical pharmacokinetic 
data from the current study and pharmacokinetic simulation data.  
In the Phase 1, the initial starting dose level of RX-3117 will be 30 mg/day.  The dose 
escalation will begin with an accelerated design in single subjects (Simon et al., 1997).  
After the occurrence in Cycle 1 of a single ≥ Grade 2 adverse event that is considered 
related to RX-3117, the study will transition to a standard 3 + 3 design using a modified 
Fibonacci sequence (see Section 6.2 for details).   
In the Phase 1 portion of the study subjects with advanced solid tumor malignancies will 
be enrolled.  During the Phase 1 portion of the study, the maximum tolerated dose 
(MTD) or a recommended Phase 2 dose (RP2D) and schedule will be determined and 
the pharmacokinetics of RX-3117 characterized in eligible subjects.  Following 
determination of the MTD or RP2D dose a Phase 1 Dose Expansion will occur.  In the 
Dose Expansion, subjects will be enrolled in 1 of 3 diagnosis groups: relapsed or 
refractory pancreatic, colorectal or advanced  bladder cancers.  In the Phase 2 portion, 
subjects will be enrolled in 1 of 2 diagnosis groups: relapsed or refractory pancreatic or 
bladder cancers.  The Phase 2 part of the study will follow a 2-stage design (Simon, 
1989).  An interim analysis will be conducted when 10 response evaluable subjects in 
each tumor indication are enrolled and have had the opportunity to complete a minimum 
of 4 cycles of therapy or have discontinued therapy due to progressive disease.  In the 
second stage, efficacy will be further evaluated in the disease groups that continue 
beyond the first stage.   
Subjects will receive up to 8 cycles of RX-3117 or until disease progression (per RECIST 
ver 1.1 see Appendix C), an intolerable RX-3117 related adverse event, withdrawal of 
consent, pregnancy, substantial noncompliance, or if the principal investigator feels it is 
in the best interest of the subject to stop treatment.  After 8 cycles of therapy if in the 
opinion of the investigator, a subject is receiving benefit, additional cycles of RX-3117 
may be administered following discussions with the sponsor and medical monitor. 
The study endpoints are defined in Section 10.1. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 32 of 108 
3.2 Number of Centers 
Approximately 12 sites in the US will participate in this study.  Sites that do not enroll 
subjects within 3 months of site initiation may be terminated.   
3.3 Number of Subjects 
The number of subjects enrolled into this study may vary depending upon the number of 
dose levels needed to determine the maximum tolerated dose or recommended Phase 2 
dose.  It is anticipated that approximately 152  subjects will be enrolled in this study (40 
subjects in the Phase 1, 12 subjects in the Phase 1 Dose Expansion, 20 subjects (10 per 
cancer indication) in Stage 1 of the Phase 2 and 80 subjects (40 per cancer indication) in 
Stage 2 of the Phase 2.   
3.4 Estimated Study Duration 
3.4.1 
Study Duration for Participants 
The study will consist of a screening period (14 days), up to 8 treatment cycles (i.e., 
cycle = 28 days), an end-of-treatment visit, and a follow-up visit 30 +7 days after the last 
dose of RX-3117.   Subject participation is anticipated to be approximately 10 months.  
Subjects may receive RX-3117 until the earliest sign of disease progression (per 
RECIST ver 1.1 see Appendix C), an intolerable RX-3117-related toxicity, withdrawal of 
consent, pregnancy, substantial noncompliance with study procedures, principal 
investigator judgment that it is in the best interest of the subject to stop treatment, or 
study discontinuation. 
3.4.2 
End of Study 
The study will end when the last subject treated completes their safety follow-up visit. 
4. 
SUBJECT ELIGIBILITY 
This clinical trial can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select subjects for whom study participation is 
considered appropriate.  All relevant medical and non-medical conditions should be 
taken into consideration when deciding whether this protocol is suitable for a particular 
subject.  Eligibility criteria may not be waived by the investigator and conformance to the 
eligibility criteria is subject to review in the case of a Good Clinical Practice (GCP) or a 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 33 of 108 
regulatory authority audit.  Any questions regarding a subject’s eligibility should be 
discussed with the study sponsor and medical monitor prior to enrollment. 
4.1 
Screening Log 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (i.e., age, sex, 
race), date, and outcome of the screening process (e.g., enrolled into study, reason for 
ineligibility, or declined to participate). 
4.2 Inclusion Criteria 
4.1.1 Disease related 
- 
Confirmed histologic or cytologic evidence of metastatic or locally advanced 
solid neoplasm that has failed to respond to standard therapy, progressed 
despite standard therapy or for which standard therapy does not exist. There 
is no limit on the number of prior treatment regimens (Phase 1). 
- 
Confirmed histologic or cytologic evidence of metastatic pancreatic, colorectal 
or advanced bladder cancer that failed to respond to standard therapy, 
progressed despite standard therapy or for which standard therapy does not 
exist. There is no limit on the number of prior treatment regimens (Phase 1 
Dose Expansion) 
- 
Confirmed histologic or cytologic evidence of metastatic pancreatic or 
advanced bladder cancer that failed to respond to standard therapy, 
progressed despite standard therapy or for which standard therapy does not 
exist. There is no limit on the number of prior treatment regimens (Phase 2) 
- 
Measurable or evaluable disease using Response Evaluation Criteria in Solid 
Tumors (RECIST) v 1.1. 
- 
Life expectancy of ≥ 3 months 
- 
ECOG performance score 0, 1 or 2 (Phase 1) 
- 
ECOG performance score 0 or 1 (Phase 2) 
- 
Discontinuation of all therapy (including radiotherapy, chemotherapy, 
immunotherapy, systemic corticosteroids, or investigational therapy) for the 
treatment of cancer within 2 weeks before the planned start of study therapy. 
- 
All acute toxic effects of any prior antitumor therapy resolved to Grade  1 
before the start of study therapy (with the exception of alopecia [Grade 1 or 2 
permitted], or neurotoxicity [Grade 1 or 2 permitted], or anemia [Grade 2 
permitted]). 
4.1.2 Demographic 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 34 of 108 
- 
Males or females who are 18 years or older 
- 
Able to swallow capsules 
4.1.3 Laboratory 
- 
Hemoglobin ≥ 9.0 g/dL 
- 
Absolute neutrophil count ≥ 1.5 x 109/L 
- 
Platelet count ≥ 100 x 109/L  
- 
Serum creatinine ≤ 1.5 times the upper limit of normal OR 24-hour measured 
urine creatinine clearance ≥ 50 mL/min for subjects with serum creatinine 
levels > 1.5 times the upper limit of normal 
- 
Serum bilirubin ≤ 1.5 times the upper limit of normal OR ≤ 3 times the upper 
limit of normal in the presence of known liver metastases 
- 
Aspartate aminotransferase (AST; SGOT) and alanine amino transferase 
(ALT; SGPT) ≤ 2.5 times the upper limit of normal OR ≤ 5 times the upper 
limit of normal in the presence of known liver metastases 
- 
Alkaline phosphatase ≤ 2.5 times the upper limit of normal OR ≤ 5 times the 
upper limit of normal in the presence of known liver or bone metastases 
- 
Prothrombin time (PT) < 1.2 times the upper limit of normal unless receiving 
therapeutic anticoagulation, International normalized ratio (INR) up to 3-4 
times the upper limit of normal if on therapeutic anticoagulation and partial 
thromboplastin time (PTT) < 1.2 times the upper limit of normal unless 
receiving therapeutic anticoagulation. 
- 
For women of childbearing potential: Negative serum pregnancy test during 
screening and negative serum or urine pregnancy test at start of study 
therapy (Cycle1 Day 1) 
4.1.4 Reproductive 
- 
For female subjects of childbearing potential, willingness to abstain from 
heterosexual intercourse or use a protocol-recommended method of 
contraception from the screening visit throughout the study treatment period 
and for 30 days following the last dose of study drug (see Section 6.8.6 for 
definition of child-bearing potential).  
- 
For fertile male subjects having intercourse with females of childbearing 
potential, willingness to abstain from heterosexual intercourse or use a 
protocol-recommended method of contraception from the start of study 
therapy throughout the study treatment period and for 30 days following the 
last dose of study drug and to refrain from sperm donation from the start of 
study treatment throughout the study treatment period and for 30 days 
following the last dose of study drug.  (see Section 6.8.6 for definition of male 
fertility) 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 35 of 108 
4.1.5 Ethical 
- 
In the judgment of the investigator, participation in the protocol offers an 
acceptable benefit-to-risk ratio when considering current disease status, 
medical condition, and the potential benefits and risks of alternative 
treatments for the subject’s cancer. 
- 
Before any study-specific procedure, the appropriate written informed 
consent must be obtained (see Section 12.1).   
4.3 Exclusion Criteria 
4.2.1 Disease Related 
- 
Primary brain tumors or clinical evidence of active brain metastasis 
4.2.2 Medications 
- 
Systemic corticosteroid use within 7 days before planned start of study 
therapy 
4.2.3 General 
- 
Active infection requiring parenteral or oral antibiotics within 2 weeks before 
planned start of study therapy 
- 
Uncontrolled diabetes as assessed by the investigator  
- 
Second malignancy other than curatively resected basal cell carcinoma of the 
skin, squamous cell carcinoma of the skin, in situ carcinoma of the cervix, or 
other cancers treated with curative intent and no known active disease in the 
3 years before planned start of study therapy 
- 
QTcF interval greater than 470 msec, with a known history of QTcF 
prolongation, is taking medications known to prolong QTcF, or has history of 
torsade de pointes. 
- 
Documented history of hepatitis B, hepatitis C or human immunodeficiency 
virus 
- 
History of any other concurrent conditions that could preclude the subject’s 
participation in the study, pose an undue medical hazard, or interfere with the 
interpretation of the study results, including, but not limited to, subjects with 
congestive heart failure (New York Heart Association [NYHA] Class III or IV), 
cardiac arrhythmia, or acute coronary syndromes within 6 months before 
planned start of study therapy 
- 
History of prior allogeneic bone marrow progenitor cell or solid organ 
transplantation. 
- 
Any other medical, psychiatric, or social condition, which in the opinion of the 
investigator, would preclude participation in the study, pose an undue medical 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 36 of 108 
hazard, interfere with the conduct of the study, or interfere with interpretation 
of the study results 
- 
Pregnant, planning a pregnancy or breast feeding during the study 
- 
Concurrent participation in another therapeutic clinical trial 
- 
Has any disorder that may interfere with drug absorption, distribution, 
metabolism, or excretion (including gastrointestinal surgery, bariatric surgery)  
- 
Has known hypersensitivity to prior gemcitabine, azacytidine or cytosine 
arabinoside exposure  
- 
Unwilling or unable to comply with study requirements or planned 
unavailability for follow-up assessments 
5. 
SUBJECT ENROLLMENT 
5.1 
Subject Recruitment 
Subjects will be enrolled from the cancer populations being followed at the 
investigational sites.  The site personnel will discuss the possibility of participation 
directly with subjects being seen in the center who may be appropriate candidates for 
the study.  A description of the protocol will be posted on the www.clinicaltrials.gov 
website.   
5.2 
Subject Registration, Enrollment and Treatment Assignment 
Before subjects may be entered into the study, the sponsor requires a copy of the site’s 
written institutional review board approval of the protocol, informed consent form, and all 
other subject information and/or recruitment material, if applicable (see Section 12.3).   
All subjects must personally sign and date the consent form before study specific 
procedures are performed during the screening period.  After a subject has completed 
the necessary screening assessments, any questions regarding the eligibility of a 
subject should be discussed with the study sponsor before enrollment of the subject into 
the study. 
The study sponsor or its designee will assign each subject a unique subject identification 
number (a 2-digit site number followed by a 3-digit subject number).  The subject 
number must be used for subject identification on all study-related documents (e.g., 
electronic case report forms [eCRFs], clinic notes, laboratory samples, CT scans, PET 
scans, MRIs, etc). In order to obtain a subject number, the site must provide completed 
eligibility documents to the study sponsor or designee.  In order for the subject to begin 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 37 of 108 
study treatment, the study sponsor or designee will provide confirmation of eligibility by 
either fax or e-mail to the site.  Of note, subjects may be rescreened only once for 
laboratory values not meeting the criteria for study eligibility.  A subject will be enrolled 
when the treatment dose has been assigned.   
5.3 Subject Enrollment and Treatment Assignment 
The site will provide documentation showing that the subject meets the eligibility 
requirements.  Following a review of supporting documentation, by the sponsor or its 
designee, the site will receive the treatment assignment, dosing schedule and a 
confirmation of enrollment.  Ideally subjects will be dosed within 3 days of enrollment. 
5.4 Subject Replacement 
In the Phase 1, including the Dose Expansion, subjects who are enrolled but not treated 
and subjects who discontinue treatment before completion of Cycle 1 for reasons other 
than the occurrence of a DLT may be replaced.  Any replacement subject will be 
enrolled into the same dosing level and schedule as that for the subject who withdrew. 
In the Phase 2 portion, non-evaluable subjects will be replaced. 
6. 
TREATMENT PROCEDURES 
The only investigational product in this study is RX-3117. For details on the study drug 
description, storage and handling see Section 11. 
6.1 
Study Drug Administration 
6.1.1 
Dosing Schedule 
RX-3117 will be administered on a cyclical basis.  A cycle is defined as the period 
elapsing from the first day of RX-3117 administration through Day 28 of the cycle or to 
the recovery from any adverse events sufficient that a new cycle can be administered 
(e.g., on Day 36 or Day 43), whichever occurs later.  Once a new cycle is initiated, the 
prior cycle is considered to be completed.  
In each 28-day cycle, RX-3117 will be taken by the study subjects 3 times per week 
(e.g., Monday, Wednesday, Friday), 5 times per week (i.e., for 5 consecutive days 
followed by 2 days off) or daily (e.g., 7 days per week) for 3 successive weeks followed 
by  1-week of washout.  Study drug should be taken at approximately the same time 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 38 of 108 
each day (e.g., at ~8 AM on each planned day of dosing).  Ideally, doses should be 
taken at ~48-hour intervals, for 3 times per week, or ~24- hour intervals, for 5 and 7 
times per week dosing schedule.  While it is realized that variations in dosing schedule 
may occur in the outpatient setting, the prescribed regimen should be followed as closely 
as possible, especially in the clinic. 
At specified clinic visits in Cycle 1, the study drug will be administered in the clinic with 
dosing appropriately timed relative to blood sampling for RX-3117 pharmacokinetics.  As 
detailed in Section 7, clinic staff should record RX-3117 administration information, 
including the exact time each dose of RX-3117 is administered in the clinic or hospital.  
6.1.2 
Dose Administration 
At each RX-3117 dose administration, the capsule types and numbers corresponding to 
the appropriate dose of RX-3117 are to be swallowed whole with 100 to 200 mL (~ 4 to 
8 ounces) of water.  Subjects should be instructed not to bite or chew on the capsules.  
In case of breakage of the capsules in the oral cavity, additional water should be taken 
as a rinse.  
Subjects will be instructed to refrain from eating for 8 hours before each dose is 
administered.  Subjects may eat  1 hour after dose administration. 
6.2 Dose Escalation and Stopping Rules 
Dose escalation in this study will begin with an accelerated design involving single 
subjects (Simon et al., 1997) until the occurrence of any adverse event of Grade  2 that 
is considered related to RX-3117.  Thereafter, the dose escalation will transition to a 
standard 3 + 3 design using a modified Fibonacci sequence. Dose escalation will 
proceed according to the specified dose escalation scheme described in Tables 1 and 2.  
The doses will be administered from the least number of capsules available at the time 
of dosing. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 39 of 108 
Table 1:  Dose Escalation Three times per Week 
Dose 
Group 
Capsule Size, mg 
Actual 
dose, 
mg 
Escalation 
Fold-
Increase 
Total 
weekly 
dose, mg 
Total cycle 
dose, mg 
30 
100 
200 
500 
1 
1 
0 
0 
0 
30 
- 
90 
270 
2 
2 
0 
0 
0 
60 
2.00 
180 
540 
3 
0 
1 
0 
0 
100 
1.67 
300 
900 
4 
5 
0 
0 
0 
150 
1.50 
450 
1,350 
5 
0 
2 
0 
0 
200 
1.33 
600 
1,800 
6 
0 
1 
2 
0 
500 
2.50 
1,500 
4,500 
7 
0 
0 
5 
0 
1,000 
2.00 
3,000 
9,000 
8 
0 
0 
0 
3 
1,500 
1.50 
4,500 
13,500 
9 
0 
0 
0 
4 
2,000 
1.33 
6,000 
18,000 
 
In the revised dosing schedule, the total weekly doses, total weekly exposures (AUCs), 
and total cycle doses are initially planned (Table 2, groups 10 through 15) not to exceed 
doses administered previously on a weekly dosing schedule. Dose groups 16 through 
19, if administered, will use all available safety data to make dose escalation decisions 
between the Sponsor, principal investigators and medical monitor. Subjects receiving 
doses that are similar based upon total weekly dosing, despite differing schedules, may 
be enrolled at the same time. 
Table 2.  Dose Escalation -  5 and 7 Times per Week 
Dose 
Group 
Doses 
per 
week 
Capsule Size, mg 
Total daily 
dose, 
mg 
Total 
weekly 
dose, mg 
Escalation 
fold 
Increase 
Total 
cycle 
dose, mg 
100 
200 
500 
10 
5 
0 
0 
1 
500 
2500 
-0.831 
7500 
11 
5 
0 
1 
1 
700 
3500 
1.161 
10500 
12 
7 
0 
0 
1 
500 
3500 
1.161 
10500 
13 
7 
0 
1 
1 
700 
4900 
1.082 
14700 
14 
5 
0 
0 
2 
1000 
5000 
-0.833 
15000 
15 
5 
0 
1 
2 
1200 
6000 
1.003 
18000 
16 
7 
0 
0 
2 
1000 
7000 
1.164 
21000 
17 
5 
0 
0 
3 
1500 
7500 
1.074 
22500 
18 
7 
0 
1 
2 
1200 
8400 
1.124 
25200 
19 
5 
0 
1 
3 
1700 
8500 
1.124 
25500 
20 
5 
0 
0 
4 
2000 
10000 
1.174 
30000 
*Doses will be daily for 5 consecutive days with 2 days off per week (5) or daily for 7 days per week (7) 
1 compared to 3000 mg weekly dose Table 1; 2 compared to 4500 mg weekly Table 1; 3 compared to 
6000 mg weekly Table 1, 4 compared to the previous dose in Table 2. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 40 of 108 
 
In the accelerated portion, dose-escalation decisions will be made after a single subject 
has been treated for 1 cycle of therapy (i.e., 3 weeks of treatment followed by  1 week 
of rest) and doses will be escalated following review of data from Cycle 1 by the 
investigators, medical monitor and sponsor.  The accelerated design schedule will 
continue until there is an adverse event of a  Grade 2 in Cycle 1 that the investigator 
considers related to RX-3117.  After the occurrence of such an adverse event in the first 
subject at that dose level, dose escalation will proceed according to the standard 3+3 
design, with 2 to 5 additional subjects to be treated at the same dose level and schedule 
(depending upon the toxicities observed).  
If a DLT occurs at one dose and dosing schedule (i.e., 5 or 7 times per week), that dose 
and schedule will follow the rules described below for enrolling additional subjects. 
Once the standard 3+3 dose escalation is initiated, the following dose-escalation rules 
will be employed: 
 
If 0 of the first 3 subjects experience DLT during the first 4 weeks of treatment, then 
the dose and schedule will be escalated to the next higher dose group in 
3 subsequent subjects. 
 
If 1 of the first 3 subjects experiences DLT at the current dose and schedule during 
the first 4 weeks of treatment, then 3 more subjects will be accrued at the same dose 
level and schedule.  
 
If 0 of the 3 additional subjects experience DLT during the first 4 weeks of treatment, 
then the dose and schedule will be escalated to the next dose group level in 3 
subsequent subjects. 
 
If  1 of the 3 additional subjects in a dose group experiences DLT in the first 4 
weeks of treatment, the MTD has been exceeded and 3 more subjects will be treated 
at the next lower dose group (if only 3 subjects were previously treated at that prior 
dose group). 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 41 of 108 
 
If  2 of 3 or  2 of 6 subjects experience DLT during the first 4 weeks of treatment, 
then the MTD has been exceeded and 3 more subjects will be treated at the next 
lower dose group (if only 3 subjects were previously treated at that prior dose level).  
 
Each group of 3 subjects within a dose group must be observed for a minimum 
period of 4 weeks without DLT before subsequent subjects are enrolled at the next 
higher dose level.  
 
Escalation to the next dose group of the study can occur upon review of the safety 
data from all ongoing and previous subjects and with the concurrence of the study 
sponsor and the principal investigators.  
In the event that attribution of causality, of potential DLTs, to study drug may be 
equivocal, discussions with the investigators, medical monitor and sponsor will occur 
and additional subjects may be enrolled at that dose level and schedule.  Reviews will 
be conducted by the investigators, medical monitor and sponsor of all available safety 
data on an ongoing basis throughout the study.  The study sponsor or its designee will 
notify the sites when enrollment into a dose level and schedule is complete and when 
the next dose level and schedule is open to enrollment.  
6.3 
Determination of MTD and Recommended Phase 2 Starting Dose 
The establishment of the MTD or recommended Phase 2 dose will be based on a review 
of the overall safety data by the investigators, medical monitor and sponsor.  The MTD is 
the highest dose level and schedule below the dose and schedule associated with first-
cycle DLTs in < 33.3% of subjects.  Once the MTD is initially established, additional 
subjects (up to 12 subjects with metastatic pancreatic cancer or advanced bladder 
cancer) may be enrolled to receive RX-3117 at the MTD or a lower dose and 
corresponding schedule if further confirmation of the safety profile appears warranted.  
Selection of a recommended Phase 2 starting dose from within the tested dose range 
and schedules will be based on evaluation of short- and long-term safety information but 
also considering findings regarding compliance, pharmacokinetics, pharmacodynamics 
and antitumor activity, if applicable.  The review committee may recommend that a 
previous dose level and schedule be considered the MTD or recommended Phase 2 
dose or that another dose level and schedule between the highest previously tolerated 
dose level and schedule, and the dose level and schedule exceeding the MTD be tested 
in additional subjects. While the Phase 2 is ongoing the review committee may 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 42 of 108 
recommend that subjects receiving benefit may also be dosed for 4 weeks without a 
rest. 
6.4 
Definitions of Dose-Limiting Toxicity 
Reference should be made to the CTCAE, Version 4.03 for grading of the severity of 
adverse events and laboratory abnormalities.  A DLT will be defined as any of the 
following adverse events that is considered by the investigator as related to RX-3117: 
 
Grade 4 neutropenia (ANC < 0.5 x 109/L)  
 
Grade  3 neutropenia (ANC < 1.0 x 109/L) with fever greater than 38.5°C 
(101.3°F) 
 
Grade 4 thrombocytopenia (platelet count < 25 x 109/L) 
 
Grade  2 vomiting despite maximal oral antiemetic therapy, or a requirement for 
IV antiemetics to control RX-3117-related nausea and vomiting 
 
Other Grade  3 adverse events or laboratory abnormalities 
6.5 
Delayed, Missed and Vomited Doses 
Subjects receiving RX-3117 at 3 times per week who have a delay in the administration 
of a dose of RX-3117 of < 12 hours should take the planned dose as soon as possible 
after the intended time of administration.  For subjects who have a delay in 
administration of RX-3117 of  12 hours, the dose should not be taken.  RX-3117 
administration may continue but the missed dose should not be made up and the 
planned timing of subsequent RX-3117 dosing should not be altered. 
Subjects receiving RX-3117 at 5 times per week who have a delay in the administration 
of a dose of RX-3117 of ≤ 8 hours should take the planned dose as soon as possible 
after the intended time of administration.  For subjects who have a delay in 
administration of RX-3117 of  8 hours, the dose should not be taken.  RX-3117 
administration may continue but the missed dose should not be made up and the 
planned timing of subsequent RX-3117 dosing should not be altered. 
Subjects receiving RX-3117 daily (e.g., 7 times per week) who have a delay in the 
administration of a dose of RX-3117 of ≤ 8 hours should take the planned dose as soon 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 43 of 108 
as possible after the intended time of administration.  For subjects who have a delay in 
administration of RX-3117 of  8 hours, the dose should not be taken.  RX-3117 
administration may continue but the missed dose should not be made up and the 
planned timing of subsequent RX-3117 dosing should not be altered. 
Vomited doses should not be retaken. 
6.6 
Dosage Modifications 
Whenever possible, dose and scheduling modifications should be discussed between 
the investigator and the sponsor prior to implementation.  The appropriate clinic staff 
should dispense the study drug for the new dose level or schedule and instruct the 
subject/caregiver about the change in dose level or schedule.  
6.6.1 
Dose Modifications During a Cycle 
If a subject experiences a RX-3117-related DLT (as defined in Section 6.4) and requires 
a dose and/or frequency reduction, RX-3117 administration should be interrupted, as 
necessary, until the adverse event resolves or stabilizes to an acceptable degree 
(generally to the pretreatment severity grade).  If appropriate, more frequent laboratory 
monitoring may be instituted until abnormalities have recovered to the pretreatment 
severities.  Thereafter, RX-3117 may be reinstituted, but the dose and/or frequency of 
RX-3117 for the remainder of that cycle should be reduced by 1 dose level or as directed 
by the Sponsor.  Successive adjustments to progressively lower dose levels can be 
made.  If the subject cannot tolerate RX-3117 at Dose Level 1 (30 mg/dose) then the 
subject should be discontinued from RX-3117 therapy.  If necessary, the subject should 
be instructed to return to the clinic to receive RX-3117 of the appropriate strength(s) for 
the reduced dose level.  Doses during missed days of treatment should not be made up 
(e.g., if a subject experiences an RX-3117-related adverse event, after 1 week of 
treatment, and the event lasts for 1 week, the missed doses during week 2 should be 
omitted and the new reduced dose level should be administered only for the remaining 
doses so that the total planned cycle duration remains 28 days).  
6.6.2 
Dose Modifications at the Beginning of the Next Cycle 
A new cycle of RX-3117 treatment may begin no earlier than Day 28 but should be 
delayed, as necessary, until adverse events or laboratory abnormalities have returned to 
baseline levels.  If adverse events or laboratory abnormalities are not resolved to 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 44 of 108 
baseline, weekly delays in initiating the new cycle of treatment should be instituted.  
Once all toxicities have returned to baseline, the next cycle of therapy can be initiated.  
Subjects experiencing any of the DLTs described in Section 6.4 in the current cycle of 
therapy should have the dose and/or frequency in the next cycle of therapy reduced by 1 
dose level and/or frequency (see Table 1 and Table 2) or as directed by the Sponsor.  
Subjects who required an intra-cycle dose and/or frequency reduction, during the current 
cycle of therapy, should have the dose and/or frequency in the next cycle of therapy 
administered at no higher than the highest dose and/or frequency tolerated in the current 
cycle.  Successive inter-cycle adjustments to progressively lower dose levels and/or 
frequencies can be made.  If the subject cannot tolerate RX-3117 at Dose Level 1 
(30 mg/dose) then the subject should be discontinued from RX-3117 therapy.  
Subjects receiving a lower dose and/or frequency but who the principal investigator feels 
is benefiting from treatment, may after discussions with the Sponsor, receive a higher 
dose and at more frequent dosing, for which there is already safety data. 
6.6.3 
Dose Re-Escalation 
After a dose and/or frequency is reduced, the dose and/or frequency need not be re-
escalated, even if there is minimal or no toxicity with the reduced dose and/or frequency.  
However, if the subject tolerates a reduced dose and/or frequency of RX-3117 for 
≥ 4 weeks then the RX-3117 dose may be increased to the next higher dose level and/or 
frequency, at the discretion of the investigator.  Such re-escalation may be particularly 
warranted if further evaluation reveals that the adverse event that led to the dose and/or 
frequency reduction was not RX-3117-related.  Successive adjustments to progressively 
higher dose and/or frequency levels can be made at 4-week intervals but the dose 
and/or frequency must not exceed the highest dose and/or frequency level for which 
there is already Cycle 1 safety data.  
6.7 
Discontinuation of Study Treatment 
All study participants may receive study treatment for up to 8 cycles.  Therapy beyond 
8 cycles may be considered following discussions among the sponsor, investigator and 
medical monitor. However: 
 
Any subject has the right to withdraw from study treatment or study follow-up at any 
time. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 45 of 108 
 
Any subject who has objective evidence of cancer progression should be withdrawn 
from study treatment. 
 
Any subject who cannot tolerate RX-3117 at the 30-mg dose level despite 
appropriate supportive care should be withdrawn from study treatment. 
 
Any subject whose medical condition substantially changes after entering the study 
should be carefully evaluated by the investigator in consultation with the sponsor; 
such subjects should be withdrawn from study treatment if continuing would place 
them at risk. 
 
Any subject who becomes pregnant or begins breastfeeding should be withdrawn 
from study treatment. 
 
Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should be withdrawn from study treatment 
in circumstances that increase risk or substantially compromise the interpretation of 
study results. 
 
The investigator, in consultation with the sponsor, may withdraw any subject from the 
study treatment, if, in the investigator’s opinion, it is not in the subject’s best interest 
to continue.  
 
The sponsor, relevant regulatory agencies, or the institutional review board may 
request discontinuation of the study at any time. 
The date the subject is withdrawn from study treatment or from the study and the reason 
for discontinuation will be recorded in the subject’s medical record and on the 
appropriate eCRF. 
When a subject is withdrawn from study treatment or is permanently removed from study 
treatment (regardless of the reason), all of the evaluations required at the end-of-
treatment visit should be performed and any additional evaluations should be completed 
that may be necessary to ensure that the subject is free of untoward effects.  The 
subject should be encouraged to seek appropriate follow up for any continuing health 
problems. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 46 of 108 
Subjects who discontinue study treatment may still continue on study follow-up.  Thus, 
all subjects receiving study drug will be followed during the post treatment follow-up 
assessments unless the subject withdraws consent for such follow-up. 
6.8 
Concomitant and Supportive Therapy 
To the extent possible, administration of any prescription or over-the-counter drug 
products other than study medication should be minimized during the study period. 
Subjects should be discouraged from use of street drugs, herbal remedies, self-
prescribed drugs, tobacco products, or excessive alcohol at any time during the clinical 
study. 
If considered necessary for the subject’s well-being, drugs for concomitant medical 
conditions or for symptom management may be given at the discretion of the 
investigator.  The decision to authorize the use of any drug other than study drug should 
take into account subject safety, the medical need, the potential for drug interactions, the 
possibility for masking symptoms of a more significant underlying event, and whether 
use of the drug will compromise the outcome or integrity of the study 
Subjects should be instructed about the importance of the need to inform the clinic staff 
of the use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) 
before and during the course of the study.  Any concomitant drugs taken by a subject 
during the course of the study and the reason for use should be recorded on the 
electronic case report forms (eCRFs). 
6.8.1 
Analgesics 
Investigators may give analgesics, as necessary, for pain control.  
6.8.2 
Antibiotics 
For subjects who develop an infection, appropriate medical therapy (e.g., with 
antibiotics, antifungals, or antivirals) or other interventions should be instituted. 
Investigators should use appropriate medical judgment in determining whether a subject 
continues with RX-3117 during treatment for the infection. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 47 of 108 
6.8.3 
Anticancer or Experimental Systemic Therapies Other than 
Investigational Treatments 
No other systemic anticancer therapies (including chemotherapy, antibody therapy, 
immunotherapy, or other experimental therapies) of any kind are permitted while the 
subject is receiving study treatment.  Subjects are not allowed to participate concurrently 
in any other therapeutic clinical study. 
6.8.4 
Antidiarrheals 
For subjects who develop diarrhea, causes related to existing medical conditions, 
concomitant medications, or gastrointestinal infection should be considered and 
eliminated.  Depending upon the clinical circumstances, endoscopy and biopsy may be 
warranted.  
Antidiarrheals are not allowed prior the administration of RX-3117 on Cycle 1 Day 1 and 
antidiarrheals should not be taken prophylactically in subsequent cycles.  However, 
antidiarrheals can be administered on subsequent treatment days and in subsequent 
cycles, based on the judgment of the treating physician and local institutional practices.  
Subjects should be instructed to begin taking antidiarrheal medication at the first sign of 
any of the following: (1) poorly formed or loose stool, (2), occurrence of more bowel 
movements than usual in 1 day, or (3) an unusually high volume or increased liquidity of 
stool.  
A recommended symptomatic antidiarrheal is loperamide, which may be taken in the 
following manner: 4 mg at the first onset of diarrhea, then 2 mg every 2 hours around the 
clock until diarrhea-free for at least 12 hours.  Subjects may take loperamide 4 mg every 
4 hours during the night.  Subjects who appear prone to drug-related diarrhea should be 
provided with loperamide so that they have sufficient supply on hand in case 
antidiarrheal support is required.  Alternate or additional antidiarrheal measures may be 
used at the discretion of the treating physician.  Subjects should be instructed to 
increase fluid intake to help maintain hydration during episodes of diarrhea. 
Depending upon the type and severity of the diarrhea, interruption of RX-3117 and 
rechallenge at the same or a reduced dose level and with appropriate support care 
should be considered. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 48 of 108 
6.8.5 
Antiemetics 
Antiemetics are not allowed prior the administration of RX-3117 on Cycle 1 Day 1.  
However, antiemetics can be administered on subsequent treatment days and in 
subsequent cycles, based on the judgment of the treating physician and local 
institutional practices.  
At the occurrence of drug-related nausea or vomiting of severity Grade  1, it is 
suggested that the subject receive an oral or transdermal serotonin antagonist (e.g., 
dolasetron, granisetron, ondansetron, tropisetron, palonosetron).  The neurokinin 
receptor antagonist, aprepitant, may also be considered.  Other classes of antiemetic 
medications that may be employed include dopamine antagonists or benzodiazepines.  
If possible, systemic corticosteroids should be avoided due to their many non-specific 
effects. 
Depending upon the type and severity of the vomiting, interruption of RX-3117 and 
rechallenge at the same or a reduced dose level and with appropriate support care 
should be considered. 
6.8.6 
Contraception 
Sexually active females of childbearing potential must accept continuous heterosexual 
abstinence as a lifestyle choice or agree to use a protocol-recommended method of 
contraception during heterosexual intercourse throughout the study treatment period and 
for 30 days following discontinuation of RX-3117.  A female subject is considered to be 
of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol 
and follicle-stimulating hormone [FSH] levels within the institutional postmenopausal 
range and a negative serum or urine -human chorionic gonadotropin [-HCG]), or is 
menopausal (age  55 years with amenorrhea for  6 months).  Protocol-recommend 
methods of contraception include barrier method with spermicide, intrauterine device 
(IUD), or steroidal contraceptive (oral, transdermal, implanted, or injected).   
Sexually active male subjects who can father a child (i.e., are fertile) must accept 
continuous heterosexual abstinence as a lifestyle choice; limit intercourse to female 
partners who are surgically sterile, post-menopausal, or using effective contraception (as 
noted in Table 3; or agree to use a protocol-recommended method of contraception 
during heterosexual intercourse throughout the study treatment period and for 30 days 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 49 of 108 
following discontinuation of RX-3117 (as noted in Table 3). A male subject is considered 
fertile unless he has had a bilateral vasectomy with documented aspermia or a bilateral 
orchiectomy.  The investigator should counsel subjects on the most effective methods 
for avoiding pregnancy during the trial.  Protocol-recommended contraceptive methods 
are described in Table 3.    
 
Table 3. 
Protocol-Recommended Contraceptive Methods 
Individual Methods 
Combination Methods 
Hormonal Methods 
(One method to be used  
with a barrier method) 
Barrier Methods 
(Both of these methods to be used OR one of 
these methods to be used with a hormonal 
method) 
IUD 
Estrogen and 
progesterone 
 
Diaphragm with spermicide 
 
Copper T 380A 
IUD 
 
Oral 
contraceptives 
 
Male condom (with spermicide) 
 
LNg 20 IUD 
 
Transdermal 
patch 
 
Tubal sterilization 
 
Vaginal ring 
 
Hysterectomy 
Progesterone 
 
 
 
Injection 
 
 
 
Implant 
 
Abbreviation: IUD=intrauterine device 
The sponsor should be consulted regarding any questions relating to childbearing status 
or contraception. 
6.8.7 
Corticosteroids 
Systemic or enteric corticosteroids are not allowed prior the administration of RX-3117 
on Cycle 1 Day 1.  Subjects may receive topical or inhaled corticosteroids while on 
study.  In addition, subjects who develop conditions that may be alleviated by systemic 
or enteric corticosteroid therapy are permitted to receive such drugs and are not required 
to discontinue study participation 
6.8.8 
Diet 
There are no specific dietary restrictions in the study other than that subjects should 
refrain from eating for 8 hours before and for 1 hour after each study drug dose is taken.  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 50 of 108 
6.8.9 
Drugs with Potential for Interactions with RX-3117 
As described in Section 2.2.4, in vitro studies indicate that RX-3117 does not inhibit drug 
transporters or CYP enzymes at clinically relevant concentrations; thus, it is not 
expected that RX-3117 would induce interactions with drugs for which absorption or 
metabolism would be modulated by inhibition of these enzymes. 
As also described in Section 2.2.4, the primary metabolic route for disposition of 
RX-3117 is deamination by cytidine deaminase.  These data imply that strong inhibitors 
or inducers of cytidine deaminase could theoretically increase or decrease RX-3117 
plasma concentrations.  However, such agents are unlikely to be administered in clinical 
practice and thus the risk of altered RX-3117 exposure due to such a drug interaction is 
considered low. The effect of RX-3117 on CYP induction has not been evaluated. 
6.8.10 
Erythropoietin and Granulocyte Colony-Stimulating Factors 
Use of erythropoietic agents (e.g., erythropoietin or darbepoetin alpha) is not permitted 
during Cycle 1 of therapy.  Thereafter, such agents may be administered for Grade  3 
anemia, but their use in this study is discouraged. 
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be 
administered given the potential for GM-CSF-related inflammatory symptoms. 
Use of granulocyte colony-stimulating factor (G-CSF)(e.g., filgrastim, PEG-filgrastim, 
lenograstim) is not allow in Cycle 1 of therapy.  Prophylactic administration of G-CSF 
and concomitant administration of RX-3117 and G-CSF is not permitted in support of 
protocol therapy.  However, administration of G-CSF may be considered in a subject 
who, despite RX-3117 dose modification to 30 mg administered 3 times per week, is 
experiencing recurrent difficulties with recovering from neutropenia in a timely fashion.  
In addition, therapeutic use of G-CSF in subjects with serious neutropenic complications 
such as tissue infection, sepsis syndrome, fungal infection, etc., may be considered at 
the investigator's discretion  
Reference may be made to the American Society of Clinical Oncology guidelines (Rizzo 
et al, 2008; Smith et al, 2006). 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 51 of 108 
6.8.11 
Immunization 
Due to its potential effects on lymphoid cells, RX-3117 might theoretically impair primary 
or secondary responses to immunization.  For subjects who are at substantial risk of an 
infection (e.g., influenza) that might be prevented by immunization, consideration should 
be given to providing the vaccine prior to initiation of study therapy. 
If a vaccine is administered during RX-3117 therapy, vaccination should not be 
performed during Cycle 1 or during any other cycle in a period when the patient is 
experiencing Grade  2 leukopenia.  The safety of immunization with live viral vaccines 
during RX-3117 has not been evaluated and vaccination with live virus vaccines during 
study treatment is not recommended. 
6.8.12 
Radiation Therapy 
Radiation therapy is not permitted during Cycle 1 of study treatment. Thereafter, short-
term, palliative radiation therapy can be used for the management of known, non-
progressing bony metastatic lesions if refractory to standard pain management 
algorithms.  
Since the radiosensitizing properties of RX-3117 have not yet been established, it is 
recommended that the study drug be stopped  2 days before radiation and re-started 
 2 days after the completion of the course of radiation.  Before treatment occurs, the 
investigator should discuss the method/frequency of radiation administration with the 
sponsor. 
6.8.13 
Surgery or Other Invasive Procedures 
The effects of RX-3117 on coagulation or wound healing are unknown.  Potential 
RX-3117 myelosuppressive or immunosuppressive effects could enhance the risk of 
peri-procedural bleeding or infection.  
Elective surgical procedures (other than placement of IV access devices) should be 
avoided during study drug administration.  However, subjects may undergo necessary 
surgical or invasive procedures for serious intercurrent medical problems; in these 
circumstances, study drug should be interrupted.  Investigators should use appropriate 
medical judgment in determining whether to resume study drug in the post-procedure 
period.  For subjects resuming study drug, any myelosuppressive effects of the drug 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 52 of 108 
should have returned to baseline levels and the subject should be clinically stable before 
reinitiating therapy. 
6.8.14 
Transfusions 
Red blood cell or platelet transfusions may be administered, as clinically indicated. 
7. 
STUDY PROCEDURES 
Refer to the Schedule of Assessments (for details see Appendix A) for an outline of 
procedures required at each visit.  All safety blood and urine samples should be 
collected and submitted to the local laboratory on the day of collection.  Blood for 
evaluation of RX-3117 pharmacokinetics, any archived tumor tissue, any tumor biopsy 
samples, and biomarker samples should be prepared and shipped to the central 
laboratory for analysis.  
Unless otherwise specified, all assessments will be done on the planned visit date.   
7.1 General Study Procedures  
A signed and dated institutional review board approved informed consent must be 
obtained before any study specific screening procedures are performed.  Assessments 
that are performed as standard of care procedures may be used for screening if 
performed before the informed consent is signed, provided that they are still within the 
screening period. 
7.2 Screening Procedures  
The following screening assessments must be performed and results available within 
14 days (unless otherwise noted) before enrollment: 
 
Written informed consent 
 
Review of inclusion and exclusion criteria 
 
Medical, surgical and psychiatric history review, documentation of diagnosis and 
previous treatments including details of tumor diagnosis (e.g., date of diagnosis, 
histology, stage at diagnosis and current stage) and most recent disease 
assessment 
 
Prior medication usage within the previous 28 days before planned study drug 
administration. 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes) and 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 53 of 108 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air) 
 
ECOG Performance status 
 
Physical examination including weight and height 
 
Laboratory tests (for analyte details see Appendix B) 
o 
Urinalysis 
o 
Hematology panel 
o 
Chemistry panel 
o Serum pregnancy test for female subjects of childbearing potential 
o Coagulation: PTT, PTT or INR 
o Tumor marker, if applicable 
 
12-lead electrocardiogram will be taken after the subject has been supine or 
recumbent (same position must be used for all measurements) for at least 
5 minutes (within 7 days before enrollment).  All electrocardiogram reports must 
include the HR, QRS, QT, QTc, and PR intervals.  A duplicate printout of the 
electrocardiogram report must be printed when the assessment is performed for 
review by a central vendor.  
 
Radiological imaging to assess disease extent.  Radiological assessment must 
include computerized tomography or magnetic resonance imaging of disease 
sites and the modality selected should be the same throughout the study.  
Disease assessment should be according to RECIST ver 1.1 (for details see 
Appendix C) within 21 days before enrollment.  Some imaging assessments may 
be collected for a second review by a central imaging vendor. 
 
Review of subject eligibility by the study sponsor or assigned designee 
 
Subject is enrolled and receives treatment assignment from the sponsor or 
assigned designee 
7.3 
Treatment Period – Cycle 1 Day 1 
7.3.1 Pre-dosing Assessments 
The following procedures will be performed within 3 days before the 1st dose of RX-3117 
is administered on Cycle 1 Day 1, unless otherwise described: 
 
Review eligibility criteria 
 
Record concomitant medication(s)  
 
Weight  
 
ECOG performance status 
 
Laboratory tests within 3 days before dosing (for analyte details see Appendix B) 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 54 of 108 
o 
Hematology panel  
o 
Chemistry panel  
o 
Urinalysis 
o 
Urine pregnancy test for female subjects of childbearing potential must be 
negative before study drug dosing can occur.  If a serum pregnancy test 
was done and determined negative within 72 hours of dosing a urine 
pregnancy test is not needed. 
o 
Coagulation tests: PT, PTT or INR  
o 
Tumor marker, if applicable 
 
Collect a blood sample for pre-dose pharmacokinetics (with recording of the date 
and actual clock time of blood collection. 
 
Collect blood samples for biomarker analysis  
 
Collection of a tumor biopsy sample pre-treatment from eligible subjects 
(optional) 
 
12 lead electrocardiogram taken while the subject is supine or recumbent (same 
position must be used for all measurements).  All electrocardiogram reports in 
this study must include HR, QRS, QT, QTc, and PR intervals. A duplicate printout 
of the electrocardiogram report must be printed when the assessment is 
performed for review by a central vendor. (Phase 1 and Dose Expansion) 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes), and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air). 
7.3.1 Post-dosing Assessments – Cycle 1 Day 1 
The following procedures will be performed after the administration of RX-3117: 
 
The required order of assessments is electrocardiogram, followed by vital signs 
and pharmacokinetic sampling when applicable. 
 
12 lead electrocardiogram taken at 1 hour ± 10 minutes, 2 hours ± 10 minutes, 
4 hours ± 10 minutes, 6 hours ± 10 minutes and 8 hours ± 10 minutes after the 
RX-3117 administration while the subject is supine or recumbent (same position 
must be used for all measurements).  All electrocardiogram reports in this study 
must include HR, QRS, QT, QTc, and PR intervals.  A duplicate printout of the 
electrocardiogram report must be printed when the assessment is performed for 
review by a central vendor. (Phase 1 and Dose Expansion) 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes) and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air) will be taken whenever a blood sample is collected for RX-3117 
pharmacokinetics.  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 55 of 108 
 
Blood samples for RX-3117 pharmacokinetics will be collected (Phase 1 and 
Dose Expansion):  
o 
At 0.5 hours ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 
3 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes and 
8 hours ± 10 minutes, after the oral administration of RX-3117 on Cycle 1 
Day 1.  
 
Collect a blood sample for biomarker analysis at approximately 4 hours ± 15 
minutes, after the oral administration of RX-3117 on Cycle 1 Day 1 (Phase 1 and 
Dose Expansion). 
 
Recording of concomitant medication(s)  
 
Record adverse event(s).  Serious adverse events will be reported immediately.  
Any adverse event that is considered related to study drug will be followed to 
resolution or return to baseline. 
 
Collection of archived tumor samples from eligible treated subjects within 
4 weeks of Cycle 1 Day 1. 
 
Dispensing of study drug and instructions for dosing at home 
 
Dispensing of diary cards 
7.4 Treatment Period – Cycle 1 Day 8 
The following procedures and assessments will be performed before RX-3117 dosing 
on Cycle 1 Day 8, unless otherwise described: 
 
Collection of unused study drug 
 
Review subject study drug compliance 
 
Record concomitant medication(s)  
 
Recording of adverse event(s).  Serious adverse events will be reported 
immediately.  Any adverse event that is considered related to study drug will be 
followed to resolution or return to baseline. 
 
Weight 
 
Laboratory tests (for details see Appendix B) 
o 
Hematology panel  
o 
Chemistry panel  
o 
Urinalysis 
o Coagulation tests: PT, PTT or INR  
 
Collect a blood sample for pre-dosing pharmacokinetics. 
 
Collect blood samples for biomarker analysis. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 56 of 108 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes) and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air).  
 
Dispensing of study drug and instructions for dosing at home 
 
Dispensing of diary cards 
 
RX-3117 may be taken orally in the clinic or at home. 
7.5 Treatment Period – Cycle 1 Day 15 
7.5.1 Pre-dosing Assessments 
The following procedures will be performed before RX-3117 dosing on Cycle 1 Day 15, 
unless otherwise described: 
 
Collection of unused study drug 
 
Review subject study drug compliance 
 
Record concomitant medication(s)  
 
Recording of adverse event(s).  Serious adverse events will be reported 
immediately.  Any adverse event that is considered related to study drug will be 
followed to resolution or return to baseline. 
 
Weight 
 
Laboratory tests within 3 days before dosing (for details see Appendix B) 
o 
Hematology panel  
o 
Chemistry panel  
o 
Urinalysis 
o 
Coagulation tests: PT, PTT or INR  
 
Collect blood sample for pre-dose pharmacokinetics (with recording of the date 
and actual clock time of blood collection. 
 
Collect blood samples for biomarker analysis  
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes), and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air). 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 57 of 108 
7.5.2 Post-dosing Assessments – Cycle 1 Day 15 
The following procedures will be performed after the administration of RX-3117 on 
Cycle 1 Day 15: 
 
The required order of assessments is vital signs before pharmacokinetic 
sampling when applicable. 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes) and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air) will be taken whenever a blood sample is collected for RX-3117 
pharmacokinetics.  
 
Blood samples for RX-3117 pharmacokinetics will be collected (Phase 1 and 
Dose expansion):  
o 
At 0.5 hours ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 
3 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes and 
8 hours ± 10 minutes, after the oral administration of RX-3117 on Cycle 1 
Day 15.  
 
Collect a blood sample for biomarker analysis at approximately 4 hours ± 15 
minutes, after the oral administration of RX-3117 on Cycle 1 Day 15 (Phase 1 
and Dose expansion). 
 
Record adverse event(s).  Serious adverse events will be reported immediately.  
Any adverse event that is considered related to study drug will be followed to 
resolution or return to baseline.  
 
Dispensing of study drug and instructions for dosing at home 
 
Dispensing of diary cards 
 
 
7.6 Treatment Period – Cycle 1 Day 22 
 
Collection of unused study drug 
 
Review subject study drug compliance 
 
Recording of concomitant medication(s)  
 
Recording of adverse event(s).  Serious adverse events will be reported 
immediately.  Any adverse event that is considered related to study drug will be 
followed to resolution or return to baseline. 
 
Laboratory tests (for details see Appendix B) 
o 
Hematology panel  
o 
Chemistry panel  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 58 of 108 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes) and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air).  
 
Tumor assessment to be performed between Days 22-28 of Cycle 1.  Results of 
the assessments must be available before the start of the next cycle, including 
CT/MRI/PET as applicable.  Some imaging assessments may be collected for a 
second review by a central imaging vendor. 
 
Blood sample for biomarker analysis will be taken around the time of the tumor 
assessment. 
 
Dispensing of study drug and instructions for dosing at home, if applicable. 
 
Dispensing of diary cards, if applicable. 
7.7 Treatment Period – Cycles 2 - 8 
For subjects receiving treatment beyond Cycle 1 the following procedures will be 
performed within 3 days before dosing on Day 1 of each new cycle, unless otherwise 
described. 
 
Collection of unused study drug 
 
Review subject study drug compliance 
 
Record concomitant medication(s)  
 
Recording of adverse event(s).  Serious adverse events will be reported 
immediately.  Any adverse event that is considered related to study drug will be 
followed to resolution or return to baseline. 
 
Weight 
 
ECOG performance status 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes) and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air).  
 
Laboratory tests (for details see Appendix B) on Day 1 and Day 15 of each cycle 
o 
Hematology panel  
o 
Chemistry panel  
o 
Tumor Marker, if applicable (Day 1) 
 
Tumor assessment, including CT/MRI/PET as applicable between Days 22 and 
28 of Cycles 2, 3, 4, 6 and 8.  Results of the assessment must be available and 
reviewed before dosing begins in the next cycle. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 59 of 108 
 
Blood samples for biomarker analysis will be collected on Day 1 of each cycle 
and around the time of the tumor assessment. 
 
Dispensing of study drug and instructions for dosing at home 
 
Dispensing of diary cards 
7.8 Treatment Period – ≥ Cycles 9 
For subjects receiving treatment beyond Cycle 8 the following procedures will be 
performed within 3 days before dosing on Day 1 of each new cycle, unless otherwise 
described. Visit schedule deviations may be permitted following discussions with the 
sponsor. 
 
Collection of unused study drug 
 
Review subject study drug compliance 
 
Record concomitant medication(s)  
 
Recording of adverse event(s).  Serious adverse events will be reported 
immediately.  Any adverse event that is considered related to study drug will be 
followed to resolution or return to baseline. 
 
Weight 
 
ECOG performance status 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes) and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air).  
 
Laboratory tests (for details see Appendix B) on Day 1 of each cycle 
o 
Hematology panel  
o 
Chemistry panel  
o 
Tumor marker, if applicable 
 
Tumor Assessment(s) as applicable between Days 22 and 28 of each even 
numbered cycle before the Day 1 of the next odd numbered cycle. Results to be 
evaluated before dosing at the next odd numbered cycle. Some imaging 
assessments may be collected for a review by a central imaging vendor. 
 
Blood samples for biomarker analysis will be collected on Day 1 of each cycle 
and around the time of the tumor assessment. 
 
Dispensing of study drug and instructions for dosing at home 
 
Dispensing of diary cards 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 60 of 108 
7.9 End of Treatment Visit or Early Termination 
The following procedures will be performed unless otherwise described: 
 
Collect unused study drug 
 
Review subject study drug compliance 
 
Record concomitant medication(s)  
 
Recording of adverse event(s).  Serious adverse events will be reported 
immediately.  Any adverse event that is considered related to study drug will be 
followed to resolution or return to baseline. 
 
Weight 
 
ECOG performance status 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes) and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air).  
 
Laboratory tests (for details see Appendix B) 
o 
Hematology panel  
o 
Chemistry panel  
o 
Urinalysis 
o 
Coagulation tests: PT, PTT or INR  
 
Tumor assessment, including CT/MRI/PET as applicable.  End of study tumor 
assessment (if the subject withdraws from the study for reasons other than tumor 
progression on a routine imaging/scan) should be performed if the last 
assessment was performed ≥ 4 weeks earlier.  Some imaging assessments may 
be collected for a second review by a central imaging vendor. 
 
Blood sample for biomarker analysis will be taken around the time of the tumor 
assessment. 
7.9.1 RX-3117 Dosing 
RX-3117 will be administered orally, at the assigned dose, with the subject in a fasted 
state (i.e.,  8 hours after a meal) with 100 to 200 mL (4 to 8 ounces) of water.  Food 
may be taken  1 hour after the dose has been administered.  The time of dosing must 
be documented. 
On days when the subject is scheduled to come into the clinic, RX-3117 will be 
administered orally in the presence of site personnel, per the assigned dose and 
schedule. This is important for days when blood is collected for pharmacokinetic analysis 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 61 of 108 
(i.e., Days 1, 8, and 15 of Cycle 1), on those days dosing will occur after that pre-dose 
pharmacokinetic sample is collected.   
When subjects self-administer RX-3117 at home, RX-3117 will be taken orally at 
approximately the same time every day after fasting for a minimum of 8 hours and with 
approximately 4-8 ounces of water. Food may be taken approximately 1 hour after the 
dose has been administered.   
7.10 Safety Follow-Up Visit 
Subjects will undergo the safety follow-up visit approximately 30 days (+ 7 days) after 
the subject receives their last dose of RX-3117.   
The following procedures will be performed: 
 
Recording of concomitant medication(s), including any anticancer therapies 
administered subsequent to the administration of study drug 
 
Recording of adverse event(s).  Serious adverse events will be reported 
immediately.  Any adverse event that is considered related to study drug will be 
followed to resolution or return to baseline. 
 
Weight 
 
ECOG performance status 
 
Resting vital signs: pulse, respiration rate and temperature measurements, blood 
pressure (i.e., after the subject has been seated for at least 5 minutes) and 
oxygen saturation (to be assessed by pulse oximetry while subject is breathing 
room air).  
 
Laboratory tests 
o Hematology panel 
o Chemistry panel  
o Tumor marker, if applicable 
 
Tumor assessment, including CT/MRI/PET as applicable.  Subjects first meeting 
criteria for complete response or partial response at the last on-treatment tumor 
assessment should have a Safety Follow-up tumor assessment if the last 
assessment was performed ≥ 4 weeks, in order to confirm the response based 
on RECIST ver 1.1 criteria.  Some imaging assessments may be collected for a 
second review by a central imaging vendor. 
 
Blood sample for biomarker analysis will be taken around the time of the tumor 
assessment, if applicable. 
7.11 
Unscheduled Visit(s) 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 62 of 108 
An unscheduled visit may be performed at any time during the study at the request of 
the subject or as deemed necessary by the investigator.  The date and reason for the 
unscheduled visit will be documented in the subject’s medical record and the eCRF, as 
well as any other data obtained (e.g., adverse events, concomitant medications and 
treatments, and results from procedures or tests). 
7.12 
Tumor measurements 
Radiographic tumor assessment(s) performed during the screening period will be used 
to prospectively identify all sites of disease present at the start of treatment.  Subjects 
with symptoms suggestive of disease progression should be objectively evaluated for 
tumor progression. 
On-study tumor assessment(s) will be performed by the investigator.  Response and 
progression will be evaluate using modified RECIST ver 1.1 (see Appendix C) after 
cycles 1 through 4 (e.g, every 4 weeks) and every 8 weeks thereafter or upon early 
termination if an assessment has not been done in the previous 4 weeks. The results of 
the tumor assessment must be available before the beginning of the next cycle.  
Radiographic tumor assessment(s) must include CT/MRI/PET of chest, abdomen, and 
pelvis, sufficient to evaluate major sites of disease.  Throughout the study, the same 
method of assessment and the same technique should be used to characterize each 
identified and reported lesion at screening. 
See Appendix C for detailed information on RECIST ver 1.1 to be used in this study.  
Some imaging assessments may be collected for a second review by a central imaging 
vendor. 
8. 
Other Assessment(s) 
8.1 
Predictive and Pharmacodynamic Biomarker  
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  In oncology, there is particular interest in the molecular changes underlying 
the oncogenic processes that may identify cancer subtypes, stage disease, assess the 
amount of tumor growth, or predict disease progression, metastasis, responses, or 
resistance to therapeutic agents.  These investigations may be useful in developing 
markers to identify disease subtypes, guide therapy, and/or predict disease progression. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 63 of 108 
A blood sample will be collected prior to treatment with RX-3117 and around the time of 
tumor assessments to measure biomarkers (e.g., including but not limited to including 
(but not limited to) concentrative nucleoside transporter (CNT) 2; equilibrative nucleoside 
transporter (ENT) 1; uridine-cytidine kinase (UCK) 1 and 2; DNA methyltransferase 
(DNMT) 1, 3a and 3b;, ribonucleotide reductases (RRM) 1 and 2) and RX-3117 
incorporation into DNA/RNA. 
In addition, any paraffin-embedded tumor samples collected independent from this study 
(whether before or during for the assessment of cancer) and the corresponding 
pathology report will be gathered by investigational sites.  If paraffin blocks cannot be 
shipped, unstained slides and a core punch biopsy will be prepared from paraffin 
embedded tumor samples collected independent of the study before and during the 
study from each subject for analysis.  These investigational studies may be useful in 
developing markers to identify disease subtypes, guide therapy and/or predict disease 
response or progression. 
A tumor biopsy will be collected pre-treatment (optional). 
Refer to the laboratory manual for detailed collection and handling procedures for all 
predictive biomarker samples. 
8.2 
Sample Storage and Destruction  
These blood and tumor samples and any other components from the cells may be stored 
for up to 20 years to research scientific questions related to cancer and/or RX-3117.  
The subject retains the right to have the sample material destroyed at any time by 
contacting the principal investigator.   
The sponsor will be the exclusive owner of any data, discoveries, or derivative materials 
from the sample materials and is responsible for the destruction of the sample(s) at the 
request of the research subject through the principal investigator or at the end of the 
storage period.  The principal investigator will provide the sponsor with the required 
study and subject numbers so that any remaining blood and tumor samples and any 
other components from the cells can be located and destroyed.  If a commercial product 
is developed from this research project, the sponsor will own the commercial product.  
The subject will have no commercial rights to such product and will have no commercial 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 64 of 108 
rights to the data, information, discoveries, or derivative materials gained or produced 
from the sample.  See Section 12.4 for subject confidentiality. 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definitions 
9.1.1 
Adverse Events 
An adverse event is any untoward medical occurrence in a trial subject who is 
administered a drug or biologic (medicinal product) or who is using a medical device; the 
event does not necessarily have a causal relationship with study drug administration or 
usage.  
For this protocol, untoward medical occurrences that should be reported as adverse 
events include the following: 
 
Any unfavorable and unintended symptom, sign (including an abnormal laboratory 
finding), or disease temporally associated with the use of study drug, whether or not 
related to the study drug.  
 
Any pre-existing condition that increases in severity or changes in nature during or 
as a consequence of study drug administration.  
 
Any complication that occurs as a result of a protocol-mandated procedure (e.g., 
venipuncture, ECG, telemetry) in the screening, study drug administration, or follow-
up periods. 
 
Any injury or accident occurring during the screening, study drug administration, or 
follow-up periods. If a medical condition is known to have caused the injury or 
accident (e.g., a fall secondary to dizziness), the medical condition (dizziness) and 
the accident (fall) should be reported as 2 separate adverse events.  
 
Any abnormality in physiological testing or a physical examination finding that 
requires clinical intervention or further investigation (beyond ordering a repeat 
[confirmatory] test). 
 
Any laboratory (e.g., clinical chemistry, hematology, urinalysis) or investigational  
abnormality (e.g., ECG, X-ray) independent of the underlying medical condition that 
requires clinical intervention, results in further investigation (beyond ordering a 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 65 of 108 
repeat [confirmatory] test), or leads to investigational medicinal product interruption 
or discontinuation unless it is associated with an already reported clinical event. If the 
laboratory abnormality is part of a syndrome, the syndrome or diagnosis (e.g., 
anemia) not the laboratory result (e.g., decreased hemoglobin) should be recorded.  
 
A complication related to pregnancy or termination of a pregnancy (see Section 9.7.2 
for additional information). 
None of the following events is considered an adverse event: 
 
Laboratory abnormalities not requiring clinical intervention or further investigation. 
Such abnormalities will be captured as part of overall laboratory monitoring. 
 
A diagnostic, medical or surgical procedure (e.g., surgery, endoscopy, tooth 
extraction, transfusion). However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event. For 
example, an acute appendicitis that begins during the adverse event reporting period 
should be reported as the adverse event and the resulting appendectomy should be 
recorded in the subject’s medical records and eCRFs.    
 
A pre-existing disease or condition or laboratory abnormality present or detected 
before the initial screening visit and that does not worsen. 
 
An intervention not associated with an untoward medical occurrence (e.g., 
hospitalization for elective surgery or for social and/or convenience reasons). 
 
An overdose without clinical sequelae. 
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an untoward medical occurrence that results in 
any of the following outcomes: 
 
Death (i.e., all deaths occurring between signing of the consent form to within 30 
days after last study drug administration), including deaths due to disease 
progression. Deaths that occur as a result of an adverse event that started during the 
study period should be reported. The reported adverse event should be the event 
that caused the death. Death is the outcome of this serious adverse event. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 66 of 108 
 
Life-threatening situation (i.e., with an immediate risk of death from the event as it 
occurred but not including an event that, had it occurred in a more serious form, 
might have caused death). 
 
In-patient hospitalization or prolongation of existing hospitalization. Of note, an 
untoward medical occurrence that occurs during hospitalization is an adverse event 
but a complication that prolongs hospitalization is a serious adverse event. In-patient 
hospitalization comprises formal admission to a hospital for medical reasons, for any 
length of time, whether or not hospitalization extends overnight. However, hospital 
admissions for administration of the study drug, procedures required by the study 
protocol, or tumor-related diagnostic procedures are not considered serious.  
 
Persistent or significant disability/incapacity. 
 
Congenital anomaly/birth defect in the offspring of a subject who received the study 
drug. 
 
Other medically significant event. Such events may not be immediately life-
threatening or result in death or hospitalization, but based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 
events might include: 
o Allergic bronchospasm requiring intensive treatment in an emergency room or at 
home 
o New cancers or blood dyscrasias 
o Convulsions that do not result in hospitalization 
o Development of drug dependency or drug abuse 
9.2 Other Events Requiring Rapid Reporting 
DLTs are events [toxicities] specifically identified in this protocol that must be reported to 
the Sponsor or designee in an expedited manner.  Information regarding DLTs should be 
recorded on a protocol-designated DLT report form and faxed or emailed to the study 
sponsor or designee within 24 hours of site personnel becoming aware of the event.  
DLTs may or may not be serious adverse events as Unexpected Adverse Event 
An unexpected adverse event is defined as an event that has a nature or severity, or 
specificity that is not consistent with the applicable investigator brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 67 of 108 
of greater severity or specificity. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the investigator brochure only 
referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism 
and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the 
investigator brochure only listed cerebral vascular accidents. “Unexpected,” as used in 
this definition, refers to an adverse drug experience that has not been previously 
observed and reported rather than an experience that has not been anticipated based on 
the pharmacological properties of the study drug.  
9.2.1 
Eliciting Adverse Event Information 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject. In addition, each study subject will be 
questioned about adverse events at each scheduled clinic visit or during each telephone 
contact with the subject following initiation of study drug administration. The type of 
question asked should be open-ended, e.g., "Have you had any new health problems?” 
or a similar type of query.  
9.3 Reporting Procedures for All Adverse Events 
All adverse events will be assessed by the investigator or qualified designee and 
recorded in the eCRFs. The investigator should attempt to establish a diagnosis of the 
event on the basis of signs, symptoms and/or other clinical information. In such cases, 
the diagnosis should be documented as the adverse event and/or serious adverse event 
and not described as the individual signs or symptoms. The following information should 
be recorded: 
 
Description of the adverse event using concise medical terminology 
 
Description as to whether or not the adverse event is serious (see Section 9.1.2) 
 
The start date (date of adverse event onset) 
 
The stop date (date of adverse event resolution) 
 
The severity of the adverse event (see Section 9.4) 
 
A description of the potential relatedness of the adverse event to study drug or a 
study procedure (see Section 9.5)  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 68 of 108 
 
The action taken due to the adverse event 
 
The outcome of the adverse event 
9.4 Grading of the Severity of an Adverse Event 
The severity of adverse events will be graded using the Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.03 (available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf). For each episode, the highest severity grade attained 
should be reported.  
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event. For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 4. 
Table 4. 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to 
have a clinically significant effect on the subject’s overall health and well-
being, does not interfere with the subject’s usual function, and is not 
likely to require medical attention. 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affect clinical 
status, and may require medical intervention. 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status 
and likely requires medical intervention and/or close follow-up. 
Grade 4 
Life-
threatening Sign or symptom results in a potential threat to life. 
Grade 5 
Fatal 
Sign or symptom results in death. 
 
The distinction between the seriousness and the severity of an adverse event should be 
noted.  Severe is a measure of intensity; thus, a severe reaction is not necessarily a 
serious reaction.  For example, a headache may be severe in intensity, but would not be 
classified as serious unless it met one of the criteria for serious events listed in Section 
9.1.2 above. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 69 of 108 
9.5 
Describing Adverse Event Relationship to Study Drug and Study 
Procedures 
The relationship of an adverse event to study drug should be assessed using clinical 
judgment, describing the event as either unrelated (no) or related (yes) consistent with 
the following definitions: 
 
No: Evidence exists that the adverse event had an etiology other than the study 
drug. For serious adverse events, an alternative causality must be provided (e.g., 
pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication). 
 
Yes:  A temporal relationship exists between the adverse event onset and 
administration of the investigational medicinal product that cannot be readily 
explained by the subject’s clinical state or concomitant therapies.  Furthermore, 
the adverse event appears with some degree of certainty to be related to the 
study drug based on the known therapeutic and pharmacologic actions or 
adverse event profile of the investigational medicinal product. In case of 
cessation or reduction of the dose, the adverse event abates or resolves. In case 
of interruption and rechallenge, the event reappears upon rechallenge. 
Of note, even in circumstances when the study drug is given intermittently or is 
interrupted temporarily before the onset of the adverse event, consideration should be 
given as to whether the study drug may have contributed to the event.  
The relationship to protocol-mandated study procedures (e.g., procedures such as 
venipuncture or performance of an ECG) should be assessed using the following 
considerations: 
 
No: Evidence exists that the adverse event has an etiology other than the study 
procedure. 
 
Yes: The adverse event occurred as a result of a protocol-mandated procedure.  
9.6 
Adverse Event Reporting Requirements 
9.6.1 
Site Reporting Requirements 
Classification of an event as serious or nonserious (see Section 9.1.2) determines the 
reporting procedures to be followed by the site.  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 70 of 108 
Site reporting requirements for adverse events are summarized in Table 5 below. 
Table 5. 
Site Reporting Requirements for Adverse Events 
Classification 
Reporting Time 
Reporting Action 
Serious 
Within 24 hours 
Fax or email report on designated serious adverse 
event report form to sponsor or designee, and to 
the site IRB, as per local IRB requirements; include 
copies of relevant source documents (e.g., 
progress notes, autopsy reports, laboratory and 
diagnostic test results, discharge summaries) 
Within 24 hours 
Telephone call or e-mail to the study sponsor 
medical monitora 
Per CRF submission 
procedure 
Record and submit information on appropriate 
CRFs 
Nonserious 
Per CRF submission 
procedure 
Record and submit information on appropriate 
CRFs 
a 
See Operations Manual for study contact information 
Abbreviations: CRF=case report form, IRB=institutional review board 
 
For serious adverse events, the Serious Adverse Event Report Form must be completed 
in addition to completing the adverse event portion of the CRF.  The information in the 
adverse event portion of the Serious Adverse Event Report Form(s) and CRF must 
match or be reconciled.  Where the same data are collected, the forms must be 
completed in a consistent manner. For example, the same adverse event term should be 
used on both forms.  
Particularly for fatal or life-threatening events, copies of progress notes, autopsy reports, 
laboratory and diagnostic test results, discharge summaries, and other relevant 
documents should be e-mailed or faxed when requested and applicable.  Follow-up 
information to the serious adverse event should be clearly documented as “follow up” in 
the serious adverse event report form and must be faxed or emailed to these same 
parties.  The study sponsor may request additional information from the investigator to 
ensure the timely completion of accurate safety reports. 
The subject’s name, address, and other personal identity information should be 
obscured on any source documents (e.g., progress notes, nurses’ notes, laboratory and 
diagnostic test results, discharge summaries) but without losing the traceability of a 
document to the study subject identifiers.  Only the subject’s study number, initials, or 
date of birth are to be provided.  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 71 of 108 
In the rare event that the investigator does not become aware of the occurrence of a 
serious adverse event immediately (for example, if a subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
to document his/her first awareness of the adverse event.  
Contact details for the study sponsor medical monitor are provided in the Operations 
Manual. 
9.6.2 
Study Sponsor Reporting Requirements 
Each serious adverse event report received from the investigator must be evaluated by 
the investigator as well as the study sponsor medical monitor.  Each is required to 
review all unanticipated problems involving risk to subjects or others, serious adverse 
events, and all subject deaths associated with the protocol and provide an unbiased 
written report of the event.  At a minimum, the study sponsor medical monitor should 
comment on the outcomes of the event or problem, and in the case of a serious adverse 
event or death, comment on the relationship to participation in the study.  The 
designated study sponsor medical monitor should also indicate whether they concur with 
the details of the report provided by the study investigator.  
For regulatory reporting purposes, the event is classified as related if any of the 
investigator or study sponsor medical monitor determines that the event is related to the 
study drug (see Section 9.5).  For reporting purposes, an adverse event will be 
considered expected if the study sponsor determines that the event is expected (see 
Section 9.2).  
The study sponsor awareness date will be used in determining adverse event regulatory 
reporting timelines. The study sponsor awareness date is defined as the earliest date the 
study sponsor or an agent (e.g., a site monitor) becomes aware of an adverse event.  
This is the date the regulatory reporting clock begins and the date is considered Day 0. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 72 of 108 
The study sponsor serious adverse event regulatory reporting requirements are 
described in Table 6. 
Table 6. 
Study Sponsor Reporting Requirements for Adverse Events 
Type of Event 
Type of Report 
Timeframe for Reporting  
To Health Authorities 
Fatal or  
Life-
Threatening 
Unexpected Related 
Yes 
Yes 
Yes 
Letter notification (may also 
include CIOMS I/MedWatch form) 
Within 7 calendar days of study 
sponsor awareness date or according 
to local regulations 
CIOMS I/MedWatch form 
Within 15 calendar days of study 
sponsor awareness date or according 
to local regulations 
No 
Yes 
Yes 
CIOMS I/MedWatch form 
Within 15 calendar days of study 
sponsor awareness date or according 
to local regulations 
Yes 
No 
Yes 
Annual report 
Annually 
No 
No 
Yes 
Yes 
Yes 
No 
No 
Yes 
No 
Yes 
No 
No 
No 
No 
No 
Abbreviations: CIOMS=  Council for International Organizations of Medical Sciences 
 
If notification of an adverse event requiring expedited reporting is received, the study 
sponsor (or designees) will contact each clinical investigator prescribing RX-3117 by 
e-mail, fax, or overnight mail such that the investigator can promptly notify the site IRB 
(within 7 calendar days for deaths or life-threatening events or within for 15 calendar 
days for other reportable events from the study sponsor awareness date).  All 
unanticipated problems involving risk to subjects or others, serious adverse events 
related to participation in the study, and subject deaths related to participation in the 
study will also be promptly reported via telephone, facsimile, or e-mail by the study 
sponsor (or designees) to appropriate health regulatory authorities. 
9.7 
Special Situation Reporting Requirements 
9.7.1 
Definitions of Special Situations  
Special situation include pregnancy; medication error, abuse, misuse, or overdose. 
 
Information regarding pregnancy is provided in Section 9.7.2.  
 
A medication error is any preventable event that can cause or lead to inappropriate 
medication use or subject harm while the medication is in the control of a healthcare 
professional or subject.  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 73 of 108 
 
Abuse is defined as persistent, sporadic or intentionally excessive use of a drug by a 
subject when such use is accompanied by harmful physical and/or psychological 
effects. 
 
Misuse is defined as any use of a drug in a way that is not in accordance with the 
protocol instructions and may be accompanied by harmful physical and/or 
psychological effects. 
 
An overdose is defined as a dose taken (accidentally or intentionally) that meets the 
criteria for overdose prescribed by the protocol (see Section 11.7).  In cases of a 
discrepancy in drug accountability, overdose will be established only when it is clear 
that the subject has taken excessive amounts of drug or the investigator has reason 
to suspect that the subject has taken excessive amounts of drug.  
9.7.2 
Pregnancy  
The following safety reporting instructions related to pregnancy are included as a 
precaution.  
Each female subject should be instructed to discontinue further study therapy and inform 
the investigator immediately if she becomes pregnant at any time between the first dose 
of study drug until 30 days after the last ingestion of study drug. 
Each male subject should be instructed to inform the investigator immediately if he 
impregnates a woman at any time between the 1st dose of study drug until 30 days after 
the last ingestion of study drug 
The investigator should counsel the subject regarding the possible effects of 
investigational medicinal product exposure on the fetus and the need to inform the study 
site of the outcome of the pregnancy. 
Neither a pregnancy itself nor an induced elective abortion to terminate the pregnancy 
without medical reasons is considered an adverse event; such occurrences should be 
reported on the appropriate pregnancy report forms.  However, if the outcome of the 
pregnancy meets the criteria for classification as a serious adverse event (i.e., 
spontaneous abortion, induced abortion due to complications, stillbirth, neonatal death, 
or congenital anomaly [including that in an aborted fetus]), the investigator should follow 
the procedures for reporting serious adverse events, i.e., report the event to the sponsor 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 74 of 108 
or designee by telephone and follow up by submission of the appropriate adverse event 
CRFs (see Section 9.6.1). 
Additional information regarding reporting pregnancy outcomes may be required:  
 
Any spontaneous abortion, including miscarriage and missed abortion will be 
reported as a serious adverse event. 
 
An induced therapeutic abortion to terminate any pregnancy due to complications or 
other medical reasons will be recorded as a serious adverse event.  The underlying 
medical reason for this procedure should be recorded as the adverse event term. 
 
All neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as serious adverse events.  In addition, any infant death after 1 
month that the investigator assesses as related to the in-utero exposure to the study 
drug should also be reported. 
 
In the case of a live birth, the “normality” of the newborn can be assessed at time of 
birth (i.e., there is no required minimum follow-up of a presumably normal infant 
before the Pregnancy Outcome Report CRF can be completed). 
 
The “normality” of an aborted fetus can be assessed by gross visual inspection 
unless there are pre-abortion laboratory findings suggestive of a congenital anomaly, 
in which case pathologic examination should be requested.  
9.7.3 
Instructions for Reporting Special Situations 
Information regarding any pregnancy in a study subject or the female partner of a male 
subject must be documented on a Pregnancy Reporting Form and forwarded to the 
sponsor or designee within 24 hours of learning of the pregnancy.  Monitoring of the 
pregnancy in both female study subjects and female partners of male study subjects 
should continue until the conclusion of the pregnancy.  The outcome of the pregnancy 
should be reported on the Pregnancy Outcome Report Form within 5 days of the 
conclusion of the pregnancy.  If the end of the pregnancy occurs after the study has 
been completed, the outcome should be reported directly to the study sponsor. 
Along with information regarding the circumstances of the special situation, any clinical 
sequelae occurring in association with that situation should be reported as adverse 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 75 of 108 
events or serious adverse events according to the reporting requirements for those 
events (see Section 9.6). Details of signs or symptoms, clinical management and 
outcome should be reported, if available defined in this protocol but may be serious 
adverse events if they meet one or more of the criteria for a serious adverse events (see 
Section 9.1.2).  If a DLT is also a serious adverse event, it should be reported both on 
the DLT report form and per the instructions for reporting serious adverse events (see 
Section 9.6.1). Recording of a DLT in the relevant CRFs will also be required. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
10.1.1 
Primary Endpoints – Phase 1 
 
Overall safety profile characterized by the type, frequency, severity, 
timing of onset, duration, and relationship to study therapy of any adverse 
events, or abnormalities of laboratory tests or ECGs 
 
Enumeration and description of any dose-limiting toxicities (DLTs) 
occurring during Cycle 1, serious adverse events, or adverse events 
leading to discontinuation of study treatment 
10.1.2 
Secondary Endpoints – Phase 1 
 
Pharmacokinetic parameters (e.g., Tmax, Cmax, Ctrough, AUC) for RX-3117 
based on blood sampling performed at initiation of RX-3117 dosing (Day 
1) and at steady state (Day 15) 
 
Indices of anti-tumor activity including: 
o Overall response rate (ORR) – defined as the proportion of 
subjects who achieve a complete response (CR) or partial 
response (PR)  
o Time to response (TTR) – defined as the interval from start of 
study therapy to the first documentation of CR or PR 
o Duration of response (DOR) – defined as the interval from the first 
documentation of CR or PR to the earlier of the first 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 76 of 108 
documentation of definitive disease progression or death from any 
cause 
 
Progression-free survival (PFS) – defined as the interval from the 
start of study therapy to the earlier of the first documentation of 
disease progression or death from any cause 
10.1.3 
Exploratory Endpoints – Phase 1 
Biomarker expression/concentration in tumor and blood samples including but not limited 
to concentrative nucleoside transporter (CNT) 2; equilibrative nucleoside transporter 
(ENT) 1; uridine-cytidine kinase (UCK) 1 and 2; DNA methyltransferase (DNMT) 1, 3a 
and 3b; ribonucleotide reductases (RRM) 1 and 2 and RX-3117 incorporation into 
DNA/RNA. 
10.1.4 
Primary endpoint – Phase 2 
 
The primary endpoint is a 20% (2 out of 10 subjects) or higher rate of 
progression free survival (PFS) benefit (i.e., proportion of subjects with stable 
disease for at least 4 months) and/or a 10% (1 of 10 subjects) partial response 
rate or better for each disease indication.  This study is not intended to 
demonstrate differences in treatment outcomes between indications.   
10.1.5 
Secondary endpoints – Phase 2 
 
The secondary efficacy parameters include overall response rate, time to 
progression and duration of response. 
TTP and DOR will be analyzed using standard survival analysis techniques 
based on the Kaplan-Meier life test method. 
ORR will be tabulated by response marker status for each disease indication, if 
applicable.  Point estimates as well as 95% confidence intervals will be 
presented. 
The efficacy endpoints analyzed for this study will include a progression free survival 
benefit and measures of disease response (complete response [CR] plus partial 
response [PR] according to RECIST ver 1.1).  For metastatic pancreatic cancer or 
advanced bladder cancer, the portion of subjects with a 5% or more reduction in target 
lesions or stable disease for at least 4 months as well as other indicators of clinical 
benefit including subject reported assessments and other markers of clinical benefit 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 77 of 108 
including tumor markers (CA 19-9 for pancreatic cancer) will also be considered in the 
response evaluation.  When reductions in tumor size, do not qualify as at least a partial 
response defined by RECIST ver 1.1, those data will be evaluated further by disease 
specific key opinion leaders.   
 
Concentration of RX-3117 and its metabolites pre-dose 
10.1.6 
Exploratory endpoints – Phase 2 
 
Biochemical levels of drug targets in blood and tumor samples 
 
Changes in tumor burden 
10.2 
Analysis Conventions 
10.2.1 
Analysis Sets 
10.2.1.1 
Full Analysis Set 
The full-analysis set includes all subjects who receive  1 dose of RX-3117.  This 
analysis set will be used in the analyses of subject characteristics, study drug treatment 
administration, safety (including first-cycle DLTs), overall response rate, and progression 
free survival. 
10.2.1.2 
Responding Analysis Set 
The responding analysis set includes subjects in the full-analysis set who have 
measurable tumor, who can be evaluated for tumor response with both baseline and on-
study tumor evaluations, and who achieve a complete response or partial response. This 
analysis set will be used in the analyses of time to response and duration of response. 
10.2.1.3 
Evaluable Analysis Sets 
The evaluable analysis sets include subjects in the full-analysis set who have baseline 
and on-study measurements to provide interpretable results for specific parameters of 
interest.  
These analysis sets will be used in the analyses of RX-3117 plasma pharmacokinetics, 
and changes in biomarkers.  
10.3 Sample Size Considerations 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 78 of 108 
The sample size calculation for this study has been empirically set.  Approximately 40 
subjects will be recruited in Phase 1 portion of this trial.  During Phase 1 study, dose 
escalation will be conducted according to a modified dose escalation rule, with 
potentially 1 subject only per dose and frequency until the appearance of a related grade 
2 or greater adverse event or the investigator, medical monitor and sponsor requesting 
that additional subjects be treated at a dose and/or schedule.   
The Dose Expansion of Phase 1 will enroll approximately 12 subjects at the 
recommended Phase 2 dose or MTD and schedule. 
For the Phase 2 portion of the study, the primary objective is to estimate the antitumor 
activity of RX-3117 in subjects with advanced solid malignancies.   
The maximum number of subjects needed for Phase 2 is approximately 100 (50 per 
solid tumor).  An estimated 20 subjects (10 per indication) will be enrolled in the first 
stage at the recommended Phase 2 dose from the Phase 1 portion.  Those dose 
expansion subjects who have measurable disease at baseline and at least 1 post-
baseline response assessment may be included in Stage 1 of the Phase2 if the disease 
type is one of those to be studied in Phase 2.  The goal is the observation of at least 2 
subjects with progression free survival for at least 4 months and/or 1 objective clinical 
response in a specific tumor indication in order for evaluation of that indication to 
advance to Stage 2. 
In Stage 2, the goal is to further evaluate primary and secondary endpoints, of efficacy.  
The number of subjects to be enrolled in the second stage will be approximately 80 (40 
per solid tumor indication). 
10.4 Randomization and Stratification 
Randomization will not be used in this study.  In the Phase 2 part of the study, subjects 
will be enrolled in a disease group based on their cancer diagnosis.  No stratification is 
planned for this study. 
10.5 Interim Analysis and Early Stopping Guidelines 
The interim analyses that are planned to be conducted in the Phase 1 are related to the 
review of available data during the dose escalation phase of the study.  The decision to 
escalate to the next dose level and schedule will be made after the evaluation of safety 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 79 of 108 
data through at least 28 days of the first cycle of the current dose level.  Each review will 
be conducted by the investigators, medical monitor and sponsor.   
The interim analysis in Stage 1 of the Phase 2 will be performed when the first 10 
subjects have been treated at the recommended Phase 2 dose and schedule, are 
evaluable for response, have the opportunity to complete up to 4 cycles of therapy or 
have discontinued therapy before 4 cycles.  If 2 responders are observed out of the 
initial 10 evaluable subjects in one of the specific cancer indication, subject enrollment 
will continue in that indication.   
For the Phase 2, an interim analysis for futility stopping may be conducted to determine 
whether continuation until study completion is warranted.  The investigator-assessed 
response rate will be used as the endpoint for the interim analysis.  Although response 
evaluations are repeated after every cycle for the first 4 cycles and then every 2 cycles 
thereafter, all available response data will be included in the interim analysis, a subject 
can be considered a responder with or without available confirmatory imaging.  Each of 
the 2 major indications enrolled in the Phase 2 portion will be evaluated independently, 
and could be subject to enrollment hold by individual indication.   
The number of subjects to be enrolled in the second stage will be determined as outlined 
in Section 10.3.  
10.5.1 
Data Handling Conventions 
10.5.1.1 
General Methods  
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: N (number 
in population), n (number with data), mean, standard deviation, 95% confidence intervals 
(CIs) on the mean, median, minimum, and maximum.  Summary tables for categorical 
variables will include: N, n, percentage, and 95% confidence intervals on the 
percentage. Unless otherwise indicated, 95% confidence intervals for binary variables 
will be calculated using the binomial distribution (exact method) and will be 2-sided.  
Data will be described and summarized by analysis set, dose level, dose schedule and 
timepoint. As appropriate, changes from baseline to each subsequent timepoint will be 
described and summarized. Similarly, as appropriate, the best change from baseline 
during the study will also be described and summarized. Graphical techniques (e.g., 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 80 of 108 
waterfall plots, Kaplan-Meier curves, line plots) may be used when such methods are 
appropriate and informative.  
The baseline value used in each analysis will be the last (most recent) pre-treatment 
value. Data from all sites will be pooled for all analyses. Analyses will be based upon the 
observed data unless methods for handling missing data are specified. If there is a 
significant degree of non-normality, analyses may be performed on log-transformed data 
or nonparametric tests may be applied, as appropriate.  
Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of significance. 
10.5.1.2 
Calculation of Pharmacokinetic Variables 
Pharmacokinetic parameters for RX-3117 will be calculated using non-compartmental 
methods. Only plasma concentrations greater than or equal to the validated lower limit of 
quantitation (LLQ) will be used in the pharmacokinetic analyses. Actual blood sampling 
times will be used in all pharmacokinetic analyses. Per-protocol times will be used to 
calculate mean plasma concentrations for graphical displays. 
The Cmax and Tmax will be taken directly from the subject’s data. The elimination rate 
constant, z, will be calculated as the negative of the slope of the terminal log-linear 
segment of the plasma concentration-time curve. The range of data to be used for each 
subject and treatment will be determined by visual inspection of a semi-logarithmic plot 
of concentration versus time and will comprise  3 data points along the elimination 
phase. Elimination t½ will be calculated according to the following equation: 
z
t

693
.0
½ 
 
The AUC to the final sample with a concentration LLQ (AUC0-t) will be calculated using 
the linear trapezoidal method and extrapolated to infinity (AUC) using: 
z
C
AUC
AUC
tf
t




0
inf
 
where Ctf is the final concentration LOQ. 
Oral clearance (CL/F) and volume of distribution (Vz/F) will be calculated according to 
AUC
Dose
F
CL

/
 and 
AUC
z
Dose
F
Vz


/
 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 81 of 108 
respectively, where AUC represents AUC. 
10.5.1.3 
Calculation of Tumor Control Variables 
Tumor control assessments will be based on the standardized RECIST ver 1.1, as 
specifically modified for this study (see Appendix C).  Tumor control will be documented 
at each assessment by response category (e.g., CR, PR, SD, PD) as defined for each 
response parameter, tumor dimension values, percentage change in tumor dimension 
values from baseline or nadir, date that response is first documented, date that response 
is confirmed, and date of disease progression.  
For time-to-event endpoints, only events occurring  30 days following the permanent 
discontinuation of study treatment will be considered as events; for subjects with events 
occurring > 30 days following the permanent discontinuation of study treatment, the data 
will be censored.  The following censoring conventions will be applied: 
 
Duration of Response (DOR): Data from surviving, non-progressing subjects will be 
censored at the earliest of the time of initiation of antitumor treatment other than the 
study treatment or the last time that lack of tumor progression was objectively 
documented while on study treatment. 
 
Progression Free Survival (PFS): Data from surviving, non-progressing subjects will 
be censored at the earliest of the time of initiation of antitumor treatment other than 
the study treatment or the last time that lack of tumor progression was objectively 
documented while on study treatment. 
10.6 
Analysis Plan 
10.6.1 
Subject Disposition and Baseline Characteristics 
A listing of all full-analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, dose level, dosing schedule, the longest 
duration of study drug treatment, and the reason for discontinuing study treatment.  
Available information on subjects who were screened or enrolled but not treated may be 
listed separately.  A table will be created summarizing these categories in terms of 
number and percent for the full-analysis set. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 82 of 108 
Subject baseline characteristics (e.g., demographic, disease-related, and prior-
treatment-variables) will be listed and summarized by dose level and schedule for the 
full-analysis set.  
10.6.2 
Exposure and Safety Analyses 
10.6.2.1 
Treatment Administration and Study Drug Compliance 
Descriptive information will be provided regarding the number of doses of study therapy 
prescribed, the total number of doses taken, the percent of expected doses taken, the 
duration of treatment, and the number and timing of prescribed dose reductions, dose 
interruptions, and dose re-escalations. 
RX-3117 compliance will be described in terms of the proportion of study drug actually 
taken based on subject diaries and returned capsule counts relative to the amount that 
was dispensed (accounting for physician-prescribed reductions and interruptions). 
10.6.2.2 
RX-3117 Pharmacokinetics 
Plasma concentrations and derived pharmacokinetic parameters (see Section 10.2.2.2) 
will be listed and graphs of individual subject concentrations by visit will be presented on 
linear and semi-logarithmic axes.  Pharmacokinetic data will be summarized by visit 
using graphical and tabular methods considering stage, dose level and schedule.  The 
data may be evaluated by baseline variables such as sex, weight, body-mass index, 
age, and cancer type.  
The relationship between the parameters Cmax, AUCinf, and AUC0-24 and dose will be 
examined using the power model, i.e., 
P = a  Doseb 
where P represents the parameter and a and b are constants. A value of b of 
approximately 1 indicates linear pharmacokinetics.  
As appropriate, data regarding plasma concentrations and pharmacokinetics parameters 
for major and/or active metabolites in retained plasma samples will be described.  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 83 of 108 
10.6.2.3 
Prior, Concomitant, and Post-Treatment Medication Use 
Prior, concomitant, and post-treatment medications will be coded by means of the World 
Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes. 
Descriptions of prior medication use will be focused on drugs and regimens used as 
treatments for cancer.  As appropriate and if available, information on the sequencing, 
and type of prior regimens will be collected. 
The type and timing of use of concomitant medications will be listed and summarized. 
Information regarding the type and use of specific supportive medications (e.g., 
antiemetics, antidiarrheals, hematopoietic growth factors, corticosteroids) during study 
treatment will be described. 
10.6.2.4 
Adverse Events 
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events.  A treatment-emergent adverse event is defined as 
an adverse event that occurs or worsens in the period from the first dose of study 
treatment to 30 days after the last dose of study treatment.  Adverse events that occur 
before the first dose of study treatment or > 30 days after the subject has been 
discontinued from study treatment will be included in data listings. 
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term. The severity of adverse events will be graded 
by the investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf), whenever possible. If a CTCAE criterion does not exist 
for a specific type of adverse event, the grade corresponding to the appropriate adjective 
will be used by the investigator to describe the maximum intensity of the adverse event: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or 
Grade 5 (fatal). The relationship of the adverse event to the study drug will be 
categorized as related or unrelated. 
Treatment-emergent adverse events will be summarized. Summary tables will be 
presented to show the number of subjects reporting treatment-emergent adverse events 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 84 of 108 
by severity grade and corresponding percentages.  A subject who reports multiple 
treatment-emergent adverse events within the same Preferred Term (or System Organ 
Class) is counted only once for that Preferred Term (or System Organ Class) using the 
worst severity grade. Adverse event descriptions will be presented in alphabetical order 
of System Organ Class, then by decreasing frequency in the “overall” column for a given 
Preferred Term. 
Separate listings and summaries will be prepared for the following types of treatment-
emergent adverse events: 
 
Dose-limiting adverse events occurring in Cycle 1 of therapy 
 
Study-drug-related adverse events 
 
Adverse events that are Grade  3 in severity 
 
Adverse events leading to study drug interruption and/or dose modification 
 
Adverse events leading to study drug discontinuation 
 
Serious adverse events (with categorization of the primary reason that the 
adverse event is considered serious, e.g., death, hospitalization, etc) 
10.6.2.5 
Laboratory Evaluations 
All laboratory data will be listed. Summaries of laboratory data will be based on observed 
data and will be reported using conventional units.  The focus of laboratory data 
summarization will be on treatment-emergent laboratory abnormalities.  A treatment-
emergent laboratory abnormality is defined as an abnormality that, compared to 
baseline, worsens by  1 grade in the period from the first dose of study treatment to 
30 days after the last dose of study treatment.  If baseline data are missing, then any 
graded abnormality (i.e., an abnormality that is Grade  1 in severity) will be considered 
treatment-emergent. Laboratory abnormalities that occur before the first dose of study 
treatment or > 30 days after the subject has been discontinued from study treatment will 
be included in data listings. 
Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable.  For parameters for which a 
CTCAE scale does not exist, reference ranges from the local laboratory will be used to 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 85 of 108 
determine programmatically if a laboratory parameter is below, within, or above the 
normal range for the subject’s age, sex, etc. 
Hematological and serum biochemistry and their changes from baseline will be 
summarized.  Summary tables will be presented for each relevant assay to show the 
number of subjects by CTCAE severity grade with corresponding percentages.  For 
parameters for which a CTCAE scale does not exist, the frequency of subjects with 
values below, within, and above the normal ranges will be summarized.  Subjects will be 
characterized only once for a given assay, based on their worst severity grade observed 
during a period of interest (e.g., during the study or from baseline to a particular visit). 
Shift tables for hematology and serum biochemistry will also be presented by showing 
change in CTCAE severity grade from baseline to each visit.  For parameters for which a 
CTCAE scale does not exist, shift tables will be presented showing change in results 
from baseline (normal, low and high [or abnormal]) to each visit (normal, low and high [or 
abnormal]).  Tables will be prepared to show frequencies adjusted for baseline values; 
for this frequency, subjects with the same or worse toxicity grade at baseline are not 
considered. 
Separate listings and summaries will be prepared for laboratory abnormalities that are 
Grade  3 in severity. 
10.6.2.6 Electrocardiography 
The ECG parameters (heart rate, PR interval, QRS interval, QT interval, and corrected 
QT [QTc] interval) at each time recorded as well as the change from screening will be 
listed and summarized.  These parameters will be determined electronically by the ECG 
machine at the clinical site.  The QT interval will be corrected by the Fridericia methods 
as follows: 
 
Fridericia: QTcF = QT/(RR)1/3 
The overall ECG assessment will be reported as “Normal” or “Abnormal” with respect to 
relevant abnormalities by the investigator.  A shift table comparing the ECG assessment 
over the study drug administration period to screening will be presented.  
The QTc data obtained by using the Fridericia corrections will be categorized separately 
into the following classifications and summarized by time after study drug dosing: 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 86 of 108 
 
QTc interval > 450 msec and ≤ 480 msec 
 
QTc interval > 480 msec and ≤ 500 msec 
 
QTc interval > 500 msec 
The change of the QTc values obtained by using the Fridericia’s correction will also be 
categorized separately as follows: 
 
QTc interval increases from baseline by > 30 msec and ≤ 60 msec 
 
QTc interval increases from baseline by > 60 msec 
QTc data will be presented in shift tables consistent with these categories. 
10.6.2.7 
Oxygen Saturation Values 
All oxygen saturation data will be listed.  Summaries of oxygen saturation data will be 
based on observed data and will be reported as percent (%) saturation.  Data and 
changes from baseline will be summarized.  Summary tables will be presented for 
values below 92% and for declines from baseline of  5% to show the number of 
subjects with corresponding percentages.  Subjects will be characterized only once for 
each of these categorizations, based on their lowest value observed during a period of 
interest (e.g., during the study or from baseline to a particular visit). 
10.6.2.8 Other Safety Variables 
Vital signs, weight, and performance status data will be appropriately described.  
10.6.3 
Efficacy Analyses 
10.6.3.1 
Categorical Endpoints  
As appropriate depending up the level of activity and the numbers of patients with 
individual tumor types that are accrued, ORR, CR and PR rates may be determined and 
described. In the analyses of ORR, subjects who do not have sufficient baseline or on-
study tumor assessment to characterize response will be counted as failures.  For all 
analyses, the corresponding 95% confidence intervals will be presented. 
10.6.3.2 
Time-to-Event Tumor Control and Survival Endpoints 
Time to response, duration of response, and progression free survival will be described 
in the appropriate analysis set using Kaplan-Meier methods. Medians, ranges, and 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 87 of 108 
corresponding 95% confidence intervals (as calculated using a Cox proportional hazards 
regression model) will be presented.  
10.6.3.3 
Continuous Endpoints 
Changes in tumor dimension values will be assessed using analysis of covariance 
(ANCOVA) with baseline values as covariates; in these analyses, both changes from 
baseline to each subsequent timepoint and best overall on-study changes will be 
evaluated. Means and standard errors will be presented. 
10.6.4 
Other Analyses 
Data explorations may be performed to evaluate potential associations among subject 
characteristics, biomarkers, RX-3117 dose, RX-3117 schedule and outcome measures. 
Explorations may also be performed to assess the potential associations between 
different outcomes measures (e.g., relationships between pharmacokinetic parameters, 
biomarkers and adverse event changes in tumor dimensions). 
10.7 
Statistical Basis for the Dose Escalation Paradigm 
In this dose-escalation trial designed to determine an MTD for RX-3117, the sample size 
for the study is not based on a formal statistical hypothesis but will be determined based 
on the observed number of first-cycle DLTs at each dose level and its schedule.  
To accelerate the early dose escalation and avoid treating excessive numbers of 
patients with innocuous but ineffective dose levels of RX-3117, the dose escalation will 
be performed initially with a single patient at each dose level. After the occurrence of at 
least one Grade  2 adverse event that is considered related to RX-3117, the study will 
transition to a standard 3 + 3 design in which 3 to 6 subjects will be treated at each of 
the proposed RX-3117 dose levels and schedules.  Based on the planned 3+3 dose-
escalation scheme, Table 7 shows the probability of escalating to the next dose level 
based on the true rate of DLT at the current dose level. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 88 of 108 
 
Table 7: Probability of Dose Escalation (N=3+3) 
True Incidence of DLT 
Probability of Escalating 
10% 
0.91 
20% 
0.71 
30% 
0.49 
40% 
0.31 
50% 
0.17 
60% 
0.08 
Abbreviation: DLT=dose-limiting toxicity 
 
Thus, if the true underlying proportion of DLT is low (e.g.,  10% at the current dose 
level, there is a high probability ( 0.91) of dose escalation to the next dose level. 
Conversely, if the true underlying proportion of DLT is high (e.g.,  60%) at the current 
dose level, there is a low probability ( 0.08) of escalation to the next dose level.  
The trial employs the standard NCI definition of MTD (starting dose associated with DLT 
in < 33.3% of subjects during the first cycle of therapy).  
10.8 
Timing of Analyses 
10.8.1 
Interim Analyses 
No formal interim analyses are planned in this Phase 1 trial.  The sponsor study team (or 
a specially delegated committee of expert clinicians) and the investigators will 
collectively discuss study conduct and accumulating safety and other data through 
teleconferences.  It is expected that these discussions will be scheduled at intervals of 
~4 weeks unless accrual to the study and the need for decisions regarding dose 
escalation or stage progression indicate the need for more frequent or less frequent 
reviews. 
10.8.2 
Final Analysis 
Final study reporting is expected to occur after all subjects have discontinued study 
treatment and completed the safety follow up visit or 24 weeks after accrual of the final 
subject.  Addenda to the study report may be created to account for subjects still on 
study at the time of the major analysis of the study.  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 89 of 108 
11. 
INVESTIGATIONAL PRODUCT 
11.1 RX-3117 
RX-3117 will be provided as 30-mg, 100-mg, 200 mg and 500 mg capsules intended for 
oral administration.  The capsules contain approximately 32 mg, 107 mg, 215-mg or 
540 mg, respectively, of RX-3117 monohydrate with the additional mass above the 
nominal respective values of 30, 100, 200 or 500 mg accounting for the water of 
hydration.  RX-3117 capsules are filled only with the active pharmaceutical ingredient 
(API).  No other excipients are contained in the formulation.  
The capsules will be a hard gelatin hydroxypropylmethyl cellulose capsule.  The 30-mg 
dosage form will be contained in a Size 4 white/yellow capsule, the 100-mg dosage form 
will be contained in a Size 2 white/white capsule, the 200 mg capsule will be contained 
in a Size 2 Swedish orange and the 500 mg will be contained in a Size 00 clear capsule. 
11.2 Packaging and Labelling 
The drug product will be packaged in white, high-density polyethylene (HDPE) bottles 
with a child-resistant closure and an induction seal.  Bottles will contain either 16 
capsules of 1 of the relevant dose strengths (30 mg or 100 mg) or 10 capsules of 1 of 
the relevant dose strengths (200 mg or 500 mg).  
All labels for study drug bottles will meet all applicable requirements of the Food and 
Drug Administration, Annex 13 of Current Good Manufacturing Practice (cGMP) 
(Manufacture of Investigational Medicinal Products, July 2003), and/or other local 
regulations, as applicable. 
11.3 Storage and Handling 
Bottles containing tablets of RX-3117 should be stored at a controlled refrigerated 
temperature of 2-8oC (i.e., 36-46o F).  
11.4 Source 
RX-3117 will be supplied without charge by Rexahn Pharmaceuticals, Inc. 
11.5 Dispensing 
The site personnel (e.g., pharmacist or other qualified person) will be responsible for 
dispensing RX-3117.  It is planned that the study drug will be dispensed at 1-week 
intervals during Cycle 1 of treatment and at 4-week intervals thereafter. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 90 of 108 
The clinic pharmacist or an alternative qualified person will provide each subject with 
directions regarding drug storage and instructions regarding how many of each 
size/color of capsule to use at each dosing.  The subject number, subject initials, dose 
assigned, and number of capsules to be taken will be written on the bottle label by site 
personnel. 
11.6 Procedures for Monitoring Subject Compliance 
Each study site will be responsible for monitoring subject compliance through subject 
interviews and counting of unused study drug capsules.  
At the time of study drug dispensing, the site personnel will show subjects how to 
complete a subject diary card with a record of the number of capsules of RX-3117 that 
they have taken daily at home and how to record any problems with drug administration 
or reasons for noncompliance.  Site personnel will instruct subjects that they must bring 
the diary card back after each study visit.  The site personnel will need to evaluate 
subjects’ diary cards for completeness after each dispensing interval. 
In addition, subjects should be instructed to return all bottles (used or unused) and any 
unused study medication to the study site at the end of each dispensing interval.  The 
quantity of RX-3117 and the date when it is returned by the subject should be recorded 
in the study drug accountability records.  All RX-3117 returned by the subject should be 
retained for review by the study site monitor prior to return to the study sponsor or 
destruction. 
If it is determined that a subject is substantially noncompliant with the study protocol in 
circumstances that increase risk or substantially compromise the interpretation of study 
results, the investigator and the sponsor should determine whether the subject should be 
withdrawn from study treatment.  If the subject is withdrawn for noncompliance, the 
institutional review board should be notified. 
11.7 Drug Accountability 
The disposition of all RX-3117 should be documented from the time of receipt at the site 
through dispensing to study subjects, drug return, or drug destruction.  All drug supplies 
and associated documentation will be periodically reviewed and verified by the study 
monitor over the course of the study. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 91 of 108 
Study personnel must ensure that all study drug is kept in a secure locked area with 
access limited to authorized personnel.  The study drug must not be used outside the 
context of this protocol.  Under no circumstances should the investigator or site 
personnel supply study drug to other investigators or clinics, or allow the study drug to 
be used other than as directed by this protocol. 
The investigator and/or the responsible site personnel must maintain accurate records of 
the receipt of all study drug shipped by the study sponsor or its designee, including, but 
not limited to: the date received, lot number, amount received, condition of the study 
drug, and the disposition of all study drug.  Study drug accountability records must also 
be maintained that include the subject number to whom the study drug was dispensed; 
the date, quantity and lot number of the study drug dispensed; and the identity of the 
person dispensing the medication. 
Depending upon the decision of the study sponsor, remaining unused study drug supply 
will be returned to the study sponsor or its designee after the study is completed or will 
be discarded or destroyed at the clinical site.  Drug may be returned or destroyed on an 
ongoing basis during the study if appropriate.  If the study drug is discarded or destroyed 
at the clinical site, standard institutional policy should be followed.  Records 
documenting the date of study drug return or destruction, relevant lot numbers, and the 
amount returned or destroyed should be maintained.  
11.8 Overdose Precautions 
There is limited prior clinical experience with RX-3117.  Administration of very high 
single IV doses of RX-3117 to monkeys induced convulsions, tremors, and lack of 
coordination.  Myelotoxicity is a known dose-dependent consequence of anti-metabolite 
administration.  
In this protocol, an overdose is defined as administration of more than the prescribed 
daily dose of RX-3117. In a subject who experiences an overdose, consideration should 
be given as to whether RX-3117 administration should be temporarily interrupted.  If the 
overdose ingestion is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered. 
Observation for any symptomatic side effects should be instituted, and biochemical and 
hematological parameters should be followed closely (consistent with the protocol or 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 92 of 108 
more frequently, as needed). Appropriate supportive management to mitigate adverse 
effects should be initiated. 
The study sponsor should be contacted if a study drug overdose occurs. Cases of study 
drug overdose will result in specific reporting requirements (see Section 9.6.1). 
11.9 Inadvertent Exposure and Spill Precautions 
Based on available data from nonclinical studies, RX-3117 may be acutely toxic and 
genotoxic.  It is not anticipated that the study drug would be irritative at levels that are 
likely to result from inadvertent exposure to the contents of broken capsules.  
Personnel handling the drug should use reasonable precautions to avoid ingestion of the 
study drug product or eye contact, skin contact, or inhalation of the study drug 
substance. Study subjects should be strongly advised to store the drug appropriately, 
keep the drug in a secure place out of the reach of children and to avoid mixing study 
drug capsules with other medications. 
For further information regarding inadvertent exposure and spill precautions, please 
consult the RX-3117 investigator brochure. 
12. 
REGULATORY OBLIGATIONS 
12.1 Informed Consent 
An initial generic informed consent form will be provided to the investigator for preparing 
the informed consent document to be used at his or her site.  Updates to the template 
will be communicated in writing from the sponsor or designee to the investigator.  The 
written informed consent document should be prepared in the language(s) of the 
potential subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational products are administered.   
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician should be documented in the subject’s medical 
records, and the informed consent form should be signed and personally dated by the 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 93 of 108 
subject and by the person who conducted the informed consent discussion (not 
necessarily an investigator).  The original signed informed consent form should be 
retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject or legally acceptable representative 
12.2 Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the institutional 
review board for written approval.  A copy of the written approval of the protocol and 
informed consent form must be received by the sponsor before recruitment of subjects 
into the study and shipment of investigational product. 
The investigator must submit and, where necessary, obtain approval from the 
institutional review board for all subsequent protocol amendments and changes to the 
informed consent document.  The investigator should notify the institutional review board 
of deviations from the protocol or serious adverse events occurring at the site and other 
adverse event reports received from the sponsor, in accordance with the institutional 
review board procedures. 
The investigator will be responsible for obtaining annual institutional review board 
approval/renewal throughout the duration of the study.  Copies of the investigator’s 
reports and the institutional review board continuance of approval must be sent to the 
sponsor or designee. 
12.3 Prestudy Documentation Requirements 
The investigator is responsible for forwarding the following documents to the sponsor or 
designee for review before study initiation can occur: 
 
Signed and dated protocol signature page (Investigator’s Agreement) 
 
Copy of approved informed consent form and subject information sheet, if 
applicable 
 
Copy of the institutional review board approval of the protocol, consent form, and 
subject information sheet 
 
Up-to-date curricula vitae of principal investigator and all sub-investigators 
 
Institutional review board composition and/or written statement that institutional 
review board is in compliance with regulations 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 94 of 108 
 
Laboratory normal ranges and documentation of laboratory certification (or 
equivalent) 
 
Signed study contract 
 
Completed Food and Drug Administration (FDA) form 1572 
 
Financial disclosure document 
12.4 Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained.  On the 
electronic case report forms or other documents submitted to the sponsor, subjects 
should be identified by their initials and a subject study number only.  Documents that 
are not for submission to the sponsor (e.g., signed informed consent forms) should be 
kept in strict confidence by the investigator. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the institutional review board direct access to review the 
subject’s original medical records for verification of study-related procedures and data.  
Direct access includes examining, analyzing, verifying, and reproducing any records and 
reports that are important to the evaluation of the study.  The investigator is obligated to 
inform and obtain the consent of the subject to permit named representatives to have 
access to his/her study-related records without violating the confidentiality of the subject. 
12.5 Investigator Signatory Obligations 
Each clinical study report should be signed by the investigator or, in the case of 
multicenter studies, the coordinating investigator. 
The coordinating investigator, identified by the sponsor, will either be: 
 
a recognized expert in the therapeutic area 
 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
 
an investigator contributing a high number of eligible subjects 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 95 of 108 
13. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 Protocol Amendments and Study Termination 
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, must be made only with the prior approval of the sponsor.  Agreement from the 
investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The institutional review board must be informed of all 
amendments and give approval.  The investigator must send a copy of the approval 
letter from the institutional review board to Rexahn. 
Both the sponsor and the investigator reserve the right to terminate the study according 
to the study contract.  The investigator should notify the institutional review board in 
writing of the study’s completion or early termination and send a copy of the notification 
to the sponsor. 
13.2 Study Documentation and Archive 
The investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on electronic case report forms will be included on the sponsor’s Delegation of Authority 
Form. 
Source documents are original documents, data, and records from which the subject’s 
electronic case report form data are obtained.  These include but are not limited to 
hospital records, clinical and office charts, laboratory and pharmacy records, diaries, 
microfiches, radiographs, and correspondence.   
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the sponsor and/or applicable regulatory 
authorities.  Elements should include: 
 
Subject files containing completed electronic case report forms, informed consent 
forms, and subject identification list 
 
Study files containing the protocol with all amendments, investigator’s brochure, 
copies of prestudy documentation (see Section 12.3), and all correspondence to 
and from the institutional review board and the sponsor 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 96 of 108 
 
Proof of receipt, Investigational Product Accountability Record, Return of 
Investigational Product for Destruction, Final Investigational Product 
Reconciliation Statement, and all drug-related correspondence 
In addition, all original source documents supporting entries in the electronic case report 
forms must be maintained and be readily available. 
No study document should be destroyed without prior written agreement between the 
sponsor and the investigator.  Should the investigator wish to assign the study records to 
another party or move them to another location, he/she must notify the sponsor in writing 
of the new responsible person and/or the new location. 
13.3 Study Monitoring and Data Collection 
The sponsor’s representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (e.g., electronic case 
report forms and other pertinent data) provided that subject confidentiality is respected. 
The sponsor’s monitor is responsible for verifying the electronic case report forms at 
regular intervals approximately every 4 to 6 weeks or more frequently if needed 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The monitor should have access to subject medical records and other study-
related records needed to verify the entries on the electronic case report forms. 
The investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing 
electronic case report forms, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by sponsor or its designee.  Inspection of site facilities (e.g., pharmacy, drug 
storage areas, laboratories) and review of study-related records will occur to evaluate 
the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
To ensure the quality of clinical data across all subjects and sites, a data management 
review will be performed on subject data received at the sponsor or designee.  During 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 97 of 108 
this review, subject data will be checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data will be reviewed for adherence to the protocol and 
good clinical practice.  To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications will be sent to the site 
for completion and returned to the sponsor or designee. 
The principal investigator will electronically sign and date the indicated places on the 
electronic case report form.  These signatures will indicate that the principal investigator 
inspected or reviewed the data on the electronic case report form, the data queries, and 
the site notifications, and agrees with the content. 
13.4 Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
13.5 Publication Policy 
To coordinate dissemination of data from this study, the sponsor encourages the 
formation of a publication committee consisting of several principal investigators and 
appropriate sponsor staff.  The committee is expected to solicit input and assistance 
from other investigators and the sponsor staff as appropriate.  Membership on the 
committee (both for investigators and the sponsor’s staff) does not guarantee 
authorship—the criteria described below should be met for every publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors, 2005), which states: 
 
Authorship credit should be based on (1) substantial contributions to conception 
and design, acquisition of data, or analysis and interpretation of data; (2) drafting 
the article or revising it critically for important intellectual content; (3) final 
approval of the version to be published.  Authors should meet conditions 1, 2, 
and 3. 
 
When a large, multicenter group has conducted the work, the group should 
identify the individuals who accept direct responsibility for the manuscript.  These 
individuals should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those 
who qualify should be listed. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 98 of 108 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (e.g., manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to the sponsor for corporate review.  The Clinical 
Study Agreement among the institution, principal investigator, and the sponsor will detail 
the procedures for, and timing of, the sponsor’s review of publications. 
13.6 Compensation  
Subject will be treated and/or compensated for any study-related illness/injury pursuant 
to the information provided in the Compensation for Injury section of the Informed 
Consent. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 99 of 108 
14. 
REFERENCES  
Albain KS, Nag S, Calderillo-Ruiz G. Global phase III study of gemcitabine plus 
paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): 
First report of overall survival. Proc ASCO 22, No 14S (July 15 Supplement) 2004;510. 
American Cancer Society Global Cancer Facts & Figures 3rd Edition 2015; 
http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-
044738.pdf 
Burris HA, III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. 
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for 
patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 
1997;15(6):2403-13. 
Carmichael J, Fink U, Russell RC, Spittle MF, Harris AL, Spiessi G, et al. Phase II study 
of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer 
1996;73(1):101-5. 
Casper ES, Green MR, Kelsen DP, Heelan RT, Brown TD, Flombaum CD, et al. Phase 
II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the 
pancreas. Invest New Drugs 1994;12(1):29-34. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer 2009;45(2):228-47. 
Gandhi V, Plunkett W. Modulatory activity of 2',2'-difluorodeoxycytidine on the 
phosphorylation and cytotoxicity of arabinosyl nucleosides. Cancer Res 
1990;50(12):3675-80. 
Globocan, 2012; http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx  
Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB. Inhibition of 
ribonucleotide reduction in CCRF-CEm cells by 2', 2'-difluorodeoxycytidine. Mol 
Pharmacol 1990;38:567-72. 
Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, et al. Cellular 
elimination of 2',2'-difluorodeoxycytidine 5'-triphosphate: a mechanism of self-
potentiation. Cancer Res 1992;52(3):533-9. 
Hertel LW, Boder GB, Kronin JS. Evaluation of the antitumor activity of gemcitabine (2', 
2'-difluoro-2'-deoxycytidine). Cancer Res 1990; 50:4417-22. 
Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2',2'-
difluorodeoxycytidine on DNA synthesis. Cancer Res 1991;51(22):6110-7. 
Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. 
Ann Oncol 2006;17 Suppl 5:v7-12. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
19 February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 100 of 108 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5:649-55. 
Peters GJ. Mechanism of action of fluorocyclopentenylcytosine (RX-3117) [unpublished]. 
Laboratory Medical Oncology 2011. 
Pourquier P, Gioffre C, Kohlhagen G, Urasaki Y, Goldwasser F, Hertel LW, et al. 
Gemcitabine (2',2'-difluoro-2'-deoxycytidine), an antimetabolite that poisons 
topoisomerase I. Clin Cancer Res 2002;8(8):2499-504. 
Rizzo JD, Somerfield MR, Hagerty KL et a., Use of epoetin and darbepoetin in patients 
with cancer. 2007 American Society of Clinical Oncology/American Society of 
Hematology Clinical practice guideline update.  J. Clin Oncol 2008 26: 132-149. 
Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burris HA, III, et al. 
A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann 
Oncol 1996;7(4):347-53. 
Ruiz van Haperen VW, Veerman G, Vermorken JB, Peters GJ. 2',2'-Difluoro-
deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. 
Biochem Pharmacol 1993;46(4):762-6. 
Sandler AB, Nemunaitis J, Denham C, von PJ, Cormier Y, Gatzemeier U, et al. Phase III 
trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced 
or metastatic non-small-cell lung cancer. J Clin Oncol 2000;18(1):122-30. 
Schy WE, Hertel LW, Kroin JS, Bloom LB, Goodman MF, Richardson FC. Effect of a 
template-located 2',2'-difluorodeoxycytidine on the kinetics and fidelity of base insertion 
by Klenow (3'-->5'exonuclease-) fragment. Cancer Res 1993;53(19):4582-7. 
Senderowicz AM. Information needed to conduct first-in-human oncology trials in the 
United States: a view from a former FDA medical reviewer. Clin Cancer Res 
2010;16(6):1719-25. 
Simon R, Optimal Two-Stage Designs for Phase II Clinical Trials Controlled Clinical 
Trials 1989 10: 1-10. 
Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC Accelerated 
Titration Designs for Phase 1 Clinical Trials in Oncology.  J. Natl Cancer Inst 1997; 89: 
1138-1147. 
Smith TJ, Khatcheressian J, Lyman GH et al, 2006update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice guideline.  J. 
Clin Oncol 24: 3187-3205. 
von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. 
Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in 
advanced or metastatic bladder cancer: results of a large, randomized, multinational, 
multicenter, phase III study. J Clin Oncol 2000;18(17):3068-77. 


Protocol Number:  RX-3117-P1-01 
 
 
 
 
       Product:  RX-3117 
19 February 2016 
 
 
 
 
 
Amendment 04 
 
CONFIDENTIAL 
 
 
 
 
Page 101 of 108 
15. 
APPENDICES  
Appendix A.  Schedule of Assessments 
 
SCRa 
Cycle 1 
Cycles 
2-6 
≥Cycle 
8 
EOT/ 
ET 
SFU
c 
Procedures and Treatments                             Day 
-14 
1 
8b 
15 
22b 
1c 
1 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical, surgical, cancer and psychiatric histories 
X 
 
 
 
 
 
 
 
 
Prior medication usaged 
X 
Xe 
 
 
 
 
 
 
 
Eligibility review, enrollment 
X 
Xf 
 
 
 
 
 
 
 
Pregnancy test 
Xg 
Xg 
 
 
 
 
 
 
 
Physical examination including height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
 
X 
X 
X 
X 
ECOG performance status 
X 
X 
 
 
 
X 
X 
X 
X 
Tumor biopsy samples (optional)h 
 
X 
 
 
 
 
 
 
 
Hematology and serum chemistry 
X 
Xi 
X 
X 
X 
Xj 
X 
X 
X 
Coagulation profile and Urinalysis 
X 
Xi 
X 
X 
 
 
 
X 
 
Vital sign measurementsk,l 
X 
X 
X 
X 
X 
X 
 
X 
X 
12-lead electrocardiogramk,m 
Xa 
X 
 
 
 
 
 
 
 
Pharmacokinetic samplingk,n 
 
Xn 
Xn 
Xn 
 
 
 
 
 
Study drug administration - 3 times per weeko,p 
 
X 
X 
X 
 
X 
X 
 
 
Study drug administration - 5 times per weeko,q 
 
X 
X 
X 
 
X 
X 
 
 
Dispensing of study drugr 
 
Xr 
Xr 
Xsr 
X 
Xr 
X 
 
 
Unused study drug collection & subject compliance 
 
 
X 
 
X 
X 
X 
X 
 
Tumor assessment(s)s 
Xa 
 
 
 
Xt 
Xt 
Xt 
Xt 
Xu 
Tumor Marker, if applicable 
X 
Xi 
 
 
 
X 
X 
X 
 
Adverse event assessmentv 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant med review 
 
X 
X 
X 
X 
X 
X 
X 
X 
Archived tumor tissuew 
 
X 
 
 
 
 
 
 
 
Biomarker blood sample 
 
Xx 
Xx 
Xx 
Xy 
Xy 
Xy 
Xy 
Xy 
 
ECOG = Eastern Cooperative Oncology Group; ET = Early Termination; EOT = End of Treatment; SFU = Safety Follow up; SCR = Screening 


Protocol Number:  RX-3117-P1-01 
 
 
 
 
       Product:  RX-3117 
19 February 2016 
 
 
 
 
 
Amendment 04 
 
CONFIDENTIAL 
 
 
 
 
Page 102 of 108 
Footnotes for Schedule of Assessments 
a 
Screening procedures will be performed within 14 days of Cycle 1 Day 1, except baseline tumor assessment, which can be 
evaluated within 21 days of Cycle 1 Day 1.  ECG must be done within 7 days of enrollment. 
b 
The Cycle 1 Day 8 and Day 22 visits may occur on Days 8 or 22 (+1 day). 
 
c 
Safety follow-up visit will be between 30 and 37 days after the last dose of study drug. 
d 
Medications taken within 28 days Cycle 1 Day 1. 
e 
Review prior medication usage for any medications started since the screening visit. 
f 
Confirm that the subject is still is eligible for enrollment in the study. 
g 
A serum pregnancy test will be performed at screening (for women of childbearing potential).  A serum pregnancy test or urine 
pregnancy test will be performed at baseline (day 1 of cycle 1) unless the screening serum pregnancy test was performed within 72 
hours of dosing on Cycle 1 Day 1.  
h 
Tumor biopsies will be taken following enrollment but before first dose of study treatment (optional) 
i 
If screening laboratory tests were performed within 72 hours of Cycle 1 Day 1, they do not need to be repeated on Cycle 1 Day 1. 
j 
Hematology and chemistry will be assessed on Days 1 and 15 in Cycles 2 through 8 and Day 1 for Cycles > 8. 
k 
The required order of assessments is ECG, followed by vital signs and then PK sampling when applicable 
l 
Vital signs measurements will include resting blood pressure, pulse, respiratory rate, pulse oximetry, and temperature. 
m ECG to be assessed pre dose, 1, 2, 4, 6, and 8 hours after RX-3117 oral administration on Cycle 1 Day 1 (Phase 1 and Dose 
Expansion). 
n 
Pharmacokinetic (PK) samples will be collected pre-dose  and 0.5, 1, 2, 3, 4, 6 and 8 hours after oral administration on Days 1 and 
15 in Cycle 1 for Phase 1 and Dose Expansion.  PK will be collected pre-dose only in Cycle 1 on Days 1, 8 and 15 in Phase 2. 
o 
Orally after having fasted for a minimum of 8 hours.  
 
p 
Administered 3 times per week (preferably Monday, Wednesday and Friday) followed by 2 days off each week for 3 weeks then 1 
week off. If a dose is administered on the same day as PK sampling, the PK sample will be collected first. 
 
q 
Administered for 5 consecutive days followed by 2 days off per week for 3 weeks then 1 week off. If a dose is administered on the 
same day as PK sampling, the PK sample will be collected first. 
 
 
r 
Study drug and diary cards will be dispensed at 1 week intervals during Cycle 1 and at least once every cycle thereafter. 
s 
Tumor assessments will be evaluated using RECIST v1.1 between Days 22-28 of cycles.  The results of the assessments must be 
available before the start of the next cycle. Depending on the tumor type, specific assessments may include CT (preferred for lung 
lesions) or MRI scans and any other appropriate radiographic or scintigraphic procedures and/or physical examinations. The 
method of assessment for an individual tumor or lesion that was used at baseline must be used consistently throughout the study 
and follow-up visit. 
tu Tumor evaluation, including CT/MRI/PET will be performed between Days 22-28 of cycles. The results of the assessments must be 
available before the start of the next cycle.  For subjects who end treatment on a cycle for which response assessments are not 
planned (i.e., cycle 5 or 7) and if an assessment has not been done in the previous 4 weeks. 


Protocol Number:  RX-3117-P1-01 
 
 
 
 
       Product:  RX-3117 
19 February 2016 
 
 
 
 
 
Amendment 04 
 
CONFIDENTIAL 
 
 
 
 
Page 103 of 108 
uv Subjects meeting criteria for complete response or partial response at the last on-treatment tumor assessment should have a 
Safety Follow-up tumor assessment if the last assessment was performed ≥ 4 weeks, to confirm the response based upon RECIST. 
vw Adverse events include all worsening of pre-existing conditions from the time the subject receives study treatment.  All adverse 
events attributed to study drug will be assessed until resolved or returned to baseline.  
wx To be collected within 4 weeks after enrollment 
xy Biomarker samples will be collected pre-dose on Days 1, 8 and 15 of Cycle 1 and also post-dose at 4 hours ± 15 minutes on Day 1 
and Day 15 of Cycle 1 during Phase 1 and the Dose Expansion.  
yz Biomarker samples will be collected pre-dose on Day 1 of Cycle n, and when tumor assessments are done. 
 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
XX February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 104 of 108 
Appendix B.  Analytes 
 
 
Chemistry 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Specific gravity 
RBC 
Urine -HCG 
Potassium 
pH 
Hemoglobin 
Serum -HCG 
Chloride 
Hemoglobin 
ANC 
PT; PTT or INR 
Bicarbonate 
Protein 
Platelets 
PK 
Magnesium 
Glucose 
WBC 
Blood samples 
for RX-3117 
and its 
metabolites 
concentration 
Calcium 
Bilirubin 
Differential 
BUN 
Ketones 
 Eosinophils 
Serum Creatinine WBC 
 Basophils 
Blood samples 
for biomarkers 
AST (SGOT) 
RBC 
 Lymphocytes 
Tumor Marker, 
if applicable 
ALT (SGPT) 
Epithelial cells 
 Neutrophils 
 
Alkaline 
phosphatase 
Bacteria 
 Monocytes 
 
Lactate 
dehydrogenase 
 
 
 
Total bilirubin 
 
 
 
Creatine 
phosphokinase 
 
 
 
Total protein 
 
 
 
Albumin 
 
 
 
Glucose  
 
 
 
-HCG = beta human chorionic gonadotropin; ALT = alanine amino transferase; 
ANC = absolute neutrophil count; AST aspartate amino transferase; BUN = 
blood, urea, nitrogen, INR = international normalized ratio; PT = prothrombin 
time; PTT = Partial prothrombin time; RBC = red blood cells; WBC = white blood 
cells 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
XX February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 105 of 108 
Appendix C.  Response Evaluation Criteria in Solid Tumors 
 
(Eisenhauer et al, 2009) 
 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
- 
Measurable Disease - the presence of at least one measurable lesion. If 
the measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
- 
Measurable Lesions - lesions that can be accurately measured in at least 
one dimension with longest diameter  20 mm using chest X-ray or  10 mm 
with CT scan. 
- 
Non-measurable Lesions - all other lesions, including small lesions 
(longest diameter <20 mm with chest X-ray or ≥ 10 but < 15 mm with CT 
scan), i.e., bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic 
lesions, and also abdominal masses that are not confirmed and followed by 
imaging techniques; and. 
 
All measurements should be taken and recorded in metric notation, using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 28 days before study day 1.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion throughout the trial. 
 
Clinical lesions (e.g., skin nodules and palpable lymph nodes) will only be 
considered measurable target lesions when they ≥ 15 mm. For the case of skin 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
 
Lymph nodes that are < 10 mm will be considered non-pathological 
 
Methods of Measurement  
 
CT and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment. Conventional CT and 
MRI should be performed with cuts no greater than 5 mm in slice thickness 
contiguously. This applies to tumors of the chest, abdomen and pelvis. Head and 
neck tumors and those of extremities usually require specific protocols. 
 
When the primary endpoint of the study is objective response evaluation, 
ultrasound should not be used to measure tumor lesions.  It is, however, a 
possible alternative to clinical measurements of superficial palpable lymph 
nodes, subcutaneous lesions and thyroid nodules. Ultrasound might also be 
useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has 
not yet been fully and widely validated. Their uses in this specific context require 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
XX February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 106 of 108 
sophisticated equipment and a high level of expertise that may only be available 
in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. 
However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained. 
 
Cytology and histology can be used to differentiate between partial response and 
complete response in rare cases (e.g., after treatment to differentiate between 
residual benign lesions and residual malignant lesions in tumor types such as 
germ cell tumors). 
 
Baseline Documentation of “Target” and “Non-Target” Lesions 
 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs should be identified as target lesions 
and recorded and measured during screening.  
 
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinically).  
 
A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the objective tumor. 
 
All other lesions (or sites of disease) should be identified as non-target lesions 
and should also be recorded during screening. Measurements of these lesions 
are not required, but the presence or absence of each should be noted 
throughout the study.  
 
Response Criteria 
Evaluation of Target Lesions 
* Complete Response (CR): 
Disappearance of all target lesions.  Any pathologic 
lymph nodes (whether target or non-target) mush have 
reduction in short axis to < 10 mm 
* Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
* Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum 
diameters recorded since the treatment started or the 
appearance of one or more new lesions.  In addition the 
relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
Appearance of one or more new lesions is also 
considered progression. 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for progressive disease, 
taking as reference the smallest sum diameters while 
on study. 


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
XX February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 107 of 108 
 
Evaluation of Non-Target Lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions.  All lymph 
nodes must be non-pathological in size (i.e., < 10 mm 
short axis) 
* Incomplete Response/         
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
(1)  
(1) Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail. 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). In general, the subject's 
best response assignment will depend on the achievement of both measurement and 
confirmation criteria   
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non CR/Non-PD 
No 
PR 
CR 
Not Evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = compete response, PR = partial response, SD = stable disease, PD = progressive 
disease, NE = inevaluable 
 
 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having “symptomatic deterioration”. Every effort should be made 
to document the objective progression even after discontinuation of treatment.  


Protocol Number:  RX-3117-P1-01 
 
Product:  RX-3117 
XX February 2016 
 
Amendment 04 
 
 
CONFIDENTIAL 
Page 108 of 108 
 
In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response status. 
 
Confirmation 
 
The main goal of confirmation of objective response is to avoid overestimating 
the response rate observed.  In cases where confirmation of response is not 
feasible, it should be made clear when reporting the outcome of such studies that 
the responses are not confirmed. 
 
To be assigned a status of partial response or complete response, changes in 
tumor measurements must be confirmed by repeat assessments during the 
study.   
 
In the case of SD, follow-up measurements must have met the SD criteria no 
earlier than 49 days after the date of enrollment/randomization during the study.    
 
Duration of Overall Response 
 
The duration of overall response is measured from the time measurement criteria 
are met for complete response or partial response (whichever status is recorded 
first) until the first date that recurrence or progressive disease is objectively 
documented, taking as reference for progressive disease the smallest 
measurements recorded since the treatment started. 
Duration of Stable Disease 
 
SD is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements recorded 
since the treatment started.