Clinical trial NCT03189914
Conditions: Metastatic Pancreatic Cancer
Keywords: pancreatic cancer Abraxane first line
Sponsor: Processa Pharmaceuticals
Start date: 2017-10-02; Completion date: 2019-11-21
Enrollment: 46 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This will be a Phase 1b/2a multicenter 2-stage study. Phase 1 will be conducted as a dose-finding, open-label study of oral RX-3117 administered in combination with Abraxane® to subjects with metastatic pancreatic cancer. After completion of the Phase 1 portion, a Phase 2a study will be conducted using a 2 stage, open-label design, of RX 3117 and Abraxane® in combination to treat subjects with metastatic pancreatic cancer as first line therapy.

Detailed description:
This will be a Phase 1b/2a multicenter 2-stage study. Phase 1 will be conducted as a dose-finding, open-label study of oral RX-3117 administered in combination with Abraxane® to subjects with metastatic pancreatic cancer. The recommended phase 2 dose (RP2D) and schedule of RX-3117, in combination with Abraxane®, will be determined based on the safety profile, dose modification, and pharmacokinetics (PK). Phase 1 will be conducted using a combination of the single agent maximum tolerated dose (MTD) for RX-3117 and the Abraxane dose as per the package insert for patients with pancreatic cancer in combination with gemcitabine.

After completion of the Phase 1 portion, a Phase 2a study will be conducted using a 2 stage, open-label design, of RX 3117 and Abraxane® in combination to treat subjects with metastatic pancreatic cancer as first line therapy. Approximately 10 subjects will participate in the Stage 1 at the dose identified in Phase 1 (RP2D). Subjects will be treated for up to 8 cycles of combined therapy. An interim analysis will be conducted after 10 evaluable subjects have been treated at the RP2D, have completed a minimum of 4 cycles of therapy, or have discontinued therapy due to progressive disease before completing 4 cycles. If an adequate number of Responders are observed out of the initial 10 evaluable subjects, then 40 additional subjects will be enrolled to participate in Stage 2. Subjects will be treated for up to 8 cycles of combined therapy.

Arms: arm 1: RX-3117: oral, 500 - 700 mg/ day for 5 days on/ 2 days off for 3 weeks. 1 washout week/ cycle.

Abraxane: 75 - 125 mg/m\^2, infused once per week for 3 weeks. 1 washout week/ cycle.
Interventions: intervention 1: RX-3117
Intervention descriptions: intervention 1: RX-3117 will be administered orally in combination with Abraxane.

Protocol documents:
Prot_000.pdf: 
Protocol Number:  RX3117-003 
  
Product:  RX-3117 
 08 August 2018 
 
 
 
 
 
 
 
Amendment 03 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Page 1 of 100 
A Phase 1/2 Open-Label, Safety, Pharmacokinetic, Pharmacodynamic and Efficacy 
Study of RX-3117 in Combination with Abraxane® in Subjects with Metastatic 
Pancreatic Cancer 
 
Rexahn Protocol Number RX3117-003 
 
 
 
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: 
Callie Heaton, MS, CCRA 
Rexahn Pharmaceuticals, Inc 
15245 Shady Grove Road, Suite 455 
Rockville, MD 20850 USA 
Telephone: (240) 268-5300 x 312 
Fax: (240) 268-5310 
Email: heatonc@rexahn.com 
Key CRO Contact 
Meredith Gartner 
Advanced Clinical  
10 Parkway North, Suite 350 
Deerfield, IL 60015 
Telephone: 919-522-8539  
Fax: 847-267-1432 
Email: mgartner@advancedclinical.com 
 
Amendment 03 Date: 
Amendment 02 Date: 
Amendment 01 Date: 
Original Protocol Date: 
02 August 2018 
20 December 2017 
05 September 2017 
08 March 2017 
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 or scientific review boards. 
 
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. 
  


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Product:  RX-3117 
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Investigator’s Agreement 
I have read the attached protocol, “A Phase 1/2 Open-Label, Safety, Pharmacokinetic, 
Pharmacodynamic, and Efficacy Study of RX-3117 in Combination with Abraxane® in 
Subjects with Metastatic Pancreatic Cancer”, Amendment 03 dated  08 August 2018, 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 sub-investigators (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) 
As representative of Rexahn, I agree to the provisions described in this protocol. 
 
 
 
Signature 
 
 
 
Name of Rexahn Representative 
Rexahn Pharmaceuticals Inc. 
 
Date (DD Month YYYY) 


Protocol Number:  RX3117-003 
  
Product:  RX-3117 
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Protocol Synopsis 
Title:   A Phase 1/2 Open-Label, Safety, Pharmacokinetic, Pharmacodynamic and Efficacy Study 
of RX-3117 in Combination with Abraxane® in Subjects with Metastatic Pancreatic 
Cancer  
Study Phase:  Phase 1b/2a 
Indications:  Metastatic Pancreatic Cancer 
 
Objectives: 
Phase 1 Objectives: 
Primary Objectives 
To evaluate the safety and tolerability of RX-3117 in combination with 
Abraxane® in subjects with metastatic pancreatic cancer 
To determine the Recommended Phase 2 Dose (RP2D) of RX-3117 when 
administered orally in combination with Abraxane® to subjects with metastatic 
pancreatic cancer 
Secondary Objectives 
To determine the pharmacokinetic (PK) profiles of RX-3117 and Abraxane® on 
Day 1 (single dose) and Day 15 (steady-state) in Cycle 1 
To evaluate the antitumor activity of RX-3117 in combination with Abraxane® 
Exploratory Objective 
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 
 
Phase 2 Objectives: 
Primary Objective 
To estimate the antitumor activity of RX-3117 in combination with Abraxane® 
as first-line therapy in subjects with metastatic pancreatic cancer  
Secondary Objectives 
To assess additional measures of antitumor activity  
To characterize the safety profile of RX-3117 in combination with Abraxane® 
To evaluate the PK of RX-3117 and Abraxane® at the recommended Phase 2 
dose (RP2D) 
Exploratory Objectives 
To investigate the effect of RX-3117 in combination with Abraxane® on 
potential cellular or molecular biomarkers in blood or tumor samples 
To evaluate the change in tumor burden response 
To evaluate the effect on Quality of Life (QOL) 
 


Protocol Number:  RX3117-003 
  
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Endpoints:  
Phase 1 Endpoints: 
• 
Primary Endpoints 
o Overall safety profile characterized by the type, frequency, severity, timing 
of onset, duration and relationship to study therapies of any adverse events 
(AEs), clinical laboratory abnormalities, vital signs, and electrocardiograms 
(ECGs)  
o Enumeration and description of any dose limiting toxicities (DLTs) that 
occur during Cycle 1, serious adverse events (SAEs), or AEs leading to 
discontinuation of study treatment. 
• 
Secondary Endpoints 
o RX-3117 and Abraxane® plasma PK parameters (e.g., time to maximum 
observed concentration [Tmax], maximum observed concentration [Cmax],  
and area under the concentration-time curve [AUC]) 
o 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 Endpoint 
o Expression or concentration of various cellular or molecular biomarkers  
Phase 2 Endpoints: 
• 
Primary Endpoint 
o An adequate number of responders based on PFS and/or objective clinical 
response  
• 
Secondary Endpoints 
o Time to progression, ORR and DOR 
o Overall safety profile of RX-3117 in combination with Abraxane® 
o RX-3117 and Abraxane® PK parameters  
• 
Exploratory Endpoints 
o Enumeration,  expression, or concentration of various cellular or molecular 
biomarkers  
o Changes in tumor burden 
o QOL 
Study Design: 
This will be a Phase 1b/2a multicenter 2-stage study.  
Phase 1 will be conducted as a dose-finding, open-label study of oral RX-3117 
administered in combination with Abraxane® to subjects with metastatic pancreatic 
cancer. The recommended phase 2 dose (RP2D) of RX-3117, in combination with 
Abraxane®, will be determined based on the safety profile, dose modification, and PK. 


Protocol Number:  RX3117-003 
  
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Phase 1 will be conducted using a combination of the single agent MTD for RX-3117 and 
the Abraxane® dose as per the package insert when Abraxane® is given in combination 
for patients with pancreatic cancer. A safety committee will assess the safety and the 
tolerability of the combination after the first 5 patients and may make recommendation to 
confirm the MTD or RP2D in another 5 patients. For dosing information, please refer to 
Investigational Product Dosage and Administration.  
After completion of the Phase 1 portion, a Phase 2a study will be conducted using a 
2-stage, open-label design, of RX-3117 and Abraxane® in combination to treat subjects 
with metastatic pancreatic cancer as first-line therapy. Approximately 10 subjects will 
participate in the Stage 1 at the dose identified in Phase 1 (RP2D). Subjects will be treated 
for up to 8 cycles of combined therapy. An interim analysis will be conducted after 
10 evaluable subjects have been treated at the RP2D, have completed a minimum of 4 
cycles of therapy, or have discontinued therapy due to progressive disease before 
completing 4 cycles. If an adequate number of Responders are observed out of the initial 
10 evaluable subjects, then approximately 30 additional evaluable subjects will be 
enrolled to participate in Stage 2. Subjects will be treated for up to 8 cycles of combined 
therapy. 
Sample Size:   
The number of planned subjects is approximately 50 (approximately 10 subjects in the 
Phase 1, depending upon the number of dose levels needed to identify the RP2D, 
10 evaluable subjects in Stage 1 of Phase 2 and approximately 30 evaluable 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 9 months. Additional cycles of therapy may be provided 
following discussions with the investigator, sponsor and medical monitor.  
Subjects may be discontinued from study treatment due to progressive disease (PD), an 
intolerable treatment-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. 
Subject Eligibility Criteria:   
Inclusion Criteria 
Disease Related 
1. Subject has confirmed histologic or cytologic evidence of pancreatic cancer, 
metastatic pancreatic cancer by at least radiographic evidence, and has no prior 
treatment for metastatic pancreatic cancer. Subjects who received gemcitabine in 
the neoadjuvant or adjuvant setting can be considered. 


Protocol Number:  RX3117-003 
  
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2. Subject has measurable disease using Response Evaluation Criteria in Solid 
Tumors (RECIST) ver. 1.1. 
3. Subject has a life expectancy of at least 3 months. 
4. Subject has an ECOG performance status 0 or 1.  
 
Demographic 
5. Males or females ≥ 18 years of age  
6. Subject must be able to swallow capsules 
7. Subject must have adequate venous access for intravenous (IV) infusion  
 
Laboratory 
8. Subject has hemoglobin ≥ 9.0 g/dL at Screening 
9. Subject has absolute neutrophil count (ANC) ≥ 1.5 x 109/L at Screening 
10. Subject has platelet count ≥ 100 x 109/L at Screening 
11. Subject has serum creatinine ≤ 1.5 times the upper limit of normal (ULN) at 
Screening. 
• 
Subjects with serum creatinine levels > 1.5 times the ULN must have a 
24-hour urine creatinine clearance ≥ 50 mL/min  
12. Subject has serum bilirubin ≤ 1.5 times the ULN (except in subjects with Gilbert’s 
Syndrome who must have serum bilirubin < 3.0 x ULN) 
13. Subject 
has 
aspartate 
aminotransferase 
(AST; 
SGOT) 
and 
alanine 
aminotransferase (ALT; SGPT) ≤ 2.5 times the ULN (OR, AST and ALT ≤ 5 times 
the ULN in the presence of known liver metastases) 
14. Subject has alkaline phosphatase ≤ 2.5 times the ULN (OR ≤ 5 times the ULN in 
the presence of known liver or bone metastases) 
15. Subject has normal coagulation parameters (prothrombin time [PT] and/or 
international normalized ratio [INR], and partial thromboplastin time [PTT] within 
normal limits [<1.2 x ULN]) 
16. Subject has potassium concentration within normal range, or correctable with 
supplements.  
17. Oxygen saturation by pulse oximetry ≥ 92% at rest.  
18. 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 
19. 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.  


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20. Female subjects of non-childbearing potential defined as having amenorrhea for 
at least 24 consecutive months, a documented hysterectomy, or a documented 
bilateral oophorectomy) 
21. 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 
22. 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. 
23. Before any study-specific procedure, the appropriate written informed consent 
must be obtained 
 
Exclusion Criteria: 
Disease Related 
1. Subject has primary brain tumors or clinical evidence of active brain metastasis 
2. Subject has undergone major surgery within 4 weeks of the start of study 
treatment. Laparoscopy and central venous catheter placement are not considered 
major surgery 
 
Medications 
3. Subject has a history of systemic corticosteroid use within 7 days before Day 1 of 
Cycle 1 
 
General 
4. Subject has an active infection requiring parenteral or oral antibiotics within 2 
weeks before planned start of study therapy 
5. Subject has uncontrolled diabetes as assessed by the investigator  
6. Subject has a 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 
7. Subject has an active infection of hepatitis B, hepatitis C or human 
immunodeficiency virus 
8. Female subjects who are pregnant, planning a pregnancy or breast feeding during 
the study  
9. Subject has a high cardiovascular risk, including, but not limited to, subjects with 
congestive heart failure (New York Heart Association [NYHA] Class III or IV), 
cardiac arrhythmia, unstable angina, coronary stenting or acute coronary 
syndromes within 6 months before planned start of study therapy or myocardial 
infarction within one year before planned start of study therapy 


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10. Subject has a history of peripheral artery disease (e.g., claudication, Leo Buerger's 
disease). [Criterion removed] 
11. Subject has a history of prior allogeneic bone marrow progenitor cell or solid organ 
transplantation. 
12. Subject has known acute or chronic pancreatitis. 
13. Subject has persistent diarrhea, malabsorption, or known sub-acute bowel 
obstruction ≥ NCI CTCAE Grade 2, despite medical management. 
14. Subject has any disorder that may interfere with drug absorption, distribution, 
metabolism, or excretion (including gastrointestinal surgery and bariatric surgery) 
15. 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, Grade 3 
or higher is excluded] 
16. Subject has 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 
17. Subject has a history of interstitial lung disease, slowly progressive dyspnea and 
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, 
pulmonary hypersensitivity pneumonitis or multiple allergies. Any lung disease that 
may interfere with the detection or management of suspected drug-related 
pulmonary toxicity. 
18. Subject is currently enrolled in any other clinical protocol or investigational trial that 
involves administration of experimental therapy and/or therapeutic devices, or 
investigational drug.  
19. Subject has a history of hypersensitivity to RX-3117, gemcitabine, azacytidine 
cytosine arabinoside, paclitaxel, nab-paclitaxel, or their excipients. 
20. Subject is unwilling or unable to comply with study requirements or planned 
unavailability for follow-up assessments. 
 
Investigational Product Dosage and Administration:    
RX-3117 
RX-3117 will be provided as 200 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 five times per week (i.e. 5 consecutive days followed by 2 days 
off) for 3 consecutive weeks followed by 1 week of rest during each 28-day cycle. Subjects 
should fast for a minimum of 8 hours prior to RX-3117 administration. RX-3117 will be 
taken orally with 4 to 8 ounces of water. A light meal is permitted approximately 1 hour 
after dosing.  


Protocol Number:  RX3117-003 
  
Product:  RX-3117 
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For Cycle 1, RX-3117 doses will be dispensed each week. For Cycles 2 and higher, RX-
3117 doses will be dispensed at the start of each cycle. 
During Phase 1, 700 mg of RX-3117 will be investigated in combination with Abraxane® 
as per Table 1. 
Additional doses may be recommended by the review committee which includes 
investigators, medical monitor and sponsor. For Phase 2, RX-3117 be administered based 
on the RP2D identified after completion of Phase 1.  
Abraxane® 
Abraxane® for Injectable Suspension (paclitaxel albumin-bound particles for injectable 
suspension) is formulated as nanoparticles with a mean particle size of approximately 130 
nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. 
Abraxane® is supplied as a white to yellow, sterile, lyophilized powder for reconstitution 
with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each 
single-use vial contains 100 mg of paclitaxel (bound to human albumin) and approximately 
900 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate). 
Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel formulated as 
albumin-bound particles. Abraxane® is free of solvents. 
Abraxane® will be administered as follows: 
Intravenously at a dose of 125, 100 or 75 mg/m2 as per Table 1 infused over 30 to 40 
minutes once a week for 3 weeks (Days 1, 8, and 15) followed by 1 week of rest during 
each 28-day cycle.  
On days when both RX-3117 and Abraxane® are administered on the same day, 
Abraxane® should be administered first followed by RX-3117. RX-3117 will be 
administered no sooner than 1 hour after the start of the Abraxane® infusion. 
Control Group:  There will be no control group. 
Key Screening Procedures:  (see Section 7.2 and the Schedule of Assessments for more 
detail): 
• 
Informed Consent 
• 
Review of inclusion and exclusion criteria 
• 
Medical, surgical, and cancer history including histology report confirming diagnosis of 
metastatic pancreatic cancer 
• 
Medication history (including cancer therapies) 
• 
Physical examination including height and weight 
• 
Vital signs (heart rate, body temperature, respiratory rate, blood pressure, and pulse 
oximetry) 
• 
12-lead ECG 


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• 
Performance status assessment (i.e., ECOG) 
• 
Tumor imaging assessment 
• 
Blood and urine collection for clinical laboratory tests (hematology, serum chemistry 
[including serum pregnancy in females of childbearing potential], coagulation, and 
urinalysis) 
• 
Blood collection for tumor markers 
 
Key Treatment Procedures (see Section 7.3 and the Schedule of Assessments for more 
detail): 
• 
QOL (before other study procedures are performed) 
• 
Review inclusion and exclusion criteria 
• 
Study drug dispensing and administration 
• 
Concomitant medication assessments 
• 
AE/SAE assessments 
• 
Vital signs (heart rate, body temperature, respiratory rate, blood pressure) 
• 
12-lead ECG (Cycle 1 only) 
• 
Body weight 
• 
ECOG performance status  
• 
Blood collection for PK assessments in Cycle 1 only (Phase 1 and Phase 2 - Stage 1) 
• 
Blood and urine collection for clinical laboratory tests (hematology, serum chemistry 
[including serum pregnancy in females of childbearing potential], coagulation, and 
urinalysis) 
• 
Blood collection for appropriate biomarkers at baseline and at the time of tumor 
imaging assessments 
• 
Collection of blood for tumor markers 
• 
Collection of archival tumor tissue if available 
• 
Collection of tumor biopsy for biomarker (optional) 
• 
Tumor imaging assessments (after every 2 cycles of treatment) 
 
Adverse Event Evaluation:  AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and will be graded using NCI CTCAE, Version 4.03. The 
CTCAE will also be used to grade abnormalities in vital signs, laboratory assessments 
(serum chemistry, hematology, coagulation and urinalysis) and ECGs. 


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Statistical Considerations:   
Analysis Methods  
This section provides a brief summary of the planned analysis methods for this protocol. 
More information will be provided in the formal Statistical Analysis Plan (SAP), which will 
be developed and finalized before database lock. 
For Phase 1, the statistical methods will be descriptive in nature. Appropriate data analysis 
populations will be defined within Section 10.4 and further described in the SAP. Subject 
characteristics and safety profiles will be summarized including summaries of RX-3117 
dose levels, RX-3117 plasma concentrations, and PK parameters (Cmax, Tmax, Half-life, 
AUC, etc.). Pharmacodynamic markers will also be described and summarized for the PK 
analysis set. PK parameters will be derived from the RX-3117 concentration-time profiles 
using non-compartmental methods for the relevant analysis sets.  
Phase 2 will follow a simple 2-stage design. An interim analysis will be conducted when 
10 response-evaluable subjects have been enrolled and treated with the RP2D, and have 
had the opportunity to complete a minimum of 4 cycles of therapy or have discontinued 
therapy due to disease progression (PD). The study will proceed to Stage 2 if an adequate 
number of Responders are seen. An adequate number of Responders is defined as either 
at least 2 out of the 10 subjects (20%) having a measured benefit in PFS noted as PFS 
>= 4 months/ cycles or if at least 1 subject (10%) has 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. The study may 
stop after the interim analysis if an adequate number of Responders are not seen. 
However, if an adequate number of Responders are seen, approximately 30 evaluable 
subjects will be enrolled and evaluated.  
Sample Size Calculations 
For the Phase 1 dose-finding, approximately 10 subjects are planned. The sample size is 
not based on formal statistical hypothesis testing but will be determined based on 
observed number of first-cycle DLTs at each dose level. The intent is to limit the number 
of subjects who are exposed to excessively toxic doses or sub-therapeutic doses of a drug 
in a Phase 1 evaluation of anticancer agents being used in combination for the first time.  
For Phase 2, approximately 40 subjects are planned. Once the RP2D is identified 
approximately 10 subjects will participate in Stage 1. Depending on the results of the 
interim analysis, approximately 30 additional subjects will participate in Stage 2.   
 


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Study Glossary 
Abbreviation 
Definition 
ANC 
Absolute neutrophil count 
AUC 
Area under the plasma concentration time curve 
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 
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  
PFS 
Progression free survival 
PK 
Pharmacokinetics 
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 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
Tmax 
Time to maximum observed plasma concentration 
TTR 
Time to response 
UCK 
Uridine-cytidine kinase 
ULN 
Upper limit of normal 


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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. 
Enrollment 
The date the subject is assigned a dose of RX-3117 and Abraxane®. 
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 (SD) 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 a 
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 
 


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Table of Contents 
 
Page 
Investigator Agreement ................................................................................................... 2 
Protocol Synopsis ............................................................................................................ 5 
Study Glossary .............................................................................................................. 12 
Study Definitions…………………………………………………………………..……………13 
1. 
OBJECTIVES ....................................................................................................... 19 
1.1 
Phase 1 Primary ........................................................................................ 19 
1.2 
Phase 1 Secondary ................................................................................... 19 
1.3 
Phase 1 Exploratory .................................................................................. 19 
1.4 
Phase 2 Primary ........................................................................................ 19 
1.5 
Phase 2 Secondary ................................................................................... 19 
1.6 
Phase 2 Exploratory .................................................................................. 19 
2. 
BACKGROUND AND RATIONALE ...................................................................... 19 
2.1 
Disease ..................................................................................................... 19 
2.2 
Cytidine Analogs in the Therapy of Cancer ............................................... 20 
2.3 
RX-3117 .................................................................................................... 20 
2.3.1 
Mechanism of Action and Nonclinical Pharmacology 
Studies ...................................................................................... 21 
2.3.2 
Nonclinical Safety Pharmacology Studies.................................. 21 
2.3.3 
Nonclinical Pharmacokinetic and Drug Metabolism 
Studies ...................................................................................... 22 
2.3.4 
Nonclinical Toxicology Studies .................................................. 22 
2.3.5 
Exploratory Clinical Study .......................................................... 23 
2.4 
Phase 1b/2a, dose-ranging study of RX-3117 in patients with 
advanced malignancies ............................................................................. 24 
2.4.1 
Stage 1 Phase 2a, study of RX-3117 in patients with 
metastatic pancreatic cancer ..................................................... 24 
3. 
EXPERIMENTAL DESIGN ................................................................................... 24 
3.1 
Study Design ............................................................................................. 24 
3.2 
Number of Centers .................................................................................... 25 
3.3 
Number of Subjects ................................................................................... 26 
3.4 
Estimated Study Duration .......................................................................... 26 
3.4.1 
Study Duration for Participants .................................................. 26 
3.4.2 
End of Study .............................................................................. 26 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 26 
4.1 
Screening Log ........................................................................................... 26 
4.2 
Inclusion Criteria ....................................................................................... 27 
4.3 
Exclusion Criteria: ..................................................................................... 28 
5. 
SUBJECT ENROLLMENT .................................................................................... 29 


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5.1 
Subject Recruitment .................................................................................. 29 
5.2 
Subject Registration, Enrollment and Treatment Assignment .................... 30 
5.3 
Subject Replacement ................................................................................ 30 
6. 
TREATMENT PROCEDURES .............................................................................. 30 
6.1 
Study Drug Administration ......................................................................... 30 
6.1.1 
RX-3117 Dosing Schedule ........................................................ 30 
6.1.2 
RX-3117 Dose Administration ................................................... 31 
6.1.3 
Abraxane® Dose Schedule and Administration .......................... 31 
6.2 
Dose Finding and Stopping Rules ............................................................. 32 
6.3 
Determination of MTD and Recommended Phase 2 Starting 
Dose ......................................................................................................... 33 
6.4 
Definitions of Dose-Limiting Toxicity .......................................................... 33 
6.5 
Delayed, Missed and Vomited Doses of RX-3117 ..................................... 34 
6.6 
Delayed and Missed Doses of Abraxane® ................................................. 34 
6.7 
Dosage Modifications ................................................................................ 35 
6.7.1 
Dose Modifications During a Cycle ............................................ 35 
6.7.2 
Dose Modifications at the Beginning of the Next Cycle .............. 36 
6.7.3 
Dose Re-Escalation ................................................................... 37 
6.8 
Discontinuation of Study Treatment ........................................................... 37 
6.9 
Concomitant and Supportive Therapy ....................................................... 38 
6.9.1 
Analgesics ................................................................................. 39 
6.9.2 
Antibiotics .................................................................................. 39 
6.9.3 
Anticancer or Experimental Systemic Therapies Other 
than Investigational Treatments ................................................. 39 
6.9.4 
Antidiarrheals ............................................................................ 39 
6.9.5 
Antiemetics ................................................................................ 40 
6.9.6 
Contraception ............................................................................ 40 
6.9.7 
Corticosteroids .......................................................................... 41 
6.9.8 
Diet ............................................................................................ 41 
6.9.9 
Drugs with Potential for Interactions with RX-3117 .................... 41 
6.9.10 
Erythropoietin and Granulocyte Colony-Stimulating 
Factors ...................................................................................... 42 
6.9.11 
Immunization ............................................................................. 42 
6.9.12 
Radiation Therapy ..................................................................... 42 
6.9.13 
Surgery or Other Invasive Procedures ....................................... 43 
6.9.14 
Transfusions .............................................................................. 43 
7. 
STUDY PROCEDURES ....................................................................................... 43 
7.1 
General Study Procedures ........................................................................ 43 
7.2 
Screening Procedures ............................................................................... 44 
7.3 
Treatment Period – Cycle 1 Day 1 ............................................................. 45 
7.3.1 
Pre-dosing Assessments ........................................................... 45 
7.3.2 
Post-dosing Assessments – Cycle 1 Day 1 ............................... 46 


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7.4 
Treatment Period – Cycle 1 Day 2 (Phase 1 and Phase 2 - 
Stage 1) .................................................................................................... 47 
7.5 
Treatment Period – Cycle 1 Day 8 ............................................................. 48 
7.6 
Treatment Period – Cycle 1 Day 15 ........................................................... 49 
7.6.1 
Pre-dosing Assessments ........................................................... 49 
7.6.2 
Post-dosing Assessments – Cycle 1 Day 15 ............................. 50 
7.7 
Treatment Period – Cycle 1 Day 22 ........................................................... 51 
7.8 
Treatment Period – Cycles 2 – 8, Day 1 .................................................... 52 
7.9 
Treatment Period – Cycles 2 – 8, Days 8 and 15 ...................................... 53 
7.10 
Treatment Period – Cycles 2 – 8, Day 22 .................................................. 54 
7.11 
Treatment Period: ≥ Cycle 9, Day 1 ........................................................... 54 
7.12 
Treatment Period: ≥ Cycle 9, Days 8, 15, and 22 ...................................... 56 
7.13 
End of Treatment Visit or Early Termination .............................................. 56 
7.14 
Safety Follow-Up Visit ............................................................................... 58 
7.15 
Unscheduled Visit(s) ................................................................................. 59 
7.16 
RX-3117 Dosing ........................................................................................ 59 
7.17 
Tumor measurements ............................................................................... 59 
8. 
OTHER ASSESSMENT(S) ................................................................................... 61 
8.1 
Predictive and Pharmacodynamic Biomarkers .......................................... 61 
8.1.1 
Sample Storage and Destruction ............................................... 61 
8.2 
Quality of Life (QOL) Questionnaires ......................................................... 62 
8.2.1 
EORTC QLQ-C30 and PAN26 .................................................. 62 
8.2.2 
FACT-Hep ................................................................................. 62 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 63 
9.1 
Definitions ................................................................................................. 63 
9.1.1 
Adverse Events ......................................................................... 63 
9.1.2 
Serious Adverse Events ............................................................ 64 
9.2 
Other Events Requiring Rapid Reporting ................................................... 65 
9.2.1 
Eliciting Adverse Event Information ........................................... 66 
9.3 
Reporting Procedures for All Adverse Events ............................................ 66 
9.4 
Grading of the Severity of an Adverse Event ............................................. 66 
9.5 
Describing Adverse Event Relationship to Study Drug and Study 
Procedures ................................................................................................ 67 
9.6 
Adverse Event Reporting Requirements .................................................... 68 
9.6.1 
Site Reporting Requirements ..................................................... 68 
9.6.2 
Study Sponsor Reporting Requirements.................................... 69 
9.7 
Special Situation Reporting Requirements ................................................ 70 
9.7.1 
Definitions of Special Situations ................................................ 70 
9.7.2 
Pregnancy ................................................................................. 71 
9.7.3 
Instructions for Reporting Special Situations ............................. 72 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 72 


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10.1 
Study Endpoints ........................................................................................ 73 
10.2 
General Statistical Considerations ............................................................. 73 
10.3 
Sample Size Calculation ........................................................................... 74 
10.4 
Analysis Populations ................................................................................. 74 
10.4.1 
Intent-to-Treat (ITT) Analysis Population ................................... 74 
10.4.2 
Modified Intent-to-Treat (mITT) Analysis Population .................. 74 
10.4.3 
Per Protocol (PP) Analysis Population ....................................... 75 
10.5 
Randomization and Blinding ...................................................................... 75 
10.6 
Missing Data and Other Data Handling Conventions ................................. 75 
10.7 
Adjustments for Covariates, Multiple Comparisons, and/or 
Multiplicity ................................................................................................. 76 
10.8 
Multi-Center Studies and Pooling of Centers ............................................. 76 
10.9 
Interim Analysis ......................................................................................... 76 
10.10 Data Tabulations and Analyses ................................................................. 76 
10.10.1 
Tabulation and Analysis of Disposition, 
Demographics, and Baseline Characteristics ............................ 77 
10.10.2 
Tabulation and Analysis of Efficacy ........................................... 77 
10.10.3 
Tabulation and Analysis of Safety ............................................. 78 
10.10.4 
Pharmacokinetics and Pharmacodynamics ............................... 79 
11. 
INVESTIGATIONAL PRODUCT ........................................................................... 80 
11.1 
Abraxane® ................................................................................................. 80 
11.2 
RX-3117 .................................................................................................... 80 
11.3 
Packaging and Labelling ........................................................................... 80 
11.4 
Storage and Handling ................................................................................ 80 
11.5 
Source ....................................................................................................... 80 
11.6 
Dispensing ................................................................................................ 80 
11.7 
Procedures for Monitoring Subject Compliance ......................................... 81 
11.8 
Drug Accountability ................................................................................... 81 
11.9 
Overdose Precautions ............................................................................... 82 
11.10 Inadvertent Exposure and Spill Precautions .............................................. 82 
12. 
REGULATORY OBLIGATIONS ............................................................................ 83 
12.1 
Informed Consent ...................................................................................... 83 
12.2 
Institutional Review Board ......................................................................... 83 
12.3 
Prestudy Documentation Requirements .................................................... 84 
12.4 
Subject Confidentiality ............................................................................... 84 
12.5 
Investigator Signatory Obligations ............................................................. 84 
13. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 85 
13.1 
Protocol Amendments and Study Termination ........................................... 85 
13.2 
Study Documentation and Archive ............................................................ 85 
13.3 
Study Monitoring and Data Collection........................................................ 86 
13.4 
Language .................................................................................................. 87 


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13.5 
Publication Policy ...................................................................................... 87 
13.6 
Compensation ........................................................................................... 88 
14. 
REFERENCES ..................................................................................................... 89 
15. 
APPENDICES ...................................................................................................... 90 
 
List of Appendices 
 
Appendix A.  Schedule of Assessments Cycle 1 ................................................ 90 
Appendix B.  Schedule of Assessments Cycles 2 to 8 ....................................... 92 
Appendix C.  Schedule of Assessments Cycle 9 and beyond ............................ 94 
Appendix D.  Analytes ....................................................................................... 96 
Appendix E.  Response Evaluation Criteria in Solid Tumors .............................. 97 
 


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1. OBJECTIVES 
1.1 Phase 1 Primary  
• 
To evaluate the safety and tolerability of RX-3117 in combination with Abraxane® in 
subjects with metastatic pancreatic cancer 
• 
To determine the Recommended Phase 2 Dose (RP2D) of RX-3117 when 
administered orally in combination with Abraxane® to subjects with metastatic 
pancreatic cancer  
1.2 Phase 1 Secondary  
• 
To determine the pharmacokinetic (PK) profiles of RX-3117 and Abraxane® on Day 1 
(single dose) and Day 15 (steady-state) in Cycle 1 
• 
To evaluate the antitumor activity of RX-3117 in combination with Abraxane® 
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 combination with Abraxane® as first-
line therapy in subjects with metastatic pancreatic cancer  
1.5 Phase 2 Secondary  
• 
To assess additional measures of antitumor activity  
• 
To characterize the safety profile of RX-3117 in combination with Abraxane® 
• 
To evaluate the PK of RX-3117 and Abraxane® at the recommended Phase 2 dose 
(RP2D) 
1.6 Phase 2 Exploratory 
• 
To investigate the effect of RX-3117 in combination with Abraxane® on potential 
cellular or molecular biomarkers in blood or tumor samples 
• 
To evaluate the change in tumor burden response 
• 
To evaluate the effect on Quality of Life (QOL) 
2. BACKGROUND AND RATIONALE 
2.1 Disease  
According to the latest statistics (American Cancer Society, 2015), 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 (Globocan, 2012). 
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 


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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 current National Comprehensive Cancer Network recommendations suggest 
acceptable chemotherapy combinations for patients with good performance status (i.e., 
Eastern Cooperative Oncology Group performance status [ECOG] of 0 or 1), good pain 
management, patent biliary stent, and adequate nutritional intake; these combinations 
include FOLFIRINOX, gemcitabine plus nab-paclitaxel, and gemcitabine plus erlotinib. 
The only recommended option for patients with poor performance status is gemcitabine 
monotherapy. Clinical trials are still recommended for first-line patients. The guidelines for 
choosing an appropriate treatment regimen for patients with metastatic pancreatic cancer 
thus remain ambiguous, and in the absence of a randomized trial comparing the 
combination regimens head to head, the dilemma remains regarding appropriate first-line 
therapy for these patients.  
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 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. 
2.3 RX-3117  
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. 


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2.3.1 
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 2 (UCK2), 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 effect of RX-3117 on DNA and RNA was also 
evaluated; the majority of cell lines investigated showed a concentration-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.  
RX-3117 demonstrated an anti-proliferative IC50 of 6.3 μM against 5 pancreatic cancer 
cell lines tested, with one cell line being resistant (PANC1). RX-3117 demonstrated an 
added anti-proliferative effect when combined with paclitaxel in MiaPaca2 pancreatic 
cancer cell line. In a MiaPaca-2 xenograft model, RX-3117 at oral doses of 50 mg/kg (5 
days/2 days off, 3 weeks) and 500 mg/kg (3 times a week for 3 weeks) demonstrated 
tumor growth delays of 30-50%. 
2.3.2 
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, 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. 


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Further nonclinical safety pharmacology information can be found in the RX-3117 
Investigator’s Brochure. 
2.3.3 
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. 
2.3.4 
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).  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.  Specific 
observations are detailed in the RX-3117 Investigator’s Brochure. 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).  The dose of 
500 mg/kg/day was considered to be the maximum tolerated dose (MTD) in this study. 
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 


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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, which were fully 
recoverable by the end of the recovery period. 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 which RX-3117 dogs were given orally at doses of 15 and 30 mg/kg 
3 times per week for a total of 6 administrations.  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.  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.   
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. 
2.3.5 
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 tumors and had not received any chemotherapy for 2 weeks 
prior to receiving the study drug. 
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.  


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Further nonclinical safety information can be found in the RX-3117 Investigator’s 
Brochure. 
2.4 
Phase 1b/2a, dose-ranging study of RX-3117 in patients with advanced 
malignancies 
A Phase 1 study (NCT02030067) was designed to evaluate safety, tolerability and 
pharmacokinetics (PK) following increasing doses and schedules of RX-3117 to identify a 
recommended Phase 2 dose. Subjects received oral RX-3117 3, 5 or 7 times per week 
for 3 weeks followed by 1 week of rest for up to 8 cycles. RX-3117 PK demonstrated a 
dose proportional exposure and was rapidly absorbed without a marked lag time, and a 
median Tmax between 2 to 3 hours; accumulation was generally minimal. The most 
frequent related adverse events were moderate to severe anemia, mild to moderate 
fatigue and nausea, mild diarrhea, vomiting, and anorexia. The recommended phase 2 
dose and schedule was 700 mg daily for 5 times per week for three weeks, followed by a 
week off in a 28-day cycle. (Rasco 2016)  
2.4.1 Stage 1 Phase 2a, study of RX-3117 in patients with metastatic pancreatic 
cancer 
The Phase 1 study (NCT02030067) was amended to evaluate safety, tolerability and 
efficacy following treatment with the recommended phase 2 dose identified earlier. Eligible 
subjects (aged ≥ 18 years) were those with relapsed/refractory metastatic pancreatic 
cancer. The most frequent adverse events were moderate to severe anemia, mild to 
severe fatigue, mild diarrhea, and moderate to severe leukopenia (Rasco 2017).  This 
ongoing trial is designed to detect an early efficacy signal using single agent RX-3117 in 
subjects with advanced pancreatic cancer. In the first stage of Phase 2, 2 of the 10 
evaluable subjects reached the study endpoint of 4 months progression free survival. Data 
collection is ongoing in the second stage of Phase 2.   
Further clinical safety information can be found in the RX-3117 Investigator’s Brochure. 
3. Experimental Design 
3.1 Study Design 
This will be a Phase 1b/2a multicenter 2-stage study.  
Phase 1 will be conducted as a dose-finding, open-label study of oral RX-3117 
administered in combination with Abraxane® to subjects with metastatic pancreatic cancer. 
The recommended phase 2 dose (RP2D) of RX-3117, in combination with Abraxane®, will 
be determined based on the safety profile, dose modification, and PK. Phase 1 will be 
conducted using a combination of the single MTD for RX-3117 and the Abraxane® dose 
as per the package insert when Abraxane® is given in combination for patients with 
pancreatic cancer. A safety committee will assess the safety and the tolerability of the 
combination after the first 5 patients and may make recommendation to confirm the MTD 


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in another 5 patients. For dosing information, please refer to Section 6.1 Study Drug 
Administration.  
After completion of the Phase 1 portion, a Phase 2a study will be conducted using a 
2-stage, open-label design, of RX-3117 and Abraxane® in combination to treat subjects 
with metastatic pancreatic cancer as first-line therapy. Approximately 10 subjects will 
participate in the Stage 1 at the dose identified in Phase 1 (RP2D). Subjects will be treated 
for up to 8 cycles of combined therapy. An interim analysis will be conducted after 
10 evaluable subjects have been treated at the RP2D, have completed a minimum of 4 
months/ cycles of therapy, or have discontinued therapy due to progressive disease before 
completing 4 cycles. If an adequate number of Responders are observed out of the initial 
10 evaluable subjects, then 30 evaluable additional subjects will be enrolled to participate 
in Stage 2. An adequate number of Responders is defined as either at least 2 out of the 
10 subjects (20%) having a measured benefit in PFS noted as PFS ≥ 4 months/ cycles or 
if at least 1 subject (10%) has 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. The study may stop after the interim 
analysis if an adequate number of Responders are not seen. However, if an adequate 
number of Responders are seen, approximately 30 evaluable subjects will be enrolled and 
evaluated. Subjects will be treated for up to 8 cycles of combined therapy. 
RX-3117 will be administered orally for 5 consecutive days followed by 2 days off each 
week for 3 weeks and a 1-week hiatus in repeated 4-week cycles.   
Abraxane® will be administered intravenously over 30-40 min. on Days 1, 8, and 15 of 
each cycle at the dose level assigned in Phase 1 or the RP2D determined for Phase 2. 
Subjects will receive up to 8 cycles of RX-3117 in combination with Abraxane® or until 
disease progression (per RECIST ver. 1.1 see Appendix E), clinical progression, 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 clinical 
benefit (as determined by patient care, quality of life, and tumor reduction), additional 
cycles of RX-3117 in combination with Abraxane® may be administered following 
discussions with the sponsor and medical monitor. 
The study endpoints are defined in Section 10.1. 
3.2 Number of Centers 
Approximately 5 sites will participate in the Phase 1 portion and up to 15 enrolling sites in 
the US will participate in the Phase 2 study.  Sites that do not enroll subjects within 3 
months of site initiation may be terminated.   


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3.3 Number of Subjects 
Number of planned subjects is approximately 5040 subjects (approximately 10 subjects in 
the Phase 1, depending upon the number of dose levels needed to identify the RP2D, 
approximately 10 evaluable subjects in Stage 1 of Phase 2 and approximately 
30 evaluable subjects 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 (up to 14 days; up to 21 days for tumor 
assessments), up to 8 treatment cycles (i.e., cycle = 28 days), an end-of-treatment visit, 
and a safety follow-up visit 30 +7 days after the last dose of RX-3117.  Subject participation 
is anticipated to be approximately 9 months.  
Subjects may receive RX-3117 until the earliest sign of disease progression (per RECIST 
ver. 1.1 see Error! Reference source not found.), clinical progression, an intolerable R
X-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 all subjects have completed the study or have been discontinued.  
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..  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). 


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4.2 Inclusion Criteria 
Disease Related 
1. Subject has confirmed histologic or cytologic evidence of pancreatic cancer, at 
least radiographic evidence of metastatic pancreatic cancer, and has no prior 
treatment for metastatic pancreatic cancer. Subjects who received gemcitabine in 
the neoadjuvant or adjuvant setting can be considered. 
2. Subject has measurable disease using Response Evaluation Criteria in Solid 
Tumors (RECIST) ver. 1.1 
3. Subject has a life expectancy of at least 3 months 
4. Subject has an ECOG performance status 0 or 1 
 
Demographic 
5. Males or females ≥ 18 years of age  
6. Subject must be able to swallow capsules 
7. Subject must have adequate venous access for intravenous (IV) infusion  
 
Laboratory 
8. Subject has hemoglobin ≥ 9.0 g/dL at Screening 
9. Subject has absolute neutrophil count (ANC) ≥ 1.5 x 109/L at Screening 
10. Subject has platelet count ≥ 100 x 109/L at Screening 
11. Subject has serum creatinine ≤ 1.5 times the upper limit of normal (ULN) at 
Screening. 
• 
Subjects with serum creatinine levels > 1.5 times the ULN must have a 
24-hour urine creatinine clearance ≥ 50 mL/min  
12. Subject has serum bilirubin ≤ 1.5 times the ULN (except in subjects with Gilbert’s 
Syndrome who must have serum bilirubin < 3.0 x ULN) 
13. Subject 
has 
aspartate 
aminotransferase 
(AST; 
SGOT) 
and 
alanine 
aminotransferase (ALT; SGPT) ≤ 2.5 times the ULN (OR, AST and ALT ≤ 5 times 
the ULN in the presence of known liver metastases) 
14. Subject has alkaline phosphatase ≤ 2.5 times the ULN (OR ≤ 5 times the ULN in 
the presence of known liver or bone metastases) 
15. Subject has normal coagulation parameters (prothrombin time [PT] and/or 
international normalized ratio [INR], and partial thromboplastin time [PTT] within 
normal limits [<1.2 x ULN]) 
16. Subject has potassium concentration within normal range, or correctable with 
supplements 
17. Oxygen saturation by pulse oximetry ≥ 92% at rest 
18. 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) 
 


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Reproductive 
19. 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  
20. Female subjects of non-childbearing potential defined as having amenorrhea for 
at least 24 consecutive months, a documented hysterectomy, or a documented 
bilateral oophorectomy) 
21. For fertile male subjects 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 
22. 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. 
23. Before any study-specific procedure, the appropriate written informed consent 
must be obtained 
 
4.3 Exclusion Criteria: 
Disease Related 
1. Subject has primary brain tumors or clinical evidence of active brain metastasis 
2. Subject has undergone major surgery within 4 weeks of the start of study 
treatment. Laparoscopy and central venous catheter placement are not considered 
major surgery 
 
Medications 
3. Subject has a history of systemic corticosteroid use within 7 days before Day 1 of 
Cycle 1 
 
General 
4. Subject has an active infection requiring parenteral or oral antibiotics within 2 
weeks before planned start of study therapy 
5. Subject has uncontrolled diabetes as assessed by the investigator  
6. Subject has a 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 
7. Subject has an active infection of hepatitis B, hepatitis C or human 
immunodeficiency virus 


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8. Female subjects who are pregnant, planning a pregnancy or breast feeding during 
the study  
9. Subject has a high cardiovascular risk, including, but not limited to, subjects with 
congestive heart failure (New York Heart Association [NYHA] Class III or IV), 
cardiac arrhythmia, unstable angina, coronary stenting or acute coronary 
syndromes within 6 months before planned start of study therapy or myocardial 
infarction within one year before planned start of study therapy 
10. Subject has a history of peripheral artery disease (e.g., claudication, Leo Buerger's 
disease). [Criterion removed] 
11. Subject has a history of prior allogeneic bone marrow progenitor cell or solid organ 
transplantation. 
12. Subject has known acute or chronic pancreatitis. 
13. Subject has persistent diarrhea, malabsorption, or known sub-acute bowel 
obstruction ≥ NCI CTCAE Grade 2, despite medical management. 
14. Subject has any disorder that may interfere with drug absorption, distribution, 
metabolism, or excretion (including gastrointestinal surgery and bariatric surgery)  
15. 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 is permitted; Grade 3 
or higher is excluded] 
16. Subject has 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 
17. Subject has a history of interstitial lung disease, slowly progressive dyspnea and 
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, 
pulmonary hypersensitivity pneumonitis or multiple allergies. Any lung disease that 
may interfere with the detection or management of suspected drug-related 
pulmonary toxicity. 
18. Subject is currently enrolled in any other clinical protocol or investigational trial that 
involves administration of experimental therapy and/or therapeutic devices, or 
investigational drug.  
19. Subject has a history of hypersensitivity to RX-3117, gemcitabine, azacytidine 
cytosine arabinoside, paclitaxel, nab-paclitaxel, or their excipients. 
20. Subject is 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 population being followed at or referred to 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.   


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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) at screening.  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, 
MRIs, etc.). In order to obtain a subject number, the site must notify the sponsor or its 
designee that the subject has completed consent.  In order for the subject to begin study 
treatment, the site must provide completed eligibility documents to the study sponsor or 
designee and 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.   
Please note: a subject will be enrolled when the treatment dose has been assigned. Ideally 
subjects will be dosed no later than 3 business days after enrollment.  
5.3 Subject Replacement 
In the Phase 1 and Phase 2-Stage 1, 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 as that for the subject who withdrew. 
In the Phase 2-Stage 2 portion, subjects who are enrolled but not treated will be replaced. 
6. TREATMENT PROCEDURES 
The investigational product in this study is RX-3117. RX-3117 will be administered in 
combination with Abraxane®. Abraxane® will not be provided by the sponsor. For details 
on RX-3117 description, storage and handling see Section 11. 
6.1 
Study Drug Administration 
6.1.1 
RX-3117 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 


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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 subject 5 times per week (i.e., for 5 
consecutive days followed by 2 days off) for 3 consecutive weeks followed by 1 week of 
rest in each 4 week cycle.  Study drug should be taken at approximately the same time 
each day (e.g., at ~8 AM on each planned day of dosing).  Ideally, doses should be taken 
at ~24- hour intervals.  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, RX-3117 will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for Abraxane® and 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 
RX-3117 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 approximately 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 that is then swallowed.  
Subjects will be instructed to refrain from eating for 8 hours before each dose is 
administered.  Subjects may eat  1 hour after dose administration. 
6.1.3 
Abraxane® Dose Schedule and Administration 
Abraxane® will be administered once a week for 3 weeks on Days 1, 8, and 15 followed 
by 1 week of rest during each 28 day cycle.  Abraxane® will be administered intravenously 
infused over 30 to 40 minutes. The date, time (i.e., start and stop) and volume infused 
(i.e., either initial and remaining volumes or volume infused off the pump) will be recorded 
in the subject’s medical record and eCRFs. 
On days when both RX-3117 and Abraxane® are administered on the same day, 
Abraxane® should be administered first, followed by RX-3117 dose given no sooner than 
1 hour after the start of Abraxane® infusion. Abraxane® should not be mixed with or 
administered as an infusion simultaneously with other medicinal products. 
At specified clinic visits in Cycle 1, Abraxane® will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for Abraxane® and RX-3117 


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pharmacokinetics, if applicable. Pharmacokinetic samples should not be obtained from a 
port or PICC line if the line is used for the administration of Abraxane®.   
6.2 Dose Finding and Stopping Rules 
During Phase 1, 700 mg or lower doses of RX-3117 may be investigated in combination 
with Abraxane®, RX-3117 dosing will begin at 700 mg daily/ 5 days consecutively per week 
with 2 days rest for 3 weeks and then 1 week of rest in each Cycle. The Abraxane® starting 
dose will be 125 mg/m2 administered on Days 1, 8 and 15 of each cycle.  Abraxane® and 
RX-3117 dose reductions will follow Table 1 below. 
Table 1. Dosage Reductions  
Dose Level 
Abraxane® (mg/m2) 
RX-3117 (mg) 
Full dose 
125 
700 
1st dose reduction 
100 
600 
2nd dose reduction 
75 
500 
 
This will be a Phase 1b/2a multicenter 2-stage study. The Phase I portion of the study is 
similar in nature to the traditional 3+3 design however it allows for a target DLT probability 
of 0.40 or 40%. The decision to increase the threshold from 33% to 40% is due to the 
known AE profiles of both drugs, the current recommended dose of Gemcitabine plus 
Abraxane®, and the desire not to expose first line subjects to subtherapeutic doses. 
Therefore if 0 or 1 of the first 5 subjects that complete one cycle of treatment experience 
a DLT, then the full dose may be confirmed as the RP2D.  If 3 or more of the first 5 subjects 
that complete one cycle of treatment experience a DLT, then there will be a dose reduction 
and 5 subjects will be treated at the next lowest dose level.  If 2 of the first 5 subjects that 
complete one cycle of treatment experience a DLT, then the safety review committee may 
recommend an additional 5 subjects are to be treated at the full dose.  In this case, if 3 or 
less of the 10 subjects experience a DLT, then the full dose will be confirmed as the RP2D.  
Otherwise, if 4 or more of the 10 subjects experience a DLT, then a dose reduction will 
occur. Additional doses may be recommended by the review committee which includes 
investigators, medical monitor and sponsor. For Phase 2, the RX-3117 and Abraxane® 
dosing will be administered based on the RP2D identified after completion of Phase 1.  
The RX-3117 doses will be administered from the least number of capsules available at 
the time of dosing shown in Table 2. 


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Table 2. RX-3117 Capsule Size and Dosing 
Actual daily 
dose, mg 
Number of capsules/ day 
Total 
weekly 
dose, mg 
Total cycle 
dose, mg 
 
200 mg 
500 mg 
 
 
500 
0 
1 
2,500 
7,500 
600 
3 
0 
3,000 
9,000 
700 
1 
1 
3,500 
10,500 
If a DLT occurs at one dose and dosing schedule (e.g., Abraxane® administered for once 
weekly for 3 weeks), that dose will follow the rules described below for enrolling additional 
subjects. 
Since the frequency and severity of treatment related toxicities associated with single 
agent Abraxane® and RX-3117 do not overlap, a dose de-escalation design will be used. 
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 of RX-3117 and/or Abraxane®.  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 is complete and when the next dose level 
is open to enrollment.  
6.3 
Determination of MTD and Recommended Phase 2 Starting Dose 
The establishment of the recommended Phase 2 dose will be based on a review of the 
overall safety data by the investigators, medical monitor and sponsor.  Selection of a 
recommended Phase 2 starting dose from within the tested doses of RX-3117 and/or 
Abraxane® 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 lower dose 
level of RX-3117 and/or Abraxane® be considered the recommended Phase 2 dose or that 
another dose level of RX-3117 and/or Abraxane® between the highest previously tolerated 
dose level, and the dose level exceeding the MTD be tested in additional subjects.  
Upon review of the Phase 1 safety data, the investigators, medical monitor, and the 
sponsor determined the Phase 2 dose to be 700 mg RX-3117 and 125 mg/m2 Abraxane 
following the schedules defined in Sections 6.1.1 and 6.1.3. 
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.  The DLT assessment period is defined as 


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the first cycle of treatment in the Phase 1 portion of the study.  The minimum exposure to 
the investigation regimen for DLT assessments will be defined as subjects who receive at 
least 10 doses of RX-3117 and 2 doses of Abraxane.  A DLT will be defined as any of the 
following adverse events that is considered by the investigator as possibly, probably or 
definitely-related to RX-3117, Abraxane or the combination: 
• 
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 3 nausea or vomiting lasting >3 days despite optimal management 
• 
Grade 3 fatigue lasting > 7 days 
• 
Grade 4 fatigue 
• 
Treatment interruptions of ≥ 7 days 
• 
Any Grade thrombocytopenia that occurs with clinically significant bleeding 
 
Any other non-hematological Grade  3 adverse events will be considered DLTs with the 
exception of the following:  
• 
Alopecia 
• 
Grade 1 or 2 sensory neuropathy 
• 
For subjects with bone or liver metastases and baseline levels of AST or ALT > 2.5 x 
ULN or alkaline phosphatase > 2x ULN, DLTs do not include elevations in AST, ALT, 
and alkaline phosphatase unless the following criteria are met: 
• 
AST > 8 x ULN, if the baseline level was between 2.5 to 5 x ULN in subjects with liver 
metastases 
• 
ALT > 8 x ULN, if the baseline level was between 2.5 to 5 x ULN in subjects with liver 
metastases 
• 
Alkaline phosphatase > 8 x ULN, if the baseline level was between 2 to 5 x ULN in 
subjects with bone or liver metastases 
 
6.5 
Delayed, Missed and Vomited Doses of RX-3117 
Subjects 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. 
Vomited doses should not be retaken. 
6.6 
Delayed and Missed Doses of Abraxane® 
If a subject has an AE or other event causing the delay or missed dose of Abraxane®, the 
investigator should discuss, whenever possible, the restart and potential dose 
modifications of Abraxane® with the sponsor and medical monitor.  


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6.7 
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 and instruct the subject/caregiver about 
the change in dose level.  
6.7.1 
Dose Modifications During a Cycle 
RX-3117 
If a subject experiences a RX-3117-related DLT or AE (as defined in Section 6.4) and 
requires a dose 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 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 the lowest dose level (500 mg/day for 5 days) 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.  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).  
Abraxane® 
In Phase 1, dose adjustments for Abraxane® will be made after discussion amongst the 
investigator, medical monitor, and sponsor.  
In Phase 2, dose adjustments for Abraxane® will be allowed for adverse events according 
to the approved package insert. Refer to Table 1. Dosage Reductions  for the dose 
reduction schedule. Additional dose recommendations and modifications due to adverse 
reactions are detailed in Table 3 and Table 4. If the start of a cycle (i.e., day 1 of a cycle) 
is delayed due to an Abraxane®-related toxicity, then RX-3117 dosing may continue on 
schedule.  
 
Table 3. Dose Recommendation and Modifications of Abraxane® for Neutropenia 
and/or Thrombocytopenia at the Start of a Cycle or within a Cycle 
Cycle Day 
ANC 
(cells/mm3) 
 
Platelet count 
(cells/mm3) 
Abraxane® 
Day 1  
< 1500 
OR 
< 100,000 
Delay dose until recovery 


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Day 8 
500 to < 1000 
OR 
50,000 to 75,000 
Reduce 1 dose level 
 
< 500 
OR 
< 50,000 
Withhold dose 
Day 15: IF Day 8 dose was reduced or given without modification: 
 
500 to < 1000 
OR 
50,000 to 75,000 
Reduce 1 dose level 
 
< 500 
OR 
< 50,000 
Withhold dose 
Day 15: IF Day 8 dose was withheld 
 
≥ 1000 
OR 
≥ 75,000 
Reduce 1 dose level from 
Day 1 
 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 2 dose levels 
from Day 1 
 
< 500 
OR 
< 50,000 
Withhold dose 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021660s037lbl.pdf 
Table 4. Dose Modifications of Abraxane for Other Adverse Drug Reactions 
Adverse Drug Reaction 
Abraxane® 
Febrile Neutropenia: 
Grade 3 or 4 
Withhold until fever resolves and ANC ≥ 1500;  
resume at next lower dose level 
Peripheral Neuropathy: 
Grade 3 or 4 
Withhold until improves to ≤ Grade 1;  
resume at next lower dose level 
Cutaneous Toxicity: 
Grade 2 or 3 
Reduce to next lower dose level; discontinue 
treatment if toxicity persists 
Cutaneous Toxicity: 
Grade 3 mucositis or diarrhea 
Withhold until improves to ≤ Grade 1;  
resume at next lower dose level 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021660s037lbl.pdf 
RX-3117 and Abraxane® 
If an adverse event occurs that is related to RX-3117, Abraxane® may continue on 
schedule.  
If an adverse event occurs that is related to Abraxane®, RX-3117 may continue on 
schedule.  
If an adverse event occurs that is related to the combination of RX-3117 and Abraxane®, 
dosing of both drugs may be delayed until the event is resolved. 
6.7.2 
Dose Modifications at the Beginning of the Next Cycle 
A new cycle of RX-3117 treatment may 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 baseline, weekly delays in initiating the new cycle of 
treatment should be instituted.  Once all toxicities have returned to baseline, the next cycle 


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of therapy can be initiated. If the start of a cycle (i.e., day 1 of a cycle) is delayed due to 
RX-3117 related toxicity, then Abraxane® dosing may continue on schedule.  
Subjects receiving a lower dose but who the principal investigator feels are benefiting from 
treatment, may after discussions with the Sponsor, receive a higher dose of either RX-
3117 or Abraxane®, for which there is already safety data. 
6.7.3 
Dose Re-Escalation 
After a dose reduction for either RX-3117 or Abraxane®, the dose need not be re-
escalated, even if there is minimal or no toxicity with the reduced dose.  However, if the 
subject tolerates a reduced dose of RX-3117 or Abraxane® for ≥ 4 weeks then the 
RX-3117 and/or Abraxane® doses may be increased to the next higher dose level, 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 reduction was not RX-3117 
or Abraxane®-related.  Successive adjustments to progressively higher dose levels can 
be made at 4-week intervals but the dose must not exceed the highest dose level for which 
there is already Cycle 1 safety data.  
6.8 
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. 
• 
Any subject who has objective evidence of cancer progression should be 
withdrawn from study treatment. 
• 
Any subject who cannot tolerate 500 mg RX-3117 or 75 mg/m2 Abraxane® 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 


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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. 
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. 
6.9 
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 protocol prescribed therapies 
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, recreational 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). 


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6.9.1 
Analgesics 
Investigators may give analgesics, as necessary, for pain control.  
6.9.2 
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 or Abraxane® during treatment for the infection. 
6.9.3 
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 protocol prescribed therapy.  Subjects are not allowed to participate 
concurrently in any other therapeutic clinical study. 
6.9.4 
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 Abraxane® or 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. 


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Depending upon the type and severity of the diarrhea, interruption of Abraxane® or RX-
3117 and rechallenge at the same or a reduced dose level and frequency of either and 
with appropriate support care should be considered. 
6.9.5 
Antiemetics 
Antiemetics are not allowed prior the administration of Abraxane® or RX-3117 on Cycle 1 
Day 1 in Phase 1.  However, antiemetics can be administered on subsequent treatment 
days and in subsequent cycles and prophylactically in Phase 2, 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 Abraxane® or RX-
3117 and rechallenge at the same or a reduced dose level and with appropriate support 
care should be considered. 
6.9.6 
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 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 


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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. 
6.9.7 
Corticosteroids 
Systemic or enteric corticosteroids are not allowed prior the administration of Abraxane® 
or 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 
6.9.8 
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 RX-3117 is taken.  
6.9.9 
Drugs with Potential for Interactions with RX-3117 and Abraxane 
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. 


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The package insert for Abraxane indicates that Abraxane is metabolized by CYP2C8 and 
CYP3A4. Refer to the current package insert for potential drug interactions with Abraxane 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021660s037lbl.pdf). 
6.9.10 
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 allowed 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.  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). 
6.9.11 
Immunization 
Due to its potential effects on lymphoid cells, Abraxane® and/or 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 Abraxane® and 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.  There have been reports of Abraxane® having major 
interactions with various drugs, including live vaccines. 
6.9.12 
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.  


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RX-3117 appears to sensitize tumor cells to radiotherapy in an in vitro setting. However, 
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. 
Abraxane® is a radiosensitizing agent.  Discontinuation of Abraxane® before radiation 
should follow institutional standards. 
6.9.13 
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 RX-3117 or Abraxane® 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 should have returned to baseline levels and the subject should be clinically stable 
before reinitiating therapy. 
6.9.14 
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, Appendix B, and 
Appendix C) for outlines 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 or Abraxane® pharmacokinetics, any archived tumor 
tissue, any tumor biopsy samples, and biomarker samples should be prepared and 
shipped to the central laboratories 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 


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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 - 21 days allowed for imaging assessments) before 
enrollment: 
• 
Written informed consent 
• 
Review of inclusion and exclusion criteria 
• 
Medical, surgical, cancer and psychiatric history review, documentation of 
diagnosis and previous treatments with responses 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, temperature, 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) 
• 
ECOG Performance status 
• 
Physical examination (excluding genitourinary system) including weight and height 
Laboratory tests (for analyte details see 


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• 
Appendix D) 
o Urinalysis 
o Hematology panel 
o Chemistry panel 
o Serum pregnancy test for female subjects of childbearing potential 
o Coagulation: PT/INR and PTT 
o Tumor marker 
• 
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, QTcF, 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 E) 
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 when they receive the 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 5 days before the 1st dose of Abraxane® 
and RX-3117 are administered on Cycle 1 Day 1, unless otherwise described: 
Laboratory tests within 5 days before dosing (for analyte details see 


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• 
Appendix D) 
o Hematology panel  
o Chemistry panel  
o Urinalysis 
o 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/INR and PTT  
o Tumor marker 
• 
Subject will complete Quality of Life Questionnaires before any of the following 
study procedures are performed.  
• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep  
• 
Review medication usage for any medications started since the screening visit 
• 
Weight  
• 
ECOG performance status 
• 
Collection of a tumor biopsy sample pre-treatment from enrolled 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, QTcF, 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 Phase 2 – Stage 1 only) 
• 
Resting vital signs: pulse, respiration rate, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes). 
• 
Collect a blood sample for pre-dose Abraxane® and RX-3117 pharmacokinetics 
(with recording of the date and actual clock time of blood collection).(Phase 1 and 
Phase 2 – Stage 1) 
• 
Collect blood sample for biomarker analysis.  
7.3.2 Post-dosing Assessments – Cycle 1 Day 1 
The following procedures will be performed after the administration of Abraxane® but 
before the administration of RX-3117:  
• 
Blood samples for Abraxane® pharmacokinetics will be collected (Phase 1 and 
Phase 2 – Stage 1): 


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o At the end of infusion of Abraxane on Cycle 1 Day 1, and just prior (no more 
than15 minutes) to RX-3117 administration (pre-dose). 
RX-3117 will be administered no earlier than 1 hour after the start of Abraxane® infusion. 
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. 
 
Post-RX-3117 Dose Procedure 
(Phase 1 and Phase 2 – Stage 1 only) 
Time (in hours)  
elapsed since 
dose 
 
12 lead ECGa 
Vital Signsb 
PK 
0.5 (±5 minutes) 
 
X 
X 
1 (±10 minutes) 
X 
X 
X 
2 (±10 minutes) 
X 
X 
X 
3 (±10 minutes) 
 
X 
X 
4 (±10 minutes) 
X 
X 
X 
6 (±10 minutes) 
X 
X 
X 
a  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, QTcF, and PR intervals.  A duplicate printout of 
the electrocardiogram report must be printed when the assessment is 
performed for review by a central vendor. 
b  pulse, respiration rate, body temperature, and blood pressure (i.e., after 
the subject has been seated for at least 5 minutes) 
• 
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 (Phase 2 – Stage 2 
only) 
• 
Dispensing of diary cards (Phase 2- Stage 2 only) 
7.4 Treatment Period – Cycle 1 Day 2 (Phase 1 and Phase 2 - Stage 1) 
• 
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. 
• 
Record concomitant medication(s). 
• 
12 lead electrocardiogram taken at 24 hours 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, QTcF, and PR intervals.  A duplicate printout of the electrocardiogram report 
must be printed when the assessment is performed for review by a central vendor.  


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• 
Resting vital signs: pulse, respiration rate, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes). 
• 
Blood sample for RX-3117 pharmacokinetics will be collected: 
• 
At 24 hours ± 1 hour (Cycle 1 Day 2) after the first dose of the RX-3117 
and before the second dose  
• 
Dispensing of study drug and instructions for dosing at home 
• 
Dispensing of diary cards 
• 
RX-3117 will be taken orally at the clinic. The time of the dosing will be recorded.  
7.5 Treatment Period – Cycle 1 Day 8 
The following procedures and assessments will be performed before Abraxane® dosing 
on Cycle 1 Day 8, unless otherwise described: 
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed:  
• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep 
• 
Collection of unused RX-3117 
• 
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. 
Laboratory tests within 3 days before dosing (for details see 


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• 
Appendix D)  
o Hematology panel  
o Chemistry panel  
o Urinalysis 
o Coagulation tests: PT/INR and PTT  
• 
Resting vital signs: pulse, respiration rate, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes).  
The following procedures and assessments will be performed after the completion of 
Abraxane® dosing on Cycle 1 Day 8: 
• 
Record concomitant medication(s)  
• 
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. 
7.6 Treatment Period – Cycle 1 Day 15 
7.6.1 Pre-dosing Assessments 
The following procedures will be performed before Abraxane® dosing on Cycle 1 Day 15, 
unless otherwise described. If Abraxane® is not being administered on Cycle 1 Day 15, 
the following procedures will be performed before RX-3117 dosing unless otherwise 
described: 
Laboratory tests within 3 days before dosing (for details see 


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• 
Appendix D) 
o Hematology panel  
o Chemistry panel  
o Urinalysis 
o Coagulation tests: PT/INR and PTT  
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed (except the laboratory tests listed above):  
• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep 
• 
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. 
• 
Collect blood sample for pre-dose pharmacokinetics (with recording of the date 
and actual clock time of blood collection) (Phase 1 and Phase 2 - Stage 1). 
• 
Resting vital signs: pulse, respiration rate, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes). 
7.6.2 Post-dosing Assessments – Cycle 1 Day 15 
The following procedures will be performed after the administration of Abraxane® but 
before the administration of RX-3117:  
• 
Blood samples for Abraxane® pharmacokinetics will be collected (Phase 1 and 
Phase 2 – Stage 1): 
o At the end of infusion of Abraxane® on Cycle 1 Day 15, and just prior (no more 
than15 minutes) to RX-3117 administration (pre-dose).  
The following procedures will be performed after the administration of RX-3117 on Cycle 1 
Day 15: 


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• 
The required order of assessments is vital signs followed by pharmacokinetic 
sampling when applicable. 
 
Time (in hours)  elapsed 
since dose 
Post-RX-3117 Dose Procedure  
(Phase 1 and Phase 2 – Stage 1 only) 
 
Resting Vital Signsa 
PK 
0.5 (±5 minutes) 
X 
X 
1 (±10 minutes) 
X 
X 
2 (±10 minutes) 
X 
X 
3 (±10 minutes) 
X 
X 
4 (±10 minutes) 
X 
X 
6 (±10 minutes) 
X 
X 
a  pulse, respiration rate, body temperature, and blood pressure (after the subject 
has been seated for at least 5 minutes) 
• 
Record 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.  
• 
Dispensing of study drug and instructions for dosing at home 
• 
Dispensing of diary cards 
7.7 Treatment Period – Cycle 1 Day 22 
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed:  
• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep 
• 
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 within 3 days before dosing (for details see 


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• 
Appendix D) 
o Hematology panel  
o Chemistry panel  
• 
Resting vital signs: pulse, respiration rate, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes).  
7.8 Treatment Period – Cycles 2 – 8, Day 1 
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. 
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed and before the subject is informed of their disease 
status:  
• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep 
• 
Weight  
• 
ECOG performance status 
Laboratory tests (for details see 


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• 
Appendix D)  
o Hematology panel  
o Chemistry panel  
o Urinalysis 
o Coagulation tests: PT/INR and PTT  
o Tumor marker 
• 
Collect blood sample for biomarker analysis (Cycle 2 only) 
• 
Resting vital signs: pulse, respiration rate, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes)  
• 
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. 
• 
Dispensing of study drug and instructions for dosing at home (on Day 1) 
• 
Dispensing of diary cards (on Day 1) 
7.9 Treatment Period – Cycles 2 – 8, Days 8 and 15 
For subjects receiving treatment beyond Cycle 1 the following procedures will be 
performed before dosing on Days 8 and 15 of each new cycle, unless otherwise 
described. 
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed:  
• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep 
Laboratory tests within 3 days before dosing (for details see 


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• 
Appendix D) (Day 15 only) 
o Hematology panel  
o Chemistry panel  
• 
Resting vital signs: pulse, respiration rate, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes)  
• 
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. 
7.10 Treatment Period – Cycles 2 – 8, Day 22 
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed:  
• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep 
• 
Collection of unused study drug  
• 
Review subject study drug compliance  
• 
Tumor assessment, including CT/MRI as applicable between Days 22 and 28 of 
Cycles 2, 4, 6 and 8.  Results of the assessment must be available and reviewed 
before dosing begins in the next cycle. 
• 
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. 
7.11 Treatment Period: ≥ Cycle 9, Day 1 
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. 
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed and before the subject is informed of their disease 
status:  


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• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep 
• 
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, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes.  
Laboratory tests (for details see 


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• 
Appendix D)  
o 
Hematology panel  
o 
Chemistry panel  
o 
Tumor marker 
• 
Dispensing of study drug and instructions for dosing at home (on Day 1) 
• 
Dispensing of diary cards (on Day 1) 
7.12 Treatment Period: ≥ Cycle 9, Days 8, 15, and 22 
The following procedures will be performed unless otherwise described: 
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed:  
• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep 
• 
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 
• 
Dispensing of study drug and instructions for dosing at home (Days 8 and 15) 
• 
Dispensing of diary cards (Days 8 and 15) 
• 
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. 
7.13 End of Treatment Visit or Early Termination 
An End of Treatment Visit will be performed when a subject discontinues study treatment 
(see Section 6.8). The following procedures will be performed unless otherwise described: 
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed and the subject obtains knowledge of their disease 
status.  
• 
EORTC-QLQ-30 and EORTC-PAN26 
• 
FACT-Hep 
• 
Collect unused study drug 


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• 
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, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes).  
Laboratory tests (for details see 


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• 
Appendix D) 
o 
Hematology panel  
o 
Chemistry panel  
o 
Urinalysis 
o 
Coagulation tests: PT/INR and PTT  
o 
Tumor marker  
• 
Tumor assessment, including CT/MRI 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. 
• 
A biomarker blood sample will be collected.  
7.14 Safety Follow-Up Visit 
Subjects will undergo the safety follow-up visit approximately 30-37 days after the subject 
receives their last dose of RX-3117. If the End of Treatment/ Early Termination Visit occurs 
within the safety follow-up visit window (i.e. 30-37 days after last dose of RX-3117) due to 
unforeseen circumstances (i.e. hospitalization, 30-day drug interruption leading to 
discontinuation, etc.), the procedures for both visits may be performed during the same 
visit.   
The following procedures will be performed: 
• 
Subject will complete Quality of Life Questionnaires before any other study 
procedures are performed:  
o EORTC-QLQ-30 
o FACT-Hep and EORTC-PAN26  
• 
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, body temperature, and blood pressure 
(i.e., after the subject has been seated for at least 5 minutes).  
• 
Laboratory tests 
o Hematology panel 


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o Chemistry panel  
• 
Tumor assessment, including CT/MRI 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. 
7.15 
Unscheduled Visit(s) 
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 eCRFs, as 
well as any other data obtained (e.g., adverse events, concomitant medications and 
treatments, and results from procedures or tests). 
7.16 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 approximately 100 to 200 mL (4 to 8 ounces) of 
water.  The subject may have a small glass of juice, except grapefruit juice, (4- to 6 
ounces) no earlier than 10 minutes after dosing as needed. Food may be taken  1 hour 
after the dose has been administered.  The time of last meal and 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. This is 
important for days when blood is collected for pharmacokinetic analysis (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. The subject may have a small glass of juice (4-6 
ounces) no earlier than 10 minutes after dosing as needed. Food may be taken 
approximately 1 hour after the dose has been administered.   
7.17 
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 evaluated using modified RECIST ver. 1.1 (see Appendix E) after 


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Cycle 2 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 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. Computed tomography (CT) and/or magnetic resonance 
imaging (MRI) (spiral CT or MRI with ≤ 5 mm cuts) should be used for tumor assessment 
unless another modality of radiographic disease assessment is necessary for the lesions 
including bone lesions per RECIST guidelines Version 1.1, 
See Appendix E 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. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone Lesions 
Bone scan, positron emission tomography (PET) scan or plain films are not considered 
adequate imaging techniques to measure bone lesions.  However, these techniques can 
be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are nonmeasurable. 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, 
by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if noncystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 
Lesions with Prior Local Treatment 


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Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco 
regional therapy, are not considered measurable unless there has been demonstrated 
progression in the lesion. 
8.Other Assessment(s) 
8.1 
Predictive and Pharmacodynamic Biomarkers  
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. 
A blood sample will be collected prior to treatment with RX-3117 and on Day 1 in Cycles 
1 and 2, and during the Early Termination or End of Treatment visit to measure biomarkers 
in whole blood, any of its components and/or circulating tumor cells (CTCs) that may be 
involved in the response to RX-3117, alone or in combination with other agents or relevant 
to pancreatic cancer biology. 
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. 
Measurements may include, but are not limited to, nucleoside transporters; uridine-
cytidine kinase 2 (UCK2); DNA methyltransferases (DNMTs); ribonucleotide reductases 
(RRM); RX-3117 incorporation into DNA/RNA as well as other genes and/or proteins that 
may be identified to be involved in the response to RX-3117 or are relevant to pancreatic 
cancer biology.  
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. 
8.1.1 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 


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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 rights 
to the data, information, discoveries, or derivative materials gained or produced from the 
sample.  See Section 12.4 for subject confidentiality. 
8.2 Quality of Life (QOL) Questionnaires 
Three QOL questionnaires will be used in this study: EORTC QLQ-C30 version 3 with, 
EORTC PAN-26 and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-
Hep) version 4. The purpose is to pilot both assessments before being used in a larger 
trial and to determine which instrument covers all the relevant issues in a reliable and 
meaningful way.  
In principle it is the patient him/herself who has to fill out quality of life forms and preferably 
without help from others. Some patients may need help, e.g. because of reduced sight. 
Another person could then read the questions, without making any suggestions to the 
patient, and report the answers on the form.  
All subjects will complete the assessments before study treatment at baseline and at every 
visit (except Cycle 1 Day 2) until disease progression or withdrawal from the study.  Patient 
reported outcomes assessments are to take place prior to any other study procedures 
performed on a particular study day. 
8.2.1 EORTC QLQ-C30 and PAN26  
The QLQ-C30 Version 3.0 is a validated questionnaire developed by the European 
Organisation for Research and Treatment of Cancer (EORTC) to assess the quality of life 
of cancer patients. It is supplemented by the disease-specific module for pancreatic 
cancer (PAN26). The majority of people can complete the questionnaires within 10 to 15 
minutes. However, patients should be given the time they need to complete the 
questionnaire.  
8.2.2 FACT-Hep 
The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System is 
a collection of QOL questionnaires targeted to the management of chronic illness. FACT-


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Hep is designed for use with patients with Hepatobiliary cancer (liver, bile duct and 
pancreas). 
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) 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 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.  


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• 
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. 
• 
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 


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required by the study protocol, or tumor-related diagnostic procedures are not 
considered serious.  
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Congenital anomaly/birth defect in the offspring of a subject who received the study 
drug. 
• 
Other important medical events. 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 
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. 


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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)  
• 
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 refer to the Grades definition 
on page 2 of the CTCAE v4.03.  


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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. 
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, a 
suspected adverse reaction means any AE for which there is a “reasonable 
possibility” that the drug caused the AE.  For the purpose of reporting under this 
protocol, “reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE, and 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.  


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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.  
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 completed 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 
Within 3 days 
Fax or email follow up information in a serious 
adverse event report to sponsor or designee; 
include copies of relevant source documents 
((e.g., progress notes, autopsy reports, laboratory 
and diagnostic test results, discharge summaries) 
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. 


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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.  
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 expected adverse event will be 
considered expected by the study sponsor if the event is listed in the current IB, is an 
event known to be consequences of the underlying disease or condition under 
investigation (e.g., symptoms, disease progression) or an event unlikely to be related 
to the underlying disease or condition under investigation but common in the study 
population (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. 
The study sponsor serious adverse event regulatory reporting requirements are described 
in Table 6. 


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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 MedWatch form) 
Within 7 calendar days of study 
sponsor awareness date or according 
to local regulations 
MedWatch form 
Within 15 calendar days of study 
sponsor awareness date or according 
to local regulations 
No 
Yes 
Yes 
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.  
• 
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. 


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• 
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 11.9).  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. Cases of 
study drug overdose will result in specific reporting requirements (see 
Section 9.6.1).  
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 first 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 (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 


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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 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 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 
A Statistical Analysis Plan (SAP) will be finalized prior to database lock and will include 
more details of analysis populations and summary strategies. Any changes from the 
statistical analyses described in this document will be described in the SAP, and any 
deviation from the final SAP will be described in the final clinical study report.  


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10.1 
Study Endpoints 
Endpoints:  
Phase 1 Endpoints: 
• 
Primary Endpoints 
o Overall safety profile characterized by the type, frequency, severity, timing 
of onset, duration and relationship to study therapies of any adverse events 
(AEs), clinical laboratory abnormalities, vital signs, and electrocardiograms 
(ECGs)  
o Enumeration and description of any dose limiting toxicities (DLTs) that 
occur during Cycle 1, serious adverse events (SAEs), or AEs leading to 
discontinuation of study treatment. 
• 
Secondary Endpoints 
o RX-3117 and Abraxane® plasma PK parameters (e.g., time to maximum 
observed concentration [Tmax], maximum observed concentration [Cmax], 
and area under the concentration-time curve [AUC]) 
o 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 Endpoint 
o Expression or concentration of various cellular or molecular biomarkers  
Phase 2 Endpoints: 
• 
Primary Endpoint 
o An adequate number of Responders based on PFS and/or objective clinical 
response  
• 
Secondary Endpoints 
o Time to progression, ORR and DOR 
o Overall safety profile of RX-3117 in combination with Abraxane® 
o RX-3117 and Abraxane® PK parameters  
• 
Exploratory Endpoints 
o Enumeration, expression, or concentration of various cellular or molecular 
biomarkers  
o Changes in tumor burden 
o QOL 
 
10.2 
General Statistical Considerations 
Safety, Efficacy, QOL, PK, and Pharmacodynamic assessments will be summarized 
separately for Phase 1 and Phase 2 (Stage 1 and Stage 2 combined). Additional 
summaries and analyses of pooled Phase 1 and 2 data may also be generated based on 
applicability of dosing regimens.  


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Descriptive and summary statistics will be presented by dose level and overall, as 
appropriate. Summary statistics for continuous variables will include number of 
observations, mean, standard deviation, median, and range (minimum and maximum).  
Categorical variables will be summarized using the number and percentage of responses 
with 95% confidence intervals if appropriate. Unless otherwise indicated, 95% confidence 
intervals for binary variables will be calculated using the binomial distribution (exact 
method) and will be 2-sided.  Data listings will be created for all eCRF modules to 
supplemental the tabulations.  Graphical techniques (e.g., Kaplan-Meier curves, line plots) 
may be used when such methods are appropriate and informative.  
As appropriate, changes from baseline to each visit timepoint will be described and 
summarized along with the value at each visit timepoint.  The baseline value is defined as 
the last (most recent), non-missing value immediately prior to the first exposure to study 
medication. Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of 
significance. 
10.3 
Sample Size Calculation 
For the Phase 1 dose-finding, approximately 10 subjects are planned. The sample size is 
not based on formal statistical hypothesis testing but will be determined based on 
observed number of first-cycle DLTs at each dose level. The intent is to limit the number 
of subjects who are exposed to excessively toxic doses or sub-therapeutic doses of a drug 
in a Phase 1 evaluation of anticancer agents being used in combination for the first time.  
For Phase 2, approximately 40 evaluable subjects are planned. This sample size is not 
based on statistical hypothesis but rather to further evaluate efficacy and safety endpoints 
in order to plan future trials.  Once the RP2D is identified approximately 10 evaluable 
subjects will participate in Stage 1. Depending on the results of the interim analysis, 
approximately 30 evaluable subjects will participate in Stage 2. 
10.4 
Analysis Populations 
10.4.1 Intent-to-Treat (ITT) Analysis Population 
The Intent-to-Treat (ITT) population will include all subjects who were enrolled in the study 
regardless of if they actually received study medication.  
10.4.2 Modified Intent-to-Treat (mITT) Analysis Population 
The Modified Intent-to-Treat (mITT) set includes all ITT subjects who receive  1 dose of 
RX-3117.  The mITT population may also be thought of as the Safety population and is 
the primary population to be used for safety evaluations such as summaries of baseline 
characteristics, study drug exposure, subject disposition and assessment of DLTs and 
MTDs.  In addition, this population will be used in the analyses of efficacy assessments 
such as overall response rate and progression free survival.   


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A subset of the mITT population will be used in the analyses of time to response and 
duration of response.  This subset will include those 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. 
Another subset of the mITT population will be used in the analysis of PK and 
Pharmacodynamic parameters.  It will include those from the mITT population who have 
baseline and on-study measurements to provide interpretable results for specific 
parameters of interest.  
10.4.3 Per Protocol (PP) Analysis Population 
The Per Protocol (PP) population includes all subjects from the mITT population with the 
exclusion of any subjects with protocol deviations/violations that would compromise the 
safety and/or efficacy of the study treatment.  Any subjects excluded from this population 
will be identified and documented prior to database lock. 
10.5 
Randomization and Blinding 
This is a non-randomized, open-label study. Therefore, randomization and blinding are 
not applicable. 
10.6 
Missing Data and Other Data Handling Conventions 
All summaries and analyses will be based upon the observed data unless methods for 
handling missing data are specified otherwise. The details for handling of missing data will 
be described in addition detail in the SAP.  It is not anticipated that any missing data will 
be imputed with the exceptions below: 
• 
For QOL measurements, missing data will be handled as described in the scoring 
manuals and/or algorithms. 
• 
For time to event analyses: 
o Subjects without any efficacy evaluations will be considered as censored at 
time 0.  
o Subjects without the event of interest will be censored on the date they were 
last known to be event-free. 
• 
For Adverse Events: 
o Missing dates will not be imputed; however, if partial dates are available, they 
will be used to assess if the AE occurred during the treatment period.  
o Missing severities of AEs will not be imputed and will be considered missing in 
any tabulations of AE severity.  


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o If an AE is missing a response to the question regarding relationship to 
treatment, the event will be considered to be related. 
10.7 
Adjustments for Covariates, Multiple Comparisons, and/or Multiplicity 
No adjustments for covariates, multiple comparisons, and/or multiplicity are planned for 
this trial. 
10.8 
Multi-Center Studies and Pooling of Centers 
Approximately 3 enrolling sites in the US will participate in the Phase 1 portion of the study 
and up to 15 enrolling sites in the US will participate in the Phase 2 study.  Due to the 
nature of this early phase study, data from all sites will be pooled for all analyses.  
10.9 
Interim Analysis 
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 
de-escalate to the next dose level will be made after the evaluation of safety 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 after Stage 1 of the Phase 2 will be performed when the first 10 
evaluable subjects have been treated at the recommended Phase 2 dose, are evaluable 
for response, have the opportunity to complete up to 4 cycles of therapy or have 
discontinued therapy before 4 cycles (see Section 6.8).  If an adequate number of 
Responders are observed out of the initial 10 evaluable subjects, subject enrollment will 
continue with another 30 evaluable subjects enrolled (approximately 40 evaluable 
subjects combined in Phase 2).  An adequate number of Responders is defined as either 
at least 2 out of the 10 evaluable subjects (20%) having a measured benefit in PFS noted 
as PFS ≥ 4 months/ cycles or if at least 1 subject (10%) has 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. The 
study may stop after the interim analysis if an adequate number of Responders are not 
seen. However, if an adequate number of Responders are seen, an additional 30 
evaluable subjects will be enrolled and evaluated. 
10.10 Data Tabulations and Analyses 
Summary tabulations will be provided for disposition, demographic, and baseline 
characteristics, efficacy, safety, and PK/ Pharmacodynamic data as noted in the following 
sections. All data collected in the EDC will be provided in data listings to supplement the 
tabulations. 


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10.10.1 Tabulation and Analysis of Disposition, Demographics, and Baseline 
Characteristics 
A tabulation of subject disposition will be presented by study phase and dose level 
including the number in each analysis population, reasons for discontinuing treatment, 
and reasons for discontinuing from the study.  
Demographics and baseline characteristics will be summarized using descriptive statistics 
by study phase and dose level.  This includes but is not limited to medical, surgical, cancer, 
and psychiatric histories plus prior medications and physical examination results. 
10.10.2 Tabulation and Analysis of Efficacy 
10.10.2.1 Objective Response Rate and Tumor Burden 
Tumor control assessments will be based on the standardized RECIST version 1.1.  
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.  
The Objective Response Rate (ORR) will be defined as the rate of a clinical response of 
CR or PR at the completion of treatment assessment. Subjects with unknown or missing 
response will be treated as non-responders, i.e. they will be included in the denominator 
when calculating the proportion.  The ORR will be summarized using tabulations and 95% 
confidence intervals.  The change from baseline in tumor change (burden) will be 
summarized as well using summary statistics. 
10.10.2.2 Time-to-Event for TPP, DOR, and PFS 
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 calculations will be applied: 
• 
TTP (defined as the time from first treatment administration to first documentation 
of RECIST-defined objective tumor progression). Median TTP is to be estimated 
using the Kaplan-Meier method.  
• 
DOR (defined as the time from the first documentation of RECIST-defined 
objective tumor response to the first documentation of RECIST-defined objective 
tumor progression or death). Median DR is to be estimated using the Kaplan-Meier 
method. 
• 
Progression Free Survival (defined as the time from first treatment administration 
to first documentation of RECIST-defined objective tumor progression or relapse 
or death from any cause). Median PFS is to be estimated using the Kaplan-Meier 
method. 


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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 
corresponding 95% confidence intervals will be presented.  
10.10.2.3 Quality of Life Questionnaires 
The three QOL assessments used in this study will be summarized.  These are the 
EORTC QLQ-C30 version 3, EORTC PAN-26, and the Functional Assessment of Cancer 
Therapy-Hepatobiliary (FACT-Hep) version 4.  Each assessment will be scored according 
to the appropriate scoring manual and summarized overall and for subscales as available. 
In addition to the values at each timepoint, the percentage change from baseline to each 
scheduled visit will be summarized.  
10.10.3 Tabulation and Analysis of Safety 
10.10.3.1 Exposure to Study Medication and 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). 
10.10.3.2 Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
displayed in tables and listings using MedDRA system organ class (SOC) and preferred 
term. The incidence rates of treatment-emergent AEs, SAEs, DLTs, AEs of at least Grade 
3 in severity, related AEs, and AEs leading to withdrawal of treatment will be tabulated 
and summarized. Treatment-emergent adverse events (TEAEs) will be those that start or 
worsen on or after the first day dose of study treatment, through 30 days after last dose; 
related AEs will be those with an Investigator determination of related to treatment.  
AEs with partial dates will be assessed using the available date information to determine 
if treatment-emergent. AEs with completely missing dates will be assumed to be 
treatment-emergent. No formal hypothesis-testing of AE incidence rates will be performed. 
The causal relationship between the occurrence of an AE and the study drug will be judged 
by the investigator as not related, possibly related, or probably related. In the event a 
subject experiences repeat episodes of the same AE, then the event with the highest 
severity and/or strongest causal relationship to treatment will be used for purposes of 
tabulations. 


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10.10.3.3 Clinical and Biomarker Laboratory Data 
For each analyte, the actual value and percentage change from baseline to each visit 
timepoint will be summarized to include, but not limited to, hematology, clinical chemistry, 
coagulation, and biomarker data. In the event of repeat values, the last non-missing value 
per study day will be used. 
Severity of select clinical lab measures will be determined using CTCAE criteria (e.g., 
those measures that have a corresponding CTCAE grade classification). Labs with 
CTCAE grades greater than or equal to 3 will be presented in a data listing. Shift tables 
that present changes from baseline to worst on-study and baseline to last on-study values 
relative to CTCAE classification ranges will be produced. 
10.10.3.4 Vital Signs 
The actual vital signs values and percentage change from baseline to each visit timepoint 
will be summarized. 
10.10.3.5 ECGs 
The ECG parameters (heart rate, PR interval, QRS interval, QT interval, and corrected QT 
[QTc] interval) at each visit timepoint recorded as well as the percentage change from 
baseline will summarized.  These parameters will be determined electronically by the ECG 
machine at the clinical site.  The QT interval will be corrected by the Fridericia method 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 baseline will be presented.  
10.10.4 Pharmacokinetics and Pharmacodynamics 
10.10.4.1 Pharmacokinetics 
Plasma concentrations and derived pharmacokinetic parameters 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 and dose level.    
10.10.4.2 Pharmacodynamics 
The pharmacodynamics data will be summarized in the same manner as the clinical 
laboratory data.  As data allows, the correlation between PK and Pharmacodynamic 
results will be investigated. 


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11. 
INVESTIGATIONAL PRODUCT 
11.1 Abraxane®  
Abraxane® will be obtained by the site pharmacy from commercial sources.  
Administration, storage and handling will follow guidelines detailed in the approved 
package insert. Sites will track accountability following institutional guidelines and local 
standard operating procedures. 
11.2 RX-3117 
RX-3117 will be provided as 200 mg and 500 mg capsules intended for oral administration.  
The capsules contain approximately 215-mg or 540 mg, respectively, of RX-3117 
monohydrate with the additional mass above the nominal respective values of 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 200 mg 
capsule will be contained in a Size 2 Swedish orange opaque capsule and the 500 mg will 
be contained in a Size 0 opaque capsule with a Swedish orange cap and grey body. 
11.3 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 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. 
11.4 Storage and Handling 
Bottles containing capsules of RX-3117 should be stored at a controlled refrigerated 
temperature of 2-8°C (i.e., 36-46o F).  
11.5 Source 
RX-3117 will be supplied without charge by Rexahn Pharmaceuticals, Inc. 
11.6 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. 


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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 assignment, 
and number of capsules to be taken will be written on the dispensing bottle label by site 
personnel. 
11.7 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 and collect the original diary page or make 
a certified copy. 
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. 
11.8 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. 
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. 


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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.  
11.9 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 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). 
11.10 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. 


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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 
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. 


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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 
• 
Laboratory normal ranges and documentation of laboratory certification (or 
equivalent) 
• 
Signed study contract 
• 
Completed Food and Drug Administration (FDA) form 1572 
• 
Financial disclosure document(s) 
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: 


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• 
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 
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 


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• 
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 
• 
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 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 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 


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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: Writing and 
editing for biomedical publication (International Committee of Medical Journal Editors, 
2010), 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, and editors 
will ask these individuals to complete journal-specific author and conflict-of-interest 
disclosure forms. When submitting a manuscript authored by a group, the 
corresponding author should clearly indicate the preferred citation and identify all 
individual authors as well as the group name. Journals generally list other 
members of the group in the Acknowledgments. The NLM indexes the group name 
and the names of individuals the group has identified as being directly responsible 
for the manuscript; it also lists the names of collaborators if they are listed in 
Acknowledgments. 
• 
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. 


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• 
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. 


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14. 
REFERENCES  
 
American Cancer Society Global Cancer Facts & Figures 3rd Edition 2015; 
http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-
044738.pdf 
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. 
Globocan, 2012; http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx  
Highlights of prescribing information: ABRAXANE® for Injectable Suspension (paclitaxel 
protein-bound particles for injectable suspension) (albumin-bound). Retrieved 08 August 
2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021660s037lbl.pdf 
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. 
International Committee of Medical Journal Editors. Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals: Writing and editing for biomedical 
publication. Journal of Pharmacology & Pharmacotherapeutics 2010;1: 42–58. Rasco 
DW, Peterson C, Mazhari R, Benaim E, and Merchan J. RX-3117, An Oral Antimetabolite 
to Treat Advanced Solid Tumors (ST): Phase 1 and Ongoing Phase 2a Results. Annals of 
Oncology (2016) 27 (6): 114-135. 
Rasco DW, Peterson C, Benaim E, and Merchan JR. Activity of RX-3117, an oral 
antimetabolite nucleoside, in patients with pancreatic cancer: Preliminary results of stage 
1 of the phase 1a/2b. Journal of Clinical Oncology 35, no. 4_suppl (February 2017) 445-
445. 
Rexahn Pharmaceuticals. Investigator’s brochure RX-3117 version 3.0. 16 Dec 2016. 
Rizzo JD, Somerfield MR, Hagerty KL et al., 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. 
Smith TJ, Khatcheressian J, Lyman GH et al, Update of recommendations for the use of 
white blood cell growth factors: an evidence-based clinical practice guideline.  J. Clin 
Oncol 2006 24: 3187-3205. 
 


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15. APPENDICES  
Appendix A.  Schedule of Assessments Cycle 1 
 
SCRa 
Cycle 1 
EOT
/ ET 
SFUc 
Procedures and Treatments                             Day 
-14 
1 
2 
8b 
15 
22b 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Medical, surgical, cancer and psychiatric histories 
X 
 
 
 
 
 
 
 
Prior medication usage 
Xd 
Xe 
 
 
 
 
 
 
Eligibility review, enrollment 
X 
Xf 
 
 
 
 
 
 
Quality of Life measurementsg 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy testh 
X 
X 
 
 
 
 
 
 
Physical examination excluding GU including height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
X 
ECOG performance status 
X 
X 
 
 
 
 
X 
X 
Hematology and serum chemistry 
X 
Xi 
 
X 
X 
X 
X 
X 
Coagulation profile and Urinalysis 
X 
Xi 
 
X 
X 
 
X 
 
Vital sign measurementsj,k 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogramj,l 
X 
X 
X 
 
 
 
 
 
Pharmacokinetic samplingj,m 
 
X 
 
 
X 
 
 
 
Abraxane® infusionn 
 
X 
 
X 
X 
 
 
 
RX-3117 drug administrationo 
 
X 
Xp 
X 
X 
 
 
 
Dispensing of study drugq and diary cards 
 
Xq 
Xq 
Xq 
Xq 
 
 
 
Unused study drug collection & subject compliance 
 
 
 
X 
X 
X 
X 
 
Tumor assessment(s)r  
X 
 
 
 
 
 
 
Xs 
Tumor marker blood samples 
X 
Xi 
 
 
 
 
X 
 
Adverse event assessmentt 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant med review 
 
X 
X 
X 
X 
X 
X 
X 
Archived tumor tissueu 
 
X 
 
 
 
 
 
 
Biomarker blood samplev 
 
X 
 
 
 
 
X 
 
Tumor biopsy samples (optional)w 
 
X 
 
 
 
 
 
 
 
ECOG = Eastern Cooperative Oncology Group; ET = Early Termination; EOT = End of Treatment;  
 
SFU = Safety Follow up; SCR = Screening 
 
Footnotes for Schedule of Assessments 
a 
Screening procedures will be performed within 14 days of enrollment, except baseline 
tumor assessment, which can be evaluated within 21 days before enrollment. ECG 
must be done within 7 days before 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 RX-3117. 
d 
Medications taken within 28 days before 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  QoL questionnaires must be completed prior to any other study procedure. 
 
h 
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 before dosing on Cycle 1 Day 1.  


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i 
If screening laboratory tests were performed within 72 hours before Cycle 1 Day 1, they 
do not need to be repeated on Cycle 1 Day 1. 
j 
The required order of assessments is ECG, followed by vital signs and then PK 
sampling when applicable. 
k 
Vital signs measurements will include resting heart rate, blood pressure, pulse, 
respiratory rate, and temperature. Oxygen saturation (by pulse oximetry while subject is 
breathing room air) will be assessed at Screening only. 
l 
ECG to be assessed pre-dose of Abraxane®, pre-dose of RX-3117 administration, and 
at 1, 2, 4, and 6 hours after RX-3117 oral administration on Cycle 1 Day 1. (Phase 1 
and Phase 2-Stage 1 only) 
m In Phase 1 and Phase 2-Stage 1 only, Pharmacokinetic (PK) samples will be collected 
at Abraxane® pre-dose, at the end of infusion, at RX-3117 pre-dose (no more than 15 
minutes before dosing) and at 0.5, 1, 2, 3, 4, and 6  hours after oral administration of 
RX-3117 on Day 1 in Cycle 1. A sample will also be taken 24 hours after RX-3117 
dosing administration on Cycle 1 Day 1.)  
n 
Abraxane® IV infusion over 30-40 minutes on Days 1, 8, and 15. If a dose is 
administered on the same day as PK sampling (i.e. pre-dose and 24 hours), the PK 
sample will be collected first.  
o 
RX-3117 will be administered orally after having fasted for a minimum of 8 hours and no 
earlier than 1 hour after the start of  infusion of Abraxane®.  
p 
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 (i.e., pre-dose and 
24 hours), the PK sample will be collected first. 
q 
Study drug and diary cards will be dispensed at 1 week intervals during Cycle 1. 
r 
Tumor assessments will be evaluated using RECIST v1.1 and should include an 
assessment of all areas of known and suspected malignancy. 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.  
s 
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. 
t 
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.  
u 
To be collected within 4 weeks after enrollment 
v 
Biomarker samples will be collected pre-dose  
w 
Tumor biopsies will be taken following enrollment but before first dose of study 
treatment (optional) 
 
 
 
 


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Appendix B.  Schedule of Assessments Cycles 2 to 8 
 
Cycles 2 - 8 
EOT/ET 
SFUa 
Procedures and Treatments                             Day 
1 
8 
15 
22 
 
 
Quality of Life measurementsb 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
X 
X 
ECOG performance status 
X 
 
 
 
X 
X 
Hematology and serum chemistry 
X 
 
X 
 
X 
X 
Coagulation profile and Urinalysis 
X 
 
 
 
X 
 
Vital sign measurementsc 
X 
X 
X 
 
X 
X 
Abraxane® infusiond 
X 
X 
X 
 
 
 
RX-3117 drug administration e,f, 
X 
X 
X 
 
 
 
Dispensing of study drug and diary cardsg 
Xg 
 
 
 
 
 
Unused study drug collection & subject compliance 
 
 
 
X 
X 
 
Tumor assessment(s)h 
 
 
 
Xi 
Xj 
X 
Tumor marker blood samples 
X 
 
 
 
X 
 
Adverse event assessmentl 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
Biomarker blood sample 
Xm 
 
 
 
X 
 
ECOG = Eastern Cooperative Oncology Group; ET = Early Termination; EOT = End of Treatment;  
SFU = Safety Follow up; SCR = Screening 
 
Footnotes for Schedule of Assessments 
a 
Safety follow-up visit will be between 30 and 37 days after the last dose of study drug. 
b 
EORTC QLQ-C30; EORTC PAN26; FACT-Hep. QoL questionnaires must be completed 
prior to any other study procedure. 
c 
Vital signs measurements will include resting heart rate, blood pressure, pulse, 
respiratory rate, and temperature. 
d 
Abraxane® IV infusion over 30- 40 minutes on Days 1, 8, and 15.  
e 
RX-3117 will be administered orally after having fasted for a minimum of 8 hours and no 
earlier than 1 hour after the start of  infusion of Abraxane®.  
f 
Administered for 5 consecutive days followed by 2 days off per week for 3 weeks then 1 
week off.  
g 
 Study drug and diary cards will be dispensed at least once every cycle thereafter. 
h 
Tumor assessments will be evaluated using RECIST v1.1 and should include an 
assessment of all areas of known and suspected malignancy. 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.  
i 
Tumor evaluation, including CT/MRI/PET will be performed between Days 22-28 of 
Cycles 2, 4, 6 and 8.  The results of the assessments must be available before the start 
of the next cycle. Results of the assessment must be available before the start of the 
next cycle.  
j 
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. 
k 
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. 


Protocol Number:  RX3117-003 
  
Product:  RX-3117 
 08 August 2018 
 
 
 
 
 
 
 
Amendment 03 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Page 93 of 100 
l 
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.  
m Biomarker samples will be collected predose on Cycle 2 only. 
 
 


Protocol Number:  RX3117-003 
  
Product:  RX-3117 
 08 August 2018 
 
 
 
 
 
 
 
Amendment 03 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Page 94 of 100 
Appendix C.  Schedule of Assessments Cycle 9 and beyond 
 
≥Cycle 9 
EOT/ET 
SFUa 
Procedures and Treatments                             Day 
1 
8 
15 
22 
 
 
Quality of Life measurementsb 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
X 
X 
ECOG performance status 
X 
 
 
 
X 
X 
Hematology and serum chemistry 
X 
 
 
 
X 
X 
Coagulation profile and Urinalysis 
 
 
 
 
X 
 
Vital sign measurementsc 
X 
 
 
 
X 
X 
Abraxane® infusiond 
X 
X 
X 
 
 
 
RX-3117 drug administratione,f 
X 
X 
X 
 
 
 
Dispensing of study drug and diary cardsg 
X 
 
 
 
 
 
Unused study drug collection & subject compliance 
 
 
 
X 
X 
 
Tumor assessment(s)h 
 
 
 
Xi 
Xj 
Xk 
Tumor marker blood samples 
X 
 
 
 
X 
 
Adverse event assessmentl 
X 
X 
X 
X 
X 
X 
Concomitant med review 
X 
X 
X 
X 
X 
X 
Biomarker blood sample 
 
 
 
 
X 
 
 
ECOG = Eastern Cooperative Oncology Group; ET = Early Termination; EOT = End of Treatment;  
 
SFU = Safety Follow up; SCR = Screening 
 
Footnotes for Schedule of Assessments 
a 
Safety follow-up visit will be between 30 and 37 days after the last dose of study drug. 
b 
EORTC QLQ-C30; EORTC PAN26; FACT-Hep. QoL questionnaires must be 
completed prior to any other study procedure. 
c 
Vital signs measurements will include resting heart rate, blood pressure, pulse, 
respiratory rate, and temperature. 
d 
Abraxane® IV infusion over 30-40 minutes on Days 1, 8, and 15 .  
e 
RX-3117 will be administered orally after having fasted for a minimum of 8 hours and 
no earlier than 1 hour after the start of infusion of Abraxane®.  
f 
Administered for 5 consecutive days followed by 2 days off per week for 3 weeks then 
1 week off.  
g 
Study drug and diary cards will be dispensed at least once every cycle. 
h 
Tumor assessments will be evaluated using RECIST v1.1 and should include an 
assessment of all areas of known and suspected malignancy. 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.  
i 
Tumor evaluation, including CT/MRI will be performed between Days 22-28 of Cycle 
10 and every 2 cycles thereafter.  The results of the assessments must be available 
before the start of the next cycle. Results of the assessment must be available before 
the start of the next cycle.  
j 
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. 
k 
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. 


Protocol Number:  RX3117-003 
  
Product:  RX-3117 
 08 August 2018 
 
 
 
 
 
 
 
Amendment 03 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Page 95 of 100 
l 
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.  


Protocol Number:  RX3117-003 
  
Product:  RX-3117 
 08 August 2018 
 
 
 
 
 
 
 
Amendment 03 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Page 96 of 100 
Appendix D.  Analytes 
 
 
Chemistry 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Specific gravity 
RBC 
Urine -HCG 
Potassium 
pH 
Hemoglobin 
Serum -HCG 
Chloride 
 
ANC 
PT; PTT or INR 
Bicarbonate 
Protein 
Platelets 
 
Magnesium 
Glucose 
WBC 
Blood samples 
for RX-3117 
and metabolite 
concentration 
and PK 
Calcium 
Bilirubin 
Differential 
BUN 
Ketones 
• Eosinophils 
Serum Creatinine WBC 
• Basophils 
Blood samples 
for biomarkers 
AST (SGOT) 
RBC 
• Lymphocytes 
Tumor Marker 
ALT (SGPT) 
Epithelial cells 
• Neutrophils 
Blood samples 
for Abraxane® 
concentration 
and PK 
Alkaline 
phosphatase 
Bacteria 
(macroscopy 
only) 
• 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:  RX3117-003 
  
Product:  RX-3117 
 08 August 2018 
 
 
 
 
 
 
 
Amendment 03 
 
CONFIDENTIAL 
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Page 97 of 100 
Appendix E.  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. 


Protocol Number:  RX3117-003 
  
Product:  RX-3117 
 08 August 2018 
 
 
 
 
 
 
 
Amendment 03 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Page 98 of 100 
• 
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 
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) must 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. 


Protocol Number:  RX3117-003 
  
Product:  RX-3117 
 08 August 2018 
 
 
 
 
 
 
 
Amendment 03 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Page 99 of 100 
* 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. 
 
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 


Protocol Number:  RX3117-003 
  
Product:  RX-3117 
 08 August 2018 
 
 
 
 
 
 
 
Amendment 03 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Page 100 of 100 
be classified as having “symptomatic deterioration”. Every effort should be made 
to document the objective progression even after discontinuation of treatment.  
• 
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. 

SAP_001.pdf: 
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Rexahn Pharmaceuticals, Inc. 
 
Protocol Number:  Protocol Number RX3117-003 
 
A Phase 1/2 Open-Label, Safety, Pharmacokinetic, 
Pharmacodynamic and Efficacy Study of RX-3117 in 
Combination with Abraxane® in Subjects with Metastatic 
Pancreatic Cancer 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 


  
Sponsor: Rexahn Pharmaceuticals, Inc.  Protocol Number: RX3117-003   
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TABLE OF CONTENTS 
1.0 
PURPOSE ............................................................................................... 4 
2.0 
ACRONYMS ........................................................................................... 4 
3.0 
OVERALL STUDY DESIGN AND OBJECTIVE .......................................... 5 
3.1 
Study Objectives ................................................................................................ 5 
3.1.1 
Phase 1 Objectives ...................................................................... 5 
3.1.2 
Phase 2 Objectives ...................................................................... 6 
3.2 
Study Design and Study Procedures .............................................................. 6 
3.3 
Treatments and Assignment to Treatments .................................................. 8 
3.4 
Determination of Sample Size ......................................................................... 9 
4.0 
GENERAL ANALYSIS CONVENTIONS .................................................... 9 
4.1 
Study Periods ..................................................................................................... 9 
4.2 
Visit Windows ................................................................................................... 10 
5.0 
ANALYSIS POPULATIONS ................................................................... 10 
5.1 
Intent-to-Treat Population ............................................................................. 10 
5.2 
Modified Intent-to-Treat (mITT) ................................................................... 10 
5.3 
Safety Population ............................................................................................. 10 
5.4 
PK Population ................................................................................................... 10 
6.0 
SUBJECT DISPOSITION ...................................................................... 11 
7.0 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .......................... 11 
8.0 
EFFICACY VARIABLES ......................................................................... 11 
8.1 
Primary Efficacy Variable ................................................................................ 11 
8.2 
Secondary Efficacy Variables ......................................................................... 11 
9.0 
EFFICACY ANALYSES .......................................................................... 13 
9.1 
Primary Efficacy Analysis ................................................................................ 13 
9.2 
Secondary Efficacy Analyses .......................................................................... 13 
9.2.1 
Time to Progression (TTP) ....................................................... 13 
9.2.2 
Objective Response Rate (ORR) ............................................. 13 
9.2.3 
Duration of Response (DOR) ................................................... 13 
9.2.4 
Time to Response (TTR) .......................................................... 13 
9.2.5 
Progression-Free Survival (PFS) ............................................. 14 
9.2.6 
Disease Control Rate (DCR) .................................................... 14 
9.3 
Additional Efficacy Analyses ........................................................................... 14 
9.3.1 
Tumor burden ............................................................................ 14 
9.3.2 
Quality of Life (QOL) Assessments ......................................... 14 
10.0 
STATISTICAL/ANALYTICAL ISSUES ................................................... 14 


  
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10.1 
Handling of Dropouts or Missing Data ......................................................... 14 
10.2 
Pooling of Centers in Multi-Center Studies .................................................. 15 
10.3 
Multiple Comparisons/Multiplicity .................................................................. 15 
10.4 
Examination of Subgroups ............................................................................. 15 
10.5 
Interim Analysis and Data Monitoring .......................................................... 15 
11.0 
PHARMACOKINETICS/PHARMACODYNAMICS ................................... 16 
12.0 
DRUG EXPOSURE AND COMPLIANCE ................................................. 18 
13.0 
SAFETY ANALYSES .............................................................................. 19 
13.1 
Adverse Events ................................................................................................. 19 
13.2 
Treatment-Emergent Adverse Events .......................................................... 19 
13.3 
Death, Serious Adverse Events, and Adverse Events Leading to 
Discontinuation ............................................................................................................... 20 
13.4 
Dose Limiting Toxicity ..................................................................................... 20 
13.5 
Clinical Laboratory Data .................................................................................. 21 
13.6 
Vital Signs ......................................................................................................... 21 
13.7 
Electrocardiograms (ECGs) ............................................................................ 21 
13.8 
Prior and Concomitant Medications .............................................................. 22 
14.0 
QUALITY CONTROL ............................................................................. 22 
15.0 
APPENDICES ....................................................................................... 23 
15.1 
Schedule of Events .......................................................................................... 23 
15.2 
Clinical Laboratory Analytes ........................................................................... 27 
16.0 
SIGNATURE PAGE ............................................................................... 28 
 
 
 


  
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1.0 PURPOSE  
This SAP describes the methods to be used in the analysis of study data from clinical 
protocol RX3117-003 in order to answer the study objectives and is based on 
Amendment 03 of the study protocol, dated 08-August-2018.   
Populations for analysis, data handling rules, statistical methods, and formats for data 
presentation are described within this document.  The statistical analyses and summary 
tabulations described in this SAP will provide the basis for the results sections of the CSR 
for this study.  The SAP outlines any differences in data analysis methods relative to 
those planned in the study protocol.  Any changes to the data analysis methods after 
the SAP is finalized will be described in the CSR. 
 
2.0 ACRONYMS 
Below is the list of acronyms that will be used throughout this document. 
 
Abbreviation 
Definition 
AE 
Adverse Event 
BQL 
Below the Quantifiable Limit 
CI 
Confidence Interval 
CR 
Complete Response 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-Limiting Toxicity 
DOR 
Duration of Response 
eCRF 
Electronic Case Report Form 
EORTC-PAN26 
European Organization for Research and Treatment of Cancer – 
Pancreatic module 
EORTC-QLQ-C30 
European Organization for Research and Treatment of Cancer – 
Quality of Life Questionnaire 
FACT-Hep 
Functional Assessment of Cancer Therapy – Hepatobiliary 
ECG 
Electrocardiogram 
ICH 
International Conference on Harmonisation 
ITT 
Intent-to-Treat 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 


  
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Abbreviation 
Definition 
mITT 
Modified Intent-to-Treat 
MTD 
Maximum Tolerated Dose 
NR 
No Results/Not Reported 
ORR 
Objective Response Rate 
PD 
Progressive Disease or Pharmacodynamic 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Preferred Term 
QOL 
Quality of Life 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
Standard of Care 
TEAE 
Treatment-Emergent Adverse Events 
TTP 
Time-to-Progression 
TTR 
Time-to-Response 
 
 
 
 
 
3.0 OVERALL STUDY DESIGN AND OBJECTIVE 
3.1 
Study Objectives 
3.1.1 Phase 1 Objectives  
 
Primary Objectives 
o To evaluate the safety and tolerability of RX-3117 in combination with 
Abraxane® in subjects with metastatic pancreatic cancer 


  
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o To determine the Recommended Phase 2 Dose (RP2D) of RX-3117 when 
administered orally in combination with Abraxane® to subjects with 
metastatic pancreatic cancer 
 
Secondary Objectives 
o To determine the pharmacokinetic (PK) profiles of RX-3117 and 
Abraxane® on Day 1 (single dose) and Day 15 (steady-state) in Cycle 1 
o To evaluate the antitumor activity of RX-3117 in combination with 
Abraxane® 
 
Exploratory Objective 
o 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 
3.1.2 Phase 2 Objectives  
 
Primary Objectives 
o To estimate the antitumor activity of RX-3117 in combination with 
Abraxane® as first-line therapy in subjects with metastatic pancreatic 
cancer 
 
Secondary Objectives 
o To assess additional measures of antitumor activity 
o To characterize the safety profile of RX-3117 in combination with 
Abraxane® 
o To evaluate the PK of RX-3117 and Abraxane® at the recommended 
Phase 2 dose (RP2D) 
 
Exploratory Objective 
o To investigate the effect of RX-3117 in combination with Abraxane® on 
potential cellular or molecular biomarkers in blood or tumor samples 
o To evaluate the change in tumor burden response  
o To evaluate the effect on Quality of Life (QOL) 
3.2 
Study Design and Study Procedures 
This will be a Phase 1b/2a multicenter 2-stage study.  Phase 1 will be conducted 
as a dose-finding, open-label study of oral RX-3117 administered in combination 
with Abraxane® to subjects with metastatic pancreatic cancer. The 
recommended phase 2 dose (RP2D) of RX-3117, in combination with 
Abraxane®, will be determined based on the safety profile, dose modification, 


  
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and PK. Phase 1 will be conducted using a combination of the single MTD for RX-
3117 and the Abraxane® dose as per the package insert when Abraxane® is 
given in combination for subjects with pancreatic cancer.  A safety committee will 
assess the safety and the tolerability of the combination after the first 5 subjects 
and may make recommendation to confirm the MTD in another 5 subjects. 
After completion of the Phase 1 portion, a Phase 2a study will be conducted 
using a 2-stage, open-label design, of RX-3117 and Abraxane® in combination 
to treat subjects with metastatic pancreatic cancer as first-line therapy. 
Approximately 10 subjects will participate in the Stage 1 at the dose identified in 
Phase 1 (RP2D). Subjects will be treated for up to 8 cycles of combined therapy. 
An interim analysis will be conducted after 10 evaluable subjects have been 
treated at the RP2D, have completed a minimum of 4 months/ cycles of therapy, 
or have discontinued therapy due to progressive disease before completing 4 
cycles. If an adequate number of Responders are observed out of the initial 10 
evaluable subjects, then 30 evaluable additional subjects will be enrolled to 
participate in Stage 2. An adequate number of Responders is defined as either at 
least 2 out of the 10 subjects (20%) having a measured benefit in PFS noted as 
PFS ≥ 4 months/ cycles or if at least 1 subject (10%) has 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. The study may stop after the interim analysis if an 
adequate number of Responders are not seen. However, if an adequate number 
of Responders are seen, approximately 30 evaluable subjects will be enrolled and 
evaluated. Subjects will be treated for up to 8 cycles of combined therapy. 
RX-3117 will be administered orally for 5 consecutive days followed by 2 days off 
each week for 3 weeks and a 1-week rest in repeated 4-week cycles. Abraxane® 
will be administered intravenously over 30-40 min. on Days 1, 8, and 15 of each 
cycle at the dose level assigned in Phase 1 or the RP2D determined for Phase 2. 
Subjects will receive up to 8 cycles of RX-3117 in combination with Abraxane® 
or until disease progression (per RECIST 1.1), clinical progression, 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 clinical benefit (as determined by subject care, quality of life, and 
tumor reduction), additional cycles of RX-3117 in combination with Abraxane® 
may be administered following discussions with the sponsor and medical 
monitor. 


  
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3.3 
Treatments and Assignment to Treatments 
The investigational product in this study is RX-3117. RX-3117 will be 
administered in combination with Abraxane®. During Phase 1, 700 mg or lower 
doses of RX-3117 may be investigated in combination with Abraxane®. RX-3117 
dosing will begin at 700 mg daily/ 5 days consecutively per week with 2 days rest 
for 3 weeks and then 1 week of rest in each Cycle. The Abraxane® starting dose 
will be 125 mg/m2 administered on Days 1, 8 and 15 of each cycle.  Abraxane® 
and RX-3117 dose reductions will follow Table 1 below. 
Table 1. Dosage Reductions  
Dose Level 
Abraxane® (mg/m2) 
RX-3117 (mg) 
Full dose 
125 
700 
1st dose reduction 
100 
600 
2nd dose reduction 
75 
500 
 
In Phase 1, if 0 or 1 of the first 5 subjects that complete one cycle of treatment 
experiences a DLT, then the full dose may be confirmed as the RP2D.  If 3 or 
more of the first 5 subjects that complete one cycle of treatment experience a 
DLT, then there will be a dose reduction and 5 subjects will be treated at the 
next lowest dose level.  If 2 of the first 5 subjects that complete one cycle of 
treatment experience a DLT, then the safety review committee may recommend 
an additional 5 subjects are to be treated at the full dose.  In this case, if 3 or 
less of the 10 subjects experience a DLT, then the full dose will be confirmed as 
the RP2D.  Otherwise, if 4 or more of the 10 subjects experience a DLT, then a 
dose reduction will occur. Additional doses may be recommended by the review 
committee which includes investigators, medical monitor and sponsor. For Phase 
2, the RX-3117 and Abraxane® dosing will be administered based on the RP2D 
identified after completion of Phase 1. 
In the Phase 1 and Phase 2-Stage 1, 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-Stage 2 portion, subjects who are enrolled but not treated will be 
replaced. 


  
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3.4 
Determination of Sample Size 
For the Phase 1 dose-finding, approximately 10 subjects are planned. The 
sample size is not based on formal statistical hypothesis testing but will be 
determined based on observed number of first-cycle DLTs at each dose level. 
The intent is to limit the number of subjects who are exposed to excessively toxic 
doses or sub-therapeutic doses of a drug in a Phase 1 evaluation of anticancer 
agents being used in combination for the first time.   
For Phase 2, approximately 40 evaluable subjects are planned. This sample size 
is not based on statistical hypothesis but rather to further evaluate efficacy and 
safety endpoints in order to plan future studies.  Once the RP2D is identified 
approximately 10 evaluable subjects will participate in Stage 1. Depending on the 
results of the interim analysis, approximately 30 evaluable subjects will 
participate in Stage 2.  
 
4.0 GENERAL ANALYSIS CONVENTIONS 
4.1 
Study Periods 
The study consists of the following periods: 
 
Screening period: From the date of consent to date of enrollment, up to 14 
days or up to 21 days for tumor assessments. Please note: The study allows 
up to 5 days after enrollment before dosing. 
 
Treatment period: From first dose of RX-3117 to last dose of RX-3117.  
Additional cycles are allowed on a per subject basis upon agreement between 
the Sponsor, Medical Monitor, and Investigator. 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 subject 5 
times per week (i.e., for 5 consecutive days followed by 2 days off) for 3 
consecutive weeks followed by 1 week of rest in each 4-week cycle. 
Abraxane® will be administered once a week for 3 weeks on Days 1, 8, and 
15 followed by 1 week of rest during each 28-day cycle. End of Treatment 
visit will be performed when a subject discontinues study treatment. 
 
Safety follow-up period: From the day after the last dose of RX-3117 to the 
safety follow-up visit which occurs approximately 37 days after the last dose 
of RX-3117.  
Subject participation is anticipated to be approximately 9 months 


  
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4.2 
Visit Windows 
The visit windows will be analyzed per the protocol and as collected in the eCRF. 
Study Day will be calculated from the reference start date and used to show 
start/stop day of the assessments and events as follows: 
 
For assessments/events on/after the reference start date: 
Study Day= (date of assessment/event – reference start date) +1 
 
For assessments/events before the reference start date: 
Study Day= (date of assessment/event – reference start date) 
 
5.0 ANALYSIS POPULATIONS 
5.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will include all subjects who were enrolled 
in the study regardless of if they actually received any amount of either study 
medication. 
5.2 
Modified Intent-to-Treat (mITT) 
The Modified Intent-to-Treat (mITT) population includes all subjects who receive 
≥ 1 dose of RX-3117, who have measurable tumor, who can be evaluated for 
tumor response at both baseline and at least one on-study tumor evaluation with 
the exclusion of any subjects with protocol deviations/violations that would 
compromise the safety and/or efficacy of the study treatment. Any subjects 
excluded from this population will be identified and documented prior to 
database lock.   
A subset of the mITT population will be used in the analyses of time to response 
and duration of response. This subset will include those subjects who achieved a 
complete response or partial response.  
5.3 
Safety Population 
The Safety population includes all ITT subjects who receive ≥ 1 dose of RX-
3117. It is the primary population to be used for safety evaluations such as 
summaries of baseline characteristics, study drug exposure, subject disposition 
and assessment of DLTs and MTDs.  
5.4 
PK Population 
The PK Population will be a subset of the Safety population and used in the 
analysis of PK and Pharmacodynamic (PD) parameters. It will include those 


  
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subjects from the Safety population who have baseline and on-study PK/PD 
measurements to provide interpretable results for specific parameters of interest. 
 
6.0 SUBJECT DISPOSITION 
A tabulation of subject disposition will be presented by study phase including the 
number in each analysis population, reasons for discontinuing treatment, and reasons 
for discontinuing from the study. 
 
7.0 DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographics and baseline characteristics will be summarized using descriptive statistics 
by study phase. This includes but is not limited to medical, surgical, and cancer histories 
plus prior medications and physical examination results 
 
8.0 EFFICACY VARIABLES 
8.1 
Primary Efficacy Variable 
The primary efficacy variable in the study is the adequate number of Responders 
based on progression free survival (PFS) and/or objective clinical response. This 
analysis will be performed on the mITT population.  
An adequate number of responders is defined as either at least 20% subjects  
having a measured benefit in PFS noted as PFS ≥ 4 months/ cycles or if at least 
10% subject has 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. This definition 
applies to analyses of data from Stage 1 of Phase 2 (which may include subjects 
from Phase 1 if they received the RP2D), entire Phase 2, and the entire study 
overall.  
8.2 
Secondary Efficacy Variables 
The secondary efficacy variables in this study are listed below. 
 
Time to progression (TTP) is defined as the time from first treatment 
administration until first documentation of RECIST-defined objective tumor 
progression.  TTP does not include deaths.  In the TTP analysis, deaths are 


  
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censored, either at the time of death or at an earlier visit representing 
informative censoring (non-random pattern of loss from the study). 
 
Objective response rate (ORR) is defined as the rate of a clinical response of 
complete response (CR) or partial response (PR) at the completion of 
treatment assessment of tumor control.  ORR will be summarized at each 
tumor assessment as well as a combined summary at the subjects’ last 
assessment on study. Tumor response assessments will be based on the 
standardized RECIST version 1.1. Tumor response will be documented 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. Subjects with 
unknown or missing response will be treated as non-responders at the 
assessment where their response is unknown or missing. 
 
Duration of response (DOR) defined as the time from the first documentation 
of RECIST-defined objective tumor response to the first documentation of 
RECIST-defined objective tumor progression or death.  Clinical progression 
without RECIST-defined objective tumor progression will not be considered 
the end of response.  Responders who discontinue from the study for 
reasons other than tumor progression or death will be censored at the time 
of their last responding tumor assessment. This analysis is applicable for 
responders only and a subset of the mITT. 
 
Time to response (TTR) is defined as the time from first treatment 
administration to first documentation of RECIST-defined objective tumor 
response. 
 
Progression Free Survival (PFS) is defined as the time from first treatment 
administration to first documentation of RECIST-defined objective tumor 
progression or relapse or death from any cause.  Clinical progression without 
RECIST-defined objective tumor progression will not be considered to have 
progressed and follow-up data utilized or censored. 
o For all the 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. 
 


  
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9.0 EFFICACY ANALYSES 
9.1 
Primary Efficacy Analysis 
The number and percentage of Responders based on progression free survival 
(PFS) and/or objective clinical response will be summarized for Stage 1 of the 
Phase 2 portion of the study (on those subjects receiving the RP2D), and for the 
entire study in the final analysis separately, including a 95% confidence interval 
for response. The rationale for response being achieved (PFS ≥ 4 months, 
PR/CR, or both) will also be summarized. A listing of responders will be provided.  
This analysis will be performed on the ITT population as well as the mITT 
population. 
9.2 
Secondary Efficacy Analyses 
9.2.1 Time to Progression (TTP)  
The TTP analysis will be performed on the mITT population and estimated using 
the Kaplan-Meier (KM) product limit method. The median TTP time along with 
95% confidence interval will be constructed based on a log-log transformed CI 
for the survival function. Summary statistics of minimum, maximum, and range 
will be calculated. The results will be displayed graphically in a KM plot as well as 
provided in a listing. 
9.2.2 Objective Response Rate (ORR)  
The ORR analysis will be performed on the mITT population and will be 
summarized by a binomial response rate and its corresponding two-sided exact 
CI using Clopper-Pearson method. The number and percentage of subjects by 
response category (CR, PR, SD, PD, NE) will be summarized. 
9.2.3 Duration of Response (DOR)  
The DOR analysis will be performed on only those subjects with a documented 
response (CR or PR) as a subset within the mITT population as noted in Section 
5.2.  The DOR will be estimated using the KM-product limit method. The median 
DOR time along with 95% confidence interval will be constructed based on a log-
log transformed CI for the survival function. Summary statistics of minimum, 
maximum, and range will be calculated. The DOR results will be provided in a 
listing inclusive of response category, first response date, date response was lost 
or censoring, and DOR. 
9.2.4 Time to Response (TTR)  
The TTR analysis will be performed on only those subjects with a documented 
response (CR or PR) as a subset within the mITT population as noted in Section 
5.2.  The TTR will be estimated using the KM-product limit method. The median 
TTR time along with 95% confidence interval will be constructed based on a log-


  
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log transformed CI for the survival function. Summary statistics of minimum, 
maximum, and range will be calculated. Summary statistics of minimum, 
maximum, and range will be calculated. The results will be displayed graphically 
in a K-M plot as well as provided in a listing. 
9.2.5 Progression-Free Survival (PFS)  
The PFS analysis will be performed on the mITT population and estimated using 
the Kaplan-Meier (KM) product limit method. The median PFS time along with 
95% confidence interval will be constructed based on a log-log transformed CI 
for the survival function. Summary statistics of minimum, maximum, and range 
will be calculated. The results will be displayed graphically in a KM plot as well as 
provided in a listing. 
9.2.6 Disease Control Rate (DCR)  
Disease control rate (DCR) is defined as the number of subjects with a best 
overall response of a CR, PR or SD, divided by the total number of subjects.  The 
DCR analysis will be performed on the mITT population and will be summarized 
by a binomial response rate and its corresponding two-sided exact CI using 
Clopper-Pearson method. 
9.3 
Additional Efficacy Analyses 
9.3.1 Tumor burden  
The percentage change from baseline in tumor change (burden) will be 
summarized using summary statistics. 
9.3.2 Quality of Life (QOL) Assessments  
Each of the three QOL assessments (EORTC QLQ-C30 version 3, EORTC PAN26, 
and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) 
version 4) will each be summarized individually using summary statistics. Each 
QOL assessment will be scored according to the appropriate scoring manual and 
summarized overall and for subscales as available. In addition to the values at 
each timepoint, the percentage change from baseline to each scheduled visit will 
be summarized. 
 
10.0 STATISTICAL/ANALYTICAL ISSUES 
10.1 Handling of Dropouts or Missing Data 
All summaries and analyses will be based upon the observed data unless 
methods for handling missing data are specified otherwise. It is not anticipated 
that any missing data will be imputed with the exceptions below: 


  
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 
For QOL measurements, missing data will be handled as described in the 
scoring manuals and/or algorithms. 
 
For time to event analyses:  
o Subjects without any efficacy evaluations will be considered as 
censored at time 0. 
o Subjects without the event of interest will be censored on the date 
they were last known to be event-free. 
 
For Adverse Events: 
o Missing dates will not be imputed; however, if partial dates are 
available, they will be used to assess if the AE occurred during the 
treatment period. 
o Missing severities of AEs will not be imputed and will be considered 
missing in any tabulations of AE severity. 
o If an AE is missing a response to the question regarding relationship 
to treatment, the event will be considered to be related. 
10.2 Pooling of Centers in Multi-Center Studies 
Approximately 3 enrolling sites in the US will participate in the Phase 1 portion of 
the study and up to 15 enrolling sites in the US will participate in the Phase 2 
study. Due to the nature of this early phase study, data from all sites will be 
pooled for all analyses. 
10.3 Multiple Comparisons/Multiplicity 
No adjustments for multiple comparisons, and/or multiplicity are planned for this 
study. 
10.4 Examination of Subgroups 
No examination of subgroups is planned for this study. 
10.5 Interim Analysis and Data Monitoring 
The interim analyses that are planned to be conducted in the Phase 1 are related 
to an informal review of available data during the dose escalation phase of the 
study.  The review consisted of case report reviews, information from the study 
database, and discussions between the Investigators, Medical Monitor, and 
Sponsor. The decision to de-escalate to the next dose level will be made after 
the evaluation of safety data through at least 28 days of the first cycle of the 
current dose level. 


  
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The interim analysis after Stage 1 of the Phase 2 will be performed when the 
first 10 evaluable subjects have been treated at the recommended Phase 2 dose 
which may include subjects from Phase 1 on the same dose, are evaluable for 
response, have the opportunity to complete up to 4 cycles of therapy or have 
discontinued therapy before 4 cycles. If an adequate number of Responders are 
observed out of the initial 10 evaluable subjects, subject enrollment will continue 
with another 30 evaluable subjects enrolled (approximately 40 evaluable subjects 
combined in Phase 2). An adequate number of Responders is defined as either at 
least 2 out of the 10 evaluable subjects (20%) having a measured benefit in PFS 
noted as PFS ≥ 4 months/ cycles or if at least 1 subject (10%) has 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. The study may stop after the interim analysis if an 
adequate number of Responders are not seen. However, if an adequate number 
of Responders are seen, an additional 30 evaluable subjects will be enrolled and 
evaluated.  
 
11.0 PHARMACOKINETICS/PHARMACODYNAMICS 
All subjects who received study treatment, with available concentration data and no 
major protocol deviations with an impact on PK will be included in the PK analysis set as 
shown in Section 5.2. 
In order to prepare the PK analysis dataset, all plasma concentration values reported as 
No Results/Not Reportable (NR) values will be treated as missing and will appear in the 
dataset as “.”.  Values below the quantifiable limit (BQL) that occur prior to the first 
measurable concentration will be treated as zero. All other BQL values will be treated as 
missing and set to “.”. 
The following PK parameters will be calculated (Phase 1 and Phase 2 – Stage 1 only) on 
Day 1 (single dose) and Day 15 (steady-state) for RX-3117 and Abraxane, within 
Phoenix WinNonlin Version 8.0 or higher, if appropriate: 
For Day 1:  
 
Cmax: Observed maximum concentration after administration, taken directly from the 
analytical data  
 
Tmax: Time to reach maximum concentration in plasma. (obtained without 
interpolation) 
 
Kel: The terminal elimination rate constant will be estimated at terminal phase by 
linear regression after log-transformation of the concentrations 
o Only those data points that are judged to describe the terminal log-linear decline 
will be used in the regression.  


  
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o A minimum number of three descending data points in the terminal phase will be 
used in calculating Kel with the line of regression starting at any post-Cmax data 
point (Cmax should not be part of the regression slope). 
o The adjusted correlation coefficient (R2adj) in general should be greater than 
0.80.  
o An appropriate number of decimal places should be used for Kel to enable the 
reported value of t1/2 to be calculated. 
 
AUC0-t: Area under the concentration-time curve up to the last observable 
concentration calculated using linear trapezoidal summation from time 0 to time t, 
where t is the time of the last measurable concentration (Ct) 
 
AUC0-inf: Area under the concentration-time curve up to infinity calculated using 
linear trapezoidal summation from time 0 to time infinity using the linear up log 
down method, AUC(0-) = AUC(0-t) + Ct/Kel, where Kel is the terminal elimination rate 
constant (the slope of elimination phase of the log-concentration versus time plot) 
and Ct is the last measurable plasma concentration.  AUC0-inf  will not be reported if 
the percentage extrapolated exceeds 20%  
 
t1/2: Terminal half-life time estimated by 0.693/Kel (Kel is determined by the slope of 
terminal phase of log concentration versus time plot). 
For Day 15: 
 
Cmax,ss: Observed maximum concentration after administration, taken directly from 
the analytical data;  
 
Tmax,ss: Time to reach maximum concentration in plasma. (obtained without 
interpolation); 
 
Kel: The terminal elimination rate constant, will be estimated at terminal phase by 
linear regression after log-transformation of the concentrations 
o Only those data points that are judged to describe the terminal log-linear decline 
will be used in the regression.  
o A minimum number of three descending data points in the terminal phase will be 
used in calculating Kel with the line of regression starting at any post-Cmax,ss data 
point (Cmax,ss should not be part of the regression slope). 
o The adjusted correlation coefficient (R2adj) in general should be greater than 
0.80.  
o An appropriate number of decimal places should be used for Kel to enable the 
reported value of t1/2 to be calculated. 
 
AUCtau: Area under the concentration-time curve up to the last observable 
concentration calculated using linear trapezoidal summation from time 0 to time tau, 
where tau is the dosing interval 


  
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 
t1/2: Terminal half-life time estimated by 0.693/Kel (Kel is determined by the slope of 
terminal phase of log concentration versus time plot). 
The mean plasma concentration over time by treatment and day and the individual 
subject plasma concentration versus time data will be plotted. Nominal times will be 
used for plotting the mean plasma concentrations over time by treatment and day and 
actual sampling times will be used for the individual figures and for the non-
compartmental analysis.  
The PK parameters will be summarized descriptively including the number of 
observations, arithmetic mean, SD, CV, minimum, median, maximum, geometric mean 
and geometric CV%.  
All PK parameters will be rounded to 3 significant figures except for Tmax which will be 
rounded to two decimal places. 
Mean SD, median, minimum, maximum, and geometric mean will be presented to 3 
significant figures for all PK parameters except Tmax; Tmax will be presented to 2 decimal 
places; CV% and geometric CV% will be presented to 1 decimal place.  
 
12.0 DRUG EXPOSURE AND COMPLIANCE 
Descriptive information will be provided regarding the number of doses of study therapy 
prescribed, the total number of doses taken, the percentage of expected doses taken, 
the duration of treatment, relative dose intensity (RDI), and the number and timing of 
prescribed dose reductions, dose interruptions, and dose re-escalations. 
 
Duration of treatment is defined as last dose date – first dose date + 1 in days. 
 
RDI for RX-3117 is calculated as:  
o {Actual cumulative dose (mg) / actual treatment duration (day)}/375 (mg/day), 
where 375 comes from Planned cumulative dose (mg)/ planned treatment 
duration = 10500mg/28 days. 
 
RDI for Abraxane is calculated as:  
o {Actual cumulative dose (mg/m2) / actual # of infusions given per 
cycle}/{Planned cumulative dose (mg/m2) / planned # of infusions given per 
cycle}. 
 
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). 
 


  
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13.0 SAFETY ANALYSES 
13.1 Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0 and displayed in tables and listings using MedDRA 
system organ class (SOC) and preferred term (PT). AEs will be graded using 
CTCAE version 4.03.  The incidence rates of treatment-emergent AEs, SAEs, 
DLTs, AEs of at least Grade 3 in severity, related AEs, and AEs leading to 
withdrawal of treatment will be tabulated and summarized. Treatment-emergent 
adverse events (TEAEs) will be those AEs that start or worsen on or after the 
first day dose of study treatment, through 30 days after last dose; related AEs 
will be those with an Investigator determination of related to treatment. 
AEs with partial dates will be assessed using the available date information to 
determine if treatment-emergent. AEs with completely missing dates will be 
assumed to be treatment-emergent. No formal hypothesis-testing of AE 
incidence rates will be performed. 
The causal relationship between the occurrence of an AE and the study drug will 
be judged by the investigator as not related or related. In the event a subject 
experiences repeat episodes of the same AE, then the event with the highest 
severity will be used for purposes of tabulations. 
All safety analysis will be performed on the Safety population. 
13.2 Treatment-Emergent Adverse Events 
The number and percentage of subjects experiencing TEAEs will be tabulated 
according to the following categories: 
 
Overall summary of TEAEs 
 
TEAEs by system organ class and preferred term 
 
SAEs by system organ class and preferred term 
 
DLTs by system organ class and preferred term (Phase 1 only) 
 
TEAEs ≥ Grade 3 by system organ class and preferred term 
 
TEAEs Related to Study Drug by system organ class and preferred term 
 
TEAEs leading to treatment discontinuation by system organ class and 
preferred term 
 
TEAEs leading to study discontinuation by system organ class and preferred 
term 
 
TEAEs by system organ class, preferred term, and AE severity (CTCAE Grade) 


  
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 
TEAEs by system organ class, preferred term, and AE causality 
 
TEAEs by preferred term 
Listings will be provided for all AEs. 
13.3 Death, Serious Adverse Even ts, and A dverse Events Leading to 
Discontinuation 
The number and percentage of subjects experiencing Deaths, SAEs, and AEs 
leading to discontinuation will be tabulated according to the following categories: 
 
Death 
 
Serious AEs (SAEs) by system organ class and preferred term 
 
Serious AEs leading to study discontinuation by system organ class and 
preferred term 
Listings will be also provided for SAEs and AEs leading to study discontinuation.  
13.4 Dose Limiting Toxicity 
DLTs are applicable to only Phase 1 of the study.  
A DLT is defined as any of the following adverse events that is considered by the 
Investigator as possibly, probably or definitely-related to RX-3117, Abraxane or 
the combination: 
 
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 3 nausea or vomiting lasting > 3 days despite optimal management 
 
Grade 3 fatigue lasting > 7 days 
 
Grade 4 fatigue 
 
Treatment interruptions of ≥ 7 days 
 
Any Grade thrombocytopenia that occurs with clinically significant bleeding 
Any other non-hematological Grade ≥ 3 adverse events will be considered DLTs 
with the exception of the following: 
 
Alopecia 
 
Grade 1 or 2 sensory neuropathy 


  
Sponsor: Rexahn Pharmaceuticals, Inc.  Protocol Number: RX3117-003   
Plan Version: Final V1.0, 21-Oct-2019 
 
 
 
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 
For subjects with bone or liver metastases and baseline levels of AST or ALT 
> 2.5 x ULN or alkaline phosphatase > 2x ULN, DLTs do not include 
elevations in AST, ALT, and alkaline phosphatase unless the following criteria 
are met: 
 
AST > 8 x ULN, if the baseline level was between 2.5 to 5 x ULN in subjects 
with liver metastases 
 
ALT > 8 x ULN, if the baseline level was between 2.5 to 5 x ULN in subjects 
with liver metastases 
 
Alkaline phosphatase > 8 x ULN, if the baseline level was between 2 to 5 x 
ULN in subjects with bone or liver metastases. 
A listing of DLTs that occur during Cycle 1 of Phase 1 will be provided. 
13.5 Clinical Laboratory Data 
For each analyte in Appendix 15.2, the actual value and percentage change from 
baseline to each visit timepoint will be summarized to include, but not limited to, 
hematology, clinical chemistry, coagulation, and biomarker data. In the event of 
repeat values, the last non-missing value per study day will be used. 
Severity of select clinical lab measures will be determined using CTCAE (version 
4.03) criteria (e.g., those measures that have a corresponding CTCAE grade 
classification). Laboratory analytes with CTCAE grades greater than or equal to 3 
will be presented in a data listing. Shift tables that present changes from 
baseline to worst on-study and baseline to last on-study values relative to CTCAE 
classification ranges will be produced. 
13.6 Vital Signs 
The actual vital signs values and percentage change from baseline to each visit 
timepoint will be summarized using summary statistics. 
13.7 Electrocardiograms (ECGs) 
The ECG parameters (heart rate, PR interval, QRS interval, QT interval, and 
corrected QT [QTcF] interval) at each visit timepoint recorded as well as the 
percentage change from baseline will summarized using descriptive statistics. 
These parameters will be determined electronically by the ECG machine at the 
clinical site. The QT interval will be corrected by the Fridericia method as follows: 
 
Fridericia: QTcF = QT/(RR^0.33) 
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 baseline will be 
presented. 


  
Sponsor: Rexahn Pharmaceuticals, Inc.  Protocol Number: RX3117-003   
Plan Version: Final V1.0, 21-Oct-2019 
 
 
 
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Please note: the ECG data was collected on only subjects in Phase 1 and Stage 1 
of Phase 2. 
13.8 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO Drug Dictionary 
Enhanced (WHODDE) version March 2017. Concomitant medications will be 
tabulated by ATC Level 3 term and drug preferred term.  Prior medications and 
concomitant medications will also be presented in the data listings. 
 
14.0 QUALITY CONTROL 
All analysis will be performed using SAS® Version 9.4 and SAS Enterprise Guide 
version 7.12. Appropriate SOPs will be followed in the creation and quality 
control of all tables, listings, figures, and analysis. 
All data displays and analyses will adhere to the International Conference on 
Harmonisation (ICH) Harmonized Tripartite Guideline: Structure and Content of 
Clinical Study Reports (ICH Topic E3). Rexahn will review all tables, listings, and 
figures prior to final database lock. Final SAS datasets, programs and outputs will 
be transferred to the Rexahn at project completion. 
 
 
 
 
 
 
 
 


  
Sponsor: Rexahn Pharmaceuticals, Inc.  Protocol Number: RX3117-003   
Plan Version: Final V1.0, 21-Oct-2019 
 
 
 
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15.0 APPENDICES 
15.1 Schedule of Events 
 


  
Sponsor: Rexahn Pharmaceuticals, Inc.  Protocol Number: RX3117-003   
Plan Version: Final V1.0, 21-Oct-2019 
 
 
 
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Sponsor: Rexahn Pharmaceuticals, Inc.  Protocol Number: RX3117-003   
Plan Version: Final V1.0, 21-Oct-2019 
 
 
 
Template #: ST-T-002A  Ver.: 4.0                                                              Effective Date: 28FEB2019  
CONFIDENTIAL 
EXCLUSIVE PROPERTY OF ADVANCED CLINICAL, LLC 
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Sponsor: Rexahn Pharmaceuticals, Inc.  Protocol Number: RX3117-003   
Plan Version: Final V1.0, 21-Oct-2019 
 
 
 
Template #: ST-T-002A  Ver.: 4.0                                                              Effective Date: 28FEB2019  
CONFIDENTIAL 
EXCLUSIVE PROPERTY OF ADVANCED CLINICAL, LLC 
  Page 26 of 28 
 
 
 
 
 


  
Sponsor: Rexahn Pharmaceuticals, Inc.  Protocol Number: RX3117-003   
Plan Version: Final V1.0, 21-Oct-2019 
 
 
 
Template #: ST-T-002A  Ver.: 4.0                                                              Effective Date: 28FEB2019  
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15.2 Clinical Laboratory Analytes 
 
 


  
Sponsor: Rexahn Pharmaceuticals, Inc.  Protocol Number: RX3117-003   
Plan Version: Final V1.0, 21-Oct-2019 
 
 
 
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16.0 SIGNATURE PAGE 
Prepared By: 
Name 
Role 
Signature 
L. Stacey 
Arrambide 
SVP, Biometrics 
 
 
 
Approved By: 
 
The signature of the document approver means that the approver 
has read, understood and approved this document. 
Name 
Role 
Signature 
Date 
Callie Heaton 
Rexahn 
Pharmaceuticals, Inc. 
Associate Director, 
Clinical Operations 
 
 
 
Document is considered final upon date of last signature.