Clinical trial NCT02089334
Conditions: Metastatic Renal Cell Cancer
Keywords: renal cell carcinoma clear cell renal cancer metastatic renal cancer Carcinoma, Renal Cell*/therapy Humans Kidney Neoplasms*/therapy
Sponsor: Rexahn Pharmaceuticals, Inc.
Start date: 2014-08-01; Completion date: 2018-05-17
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the maximum tolerated dose of RX-0201, up to a target dose of 250 mg/m\^2/day, when given in combination with everolimus (Stage 1), and to assess the safety and efficacy of RX-0201 plus everolimus, in subjects with metastatic renal cell cancer (Stage 2).

Detailed description:
This multi-center, open-label, randomized, parallel group study of RX-0201 in combination with everolimus, versus everolimus alone to treat subjects with advanced renal cell carcinoma will be conducted in 2 stages. Stage 1 will be an open-label, dose-escalation study of RX-0201 to identify a safe and tolerable dose of RX-0201 up to a target dose of 250 mg/m\^2/day when given in combination with everolimus. Stage 2 will be a randomized, open-label, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Subjects will receive RX-0201, at the dose identified in Stage 1, in combination with everolimus or everolimus alone, for up to 8 cycles to determine safety and efficacy of the combination.

Arms: arm 1: RX-0201 and everolimus will be taken together as described in the Interventions description.
Interventions: intervention 1: RX-0201
Intervention descriptions: intervention 1: RX-0201 will be administered in a dose up to 250mg/m\^2/day as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles in Stage 1.

In Stage 2, RX-0201 will be administered the dose determined in Stage 1 as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles.

Protocol documents:
Prot_000.pdf: 
Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
08 March 2017 
 
Page 1 of 81 
 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
A Multicenter, Open-label, Phase 1b/2 Study to Evaluate the Safety and Efficacy of 
RX-0201 in Combination With Everolimus to Treat Subjects With Advanced Renal 
Cell Carcinoma 
Rexahn Protocol Number RX-0201-P2-A-09 
NCT02089334 
 
Key Sponsor Contacts: 
Callie Heaton, MS, CCRA 
Rexahn Pharmaceuticals 
15245 Shady Grove Rd Suite 455 
Rockville, MD 20850 
Telephone: 1-240-268-5300  X312 
Fax: 1-240-268-5310 
Christine Peterson, Ph.D. 
Rexahn Pharmaceuticals 
15245 Shady Grove Rd Suite 455 
Rockville, MD 20850 
Telephone: 1-240-268-5300  X320 
Key CRO Contact 
Julie Pickett, RN, BSN, MSM 
Project Manager, CRO  
Vector Oncology, LLC 
6555 Quince, Suite 400 
Memphis, TN  38119 
Telephone: 901-297-3385 
 
Original Protocol Date: 
Amendment Date: 
Amendment 2 Date: 
Amendment 3 Date: 
Amendment 4 Date: 
06 December 2013 
29 January 2014 
17 April 2015 
05 February 2016 
08 March 2017 
Confidentiality Notice 
This document contains confidential information of Rexahn Pharmaceuticals, Inc. 
This document must not be disclosed to anyone other than the study staff and members 
of the institutional review (IRB) or scientific review board members.   
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 Pharmaceuticals, Inc.  
If you have questions regarding how this document may be used or shared, call the 
Rexahn Pharmaceuticals Inc. 1-240-268-5300.  For all other study-related questions, 
continue to contact the Key Sponsor Contact.  
 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
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CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Investigator’s Agreement 
I have read the attached protocol entitled “A Multicenter, Open-label, Phase 1b/2 Study to 
Evaluate the Safety and Efficacy of RX-0201 in Combination With Everolimus to Treat Subjects 
With Advanced Renal Cell Carcinoma”, Amendment 04 dated 08 March 2017, 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 (ICH E6) and applicable local regulatory requirements. 
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 spouse [or legal partner] 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 a representative of Rexahn, I agree to the provisions described in this protocol. 
 
 
 
Signature 
 
 
Name of Rexahn Representative 
 
Date (DD Month YYYY) 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
08 March 2017 
 
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CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Title: A Multicenter, Open-label, Phase 1b/2 Study to Evaluate the Safety and Efficacy of RX-
0201 in Combination With Everolimus to Treat Subjects With Advanced Renal Cell 
Carcinoma  
Study Phase:  Phase 1b/2 
Indication:  Advanced Renal Cell Carcinoma 
Primary Objectives:  
 
To determine the maximum tolerated dose (MTD) of RX-0201, up to a target dose of 250 
mg/m2/day, when given in combination with everolimus (Stage 1) 
 
To determine progression free survival in subjects with advanced renal cell carcinoma 
treated with the combination of RX-0201 and everolimus versus everolimus alone (Stage 
2) 
Secondary Objectives:  
 
To assess the pharmacokinetics of RX-0201 in combination with everolimus (Stage 1) 
 
To evaluate parameters of clinical benefit as measured by duration of response, time to 
response, and response rate (Stage 2) 
 
To evaluate the safety and tolerability of RX-0201 in combination with everolimus versus 
everolimus alone (Stage 1 and Stage 2) 
 
 
Exploratory Objective:  
 
To investigate blood or tumor response/ resistance to RX-0201 and everolimus as 
assessed by AKT pathway biomarkers, tumor apoptosis biomarkers and other 
biomarkers (Stage 1 and Stage 2) 
 
To further evaluate the peak plasma concentration of RX-0201 at the target dose (Stage 
2) 
 
Endpoints: 
 
Primary Endpoints:  
 
Incidence of adverse events and clinical laboratory abnormalities defined as dose-limiting 
toxicities (Stage 1) 
 
Progression free survival at 4.5 months (Stage 2)  
 
Secondary Endpoints: 
 
 
Pharmacokinetic profile of RX-0201 (Stage 1) 
 
Incidence of adverse events, changes in clinical laboratory tests and vital signs over time 
(Stage 1 and Stage 2)  
 
Tumor response, duration of response, time to response, and response rates (Stage 2) 
 
Exploratory endpoints: 
Blood levels of AKT pathway biomarkers, tumor apoptosis biomarkers or other 
biomarkers (Stage 1 and Stage 2)  
Plasma concentration of RX-0201 at the end of infusion (Stage 2) 
 
Study Design: 
This study will be a 2-stage multi-center, open-label study to assess the safety and tolerability of 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
08 March 2017 
 
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CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
RX-0201 in combination with everolimus versus everolimus alone to treat subjects with 
advanced renal cell carcinoma    
• 
Stage 1 will be an open-label, dose-escalation study of RX-0201 to identify a safe and 
tolerable dose of RX-0201 up to a target dose of 250 mg/m2/day when given in 
combination with everolimus.   
• 
Stage 2 will be an open-label, 2-arm study of RX-0201 in combination with everolimus 
versus everolimus alone.  Subjects will receive RX-0201, at the dose identified in Stage 
1, in combination with everolimus for up to 8 cycles to determine safety and efficacy of 
the combination. 
 
Sample Size: 
Stage 1; n = approximately 9 subjects will be enrolled in Stage 1 to receive the 
combination of everolimus (10 mg) and RX-0201 at increasing doses of RX-0201 to the 
MTD or up to a target dose of 250 mg/m2/day.   
 
Stage 2; n = approximately 23 subjects will be treated with everolimus and RX-0201. 
 
Study Centers: Up to 20 sites in the United States  
 
Summary of Subject Eligibility Criteria:   
 
Inclusion Criteria 
Disease Related 
• 
Documented histological or cytological diagnosis of renal cell cancer with a clear-cell 
component 
• 
Measurable or evaluable disease defined by Response Evaluation Criteria for Solid 
Tumors (RECIST) ver. 1.1  
• 
Must have received at least one course of therapy with a VEGFR-targeting tyrosine 
kinase inhibitor (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib) and progressed 
within 6 months of planned first dose of study treatment 
• 
Prior therapy with cytokines (i.e., IL-2, Interferon) and/or VEGF-ligand inhibitors (i.e., 
bevacizumab) are permitted 
• 
Prior vaccine therapy in the adjuvant setting is permitted 
• 
Tissue blocks or tissue sections from initial diagnosis or upon diagnosis of advanced 
metastatic disease will be available for submission to the central laboratory within 
approximately 4 weeks after initiation of study treatment; exceptions (eg, histology 
determined by fine needle aspirate or tissue is no longer available) require written 
documentation of why a sample is not available and prior approval by the sponsor before 
enrollment/ randomization 
• 
ECOG performance status of 0,1 or 2 
• 
Life expectancy > 3 months 
 
Demographic 
• 
Males and females ≥ 18 years of age at screening  
 
Ethical  
• 
Before any study-specific procedures are performed, the appropriate written informed 
consent must be obtained 
 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
08 March 2017 
 
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CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Exclusion Criteria 
Disease Related 
• 
Disease-associated symptoms requiring immediate therapy or other interventions 
• 
Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery and stable for at least 3 months before planned first dose of 
study drug 
 
Laboratory Values 
• 
Absolute neutrophil count < 1.5 x 109/L 
• 
Platelet count < 100 x 109/L 
• 
Hemoglobin < 9 g/dL 
• 
Bilirubin > 1.5 X upper limit of normal (ULN) 
• 
Aspartate aminotransferase (AST) or  alanine aminotransferase (ALT) > 2.5 X ULN (OR 
> 5 X ULN in the presence of known liver metastases) 
• 
Serum creatinine > 1.5 X ULN OR estimated creatinine clearance ≤ 60 ml/min 
(Cockcroft-Gault) 
• 
Partial thromboplasin time (PTT) > 1.25 X ULN 
• 
Prothrombin time (PT) > 1.25 X ULN AND/OR international normalization ratio (INR) > 
1.4 
 
Medications: 
• 
Radiation therapy for bone metastasis within 2 weeks, any other external radiation 
therapy within 4 weeks before planned first dose of study drug.  Systemic treatment with 
radionuclides within 6 weeks before planned first dose of study drug.  Subjects with 
clinically relevant ongoing complications from prior radiation therapy are not eligible 
• 
Prior treatment with everolimus, or any other specific or selective TORC1/PI3K/AKT 
inhibitor (e.g., temsirolimus) 
• 
Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitor) within 2 weeks before planned first dose of study drug 
• 
Receipt of any type of anticancer antibody (including investigational antibody) within 4 
weeks before planned first dose of study drug 
• 
Taking strong inducers or inhibitors of CYP450s for subjects receiving everolimus 
• 
Chronic treatment with corticosteroids or other immunosuppressive agents 
• 
Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet 
inhibitors 
• 
Subjects with a known hypersensitivity to everolimus or other rapamycins (sirolimus, 
temsirolimus) or to its excipients 
• 
Not recovered from toxicities related to any prior treatments, unless adverse events are 
clinically non-significant and/or stable on supportive therapy 
 
General 
• 
History of any medical, psychiatric, or social (e.g., addictive disorder) conditions, or 
laboratory abnormality that in the opinion of the investigator, may increase the risks 
associated with study participation or treatments that may interfere with the conduct of 
the study or the interpretation of study results 
• 
Major surgery within 2 months before planned first dose of study drug. Complete wound 
healing from major surgery must have occurred within 1 month before planned first dose 
of study drug and from minor surgery at least 10 days before planned first dose of study 
drug 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
08 March 2017 
 
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CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
• 
Myocardial infarction within the previous 6 months before planned first dose of study 
drug 
• 
Active infection requiring parenteral antibiotics within 2 weeks before planned first dose 
of study drug 
• 
Diagnosis of another malignancy within 2 years before planned first dose of study drug, 
except for superficial skin cancers, or localized, low grade tumors 
• 
Currently enrolled in and has not yet completed at least 30 days since ending other 
investigational device or drug study before planned first dose of study drug, or subject is 
currently receiving other investigational agent(s) 
• 
Prior or current history of hepatitis B, hepatitis C or human immunodeficiency virus 
• 
Pregnant, planning a pregnancy or breastfeeding during the study 
• 
Sexually active fertile subjects (male and female) must agree to use medically accepted 
methods of contraception during the course of the study and for 30 days after the last 
dose of study treatment 
• 
Unwilling or unable to comply with study requirements or not available for follow-up 
assessments 
• 
Any other major illnesses that in the investigator’s judgment substantially increases the 
risk associated with the subject’s participation in the study  
 
Investigational Product Dosage and Administration:   
Everolimus will be administered daily at 10 mg orally at approximately the same time each day 
consistently with or without food per the approved label instructions in Stage 1 and Stage 2.   
In Stage 1, RX-0201 will be administered at a starting dose of 125 mg/m2/day, by a 24 hour 
continuous intravenous infusion for 14 days followed by 7 days of rest in each 21 day cycle.  
RX-0201 doses will be escalated until a maximum tolerated dose (MTD) or a target dose of 
250 mg/m2/day is reached.  The MTD or the target dose will be tested further in Stage 2. 
Subjects in Stage 1 and Stage 2 may receive up to 8 cycles of combined therapy until 
withdrawal of consent, pregnancy, substantial noncompliance with study procedures, intolerable 
adverse event, documented radiological disease progression or death, principal investigator 
judgment that it is in the best interest of the subject to stop treatment, or study discontinuation. 
Subjects, who the principal investigator feels are receiving benefit, may continue to receive 
additional cycles of therapy following discussions with the Sponsor. 
 
Study Duration:   
Each subject should complete all study procedures in approximately 8 months (i.e., screening 
period up to 14 days; treatment period up to eight 21-day cycles, safety follow-up approximately 
30 days after the last dose of study medication). However, for subjects approved to receive 
additional treatment cycles, the duration may be longer than 8 months.   The study duration is 
estimated at approximately 30 months. 
 
Key Screening Procedures:  (key procedures, see Section 7.2 for a complete list): 
• 
Review of inclusion and exclusion criteria 
• 
Medication, cancer history, cancer treatments and medical history 
• 
Vital signs: resting pulse, resting respiration, temperature and resting blood pressure 
• 
Physical examination including height and weight 
• 
ECOG performance status assessment 
• 
Laboratory tests 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
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CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
• 
Collection of archival paraffin embedded tumor tissue, if available. 
• 
Radiological imaging for disease assessments should be according to RECIST ver. 1.1 
as described in Appendix E (within 21 days before enrollment/randomization) and must 
include an imaging scan (i.e., computerized tomography or magnetic resonance imaging) 
of the abdomen and pelvis and other site of disease.  The imaging modality selected 
must remain the same throughout the study. 
 
Key Treatment Procedures (key procedures, for a complete list see Sections 7.3, 7.4, and 7.5): 
• 
Record adverse events and concomitant medications 
• 
Resting vital signs and weight 
• 
ECOG performance status assessment 
• 
Laboratory tests 
• 
Blood collection for biomarker assessments (within ±1 day of the imaging assessment) 
• 
Radiological imaging for a disease assessment every 6 weeks (i.e., at the end of every 2 
cycles of combined or single agent therapy) 
• 
Pharmacokinetic sampling (Cycle 1 in Stage 1 only) 
 
Statistical Considerations:   
The primary objective of Stage 1 will be to determine the dose of RX-0201 to be administered in 
combination with 10 mg of everolimus.  Approximately 9 subjects will be enrolled in Stage 1 to 
be treated with everolimus and increasing doses of RX-0201 up to a target dose or the MTD.   
After the dose of RX-0201 is determined in Stage 1, Stage 2 will begin accrual.   
Stage 2 will now be an open label study enrolling approximately 20 subjects  with the dose of 
RX-0201 selected in Stage 1 in combination with everolimus.  The primary objective of Stage 2 
will be to assess progression free survival as determined by imaging assessments after every 2 
cycles of treatment (i.e., approximately every 6 weeks).  
Other than the safety evaluation required to determine whether to proceed to Stage 2, no 
planned formal interim analysis will be performed. 
All reported adverse events will be assigned a body system, and preferred term within a body 
system, according to the current version of MedDRA the adverse event preferred term 
dictionary.  The number and percent of subjects reporting adverse events (all, serious, and 
related) will be tabulated by treatment.  


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
08 March 2017 
 
Page 8 of 81 
 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Study Glossary 
Term 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AKT 
Protein Kinase B 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DMP 
Data Management Plan 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
INR 
International Normalization Ratio 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
TKI 
Tyrosine Kinase Inhibitor 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
WHO 
World Health Organization 
 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
08 March 2017 
 
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CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Table of Contents 
 
Page 
Protocol Synopsis ............................................................................................................3 
Study Glossary ................................................................................................................8 
1. 
OBJECTIVES ....................................................................................................... 13 
1.1 
Primary ...................................................................................................... 13 
1.2 
Secondary ................................................................................................. 13 
1.3 
Exploratory: ............................................................................................... 13 
2. 
BACKGROUND AND RATIONALE ....................................................................... 13 
2.1 
Disease and Treatments ........................................................................... 13 
2.2 
AKT and Cancer ........................................................................................ 14 
2.3 
RX-0201 Background ................................................................................ 15 
 
Nonclinical Studies .................................................................... 15 
 
Prior Clinical Experience............................................................ 16 
3. 
EXPERIMENTAL PLAN ........................................................................................ 17 
3.1 
Study Design ............................................................................................. 17 
3.2 
Number of Centers .................................................................................... 18 
3.3 
Number of Subjects ................................................................................... 18 
3.4 
Estimated Study Duration .......................................................................... 18 
 
Study Duration for Participants .................................................. 18 
 
End of Study .............................................................................. 18 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 18 
4.1 
Screening Log ........................................................................................... 19 
4.2 
Inclusion Criteria ........................................................................................ 19 
4.3 
Exclusion Criteria ...................................................................................... 19 
5. 
SUBJECT ENROLLMENT .................................................................................... 21 
5.1 
Subject Recruitment .................................................................................. 21 
5.2 
Subject Registration .................................................................................. 21 
5.3 
Subject Enrollment/ Randomization and Treatment Assignment ............... 22 
5.4 
Subject Replacement ................................................................................ 22 
6. 
TREATMENT PROCEDURES .............................................................................. 23 
6.1 
Study Drug Administration ......................................................................... 23 
 
Everolimus Dose Administration ................................................ 23 
 
RX-0201 Dosing Schedule ........................................................ 23 
 
RX-0201 Dose Administration ................................................... 23 
6.2 
Rationale for the RX-0201 Dose and Dosing Interval ................................ 24 
6.3 
RX-0201 Dose Limiting Toxicity ................................................................. 24 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
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CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
6.4 
Determination of MTD or the RX-0201 Recommended Stage 2 Starting 
Dose .......................................................................................................... 25 
6.5 
Definitions of Dose Limiting Toxicity .......................................................... 26 
6.6 
RX-0201 Dosage Modifications ................................................................. 26 
 
RX-0201 Dose Modifications During a Cycle ............................. 26 
 
RX-0201 Dose Modifications at the Beginning of the Next 
Cycle ......................................................................................... 27 
 
RX-0201 Dose Re-Escalation .................................................... 27 
 
RX-0201 Dose Escalation (Stage 1 only) ................................... 27 
 
Everolimus Adjustments, and Modifications ............................... 27 
6.7 
Everolimus Dose Delays ........................................................................... 28 
6.8 
RX-0201 Dose Delays ............................................................................... 28 
6.9 
Discontinuation of Study Treatment ........................................................... 28 
6.10 
Concomitant Therapy ................................................................................ 29 
 
Analgesics ................................................................................. 29 
 
Antibiotics, Antifungals, and Antivirals ....................................... 30 
 
Anticancer or Experimental Systemic Therapies Other than 
Investigational Treatments ......................................................... 30 
 
Antidiarrheals ............................................................................ 30 
 
Antiemetics ................................................................................ 30 
 
Contraception ............................................................................ 30 
 
Corticosteroids .......................................................................... 31 
 
Diet ............................................................................................ 31 
 
Drugs with Potential for Interactions with Everolimus ................. 31 
 
Erythropoietin and Granulocyte Colony-Stimulating Factors ...... 32 
 
Immunization ............................................................................. 32 
 
Radiation Therapy ..................................................................... 32 
 
Surgery or Other Invasive Procedures ....................................... 33 
 
Transfusions .............................................................................. 33 
7. 
STUDY PROCEDURES ....................................................................................... 33 
7.1 
General Study Procedures ........................................................................ 33 
7.2 
Screening Procedures – Stage 1 and Stage 2 ........................................... 33 
7.3 
Treatment Period – Stage 1....................................................................... 34 
 
Pre-dosing Assessments Cycle 1 Day 1 - Stage 1 ..................... 34 
 
Everolimus Dosing – Cycle 1 Day 1 - Stage 1 ........................... 35 
 
RX-0201 Dosing – Cycle 1 Day 1 - Stage 1 ............................... 35 
 
Post-dosing Assessments Cycle 1 Day 1 - Stage 1 ................... 35 
 
Cycle 1 Day 2 - Stage 1 ............................................................. 36 
 
Everolimus Dosing – Cycle 1 Days 3 to 14 - Stage 1 ................. 36 
 
Cycle 1 Day 8 - Stage 1 ............................................................. 36 
 
Cycle 1 Day 15 - Stage 1 ........................................................... 36 
 
Cycle 1 Day 16 - Stage 1 ........................................................... 37 


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Everolimus Dosing – Cycle 1 Days 17 to 21 - Stage 1 ............... 37 
7.4 
Treatment Period - Cycles 2 to n – Stage 1 ............................................... 37 
7.5 
Treatment Period - Cycles 1 to n – Stage 2 ............................................... 37 
 
Pre-dosing Assessments - Cycles 1 to n, Day 1 - Stage 2 ......... 37 
 
Everolimus Dosing Cycles 1 to n, Days 1 - 21 - Stage 2 ............ 38 
 
RX-0201 Dosing – Cycles 1 to n, Day 1 - Stage 2 ..................... 38 
 
Cycles 1 to n, Day 8 - Stage 2 ................................................... 38 
 
Cycles 1 to n, Day 15 - Stage 2 ................................................. 39 
7.6 
Cycles 1 to n, Days 18-21 – Imaging Assessment – Stage 2 ..................... 39 
7.7 
Unscheduled Visit(s) – Stage 1 and Stage 2 ............................................. 40 
7.8 
End of Treatment or Early Termination Visit - Stage 1 and Stage 2 ........... 40 
7.9 
Safety Follow-Up Visit – Stage 1 and Stage 2 ........................................... 41 
7.10 
Predictive and Pharmacodynamic Biomarkers........................................... 41 
7.11 
Sample Storage and Destruction ............................................................... 42 
8. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 42 
8.1 
Definitions ................................................................................................. 42 
 
Adverse Events ......................................................................... 42 
 
Serious Adverse Events ............................................................ 43 
8.2 
Unexpected Adverse Event ....................................................................... 44 
 
Eliciting Adverse Event Information ........................................... 45 
8.3 
Reporting Procedures for All Adverse Events ............................................ 45 
8.4 
Grading of the Severity of an Adverse Event ............................................. 45 
8.5 
Describing Adverse Event Relationship to Study Drug and Study 
Procedures ................................................................................................ 46 
8.6 
Adverse Event Reporting Requirements .................................................... 47 
 
Site Reporting Requirements ..................................................... 47 
 
Study Sponsor Reporting Requirements .................................... 48 
8.7 
Special Situation Reporting Requirements ................................................ 49 
 
Definitions of Special Situations................................................. 49 
 
Pregnancy ................................................................................. 50 
 
Instructions for Reporting Special Situations .............................. 51 
8.8 
Other Events Requiring Rapid Reporting ................................................... 51 
9. 
STATISTICAL CONSIDERATIONS ...................................................................... 52 
9.1 
Study Design ............................................................................................. 52 
 
Stage 1 ...................................................................................... 52 
 
Stage 2 ...................................................................................... 52 
9.2 
Study Endpoints, Subsets, and Covariates ................................................ 52 
 
Study Endpoints ........................................................................ 52 
 
Analysis Populations ................................................................. 53 
 
Covariates ................................................................................. 53 
9.3 
Sample Size Considerations...................................................................... 53 
9.4 
Access to Individual Subject Treatment Assignments ................................ 54 


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REXAHN PHARMACEUTICALS, INC. 
9.5 
Interim Safety Analysis and Early Stopping Guidelines .............................. 54 
 
General Approach/Considerations ............................................. 54 
 
Analysis of Key Study Endpoints ............................................... 55 
 
Background Information and Other Analyses ............................. 57 
10. 
INVESTIGATIONAL PRODUCT ........................................................................... 58 
10.1 
RX-0201 .................................................................................................... 58 
10.2 
RX-0201 Labeling ...................................................................................... 58 
10.3 
Everolimus ................................................................................................ 59 
11. 
REGULATORY OBLIGATIONS ............................................................................ 59 
11.1 
Informed Consent ...................................................................................... 59 
11.2 
Institutional Review Board ......................................................................... 59 
11.3 
Pre-Study Documentation Requirements................................................... 60 
11.4 
Subject Confidentiality ............................................................................... 60 
11.5 
Investigator Signatory Obligations ............................................................. 61 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 61 
12.1 
Protocol Amendments and Study Termination ........................................... 61 
12.2 
Protocol Adherence and Deviations ........................................................... 62 
12.3 
Study Documentation and Archive............................................................. 62 
12.4 
Study Monitoring and Data Collection ........................................................ 63 
12.5 
Inspections and Auditing Procedures ........................................................ 63 
12.6 
Case Report Forms ................................................................................... 64 
12.7 
Data Collection .......................................................................................... 64 
12.8 
Publication Policy ...................................................................................... 64 
12.9 
Compensation ........................................................................................... 65 
13. 
REFERENCES ..................................................................................................... 66 
 
List of Appendices 
Appendix A.  Stage 1 Schedule of Assessments ........................................................... 68 
Appendix B.  Stage 2 Schedule of Assessments ........................................................... 70 
Appendix C.  Laboratory Analytes ................................................................................. 72 
Appendix D.  Pharmacy Guide ....................................................................................... 73 
Appendix E.  RECIST ver. 1.1 ....................................................................................... 77 
 


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1. 
OBJECTIVES 
1.1 Primary  
• 
To determine the maximum tolerated dose (MTD) of RX-0201, up to a target dose of 
250 mg/m2/day, when given in combination with everolimus (Stage 1) 
• 
To determine progression free survival in subjects with advanced renal cell 
carcinoma treated with the combination of RX-0201 and everolimus versus 
everolimus alone (Stage 2) 
1.2 Secondary  
• 
To assess the pharmacokinetics of RX-0201 in combination with everolimus 
(Stage 1) 
• 
To evaluate parameters of clinical benefit as measured by duration of response, time 
to response, and response rate (Stage 2) 
• 
To evaluate the safety and tolerability of RX-0201 in combination with everolimus 
versus everolimus alone (Stage 1 and Stage 2) 
1.3 Exploratory  
• 
To investigate blood or tumor response/ resistance to RX-0201 and everolimus as 
assessed by AKT pathway markers, tumor apoptosis markers and other biomarkers 
(Stage 1 and Stage 2) 
• 
To further evaluate the peak plasma concentration of RX-0201 at the target dose 
(Stage 2) 
2. 
BACKGROUND AND RATIONALE 
2.1 Disease and Treatments 
Renal cell carcinoma (RCC) is responsible for about 2-3% of all malignant diseases in adults 
and is the most lethal of all genitourinary malignancies (Mihaly et al., 2012). Traditionally, more 
than 40% of patients with RCC have died of their cancer, in contrast with the 20% mortality rates 
associated with prostate and bladder carcinomas (Shahani et al., 2010). Overall, 8.9 new cases 
are diagnosed per 100,000 population per year.  Clinical signs do not develop early due to the 
location of the tumor, and consequently the overall five-year survival is as low as 20-25%.  The 
most important feature in the selection of the appropriate therapy is the presence of metastases 
(Mihaly et al., 2012).  
The primary treatment is surgery ranging from partial nephrectomy for localized RCCs to 
cytoreductive nephrectomy in extended tumors with multiple metastases. Then, for advanced, 


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metastatic or recurrent disease a systemic therapy can be administered. As RCCs are generally 
resistant to chemo- and radiotherapy, this systemic management consists of the administration 
of targeted therapy agents (Mihaly et al., 2012).  
Agents representing the current standards operate on members of the RAS signal transduction 
pathway.  First line systemic treatment includes the oral, small-molecule, multi-targeted receptor 
tyrosine kinase inhibitors (TKI) sunitinib (targeting vascular endothelial growth factor), sorafenib 
(dual-specificity tyrosine kinase inhibitor), and pazopanib (a multi-targeted receptor tyrosine 
kinase inhibitor), the intravenous mTOR inhibitor, temsirolimus, and the oral mTOR inhibitor, 
everolimus (an inhibitor of the mammalian target of rapamycin), (Mihaly et al., 2012).  
Everolimus, another derivative of sirolimus, is an immunosuppressant mTOR inhibitor approved 
by the Food and Drug Administration in 2009 for patients with advanced RCC after progression 
following treatment with sunitinib or sorafenib.  An advantage of everolimus over temsirolimus is 
its oral administration leading to higher compliance (Mihaly et al., 2012).  
Based on data showing statistically significant improvement in progression free survival as 
compared with placebo, everolimus established clinical benefit as a second-line therapy in 
patients who progress on first-line targeted therapy, including sunitinib and sorafenib (Shahani et 
al. 2010).  Everolimus can be proposed as the new standard of care in the second-line setting 
for patients progressing on targeted therapy with VEGF inhibitor (George et al., 2009). 
The recent trend in the RCC clinical trials is the initial introduction of new agents in second line 
treatment which then advance into first line (Mihaly et al., 2012).  While evidence is growing 
about the role of everolimus as a second-line monotherapy for advanced RCC, the combination 
of everolimus with another agent is a viable option if the second agent targets the signaling in a 
different cancer pathway (Shahani et al., 2010).  
2.2 AKT and Cancer  
Strong evidence exists that AKT-1 protein product plays a very important role in cancer 
progression by stimulating cell proliferation and inhibiting apoptosis. In cancer cells, over-
expression of constitutively activated AKT-1 in many cell types promotes cellular transformation 
by two distinct mechanisms.  AKT-1 appears to promote proliferation under conditions in which 
cells should normally be growth arrested.  AKT-1 inhibits apoptosis by virtually all cell-death-
inducing molecules.  These mechanisms enable AKT-1 to promote the survival of tumor cells 
under conditions in which those cells should die. Therefore, AKT-1 may be an attractive drug 
target for the treatment of cancer. 


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Overexpression of p-Akt may contribute to the development and progression of malignancies 
(e.g. prostate (van de ST et al., 2005), breast (Stal et al, 2003), ovarian (Kurose et al., 2001), 
endometrial (Uegaki et al., 2005), pancreatic ductal (Yamamoto et al., 2004), thyroid (Ringel et 
al., 2001), squamous cell carcinomas (Massarelli et al., 2005), multiple myeloma (Hsu et al, 
2001) and renal cancer (Rathmell et al., 2005) have a negative impact on prognosis.  High 
antiphospho-specific AKT immunostaining was significantly associated with poor cancer specific 
survival rate and metastases in renal cell carcinoma (Horiguchi et al., 2003).  Increases in both 
cytoplasmic and nuclear p-Akt levels were independent prognostic factors for reduced renal 
cancer patient survival (Hager et al, 2009).  Molecular correlates of patient survival further 
implicate AKT as having a role in tumor progression, involving specific DNA methylation events 
in kidney cancer (Cancer Genome Atlas Research Network, 2013).  Neither tumour grade nor 
stage influenced p-Akt expression, whereas the clear cell and papillary subtypes showed 
increased p-Akt more often than chromophobe or sarcomatoid types of renal cancer (Hager et 
al, 2009).   
2.3 RX-0201 Background  
RX-0201 is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic 
acid (mRNA).  Antisense oligonucleotides are being studied for potential use as therapeutic 
agents for cancer.  Antisense oligonucleotides are short deoxyribonucleic acid (DNA) molecules 
that can interfere with gene expression by forming duplexes with complimentary sequences of 
target mRNA.  The antisense oligonucleotides can inhibit protein expression by causing AKT-1 
mRNA inactivation.  The AKT-1 (also called protein kinase B or PKB) gene family consists of 3 
widely expressed, closely related proto-oncogenes known as AKT-1, AKT-2, and AKT-3, 
respectively.  Once activated, AKT protein products can phosphorylate a range of proteins and 
thereby control several cellular processes (Staal, 1987). 
 Nonclinical Studies 
The specificity of RX-0201-mediated effect on AKT-1 mRNA levels was examined in human 
renal cell carcinoma (von Hippel-Lindau protein-deficient renal cell carcinoma cell line) UMRC2 
cells.  The treatment of UMRC2 cells with RX-0201 at concentrations of 0.1 - 0.3 μM resulted in 
almost complete reduction of AKT-1 mRNA levels. In vitro pharmacology studies have 
demonstrated that RX-0201 suppressed cell proliferation of human cancer cells of various 
origins, including pancreatic cells.  RX-0201 was evaluated for antitumor activity in athymic nude 
mice implanted with fragments of human tumors, which included PANC-1 pancreatic carcinoma 
cell line.  While no significant antitumor effects were observed in PANC-1, treatment with RX-
0201 did appear to result in increased survival benefits at the dose levels tested. 


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When treated with RX-0201 no significant effects were seen in acute toxicity studies in 
Cynomolgus monkeys and Sprague-Dawley rats.  Possible RX-0201 related effects in 14-day 
toxicity studies in Cynomolgus monkeys included decreased red blood cells and histological 
findings in the liver, kidneys, and lymphatic tissues.  Possible RX-0201 related effects in 14-day 
toxicity studies with Sprague-Dawley rats include: lower red blood cell parameters seen in all 
treated groups that persisted through the recovery period, as well as changes in kidney and liver 
histology and other hematologic and blood chemistry parameters. 
The effect of RX-0201 when given in combination with everolimus on renal cancer cell 
proliferation was studied in Caki-1 and UMRC2 cells. An additive effect on growth inhibition was 
observed when either Caki-1 or UMRC2 cells were treated with a combination of RX-0201 and 
everolimus. These results suggest that when RX-0201, when combined with everolimus, may 
increase inhibition of cell proliferation. 
 
Prior Clinical Experience 
In a phase 1 single agent dose escalation study of RX-0201, doses ranging from 6.0 to 
315 mg/m2/day were administered to 17 subjects with solid tumors.  The maximum tolerated 
dose of single agent administration was 250 mg/m2/day.  Fatigue was the most commonly 
reported adverse event in 82% of subjects (14/17).  Arthralgia (joint pain) and nausea were the 
second most commonly reported adverse events with 47% (8/17) and 35% (6/17) of subjects 
reporting these events, respectively.  Fatigue was also the most frequently reported adverse 
event determined by the investigator to be related to RX-0201, with 70.6% (12/17) of subjects 
reporting the event, 29.4% (5/17) of the subjects reported a mild fatigue, 23.5% (4/17) of 
subjects reported a moderate fatigue, and 17.6% (3/17) subjects reported a severe fatigue.   
A Phase 2 study of RX-0201 and gemcitabine in metastatic pancreatic cancer has been 
completed.  In Stage 1 of this study, 11 subjects were enrolled and received gemcitabine at 
1000 mg/m2 for 30 minutes followed by a continuous infusion of RX-0201 at a dose of 200 
mg/m2/day for 14 days.  In Stage 2 of this study, 20 additional subjects were treated with 
gemcitabine at 1000 mg/m2 for 30 minutes followed by 200 mg/m2/day of RX-0201. The most 
commonly reported treatment emergent adverse events related to RX-0201 were 
thrombocytopenia (8.7%), decreased platelet count (7.7%), neutropenia (6.7%), fatigue (5.8%), 
and decreased hemoglobin (5.8%). 
The Phase 1b portion of this study has been completed. Seven males and 3 females, (median 
age 61 years) were treated with 125 mg/m2/day (n=3), 200 mg/m2/day (n=4), and 250 mg/m2/day 
(n=3) RX-0201 in combination with 10 mg everolimus.  The most common toxicities attributed to 
the combination were rash, mouth ulceration, weight loss, thrombocytopenia, facial edema, 


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fatigue, and pruritus. No significant events were attributed to RX-0201 alone. Most events (81%) 
were mild or moderate in severity. Based on the tolerability, 250 mg/m2/day RX-0201 dose was 
declared the recommended Phase 2 dose. 
As of 06 March 2017, nine subjects have been randomized and treated in the Phase 2 portion of 
the study.  The treatment of metastatic renal cell carcinoma and recruitment for this study have 
been significantly impacted by the approval of 3 new therapies (nivolumab, cabozantinib, and 
lenvatinib + everolimus). Treatment with everolimus alone in the clinical study setting is no 
longer a preferred option for clinicians and patients. Therefore, the everolimus alone treatment 
arm and randomization component is being removed in this protocol amendment.   
3. 
EXPERIMENTAL PLAN 
3.1 Study Design 
The current study will be a phase 1b/2, multicenter, open label study conducted in 2 stages.  
Stage 1 will be an open-label, dose-escalation phase 1b study of RX-0201 administered in 
combination with everolimus.  It is expected that 250 mg/m2/day or a lower dose of RX-0201 will 
be identified as safe and well-tolerated when administered in combination with everolimus.  The 
initial dose of RX-0201 will be 125 mg/m2/day.  RX-0201 will be administered by continuous 
intravenous infusion for 14 days followed by 1 week of rest.  The dose of RX-0201 identified in 
Stage 1 will be studied further in the dose expansion portion (Stage 2).  In Stage 1 and Stage 2, 
everolimus (10 mg) will be administered daily according to the approved label instructions.   
Stage 2 will be an open-label, 2-arm phase 2 study of RX-0201 in combination with everolimus 
versus everolimus alone.  Subjects will receive either RX-0201, at the dose identified in Stage 1, 
in combination with everolimus for up to 8 cycles until withdrawal of consent, pregnancy, 
substantial noncompliance with study procedures, intolerable adverse event, documented 
radiological disease progression (per RECIST ver. 1.1 see Appendix E), death, principal 
investigator judgment that it is in the best interest of the subject to stop treatment, or study 
discontinuation. For subjects receiving RX-0201 and everolimus therapy and, in the opinion of 
the investigator, is receiving benefit after 8 cycles, additional cycles of RX-0201 plus everolimus 
may be administered following discussions with the Sponsor.  Prior to this amendment, subjects 
were randomized to receive everolimus alone. Subjects randomized to the everolimus only 
treatment arm will complete the study after 8 cycles but may continue to receive everolimus off-
study. 
The study endpoints are defined in Section 9.2. 


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3.2 Number of Centers 
Up to 20 sites in the US will participate in this study.  Sites that do not enroll subjects within 
3 months of site initiation may be terminated.   
3.3 Number of Subjects 
In Stage 1 approximately 9 subjects will be enrolled to receive escalating doses of RX-0201 in 
combination with everolimus.  The number of subjects enrolled into Stage 1 will vary depending 
upon the number of dose levels needed to determine the MTD up to a target dose of 
250 mg/m2/day of RX-0201.   
In Stage 2 approximately 23 subjects will be treated (i.e., 3 subjects in the everolimus arm and 
up to 20 subjects in the everolimus/RX-0201 arm). 
3.4 Estimated Study Duration 
 Study Duration for Participants 
Each subject should complete all study procedures in approximately 8 months (i.e., screening 
period up to 14 days; treatment period up to eight 21-day cycles, safety follow up approximately 
30 days after the last dose of study medication).   
Subjects in Stage 1 and Stage 2 may receive up to 8 cycles of RX-0201 until the earliest of 
disease progression (per RECIST ver. 1.1 see Appendix E), an intolerable RX-0201-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.  
Subjects assigned to the RX-0201 and everolimus treatment arm, who the principal investigator 
feels are receiving benefit, may continue to receive treatment beyond 8 cycles following 
discussions with the Sponsor. The duration for these subjects will be >8 months with each 
additional cycle of treatment lasting 21 days. 
The study duration is estimated at approximately 30 months. 
 End of Study 
The end of the study is estimated to be approximately 30 days after the last subject completes 
the protocol specified treatment.  
4. 
SUBJECT ELIGIBILITY 
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 


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criteria may not be waived by the investigator, and conformance to the eligibility criteria is 
subject to review in the case of a Good Clinical Practice (GCP) or a regulatory authority audit.  
Any questions regarding a subject’s eligibility should be discussed with the study sponsor and 
medical monitor prior to enrollment/randomization. 
Before any study-specific procedures are performed, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Screening Log 
Investigators will be expected to maintain a screening log of all potential study candidates that 
includes limited information about the potential candidate (i.e., age, sex, race), date, and 
outcome of the screening process (e.g., enrolled into study, reason for ineligibility, or declined to 
participate). 
4.2 Inclusion Criteria 
Disease related 
• 
Documented histological or cytological diagnosis of renal cell cancer with a clear-cell 
component 
• 
Measurable or evaluable disease defined by Response Evaluation Criteria for Solid 
Tumors (RECIST) ver. 1.1  
• 
Must have received at least one course of therapy with a VEGFR-targeting tyrosine 
kinase inhibitor (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib) and 
progressed within 6 months of planned first dose of study treatment. 
• 
Prior therapy with cytokines (i.e., IL-2, Interferon) and/or VEGF-ligand inhibitors (i.e., 
bevacizumab) are permitted 
• 
Prior vaccine therapy in the adjuvant setting is permitted 
• 
Tissue blocks or tissue sections from initial diagnosis or upon diagnosis of advanced 
metastatic disease will be available for submission to the central laboratory within 
approximately 4 weeks after inititation of study treatment; exceptions (e.g., histology 
determined by fine needle aspirate or tissue is no longer available) require written 
documentation of why a sample is not available and prior approval by the sponsor 
before enrollment/ randomization 
• 
ECOG performance status of 0, 1 or 2 
• 
Life expectancy > 3 months 
Demographic 
• 
Males and females ≥ 18 years of age at screening  
Ethical 
• 
Before any study-specific procedures are performed written informed consent must 
be obtained (see Section 11.1)   
4.3 Exclusion Criteria 
Disease Related 


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• 
Disease-associated symptoms requiring immediate therapy or other interventions 
• 
Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery and stable for at least 3 months before planned first 
dose of study drug 
Laboratory 
• 
Absolute neutrophil count < 1.5 x 109/L 
• 
Platelet count < 100 x 109/L 
• 
Hemoglobin < 9 g/dL 
• 
Bilirubin > 1.5 X upper limit of normal (ULN) 
• 
Aspartate aminotransferase (AST) or  alanine aminotransferase (ALT) > 2.5 X ULN 
(OR > 5 X ULN in the presence of known liver metastases) 
• 
Serum creatinine > 1.5 X ULN OR estimated creatinine clearance ≤ 60 ml/min 
(Cockroft-Gault) 
• 
Partial thromboplastin time (PTT) > 1.25 X ULN  
• 
Prothrombin time (PT) > 1.25 X ULN OR international normalization ratio (INR) > 1.4 
Medications 
• 
Radiation therapy for bone metastasis within 2 weeks, any other external radiation 
therapy within 4 weeks before planned first dose of study drug. Systemic treatment 
with radionuclides within 6 weeks before planned first dose of study drug. Subjects 
with clinically relevant ongoing complications from prior radiation therapy are not 
eligible 
• 
Prior treatment with everolimus, or any other specific or selective TORC1/PI3K/AKT 
inhibitor (e.g., temsirolimus) 
• 
Receipt of any type of small molecule kinase inhibitor (including investigational 
kinase inhibitor) within 2 weeks before planned first dose of study drug 
• 
Receipt of any type of anticancer antibody (including investigational antibody) within 
4 weeks before planned first dose of study drug 
• 
Taking strong inducers or inhibitors of CYP450s for subjects receiving everolimus 
• 
Chronic treatment with corticosteroids or other immunosuppressive agents  
• 
Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet 
inhibitors 
• 
Subjects with a known hypersensitivity to everolimus or other rapamycins (sirolimus, 
temsirolimus) or to its excipients 
• 
Not recovered from toxicities related to any prior treatments, unless adverse events 
are clinically non-significant and/or stable on supportive therapy 
General 
• 
History of any medical, psychiatric, or social (e.g., addictive disorder) conditions, or 
laboratory abnormality that in the opinion of the investigator, may increase the risks 
associated with study participation or treatments that may interfere with the conduct 
of the study or the interpretation of study results 


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• 
Major surgery within 2 months before planned first dose of study drug.  Complete 
wound healing from major surgery must have occurred within 1 month before 
planned first dose of study drug and from minor surgery at least 10 days before 
planned first dose of study drug 
• 
Myocardial infarction within the previous 6 months before planned first dose of study 
drug 
• 
Active infection requiring parenteral antibiotics within 2 weeks before planned first 
dose of study drug 
• 
Diagnosis of another malignancy within 2 years before planned first dose of study 
drug, except for superficial skin cancers, or localized, low grade tumors; 
• 
Currently enrolled in and has not yet completed at least 30 days since ending other 
investigational device or drug study before planned first dose of study drug, or 
subject is currently receiving other investigational agent(s). 
• 
Prior or current history of hepatitis B, hepatitis C or human immunodeficiency virus 
• 
Pregnant, planning a pregnancy or breastfeeding during the study 
• 
Sexually active fertile subjects (male and female), must agree to use medically 
accepted methods of contraception during the course of the study and for 30 days 
after the last dose of study treatment.  Female subjects must meet at least one of the 
following criteria:  
o be surgically sterile (i.e., have had bilateral tubal ligation, hysterectomy, or 
bilateral oophorectomy at least 6 months before enrollment; appropriate 
documentation will be required), 
o be post-menopausal for at least 12 months OR  
o if sexually active, be willing to use double-barrier contraception (e.g., condom 
with spermicide), intrauterine device, steroidal contraceptive (oral, transdermal, 
implanted, or injected) or other method, approved by the sponsor. 
• 
Unwilling or unable to comply with study requirements or not available for follow-up 
assessments 
• 
Any other major illnesses that in the investigator’s judgment substantially increases 
the risk associated with the subject’s participation in the study  
5. 
SUBJECT ENROLLMENT 
5.1 
Subject Recruitment 
Subjects will be enrolled from the cancer populations being followed at the investigational sites.  
The site personnel will discuss the possibility of participation directly with subjects being seen in 
the center who may be appropriate candidates for the study.  A description of the protocol will be 
posted on the www.clinicaltrials.gov website.   
5.2 
Subject Registration 
Before subjects may be entered into the study, Rexahn requires a copy of the site’s written 
institutional review board (IRB) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.3).  A subject must 


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personally sign and date the consent form before any study specific screening assessments are 
done.  Procedures that are performed as standard of care may be used for screening provided 
they are still within the 14 day screening period unless otherwise indicated.   
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/randomization of the subject into the study.  A subject will be considered enrolled or 
randomized when they are determined eligible and receive their treatment assignment.   
The study sponsor or its designee will assign each subject a unique subject identification 
number (a 2-digit site number followed by a 3-digit subject number).  The subject number must 
be used for subject identification on all study-related documents (e.g., electronic case report 
forms (eCRFs), clinic notes, laboratory samples, CT scans, MRIs, etc.). In order to obtain a 
subject number, the site must provide completed eligibility documents to the sponsor or 
designee who will provide confirmation of eligibility by either fax or e-mail to the site.  Of note, 
subjects may be rescreened for laboratory values not meeting the criteria only once for study 
eligibility.  A subject will be considered enrolled or randomized when the treatment has been 
assigned.   
5.3 Subject Enrollment/ Randomization and Treatment Assignment 
Subjects in Stage 1 will be enrolled to receive the combination everolimus with escalating doses 
of RX-0201.  Subjects in Stage 2 will no longer be randomized to 1 of 2 treatment arms (i.e., 
everolimus versus everolimus/RX-0201).  All subjects in Stage 2 will now be assigned to the 
everolimus/ RX-0201 treatment arm. 
The site will provide documentation showing that the subject meets the eligibility requirements.  
Following a review of supporting documentation, by the sponsor or its designee, the site will 
receive the treatment assignment and a confirmation of enrollment/randomization.  Subjects 
should be dosed within 5 days of enrollment/randomization. 
5.4 Subject Replacement 
Subjects in Stage 1 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 group as that for the subject who 
withdrew. 
Subjects in Stage 2 who are enrolled but not treated will be replaced. 


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6. 
TREATMENT PROCEDURES 
The only investigational product in this study will be RX-0201.  RX-0201 will be administered in 
combination with everolimus.  Everolimus will not be provided by the sponsor. 
6.1 Study Drug Administration 
 Everolimus Dose Administration 
Subjects will take 10 mg of everolimus orally, once daily at approximately the same time every 
day, consistently either with or without food.  Everolimus should be swallowed whole with 
approximately 8-10 ounces of water. 
If a subject misses a dose of everolimus, they may still take it up to 6 hours after the time they 
would normally have taken it.  If more than 6 hours have elapsed, they should be instructed to 
skip the dose for that day.  The next day, they should take everolimus at the usual time. 
Subjects should not take 2 doses to make up for the one dose that they missed. 
Drug compliance should be recorded in the subject’s medical record and in the eCRF.  This 
information will include amount of everolimus that should have been taken over a given time 
interval and the amount actually taken by the subject. (Section 10.3) 
 RX-0201 Dosing Schedule 
RX-0201 will be administered on a cyclical basis.  For subjects assigned to receive RX-0201 and 
everolimus, a cycle will be defined as the period elapsing from the first day of RX-0201 
administration through Day 21 of the cycle or to the recovery from any adverse events sufficient 
that a new cycle of therapy can be administered (e.g., on Day 29 or Day 36), whichever occurs 
later.  Once a new cycle starts, the prior cycle is considered to be completed. For subjects 
assigned to the everolimus only arm, a cycle will be defined as the period elapsing from the first 
day of everolimus administration through Day 21 of the cycle or to the recovery from any 
adverse events sufficient that a new cycle of therapy can be administered, whichever occurs 
later. 
 
RX-0201 Dose Administration 
The dose of RX-0201 will be based upon the subject’s actual weight measured on the morning 
of the planned dosing.  The body surface area will be calculated using the Dubois or Mosteller 
formulas; the same formula must be used for the subject throughout the study.  All body surface 
area and dosing calculations will be documented in the subject’s medical record and eCRF, if 
applicable.  The starting dose of RX-0201 will be 125 mg/m2/day.  This dose will be administered 
to eligible subjects in a 24 hour continuous intravenous infusion for 2 weeks followed by 1 week 
of rest in each 21 day cycle.   


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For each RX-0201 treatment cycle, a total of two 1000 ml infusion bags containing RX-0201 will 
be used.  Each infusion bag will be prepared immediately before use and will contain enough 
RX-0201 for 7 days plus 10% overage (or overage acceptable by institutional practices) of 
infusion (see Appendix D for details).  The first bag will be prepared on Day 1 of each 21 day 
cycle.  The second bag will be prepared on Day 8 of each 21 day cycle.  Day 15 will be the start 
of the 1 week rest period.   
RX-0201 will be administered via continuous infusion using an ambulatory infusion pump 
through a vein in the arm or a indwelling catheter (i.e. Port-a-Cath® or PICC line).   
RX-0201 should not be mixed with or administered as an infusion simultaneously with other 
medicinal products.  The indwelling infusion line should be flushed with saline before and after 
the investigational product administration to avoid mixing with other drug products or intravenous 
solutions.  Pharmacokinetic samples should be obtained in the opposite arm. 
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 eCRF, if 
applicable. 
6.2 Rationale for the RX-0201 Dose and Dosing Interval 
The RX-0201 dosing schedule was selected on the basis of results from a first in human    
Phase 1 single agent study (RX-0201-P1-A-03) and a Phase 2 RX-0201 combination with 
gemcitabine study in pancreatic cancer (RX-0201-P2-A-07).  Because there is no clinical data 
available using RX-0201 in combination with everolimus, Stage 1 of the study will assess the 
safety of RX-0201 in combination with everolimus.   
6.3 RX-0201 Dose Limiting Toxicity 
Initially 3 subjects will be enrolled to receive everolimus plus 125 mg/m2/day of RX-0201.  If 
there are any dose limiting toxicities (DLTs) attributed to RX-0201 the following dose-escalation 
decisions will be followed: 
 
Table 1: Phase 1 RX-0201 Dose Escalation 
Dose Group 
Theoretical 
dose(mg/m2/day) 
Escalation 
1 
125 
- 
2 
200 
1.60 
3 
250 
1.25 
 


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The following dose-escalation rules will be employed: 
• 
If 0 of the first 3 subjects experience DLT during the first 3 weeks of treatment, then the dose 
will be escalated to the next higher level in 3 subsequent subjects. 
• 
If 1 of the first 3 subjects experiences DLT at the current dose during the first 3 weeks of 
treatment, then 3 more subjects will be accrued at the same dose level.  
• 
If 0 of the 3 additional subjects experience DLT during the first 3 weeks of treatment, then 
the dose will be escalated to the next higher level in 3 subsequent subjects. 
• 
If ≥ 1 of the 3 additional subjects in a cohort experiences DLT in the first 3 weeks of 
treatment, the MTD has been exceeded and 3 more subjects will be treated at the next lower 
dose level (if only 3 subjects were previously treated at that prior dose level). 
• 
If ≥ 2 of 3 or ≥ 2 of 6 subjects experience DLT during the first 3 weeks of treatment, then the 
MTD has been exceeded and 3 more subjects will be treated at the next lower dose level (if 
only 3 subjects were previously treated at that prior dose level).  
• 
Each group of 3 subjects within a cohort must be observed for a minimum period of 3 weeks 
without DLT before subsequent subjects are enrolled at the next higher dose level.  
• 
Escalation to the next dose level of the study can occur upon review of the safety data from 
all ongoing and previous subjects and with the concurrence of the study sponsor and the 
principal investigators.  
In the event that attribution of causality of potential DLTs to study drug may be equivocal, 
discussions with the investigators, medical monitor and sponsor will occur and additional 
subjects may be enrolled at that dose level.  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 during Stage 1.  
6.4 
Determination of MTD or the RX-0201 Recommended Stage 2 Starting Dose 
The establishment of the MTD or the safety of the target RX-0201 dose of 250 mg/m2/day will be 
based on a review of the overall safety data by the investigators, medical monitor and sponsor.  
The MTD is the highest starting dose level associated with first-cycle DLTs in < 33.3% of 
subjects.  Once the safety of the MTD  of the target RX-0201 dose of 250 mg/m2/day is initially 
established, additional subjects (up to 20 subjects total) will be enrolled to receive the target RX-
0201 dose of 250 mg/m2/day in Stage 2.  Selection of a recommended Stage 2 starting dose 


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from within the tested dose range will be based on evaluation of available safety information with 
findings regarding compliance, and achievement of targeted pharmacokinetic values.   
6.5 
Definitions of Dose Limiting Toxicity 
Reference should be made to the CTCAE, Version 4.03 for grading of the severity of adverse 
events and laboratory abnormalities.  A DLT will be defined as any of the following adverse 
events that is considered by the investigator as related to RX-0201: 
• 
Grade 4 neutropenia (ANC < 0.5 x 109/L) with fever or lasting 3 days or longer 
• 
Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with ≥ Grade 1 
hemorrhage 
• 
Any ≥ Grade 3 coagulation abnormality (defined by PT and/or INR and PTT values) 
associated with clinical hemorrhage ≥ Grade 1. 
• 
Nausea/vomiting ≥ Grade 3 despite maximal antiemetic therapy; diarrhea ≥ Grade 3  
despite maximal anti-diarrheal therapy. 
• 
Grade 4 thrombocytopenia (platelet count < 25 x 109/L) 
• 
Any other non-hematological toxicity ≥ Grade 3  with the exception of alopecia 
6.6 
RX-0201 Dosage Modifications 
Whenever possible, dose modifications of study drug should be discussed between the 
investigator, medical monitor, and the sponsor prior to implementation.  The appropriate clinic 
staff should administer the new dose level and inform the subject about the change in dose 
level.  
 
RX-0201 Dose Modifications During a Cycle 
If a subject experiences a RX-0201-related DLT (as defined in Section 6.5), SAE, or other 
intolerable adverse event and requires a dose reduction, RX-0201 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-0201 may be reinstituted, but the dose of RX-0201 for the remainder of that 
cycle should be reduced by 1 dose level.  Successive adjustments to progressively lower dose 
levels can be made.  If the subject cannot tolerate RX-0201 at Dose Level 1 (125 mg/m2/day) 
then the subject should be discontinued from RX-0201 therapy.   


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RX-0201 Dose Modifications at the Beginning of the Next Cycle 
A new cycle of RX-0201 treatment may begin no earlier than Day 1 of the new cycle but should 
be delayed, as necessary, until adverse events or laboratory abnormalities have returned to 
baseline levels.  If adverse events or laboratory abnormalities are not resolved to baseline, 
week-by-week delays in initiating the new cycle of treatment should be instituted.  Once all 
toxicities have returned to baseline, the next cycle of therapy can be initiated.  
Subjects experiencing any of the DLTs described in Section 6.5 in the current cycle of therapy 
should have the dose in the next cycle of therapy reduced by 1 dose level.  Subjects who 
required an intra-cycle dose reduction, during the current cycle of therapy, should have the dose 
in the next cycle of therapy administered at no higher than the highest dose tolerated in the 
current cycle.  Successive inter-cycle adjustments to progressively lower dose levels can be 
made.  If the subject cannot tolerate RX-0201 at Dose Level 1 (125 mg/m2/day) then the subject 
should be discontinued from RX-0201 therapy.  
Subjects in Stage 1 will receive additional cycles at the same dose to which they were assigned 
in Cycle 1. 
 
RX-0201 Dose Re-Escalation 
After a dose is reduced, 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-0201 for 
≥ 3 weeks then the RX-0201 dose 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-0201-
related.  Successive adjustments to progressively higher dose levels can be made at 3-week 
intervals.  
 
RX-0201 Dose Escalation (Stage 1 only) 
Subjects receiving a dose of RX-0201 in Stage 1 that is less than the MTD or target dose and for 
whom the principal investigator feels are receiving benefit, may receive an increased dose 
following discussions with the Sponsor.  
 
Everolimus Adjustments, and Modifications 
Dose adjustments for everolimus will be allowed for adverse events according to the approved 
package insert or best clinical practices.  See everolimus package insert for full details regarding 
dose adjustment. 


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6.7 Everolimus Dose Delays 
Dose delays for everolimus will be allowed according to the approved package insert or best 
clinical practices.  If the start of a cycle (i.e., day 1 of a cycle) is delayed due to everolimus 
related toxicity, then RX-0201 dosing may continue on schedule.  
If an adverse event occurs that is related to RX-0201, everolimus may continue on schedule.   
If an adverse event occurs that is related to the combination of RX-0201 and everolimus, dosing 
of both drugs may be delayed until the event is resolved.  
6.8 RX-0201 Dose Delays 
If the start of a cycle (i.e., day 1 of a cycle) is delayed due to RX-0201 related toxicity, then 
everolimus dosing may continue on schedule.  
If an adverse event occurs that is related to the combination of RX-0201 and everolimus, dosing 
of both drugs may be delayed until the event is resolved.   
6.9 
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 and investigator. 
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 whose medical condition substantially changes after entering the study should 
be carefully evaluated by the investigator in consultation with the sponsor; such subjects 
should be withdrawn from study treatment if continuing would place them at risk. 
• 
Any subject who becomes pregnant or begins breastfeeding should be withdrawn from study 
treatment. 
• 
Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should be withdrawn from study treatment in 
circumstances that increase risk or substantially compromise the interpretation of study 
results. 
• 
The investigator, in consultation with the sponsor, may withdraw any subject from the study 
treatment, if, in the investigator’s opinion, it is not in the subject’s best interest to continue.  


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• 
The sponsor, relevant regulatory agencies, or the IRB 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. 
6.10 Concomitant Therapy 
To the extent possible, administration of any prescription or over-the-counter drug products 
other than protocol specified medication(s) should be minimized during the study period. 
Subjects should be discouraged from use of street drugs, herbal remedies, self-prescribed 
drugs, tobacco products, or excessive alcohol at any time during the clinical study. 
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator.  The decision to 
authorize the use of any drug other than study drug should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the outcome or 
integrity of the study. 
Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study.  Any concomitant drugs taken by a subject during the course of the 
study and the reason for use should be recorded on the eCRFs. 
For subjects receiving everolimus unless otherwise specified the approved label should be 
consulted. 
 
Analgesics 
Investigators may give analgesics, as necessary, for pain control.  


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Antibiotics, Antifungals, and Antivirals 
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 study 
treatment(s) during treatment for the infection. 
 
Anticancer or Experimental Systemic Therapies Other than Investigational 
Treatments 
No other systemic anticancer therapies (including chemotherapy, antibody therapy, 
immunotherapy, or other experimental therapies) of any kind are permitted while the subject is 
receiving study treatment.  Subjects are not allowed to participate concurrently in any other 
therapeutic clinical study. 
 
Antidiarrheals 
For subjects who develop diarrhea, the causal relationship 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 to the administration of study treatment(s) on Cycle 1 Day 1 
in Stage 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.   
 
Antiemetics 
Antiemetics are not allowed prior to the administration of study treatment(s) on Cycle 1 Day 1 in 
Stage 1.  However, antiemetics can be administered on subsequent treatment days and in 
subsequent cycles, based on the judgment of the treating physician and local institutional 
practices.  
 
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 study treatment(s).  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 β-human chorionic gonadotropin [β-HCG]), or is menopausal (age ≥ 55 years 
with amenorrhea for ≥ 12 months).  Protocol-recommended methods of contraception include 


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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 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-0201.  A male subject is 
considered fertile unless he has had a bilateral vasectomy with documented aspermia or a 
bilateral orchiectomy.  The investigator should counsel subjects on the most effective methods 
for avoiding pregnancy during the trial.  Protocol-recommended contraceptive methods are 
double-barrier methods (e.g., diaphragm with spermicide or male condom with spermicide) use 
of an intrauterine device, or steroidal contraceptive (oral, transdermal, implanted, or injected).   
The sponsor should be consulted regarding any questions relating to childbearing status or 
contraception. 
 
Corticosteroids 
Systemic or enteric corticosteroids are not allowed prior the administration of study treatment(s) 
on Cycle 1 Day 1 of Stage 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 
 
Diet 
There are no specific dietary restrictions in the study other than that subjects avoid grapefruit 
and grapefruit juice or using herbal remedies or dietary supplements (in particular, St. John’s 
wort) while taking everolimus.  
 
Drugs with Potential for Interactions with Everolimus 
In order for subjects to be maintained on the 10 mg dose of everolimus according to the 
approved label strong inducers and inhibitors of the P450 class should be avoided while on 
study. 
For subjects that are treated with everolimus the following should be avoided: 
• 
Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, 
nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) 
• 
Moderate CYP3A4 and/or PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, 
erythromycin, fluconazole, verapamil, diltiazem) 


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• 
Strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 
phenobarbital). 
 Erythropoietin and Granulocyte Colony-Stimulating Factors 
Use of erythropoietic agents (e.g., erythropoietin or darbepoetin alfa) is not permitted during 
Cycle 1 in Stage 1.  Thereafter, such agents may be administered for Grade ≥ 3 anemia, but 
their use in this study is discouraged. 
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms. 
Use of granulocyte colony-stimulating factor (G-CSF) (e.g., filgrastim, PEG-filgrastim, 
lenograstim) is not allow during Cycle 1 in Stage 1.  Prophylactic administration of G-CSF and 
concomitant administration of the study treatment(s) and G-CSF is not permitted in support of 
protocol therapy.  However, administration of G-CSF may be considered in a subject who, 
despite dose modification, is experiencing recurrent difficulties with recovering from neutropenia 
in a timely fashion.  In addition, therapeutic use of G-CSF in subjects with serious neutropenic 
complications such as tissue infection, sepsis syndrome, fungal infection, etc., may be 
considered at the investigator's discretion.  
Reference may be made to the American Society of Clinical Oncology guidelines (Rizzo et 
al., 2008; Smith et al., 2006). 
 Immunization 
Due to its potential effects on lymphoid cells, RX-0201 might theoretically impair primary or 
secondary responses to immunization.  Everolimus also has known immunosuppressant 
properties. 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 after the initiation of study therapy, vaccination should not be 
performed during Cycle 1 of Stage 1 or during any other cycle in a period when the patient is 
experiencing Grade ≥ 2 leukopenia.  Vaccination with live virus vaccines during study treatment 
and close contact with those who have received live vaccines should be avoided. 
 Radiation Therapy 
Radiation therapy is not permitted during Cycle 1 in Stage 1. 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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The radiosensitizing properties of RX-0201 and everolimus have not yet been established.  
Before treatment occurs, the investigator should discuss the method/frequency of radiation 
administration with the sponsor and medical monitor. 
 Surgery or Other Invasive Procedures 
The effects of RX-0201 on coagulation or wound healing are unknown.  Potential RX-0201 
myelosuppressive or immunosuppressive effects could enhance the risk of peri-procedural 
bleeding or infection.  
Elective surgical procedures (other than placement of IV access devices) should be avoided 
during study drug administration.  However, subjects may undergo necessary surgical or 
invasive procedures for serious intercurrent medical problems; in these circumstances, study 
drug should be interrupted.  Investigators should use appropriate medical judgment in 
determining whether to resume study drug in the post-procedure period.  For subjects resuming 
study drug, any myelosuppressive effects of the drug should have returned to baseline levels 
and the subject should be clinically stable before reinitiating therapy. 
 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 and Appendix B) for an 
outline of procedures required at each visit.  All safety blood and urine samples should be 
submitted to the local laboratory on the day of collection.  Blood for evaluation of RX-0201 
pharmacokinetics, any archived tumor tissue, any tumor biopsy samples and biomarker samples 
should be prepared and shipped to the central lab for analysis. 
Source documents, including but not limited to, radiological imaging including baseline scans 
must be stored and available for subsequent review by the sponsor or their designee.  
7.1 General Study Procedures  
A signed and dated IRB-approved informed consent must be obtained before any study specific 
screening procedures are performed.  Assessments that are performed as standard of care 
procedures may be used for screening if performed before the informed consent is signed, 
provided they are still within the screening period time frame.   
7.2 Screening Procedures – Stage 1 and Stage 2 
The following screening assessments must be performed and results available within 14 days 
(unless otherwise noted) before enrollment/randomization: 


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• 
Written informed consent 
• 
Review of inclusion and exclusion criteria 
• 
Medical and medication history review, documentation of diagnosis and previous 
treatments including details of tumor diagnosis (e.g., date of diagnosis, histology, stage 
at diagnosis and current stage) and most recent disease assessment 
• 
Complete physical examination including weight and height 
• 
Performance status (ECOG) 
• 
Resting vital signs: resting pulse, resting respiration rate, resting blood pressure (i.e., 
after the subject has been seated for at least 5 minutes) and temperature measurements 
• 
Laboratory tests (for details see Appendix C) 
• 
Urinalysis 
• 
Hematology panel 
• 
Chemistry panel 
• 
Coagulation  
• 
Serum pregnancy test for female subjects of childbearing potential   
• 
Radiological imaging to assess disease extent.  Radiological assessment must include 
CT scan or MRI of the abdomen and pelvis and the modality selected should be the 
same throughout the study.  Imaging assessment to be done within 21 days of 
enrollment/ randomization. Some imaging assessments may be collected for central 
review. 
• 
Assessment of archived tumor sample availability from initial diagnosis or at diagnosis of 
advanced metastatic disease; written documentation to be provided to Sponsor before 
enrollment/randomization if samples are not available 
• 
Review and confirm subject eligibility 
• 
Subject receives treatment assignment from the Sponsr or assigned designee. 
7.3 
Treatment Period – Stage 1 
For Stage 1 Study Day 1 will be defined as the day that the protocol specified treatment(s) are 
administered.  On days when pharmacokinetic sampling is planned everolimus will be taken at 
the clinic. 
 Pre-dosing Assessments Cycle 1 Day 1 - Stage 1 
The following procedures will be performed within 3 days before the administration of any study 
treatment unless otherwise described: 
• 
Record concomitant medication(s).  
• 
ECOG performance status.  
• 
Weight Measurement and BSA Calculation - The body surface area will be calculated 
using either the Dubois or Mosteller formulas and the calculations documented in the 
subject’s medical record and electronic case report form. The same formula must be 
used for a subject throughout the study. 


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• 
Resting vital signs: pulse, respiration rate, blood pressure (i.e., after the subject has been 
seated for at least 5 minutes) and temperature measurements.  
• 
Laboratory tests (for analyte description see Appendix C). If screening laboratory tests 
were performed within 72 hours of Cycle 1 Day 1, they do not need to be repeated on    
Cycle 1 Day 1. 
• 
Hematology panel  
• 
Chemistry panel  
• 
Coagulation tests  
• 
Urinalysis 
• 
Urine pregnancy test (if applicable, Cycle 1 only). If a serum pregnancy test was 
done and determined negative within 72 hours of dosing a urine pregnancy test is 
not needed. 
• 
Blood collection for biomarker analysis 
• 
Pre-treatment pharmacokinetic sample (must be collected immediately prior to 
Cycle 1 dosing). 
• 
Collection of archived tumor tissue within 4 weeks after initiation of treatment 
 Everolimus Dosing – Cycle 1 Day 1 - Stage 1 
Everolimus (10 mg) will be administered orally (for details see Section 6.1.1) at the clinic.  The 
time of the dosing will be recorded. 
 RX-0201 Dosing – Cycle 1 Day 1 - Stage 1 
RX-0201 will be prepared based upon body surface area and the assigned dose.  All dosing 
calculations will be documented in the subject’s medical records (see Appendix D for details).  
The infusion bag will be connected and the RX-0201 infusion pump turned on and the start time 
recorded. 
 Post-dosing Assessments Cycle 1 Day 1 - Stage 1 
The following assessment will be done after the start of the RX-0201 infusion: 
• 
Resting vital signs: pulse, respiration rate, blood pressure (i.e., after the subject has been 
seated for at least 5 minutes) and temperature measurements whenever a 
pharmacokinetic sample is collected. 
• 
Pharmacokinetic samples will be collected at the following time points:  
• 
1 hour ± 5 minutes, 2 hours ± 5 minutes, 3 hours ± 10 minutes, 4 hours ± 10 
minutes, and 6 hours ± 10 minutes after start of infusion. 
• 
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) 


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 Cycle 1 Day 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).  
• 
Resting vital signs: pulse, respiration rate, blood pressure (i.e., after the subject has been 
seated for at least 5 minutes) and temperature measurements.  
• 
Blood sample for RX-0201 pharmacokinetics will be collected:  
• 
At 24 hours ± 1 hour (Cycle 1 Day 2) after the start of the RX-0201 infusion on 
Cycle 1 Day 1 
• 
Everolimus (10 mg) will be taken orally at the clinic.  The time of the dosing will be 
recorded. 
 Everolimus Dosing – Cycle 1 Days 3 to 14 - Stage 1 
Everolimus (10 mg) will be administered orally at home (for details see Section 6.1.1) each day.   
 Cycle 1 Day 8 - Stage 1 
• 
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. 
• 
Resting vital signs: pulse, respiration rate, blood pressure (i.e., after the subject has been 
seated for at least 5 minutes) and temperature measurements.  
• 
Everolimus compliance – Record the number of tablets taken at home since the last visit. 
• 
Turn off the RX-0201 infusion pump, disconnect the infusion bag and record the volume 
infused during the past 7 days in the subject’s medical record and eCRF.   
• 
Weight and BSA Calculation – Calculate the body surface area using the Dubois or 
Mosteller formulas and document the calculation in the subject’s medical record and 
eCRF. 
• 
Prepare RX-0201 as described in the pharmacy manual (see details in Appendix D).  
Document dosing calculations in the subject’s medical record and eCRF. 
• 
Connect the infusion bag and turn on the RX-0201 infusion pump.  
 Cycle 1 Day 15 - Stage 1 
• 
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. 
• 
Everolimus compliance – Record the number of tablets taken at home since the last visit. 
• 
Everolimus (10 mg) will be taken orally (for details see Section 6.1.1) at the clinic.  The 
time of the dosing will be recorded. 


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• 
Resting vital signs: pulse, respiration rate, blood pressure (i.e., after the subject has been 
seated for at least 5 minutes) and temperature measurements.  
• 
Blood sample for RX-0201 pharmacokinetics will be collected:  
• 
Immediately prior to the end of RX-0201 infusion  
• 
Turn off the RX-0201 infusion pump, disconnect the infusion bag and record the volume 
infused during the past 7 days in the subject’s medical record and eCRF.   
• 
Blood sample for RX-0201 pharmacokinetics will be collected:  
• 
1 hour ± 5 minutes, 2 hours ± 5 minutes, 3 hours ± 10 minutes, 4 hours ± 10 
minutes, and 6 hours ± 10  minutes after the infusion pump has been turned off.  
 Cycle 1 Day 16 - Stage 1 
• 
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. 
• 
Resting vital signs: pulse, respiration rate, blood pressure (i.e., after the subject has been 
seated for at least 5 minutes) and temperature measurements.  
• 
Blood sample for RX-0201 pharmacokinetics will be collected:  
• 
24 hours ± 1 hour after the infusion pump has been turned off on Cycle 1 Day 15. 
• 
Everolimus (10 mg) will be taken orally (for details see Section 6.1.1) at the clinic.  The 
time of the dosing will be recorded.  
 Everolimus Dosing – Cycle 1 Days 17 to 21 - Stage 1 
Everolimus (10 mg) will be administered orally at home (for details see Section 6.1.1) each day.   
7.4 
Treatment Period - Cycles 2 to n – Stage 1 
Subjects who complete Cycle 1 in Stage 1, and for whom the principal investigator feels may 
benefit from additional treatment cycles, may continue to receive additional cycles of RX-0201 
plus everolimus therapy and will follow the treatment procedures and assessments outlined in 
Sections 7.5 and 7.6 starting at Cycle 2 Day 1. Otherwise, an End of Treatment visit should be 
completed. 
7.5 
Treatment Period - Cycles 1 to n – Stage 2 
 Pre-dosing Assessments - Cycles 1 to n, Day 1 - Stage 2 
The following procedures will be performed within 5 days before the administration of any study 
treatment unless otherwise described: 
• 
Record concomitant medication(s) (Cycles 1 – 16 only) 
• 
ECOG performance status  
• 
Weight measurement  


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• 
BSA Calculation - The body surface area will be calculated using either the Dubois or 
Mosteller formulas (Appendix D) if the subject is assigned to receive RX-0201, and the 
calculations will be documented in the subject’s medical record and eCRF. The formula 
used must be the same for the subject throughout the study. 
• 
Resting vital signs: pulse, respiration rate, blood pressure (i.e., after the subject has been 
seated for at least 5 minutes) and temperature measurements.  
• 
Laboratory tests (for analyte description see Appendix C) 
• 
Hematology panel  
• 
Chemistry panel  
• 
Coagulation tests (Cycles 1 – 16 only) 
• 
Urinalysis (Cycles 1 – 16 only) 
• 
Urine pregnancy test (if applicable, Cycle 1 only) 
• 
Blood collection for biomarker analysis (Cycle 1 only) 
• 
Tumor biopsy (optional- Stage 2 subjects)  
• 
Collection of archived tumor tissue within 4 weeks after initiation of treatment (Stage 2 
subjects) 
 Everolimus Dosing Cycles 1 to n, Days 1 - 21 - Stage 2 
Everolimus (10 mg) will be taken orally on Cycle 1 Day 1 at the clinic.  Doses after Cycle 1    
Day 1 will be taken by the subject at home at approximately the same time every day and 
consistently with or without food. 
 RX-0201 Dosing – Cycles 1 to n, Day 1 - Stage 2 
Subjects in Stage 2 that were randomized to the everolimus only arm will not receive RX-0201. 
RX-0201 will be prepared based upon body surface area and the assigned dose for subjects in 
Stage 1 or Stage 2 assigned to the everolimus/ RX-0201 treatment arm.  All dosing calculations 
will be documented in the subject’s medical record and eCRF (see Appendix D for details).  The 
bag containing RX-0201 will be connected to the infusion pump and the start time recorded 
when the pump is turned on. 
 Cycles 1 to n, Day 8 - Stage 2 
• 
Recording of concomitant medication(s). The assessment may be completed by phone 
for subjects previously randomized to the everolimus alone arm. 
• 
Recording of adverse event(s).  Serious adverse events will be reported immediately.  
Any adverse event that is considered related to study drug(s) will be followed to 
resolution or return to baseline. The assessment may be completed by phone for 
subjects previously randomized to the everolimus alone arm. 
• 
Resting vital signs: pulse, respiration rate, blood pressure (i.e., after the subject has been 
seated for at least 5 minutes) and temperature measurements. (Cycles 1 – 16 only). The 


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assessment may be completed by local physician’s office for subjects previously 
randomized to the everolimus alone arm. 
• 
Weight measurement. The assessment may be completed by local physician’s office for 
subjects previously randomized to the everolimus alone arm. 
• 
Everolimus compliance – Record the number of tablets taken at home since the last visit. 
The assessment may be completed by phone for subjects previously randomized to the 
everolimus alone arm. Confirm via drug diary or pill count at the next in site visit. 
Subjects also receiving RX-0201 
• 
Turn off the RX-0201 infusion pump, disconnect the infusion bag and record the volume 
infused during the past 7 days in the subject’s medical record and eCRF, if applicable.   
• 
BSA Calculation – Calculate the body surface area using either the Dubois or Mosteller 
formulas and document the calculation in the subject’s medical record and eCRF. 
• 
Prepare RX-0201 as described in the pharmacy manual (Appendix D).  Document dosing 
calculations in the subject’s medical record and eCRF. 
• 
Connect the infusion bag and turn on the RX-0201 infusion pump.  
 Cycles 1 to n, Day 15 - Stage 2 
• 
For subjects receiving RX-0201, a blood sample for RX-0201 plasma concentration will 
be collected immediately prior to the end of RX-0201 infusion in Cycle 1 only.  If the 
sample is inadvertently not drawn, the sample will be collected on Day 15 in a 
subsequent cycle. 
• 
Recording of concomitant medication(s). The assessment may be completed by phone 
for subjects previously randomized to the everolimus alone arm. 
• 
Recording of adverse event(s).  Serious adverse events will be reported immediately.  
Any adverse event that is considered related to study drug(s) will be followed to 
resolution or return to baseline. The assessment may be completed by phone for 
subjects previously randomized to the everolimus alone arm. 
• 
Resting vital signs: pulse, respiration rate, blood pressure (i.e., after the subject has been 
seated for at least 5 minutes), and temperature measurements. (Cycles 1 – 16 only). The 
assessment may be completed by local physician’s office for subjects previously 
randomized to the everolimus alone arm. 
• 
Everolimus compliance – Record the number of tablets taken at home since the last visit. 
The assessment may be completed by phone for subjects previously randomized to the 
everolimus alone arm. Confirm via drug diary or pill count at the next in site visit. 
Subjects also receiving RX-0201 
• 
Turn off the RX-0201 infusion pump, disconnect the infusion bag and record the volume 
infused during the past 7 days in the subject’s medical record and eCRF, if applicable.   
7.6 
Cycles 1 to n, Days 18-21 – Imaging Assessment – Stage 2 
• 
Disease assessment will occur at the end of Cycles 2, 4, 6, 8, … n (i.e., after every 6 
weeks of therapy).  
• 
Radiological imaging to assess disease extent.  Radiological assessment must include 
CT scan or MRI of the abdomen and pelvis and the modality selected should be the 
same throughout the study.  The results of the imaging assessment must be available 


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and reviewed before the start of the next cycle. Some imaging assessments may be 
collected for a second review by a central imaging vendor. 
• 
Disease assessment should be conducted according to the RECIST ver. 1.1 guidelines 
modified as described in Appendix E.   
• 
Blood collection for biomarker sample analysis within 1 day of tumor assessment 
7.7 
Unscheduled Visit(s) – Stage 1 and Stage 2 
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 eCRF, as well as any other data 
obtained (e.g., adverse events, concomitant medications and treatments, and results from 
procedures or tests). 
7.8 
End of Treatment or Early Termination Visit - Stage 1 and Stage 2 
The following procedures will be performed: 
• 
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(s) will be followed to resolution or 
return to baseline. 
• 
ECOG performance status  
• 
Vital signs: resting pulse, resting respiration rate, resting blood pressure (i.e., after the 
subject has been seated for at least 5 minutes) and temperature measurements.  
• 
Everolimus compliance – Record the number of tablets taken at home since the last visit. 
• 
Laboratory tests 
• 
Urinalysis 
• 
Hematology panel 
• 
Chemistry panel  
• 
Coagulation 
• 
Pregnancy test (if applicable, urine or serum)  
• 
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 follow-up tumor assessment at the End of Trial or Early 
Termination visit providing it is ≥ 3 weeks from the last prior tumor assessment in 
order to confirm the response based on RECIST ver. 1.1 criteria. 
Blood sample for biomarker analysis will be taken within 1 day of the tumor 
assessment. 
Subjects also receiving RX-0201 
• 
Turn off the RX-0201 infusion pump, disconnect the infusion bag and record the volume 
infused in the subject’s medical record and eCRF if applicable.   


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7.9 
Safety Follow-Up Visit – Stage 1 and Stage 2 
Subjects will undergo the safety follow-up visit 30 days (+ 7 days) after the subject receives the 
last dose of everolimus or RX-0201, whichever is administered last.   
The following procedures will be performed: 
• 
Recording of concomitant medication(s), including any anticancer therapies administered 
subsequent to the administration of either protocol specified medication. 
• 
Recording of adverse event(s).  Serious adverse events will be reported immediately.  
Any adverse event that is considered related to study drug(s) will be followed to 
resolution or return to baseline. 
• 
ECOG performance status  
• 
Vital signs resting pulse, resting respiration rate, resting blood pressure (i.e., after the 
subject has been seated for at least 5 minutes) and temperature measurements. 
• 
Other Assessment(s) 
7.10 
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 study treatment and around the time of tumor 
assessments to measure biomarkers (e.g., including but not limited AKT-1 and phosphorylated 
AKT). 
In addition, any paraffin-embedded tumor samples collected independent from this study 
(whether before or during for the assessment of cancer) and the corresponding pathology report 
will be gathered by investigational sites.  If paraffin blocks cannot be shipped, unstained slides 
and a core punch biopsy will be prepared from paraffin embedded tumor samples collected 
independent of the study before and during the study from each subject for analysis.  These 
investigational studies may be useful in developing markers to identify disease subtypes, guide 
therapy and/or predict disease response or progression. 
A tumor biopsy will be collected pre-treatment (optional Stage 2). 
Refer to the laboratory manual for detailed collection and handling procedures for all predictive 
biomarker samples. 


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7.11 
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-0201.  The subject 
retains the right to have the sample material destroyed at any time by contacting the principal 
investigator.   
The sponsor will be the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the request of the 
research subject through the principal investigator or at the end of the storage period.  The 
principal investigator will provide the sponsor with the required study and subject numbers so 
that any remaining blood and tumor samples and any other components from the cells can be 
located and destroyed.  If a commercial product is developed from this research project, the 
sponsor will own the commercial product.  The subject will have no commercial rights to such 
product and will have no commercial rights to the data, information, discoveries, or derivative 
materials gained or produced from the sample.  See Section 11.4 for subject confidentiality. 
8. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
8.1 
Definitions 
 
Adverse Events 
An adverse event is any untoward medical occurrence in a trial subject who is administered a 
drug or biologic (medicinal product) or who is using a medical device; the event does not 
necessarily have a causal relationship with study drug administration or usage.  
For this protocol, untoward medical occurrences that should be reported as adverse events 
include the following: 
• 
Any unfavorable and unintended symptom, sign (including an abnormal laboratory finding), 
or disease temporally associated with the use of study drug, whether or not related to the 
study drug.  
• 
Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration.  
• 
Any complication that occurs as a result of a protocol-mandated procedure (e.g., 
venipuncture, ECG, telemetry) in the study drug administration or follow-up periods. 
• 
Any injury or accident occurring during the 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 


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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.  
• 
A complication related to pregnancy or termination of a pregnancy (see Section 8.7.2 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 eCRF.    
• 
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.  
 
Serious Adverse Events 
A serious adverse event is defined as an untoward medical occurrence that results in any of the 
following outcomes: 


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• 
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 required by the study protocol, or tumor-related diagnostic 
procedures are not considered serious.  
• 
Persistent or significant disability/incapacity. 
• 
Congenital anomaly/birth defect in the offspring of a subject who received the study drug. 
• 
Other medically significant event. Such events may not be immediately life-threatening or 
result in death or hospitalization, but based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such events might include: 
o Allergic bronchospasm requiring intensive treatment in an emergency room or at home 
o New cancers or blood dyscrasias 
o Convulsions that do not result in hospitalization 
o Development of drug dependency or drug abuse 
8.2 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. 


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“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.  
 
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.  
8.3 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 8.1.2) 
• 
The start date (date of adverse event onset) 
• 
The stop date (date of adverse event resolution) 
• 
The severity of the adverse event (see Section 8.4) 
• 
A description of the potential relatedness of the adverse event to study drug or a study 
procedure (see Section 8.5)  
• 
The action taken due to the adverse event 
• 
The outcome of the adverse event 
8.4 Grading of the Severity of an Adverse Event 
The severity of adverse events will be graded using the Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03 (available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). For 
each episode, the highest severity grade attained should be reported.  
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the adverse event. For purposes of consistency with the 
CTCAE, these intensity grades are defined in Table 1. 


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Table 2. 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does 
not interfere with the subject’s usual function, and is not likely to require 
medical attention. 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affect clinical status, 
and may require medical intervention. 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status and 
likely requires medical intervention and/or close follow-up. 
Grade 4 
Life-
threatening Sign or symptom results in a potential threat to life. 
Grade 5 
Fatal 
Sign or symptom results in death. 
 
The distinction between the seriousness and the severity of an adverse event should be noted.  
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction.  
For example, a headache may be severe in intensity, but would not be classified as serious 
unless it met one of the criteria for serious events listed in Section 8.1.2 above. 
8.5 
Describing Adverse Event Relationship to Study Drug and Study Procedures 
The relationship of an adverse event to study drug should be assessed using clinical judgment, 
describing the event as either unrelated (no) or related (yes) consistent with the following 
definitions: 
• 
No: Evidence exists that the adverse event had an etiology other than the study drug. 
For serious adverse events, an alternative causality must be provided (e.g., pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication). 
• 
Yes:  A temporal relationship exists between the adverse event onset and administration 
of the investigational medicinal product that cannot be readily explained by the subject’s 
clinical state or concomitant therapies.  Furthermore, the adverse event appears with 
some degree of certainty to be related to the study drug based on the known therapeutic 
and pharmacologic actions or adverse event profile of the investigational medicinal 
product. In case of cessation or reduction of the dose, the adverse event abates or 
resolves. In case of interruption and rechallenge, the event reappears upon rechallenge. 
Of note, even in circumstances when the study drug is given intermittently or is interrupted 
temporarily before the onset of the adverse event, consideration should be given as to whether 
the study drug may have contributed to the event.  
The relationship to protocol-mandated study procedures (e.g., procedures such as venipuncture 
or performance of an electrocardiogram) should be assessed using the following considerations: 


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• 
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.  
8.6 
Adverse Event Reporting Requirements 
 
Site Reporting Requirements 
Classification of an event as serious or nonserious (see Section 8.1.2) determines the reporting 
procedures to be followed by the site.  
Site reporting requirements for adverse events are summarized in Table 3 below. 
Table 3. 
Site Reporting Requirements for Adverse Events 
Classification 
Reporting Time 
Reporting Action 
Serious 
Within 24 hours 
Submit the designated serious adverse event report 
form to sponsor or designee, and to the site IRB, as per 
local IRB requirements; include copies of relevant 
source documents (e.g., progress notes, autopsy 
reports, laboratory and diagnostic test results, discharge 
summaries) 
Within 24 hours 
Telephone call or e-mail to the study sponsor medical 
monitora 
Per eCRF submission 
procedure 
Record and submit information on appropriate CRFs 
Nonserious 
Per eCRF submission 
procedure 
Record and submit information on appropriate CRFs 
a 
See Safety Management Plan and Site Study Binder for study contact information 
Abbreviations: eCRF=electronic 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 will be provided in the Safety Management 
Plan and Site Study Binder. 
 
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 8.5).  For reporting purposes, an adverse event will be considered expected if the study 
sponsor determines that the event is expected (see Section 8.2).  
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. 


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The study sponsor serious adverse event regulatory reporting requirements are described in 
Table 4. 
Table 4. 
Study Sponsor Reporting Requirements for Adverse Events 
Type of Event 
Type of Report 
Timeframe for Reporting  
To Health Authorities 
Fatal or  
Life-
Threatening 
Unexpected Related 
Yes 
Yes 
Yes 
Letter notification (may also 
include CIOMS I/MedWatch form) 
Within 7 calendar days of study 
sponsor awareness date or according 
to local regulations 
CIOMS I/MedWatch form 
Within 15 calendar days of study 
sponsor awareness date or according 
to local regulations 
No 
Yes 
Yes 
CIOMS I/MedWatch form 
Within 15 calendar days of study 
sponsor awareness date or according 
to local regulations 
Yes 
No 
Yes 
Annual report 
Annually 
No 
No 
Yes 
Yes 
Yes 
No 
No 
Yes 
No 
Yes 
No 
No 
No 
No 
No 
Abbreviations: CIOMS=  Council for International Organizations of Medical Sciences 
 
If notification of an adverse event requiring expedited reporting is received, the study sponsor (or 
designees) will contact each clinical investigator prescribing RX-0201 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. 
8.7 
Special Situation Reporting Requirements 
 
Definitions of Special Situations  
Special situation include pregnancy; medication error, abuse, misuse, or overdose. 
• 
Information regarding pregnancy is provided in Section 8.7.2.  
• 
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 6.1.3).  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.  
 
Pregnancy  
The following safety reporting instructions related to pregnancy are included as a precaution.  
Each female subject should be instructed to discontinue further study therapy and inform the 
investigator immediately if she becomes pregnant at any time between the first dose of study 
drug until 30 days after the last ingestion of study drug. 
Each male subject should be instructed to inform the investigator immediately if he impregnates 
a woman at any time between the 1st dose of study drug until 30 days after the last ingestion of 
study drug 
The investigator should counsel the subject regarding the possible effects of investigational 
medicinal product exposure on the fetus and the need to inform the study site of the outcome of 
the pregnancy. 
Neither a pregnancy itself nor an induced elective abortion to terminate the pregnancy without 
medical reasons is considered an adverse event; such occurrences should be reported on the 
appropriate pregnancy reporting forms.  However, if the outcome of the pregnancy meets the 
criteria for classification as a serious adverse event (i.e., spontaneous abortion, induced abortion 
due to complications, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus]), the investigator should follow the procedures for reporting serious adverse 
events, i.e., report the event to the sponsor or designee by telephone and follow up by 
submission of the appropriate adverse event CRFs (see Section 8.6.1). 
Additional information regarding reporting pregnancy outcomes may be required:  
• 
Any spontaneous abortion, including miscarriage and missed abortion will be reported as a 
serious adverse event. 
• 
An induced therapeutic abortion to terminate any pregnancy due to complications or other 
medical reasons will be recorded as a serious adverse event.  The underlying medical 
reason for this procedure should be recorded as the adverse event term. 


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• 
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.  
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. 
 
Instructions for Reporting Special Situations 
Along with information regarding the circumstances of the special situation, any clinical sequelae 
occurring in association sequelae with that situation should be reported as adverse events or 
serious adverse events according to the reporting requirements for those events (see 
Section 8.6).  Details of signs or symptoms, clinical management and outcome should be 
reported, if available. 
8.8 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 in Stage 1.  Information regarding DLTs should be 
recorded on a protocol-designated DLT report form and sent 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 defined in this protocol but may be serious adverse events if they 
meet one or more of the criteria for a serious adverse event (see Section 8.1.2).  If a DLT is also 
a serious adverse event, it should be reported both on the DLT report form and per the 


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instructions for reporting serious adverse events (see Section 8.6.1). Recording of a DLT in the 
relevant CRFs will also be required. 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design 
 
Stage 1 
Stage 1 is a dose escalation study to determine the MTD up to a target dose of 250 mg/m2/day 
of RX-0201 in combination with everolimus.  The starting dose of RX-0201 will be 
125 mg/m2/day.  The secondary objectives of Stage 1 of the study are described in Section 1.2. 
 
Stage 2  
Prior to starting Stage 2, the principal investigators, medical monitor and sponsor will review the 
safety, laboratory and dosing information to make decisions regarding the start of Stage 2.  
Approximately 20 additional subjects will be treated with the combination of everolimus and RX-
0201. The primary objective of Stage 2 is to determine progression free survival.  The primary 
analysis will be conducted approximately 6 months after the last enrolled subject is treated.  The 
secondary objectives of Stage 2 of the study are described in Section 1.2. 
9.2 
Study Endpoints, Subsets, and Covariates 
 
Study Endpoints 
9.2.1.1 
Primary Endpoints 
• 
Incidence of adverse events and clinical laboratory abnormalities defined as dose-limiting 
toxicities (Stage 1) 
• 
Progression free survival at 4.5 months (Stage 2) 
9.2.1.2 
Secondary Endpoints 
• 
Pharmacokinetics profile of RX-0201 (Stage 1) 
• 
Incidence of adverse events, changes in clinical laboratory tests and vital signs over time 
(Stage 1 and Stage 2)  
• 
Tumor response, duration of response, time to response, and response rates (Stage 2) 
9.2.1.3 
Exploratory endpoints 
• 
Blood levels of AKT pathway biomarkers, tumor apoptosis biomarkers or other 
biomarkers (Stage 1 and Stage 2) 
• 
Plasma concentration of RX-0201 at the end of infusion (Stage 2) 


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Analysis Populations 
Data from stages 1 and 2 of this study will be combined for both safety and efficacy analyses 
when appropriate.  The following definitions of the various analysis sets to be used will therefore 
be applied to subjects in Stage 1 and Stage 2 of the study.   
Safety Analysis Set:  
The safety analysis set includes all subjects who receive at least one dose of study drug(s) with 
subjects analyzed according to the treatment received.  All safety data will be analyzed in 
accordance with this analysis set.    
Full Analysis Set: 
The Full Analysis set includes all enrolled or randomized subjects with subjects analyzed 
according to the treatment assigned at enrollment/randomization.  All efficacy endpoints will be 
analyzed using the Full Analysis set. 
Per Protocol Analysis Set: 
The Per-Protocol Analysis set will include all subjects without pre-specified major protocol 
deviations.  Sensitivity analyses of some efficacy endpoints may be performed using the per-
protocol analysis set. 
Evaluable for Tumor Response Analysis Set (Stage 2 only): 
The tumor response analysis set will includes all subjects in the Full Analysis Set (and Per-
Protocol Set if applicable) with a uni-dimensional measurable lesion at baseline (as per RECIST 
ver. 1.1 ).  
 
Covariates 
If appropriate based on sample size, the following covariates may be used to examine selected 
safety and efficacy endpoints in subgroups or in multivariate analyses. 
• 
Sex: Male and Female 
• 
Age: < 65, ≥ 65 to ≤ 75, > 75 
• 
ECOG: 0 or 1 or 2 
9.3 
Sample Size Considerations 
Approximately 9 subjects will be enrolled in Stage 1 of the study.  Stage 1 is designed to 
determine the MTD up to a target dose of 250 mg/m2/day of RX-0201, thus the sample size for 
the study is not based on a formal statistical hypothesis but will be determined based on 
observed number of first-cycle DLTs at each dose level.  The sequential 3+3 dose-escalation is 


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consistent with usual oncologic paradigms for dose ranging as the intent is to limit the number of 
subjects who are exposed to toxic doses of the treatment combination.  The trial will use the 
standard National Cancer Institute (NCI) definition of MTD (starting dose associated with DLT in 
< 33.3% of subjects during the first cycle of therapy).     
The planned sample size for Stage 2 is approximately 10 subjects in the everolimus arm and 20 
subjects in the everolimus/ RX-0201 arm. The primary goal is to provide preliminary estimates of 
safety and efficacy endpoints when combining everolimus and RX-0201. Safety endpoints will 
be reported as described in Section 8. The primary efficacy endpoint is progression free survival 
estimated using the Kaplan-Meier method and associated 90% confidence intervals. Median 
PFS is expected to be 4.5 months in the everolimus only arm and 9 months in the combination 
arm. With 10 evaluable subjects in the everolimus only arm the width of the two-sided 90% 
confidence interval for 9-month PFS will be no more than ± 0.28.  With 20 evaluable subjects in 
the combination arm the width of the two-sided 90% confidence interval for 9-month PFS will be 
no more than ± 0.20.   
9.4 
Access to Individual Subject Treatment Assignments 
Stage 1 and Stage 2 will be open-label.  Treatment assignments will be known to all personnel 
involved in the study. 
9.5 
Interim Safety Analysis and Early Stopping Guidelines 
The principal investigators, medical monitor and sponsor will be responsible for reviewing the 
ongoing safety and laboratory data, and making decisions regarding dose de-escalation and 
dose stopping in accordance with the rules set out in Section 6.3 for Stage 1.  Other than the 
safety evaluation required to determine whether to proceed to Stage 2 of accrual, no planned 
formal interim analysis will be performed. 
If concerns arise during any data reviews, the sponsor may request additional specific safety 
data be collected and recommend modifying study conduct. 
The sponsor may also terminate the study at any time for reasons which may or may not be 
related to safety or study conduct. 
 
General Approach/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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Safety, Efficacy, and PK assessments will be summarized separately for Stage 1 and Stage 2. 
Additional summaries and analyses of pooled Phase 1 and 2 data may also be generated based 
on applicability of dosing regimens. 
Descriptive statistics will be provided for selected demographic, safety, and efficacy, and 
exploratory endpoints by treatment group and time as appropriate.  Descriptive statistics on 
continuous data will include means, medians, standard deviations and ranges, while categorical 
data will be summarized using frequency counts and percentages.  Graphical summaries of 
selected endpoints may also be presented.  For any variable, unless specified otherwise, 
baseline is defined as the last assessment prior to the first dose of study specified treatment. 
 
Analysis of Key Study Endpoints 
9.5.2.1 
Adverse Events 
Each reported adverse event will be assigned a System Organ Class (SOC), a higher level 
group term, a high level term and a preferred term according to the current version of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA).  The severity of adverse events will 
be assigned in accordance with the NCI CTCAE version 4.03 guidelines.   
All adverse events will be listed by subject.  The subject incidence rate of adverse events 
occurring between informed consent and first dose of study drug will be summarized by system 
organ class and preferred term for the Safety Analysis Set.   
The incidence rate of treatment emergent adverse events, defined as all adverse events 
reported as new or worsened after the start of study drug, will be summarized by treatment 
group, system organ class, preferred term and maximum severity (where appropriate) for all 
adverse events, serious adverse events, adverse events leading to discontinuation of study 
specified treatment, adverse events leading to discontinuation from the study and fatal adverse 
events using subjects in the safety population.  In addition, summaries of exposure adjusted 
adverse event rates may also be presented.  These summary tables will also be repeated for 
treatment related adverse events. The number and percent of subjects reporting adverse events 
(all, serious, and related) will be tabulated by dose levels.  Narratives of all serious and fatal 
adverse events will also be provided. 
A listing and summary of the incidence of dose limiting toxicities present will be reviewed to 
make dose escalation decisions in Stage 1 review (dose limiting toxicity assessment set) will 
also be produced by treatment group and by subject.   


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9.5.2.2 
Laboratory Safety Data 
All hematology, chemistry, coagulation and urinalysis will be listed by treatment group and 
subject.  Where normal ranges are available, values outside of the range will be flagged.  The 
data will be summarized by treatment group using standard descriptive statistics at each of the 
scheduled time point in the study.  For continuous parameters, a summary of the changes from 
baseline to each post dose laboratory assessment will also be produced for each treatment 
group. 
Shift analysis for selected laboratory parameters between baseline and both the final visit worst-
case on-study value will be summarized according to NCI CTCAE version 4.03 toxicity grades.  
9.5.2.3 
Time to Event Analyses 
The detailed statistical analysis methods for each endpoint will be described in the statistical 
Analysis Plan (SAP).  The Kaplan-Meier method will be applied  to the following time to event 
endpoints: 
• 
Progression-Free Survival: The time from first study dose to the first observation of 
disease progression (as classified by RECIST ver. 1.1) or death due to any cause.  
• 
Time to response: The time from first study dose to the first observation of a complete or 
partial tumor response that is subsequently confirmed.   
• 
Duration of response: The time from the first observation of a complete response or 
partial tumor response (whichever comes first) to the subsequent time of disease 
progression or death (whichever comes first) will be calculated as the duration of 
response for each subject.   
Kaplan-Meier estimates and 2-sided 95% confidence interval for landmark times by 6-week 
intervals will be produced for the endpoint of progression-free survival time.  Descriptive 
statistics for the duration and time to response for the responding subjects will be calculated. 
9.5.2.4 
Tumor Response by RECIST ver. 1.1 
Tumor response data will be reported descriptively in the form of listings for all subjects in 
Stage 2.  For each treatment group, the objective response rate will be determined and 
estimated using RECIST ver. 1.1 (see Appendix E for details).   
The overall tumor response at any scheduled time points post the first dose of study specified 
treatment with missing data will be assumed to be a non-responder (i.e., not a confirmed 
complete or partial response). Subjects without at least one uni-dimensional measurable lesion 
per the modified RECIST ver. 1.1 criteria will be excluded from the analyses.  For each 


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treatment group in Stage 1 and Stage 2 of the study, the proportion of subjects with an objective 
response (a confirmed complete or partial response) will be presented.  
 
Background Information and Other Analyses 
9.5.3.1 
Subject Accountability 
Demographic and Baseline characteristics: 
Demographic and baseline characteristics for subjects in the Safety Analysis set will be 
summarized by treatment group.   
Subject Disposition: 
The number of subjects screened, number and percentage of subjects enrolled or randomized, 
received at least one dose of study drug, received no study drug, completed or discontinued any 
of their assigned treatments, completed or discontinued the study will be summarized combining 
data over all treatment groups, and with the exception of the number of subjects screened, 
separately for each dose. In addition, number and percentage of subjects in each of the 5 
analysis data sets (safety analysis set, full analysis set, per-protocol analysis set, and evaluable 
for tumor response analysis set,) will be summarized by treatment group. 
Study Discontinuation: 
The number of subjects enrolled or randomized, number and percentage of subjects completing 
and the number discontinuing the study early (including the reasons) will be summarized by 
treatment group and in total over all treatments.  Summaries of the reasons for early termination 
broken down by the cycle of treatment will also be produced. 
Treatment Discontinuation: 
The number of subjects enrolled or randomized and the number and percentage of subjects who 
discontinued any of their assigned treatments will be summarized by treatment group. This will 
also be split by the number and percentage of subjects discontinuing everolimus versus 
everolimus and RX-0201 (including the discontinuation reasons).  An additional summary 
splitting the treatment discontinuations by cycle of treatment will also be provided. 
Protocol Deviations: 
The number and percentage of subjects with important protocol deviations will be presented by 
deviation type for all enrolled or randomized subjects.  A summary will also be produced by 
treatment group and in total over all treatments.  
9.5.3.2 
Medical History 


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Medical history will be coded using MedDRA dictionary.  A by-subject listing will be presented for 
the medical history. 
9.5.3.3 
Concomitant Medications 
All concomitant medications will be grouped by medication class and by active ingredient within 
medication class according to the WHO Drug medication dictionary.  The number and 
percentage of subjects receiving each medication will be summarized by active ingredient and 
medication class for each treatment group. 
9.5.3.4 
Vital Signs 
Resting vital signs including pulse, blood pressure, respiration rate, temperature and weight, will 
be collected at screening, days 1, 8 and 15 of each cycle, end of treatment (or early 
termination), and safety follow-up visits.  They will be summarized descriptively as well as 
change from baseline results by treatment group and assessment time point. 
10. 
INVESTIGATIONAL PRODUCT 
10.1 RX-0201 
RX-0201 is a fully phosphorothioated 20-mer oligonucleotide synthesized by Avecia 
Biotechnology Inc, Milford, MA.  The study drug was manufactured by Formatech, Andover, MA.  
Labeling and clinical distribution will be done by Catalent, Mt. Laurel, NJ.  RX-0201 will be 
supplied as a sterile lyophilized powder that will be reconstituted with sterile water for injection 
immediately prior to its administration by continuous infusion.   
RX-0201 will be provided as a lyophilized powder in 10 ml glass vials with rubber stoppers for 
intravenous administration.  Each vial will contain 438 mg of RX-0201.  The formulated RX-0201 
is a lyophilized powder and is to be stored at -30o to -15oC away from light. The powder will be 
reconstituted using sterile water for injection prior to administration by continuous intravenous 
infusion. The reconstituted product should be stored at 2o to 8oC for no more than 4 hours if 
administration is delayed. Appropriate temperature monitoring should be maintained and 
recorded by the site during the study. The reconstituted drug product, diluted in 0.9% saline, is 
stable at 25°C to 40°C for up to 8 days. 
10.2 RX-0201 Labeling 
All labels for study drug vials 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. 


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10.3 Everolimus 
Subjects will take everolimus tablets at a dose of 10 mg per day.  The 10 mg tablets appears 
white to slightly yellow, elongated tablets with a beveled edge and no score, engraved with 
“UHE” on one side and “NVR” on the other.  Everolimus is packaged in blister packs. 
Everolimus will not be provided by the sponsor, nor will it be relabeled. 
11. 
REGULATORY OBLIGATIONS 
11.1 Informed Consent 
An initial generic informed consent form will be provided to the investigator for preparing the site 
specific informed consent document.  Updates to the templates will be communicated in writing 
by the clinical study manager to the investigator.  The written informed consent document should 
be prepared in the language(s) of the potential patient population and must be agreed to by the 
Sponsor and institutional review board. 
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 product is administered.   
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject. In this instance approval 
should always be given by the institutional review board and existing subjects informed of the 
changes and re-consented. This is documented in the same way as previously described. 
The Investigator should, with the consent of the subject, inform the subject’s primary physician 
about participation in the clinical study. 
The acquisition of informed consent 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).  Two 
original signed informed consents will be obtained; one form should be retained in accordance 
with institutional policy, and the other signed consent form should be provided to the subject. 
11.2 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 IRB for written approval.  A copy of 
the written approval of the protocol and informed consent form must be received by Rexahn or 
its designee before recruitment of subjects into the study and shipment of investigational 
product. 


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The investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
investigator should notify the IRB of deviations from the protocol or serious adverse events 
occurring at the site and other adverse event reports received from Rexahn, in accordance with 
local procedures. 
The investigator will be responsible for obtaining annual IRB approval and renewal throughout 
the duration of the study.  Copies of the investigator’s reports and the IRB continuance of 
approval must be sent to Rexahn or its designee. 
11.3 
Pre-Study Documentation Requirements 
The investigator is responsible for forwarding the following documents to Rexahn for review 
before study initiation from Rexahn or its designee 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 IRB approval of the protocol, consent form, and subject information sheet 
• 
Up-to-date curricula vitae of principal investigator and all co/sub-investigators 
• 
IRB 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 FDA form 1572  
• 
Completed Financial Disclosure statements for the principal investigator, all sub-
investigators, and their spouses (legal partners) and dependent children 
11.4 Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained.  On the eCRFs or 
other documents submitted to Rexahn, subjects should be identified by their initials and a 
subject study number only.  Documents that are not for submission to Rexahn (e.g., signed 
informed consent forms) should be kept in strict confidence by the investigator. 
In compliance with government regulatory/ICH GCP guidelines it is required that the investigator 
and institution permit authorized representatives of the company, of the regulatory agency(s), 
and the IRB 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 


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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. 
11.5 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 Rexahn or its designee, will either be: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 Protocol Amendments and Study Termination 
In accordance with ICH Topic E 6 (R1) Guideline for GCP the Investigator should not implement 
any deviation from, or changes of the protocol without agreement by the sponsor and 
documented approval from the IRB of a protocol amendment, except where necessary to 
eliminate an immediate hazard(s) to study subjects, or when the change(s) involves only 
logistical or administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)). 
Agreement from the investigator must be obtained for all protocol amendments and 
amendments to the informed consent document.  The IRB must be informed of all amendments 
and give approval.  The investigator must send a copy of the approval letter from the IRB to 
Rexahn or its designee. 
All amendments to the protocol must be approved in writing by both the appropriate regulatory 
authorities and the IRB, except for administrative amendments, which require notification but not 
written approval. Once approved, the protocol amendment will be distributed to all recipients of 
the original protocol, with instructions to append the amendment to the protocol. 
If, in the judgment of the local IRB, the Investigator and/or sponsor, the protocol amendment 
alters the study design, procedures and/or increases the potential risk to the subject, the 
currently approved written informed consent form will require modification. The modified 
informed consent form must also be reviewed and approved by the sponsor, appropriate 


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regulatory authorities, and the IRB. In such cases, repeat informed consent must be obtained 
from subjects enrolled or randomized in the study before participation continues. 
Both Rexahn and the investigator reserve the right to terminate the study according to the study 
contract.  The investigator should notify the IRB in writing of the study’s completion or early 
termination and send a copy of the notification to Rexahn. 
12.2 Protocol Adherence and Deviations 
The protocol must be read thoroughly and the instructions must be followed. However, 
exceptions will be made in emergency situations when the protection, safety, and well-being of 
the subject requires immediate intervention based on the judgment of the Investigator or a 
responsible, appropriately trained, and credentialed professional(s) designated by the 
Investigator as a sub-investigator.  
In the event of a significant protocol deviation due to an emergency, accident, or error, the 
Investigator or designee must contact the Medical Monitor at the earliest possible time by 
telephone. This allows for an early joint decision to be made as to whether or not the subject 
should continue in the study. The Investigator, the Sponsor, and the Medical Monitor will 
document this decision. 
12.3 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 eCRFs will 
be included on the Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s eCRF 
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 Rexahn and/or applicable regulatory authorities.  Elements 
should include: 
• 
Subject files containing completed eCRFs, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, investigator’s brochure, copies 
of pre-study documentation, and all correspondence to and from the IRB and Rexahn 


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• 
If kept, 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 eCRFs must be 
maintained and be readily available. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
No study document should be destroyed without prior written agreement between Rexahn 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 Rexahn in writing of the new responsible 
person and/or the new location. 
12.4 Study Monitoring and Data Collection 
The Rexahn 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., eCRFs and other pertinent data) 
provided that subject confidentiality is respected. 
The Rexahn monitor is responsible for verifying the eCRFs at regular intervals approximately 
every 4-8 weeks or more frequently if needed as described in the monitoring plan 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 eCRFs. 
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 eCRFs, are resolved. 
12.5 Inspections and Auditing Procedures 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected for audit 
by representatives from Rexahn’s or its designee’s Clinical Quality Assurance Department (or 
designees).  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. 
Government regulatory authorities may also inspect the Investigator during or after the study. 
The Investigator or designee should contact the Sponsor/CRO immediately if this occurs. 


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He/she must cooperate fully with regulatory authorities or other audits conducted at a convenient 
time in a reasonable manner. 
The purpose of an audit is to assess whether ethics, regulatory and quality requirements are 
fulfilled. 
12.6 Case Report Forms 
Electronic case report forms (eCRFs) will be used to store and transmit subject information. The 
file structure and format for the eCRFs will be provided by the Sponsor or their representative 
and should be handled in accordance with the instructions provided. 
The eCRFs must be reviewed, signed and dated by the Investigator. 
Data should be entered into the eCRFs completely by the appropriate site personnel. The 
eCRFs must be completed as soon as possible after any subject evaluation or communication. 
The eCRFs must be accessible to study monitors and other regulatory auditors. 
12.7 Data Collection 
All data will be captured at the site using paper or electronic source documents.  A source 
document identifier list will be created and signed during the study initiation visit  
Data management will be performed by Rexahn or its designee. Details for data management 
will be described in a data management plan (DMP) which will be finalized before start of the 
clinical conduct. 
Concomitant medications entered into the database will be coded using the WHODrug 
dictionary. AEs will be coded using the MedDRA terminology.  
After the above actions have been completed and the database has been declared to be 
complete and accurate, it will be locked for data analysis. Any changes to the database after that 
time can only be made with the approval of the Sponsor. 
12.8 Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors, 2005), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published.  Authors should meet conditions 1, 2, and 3. 


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• 
When a large, multicenter group has conducted the work, the group should identify the 
individuals who accept direct responsibility for the manuscript.  These individuals should 
fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who qualify 
should be listed. 
• 
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 Rexahn for corporate review.  The Clinical Study Agreement 
among the institution, principal investigator, and Rexahn will detail the procedures for, and 
timing of, Rexahn’s review of publications. 
12.9 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 which will 
describe any compensation that will be provided during the study.   


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13. 
REFERENCES  
Akitoshi Kobayashi, Taketo Yamaguchi, Takeshi Ishihara, Tadashi Ohshima, Takeshi Baba, 
Yoshihiko Shirai, Hiroshi Tadenuma, Kazuyoshi Nakamura, HiromitsuSaisho. Usefulness of 
Plasma Vascular Endothelial Growth Factor in the Diagnosis of Pancreatic Carcinoma. 
Differential Diagnosis, Tumor Progression, and Patient Survival. Pancreas Volume 31, Number 
1, July 2005.  
Alok A. Khorana, Ying Chuan Hu, Charlotte K. Ryan, Richard A. Komorowski, Galen Hostetter, 
Steven A. Ahrendt. Vascular Endothelial Growth Factor and DPC4 Predict Adjuvant Therapy 
Outcomes in Resected Pancreatic Cancer. Journal of Gastrointestinal Surgery. 2005; Volume 9, 
Number 7,  
Cancer Genome Atlas Research Network comprehensive molecular characterization of clear cell 
renal carcinoma Nature 2013; 499: 43-49. 
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., ... & 
Verweij, J. . New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). European journal of cancer, 2009; 45: 228-247. 
George S, Bukowski R.  Role of everolimus in the treatment of renal cell carcinoma.  Ther Clin 
Rick Manag.  2009; 5: 699-706. 
Hager M, Haufe H, Kemmerling R, Hitzi W, Mikuz G, Moser PL and Kolbitsch C.  Increased 
activated AKT expression in renal cell carcinomas and prognosis.  J. Cell Mol Med. 2009; 13: 
2181-2188 
Horiguchi A, Oya M, Uchida A, Marumo K, Murai.  Elevated Akt activation and its impact on 
clinicpathological features of renal cell carcinoma.  J. Urol 2003 169: 710-713. 
Hong-Cheng Sun, Zheng-Jun Qui, Jun Liu, Tao Jiang, Ke-Jian Huang, Min Yao, and Chen 
Huang. Expression of hypoxia-inducible factor-1 alpha and associate proteins in pancreatic 
ductal adenocarcinoma and their impact on prognosis. International Journal of Oncology 2007: 
30:1359-1367 
Hsu J, Shi Y, Krajesski S, et al. the AKT kinase is activated in multiple myeloma tumor cells.  
Blood 2001; 98: 2853-2855. 
Kurose K, Zhou XP, Araki T, et al.  Frequent loss of PTEN expression is lnked to elevated 
phosphorylated Akt levels but not associated with p27 and cyclin D1 expression, in primary 
epithelial ovarian cancercinomas.  Am J. Pathol 2001; 158: 2097-2106. 
Landen CN, Birrer MJ, Sood AK.  Early events in the pathogenesis of epithelial ovarian cancer. 
J. Clin Oncol 2008; 26: 995-1005. 
Massarelli E, Liu DD, Lee JJ, et al., AKT activiation correlates with adverse outcome in tongue 
cancer.  Cancer 2005; 104: 2430-2436. 
Mihaly Z, Sztupinski Z, Gyorffy B.  A Comprehensive Overview of Targeted Therapy in 
Metastatic Renal Cell Carcinoma.  Curr Cancer Drug Targets.  2012 September; 12(7); 857-872. 
Rathmell WK, Wright TM, Rini Bl. Molecularly targeted therapy in renal cell carcinoma.  Expert 
Rev Anticancer Ther.  2005; 5: 1031-1040. 


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Ringel MD, Hayre N. Saito J, et al. Overexpression and overactivation of AKT in throid 
carcinoma.  Cancer Res. 2001; 61: 6105-6111. 
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. 
Shahani R, Kwan K, Kapoor A.  Safety and clinical efficacy of everolimus in the treatment of 
advanced renal cell carcinoma (RCC).  Drug Healthc Patient Saf.  2010; 2: 85-91. 
Stal O, Perex-Tenorio G., Akerberg L, et al, AKT kinases in breast cancer and the results of 
adjuvant therapy.  Breast Cancer Res.  2003; 5: R37-R44. 
Staal SP Molecular cloning of the AKT oncogene and its human homologues AKT1 and AKT2: 
amplification of AT1 in a primary human gastric adenocarcinoma.  Proc Natl Acad Sci USA 
1987: 84: 5034-5037. 
Smith TJ, Khatcheressian J, Lyman GH et al., 2006. Update of recommendations for the use of 
white blood cell growth factors: an evidence-based clinical practice guideline.  J. Clin Oncol 24: 
3187-3205. 
Uegaki K, Kanamori Y, Kigawa J, et al. PTEN-positive and phosphorylated-AKT-negative 
expression is a predictor of survival for patients with advanced endometrial carcinoma.  Oncol 
Re/ 2005; 14: 389-392. 
Van de Sande, T, Roskams T, Lerut E, Joniau S, Van Poppel H, Verhoeven G and Swinnen JV.  
High level expression of farry acid synthase in human prostate cancer tissues is linked to 
activation of nuclear localization of Akt/PKB.  J. Pathol 2005; 206: 214-219. 
Yamamoto S, tomita Y, Hoshida Y, et al Prognostic significance of activated Akt expression 
inpancreatic ductal adenocarcinoma.  Clin Cancer Res.  2004; 10: 2846-2850. 
RX-0201 Investigator’s Brochure, Version 4.0.  Rockville, MD Rexahn Pharmaceuticals Inc.  27 
December 2013. 
 


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14. 
APPENDICES  
Appendix A.  Stage 1 Schedule of Assessments 
 
SCR1 
Cycle 1 
Cycle n2 
EOT or ET 
SFU3 
 
 
Day 
Day 
Visit 
Visit 
Procedures and Treatments 
-14 
1 
2 
8 
15 
16 
1 
8 
15 
18 - 21 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination including weight 
and height 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
X4 
 
 
 
 
X4 
 
 
 
X 
X 
Pregnancy test 
X5 
X4, 6 
 
 
 
 
 
 
 
 
X 
 
Weight and BSA calculation  
 
X4 
 
X 
 
 
X4 
X 
 
 
 
 
Resting vital signs 
X 
X7 
X 
X 
X 
X 
X4 
X 
X 
 
X 
X 
Hematology8, chemistry8, and coagulation8 
X 
X4 
 
 
 
 
X4 
 
 
 
X 
 
Urinalysis8 
X 
X4 
 
 
 
 
X4 
 
 
 
X 
 
Eligibility confirmation, enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
Everolimus administration9 
 
X 
 
 
 
 
 
 
 
 
 
 
Everolimus compliance10 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
 
RX-0201 infusion 
 
X 
 
 
 
 
X 
 
 
 
 
 
RX-0201 compliance 
 
 
 
X 
X 
 
 
X 
X 
 
X11 
 
Adverse events12 and concomitant medication  
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pharmacokinetic sampling13 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
Disease assessment(s) 
X1 
 
 
 
 
 
 
 
 
X14 
X15 
 
Biomarker blood sample 
 
X4 
 
 
 
 
 
 
 
X16 
X16 
 
Archival Tumor Tissue 
 
X17 
 
 
 
 
 
 
 
 
 
 


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Abbreviations: SCR = screening, ECOG = Eastern Cooperative Oncology Group, SFU = safety follow up visit; EOT = end of treatment visit; ET = 
early termination 
1 
Screening procedures will be performed within 14 days of enrollment/ randomization, except baseline tumor assessment, which can be 
evaluated within 21 days of enrollment/ randomization 
2 
Cycles 2 – 8 will follow the same assessment schedule 
3 
Safety follow-up visit will occur approximately 30 (+ 7) days after the last administration of RX-0201 or everolimus, whichever occurs later 
4 
Assessment can be performed within 3 days before Day 1 of each cycle 
5 
A serum pregnancy test must be negative for all females of childbearing potential 
6 
A urine pregnancy test must be negative for all females of childbearing potential before treatment begins. If a serum pregnancy test was done 
and determined negative within 72 hours of planned first dose a urine pregnancy test is not needed 
7 
Vital signs can be assessed up to 3 days before Day 1 and will be assessed whenever a PK sample is collected in Cycle 1 
8 
See Appendix C for analytes to be collected. If screening laboratory tests were performed within 72 hours of Cycle 1 Day 1, they do not need 
to be repeated on Cycle 1 Day 1. Samples to be taken before any RX-0201 or everolimus is administered  
9 
Everolimus will be taken at the clinic on Days 1, 2, 15, and 16 of Cycle 1, and Day 1 of all other cycles 
10 Subjects will bring all everolimus packaging (empty and full) to the clinic to determine drug compliance 
11 RX-0201 compliance will be checked at the Early Termination if the subject was receiving RX-0201 at the time of early termination. 
12 All adverse events attributed to study drug(s) will be assessed until resolution or return to baseline 
13 Blood will be collected for subjects enrolled in only Stage 1 at the following time points:  
• 
Immediately prior to Cycle 1 infusion, then at 1 hour ± 5 minutes, 2 hours ± 5 minutes, 3 hours ± 10 minutes, 4 hours ± 10 minutes, 6 
hours ± 10 minutes, and 24 hours (± 1 hour) (ie, Day 2) after start of RX-0201 infusion . 
• 
Immediately prior to the end of Cycle 1 infusion (ie, Day 15), then at 1 hour ± 5 minutes, 2 hours ± 5 minutes, 3 hours ± 10 minutes, 4 
hours ± 10 minutes, 6 hours ± 10  minutes, and 24 hours (± 1 hour) (ie, Day 16) after the RX-0201 infusion pump has been turned off  
14 Disease assessment will occur at the end of every 2 cycles  
15 Subjects first meeting criteria for complete response or partial response at the last on-treatment tumor assessment should have a follow-up 
tumor assessment at the End of treatment or Early Termination visit providing it is ≥ 3 weeks from the previous tumor assessment in order to 
confirm the response based on RECIST ver. 1.1 criteria 
16 Biomarker blood samples will be collected within 1 day of the disease assessment (approximately at the end of every 2 cycles and at EOT/ET 
if applicable)  
17 Tissue blocks or tissue sections from initial diagnosis or upon diagnosis of advanced metastatic disease will be available for submission to the 
central laboratory within approximately 4 weeks after initiation of study treatment; exceptions require written documentation of why a sample is 
not available and prior approval by the sponsor before enrollment 
 
 


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Appendix B.  Stage 2 Schedule of Assessments 
 
SCR1 
Cycle 1 
Cycle n2 
EOT or ET 
SFU3 
 
 
Day 
Day 
Visit 
Visit 
Procedures and Treatments 
-14 
1 
8 
15 
1 
8 
15 
18-21 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical and medication history 
X 
 
 
 
 
 
 
 
 
 
Complete physical examination including weight and 
height 
X 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
X4 
 
 
X4 
 
 
 
X 
X 
Pregnancy test 
X5 
X4, 6 
 
 
 
 
 
 
X 
 
Weight and BSA calculation  (everolimus/RX-0201 
arm only) 
 
X4 
X18 
 
X4 
X18 
 
 
 
 
Resting vital signs 
X 
X4 
X18 
X18 
X4, 16 
X16, 18 
X16, 18 
 
X 
X 
Hematology7, chemistry7, and coagulation7, 16 
X 
X4 
 
 
X4 
 
 
 
X 
 
Urinalysis7 
X 
X4 
 
 
X4, 16 
 
 
 
X 
 
Eligibility confirmation, randomization 
X 
 
 
 
 
 
 
 
 
 
Everolimus administration8 
 
X 
 
 
 
 
 
 
 
 
Everolimus compliance9 
 
 
X18 
X18 
X 
X18 
X18 
 
X 
 
RX-0201 infusion (everolimus/RX-0201 arm only) 
 
X 
 
 
X 
 
 
 
 
 
RX-0201 compliance (everolimus/RX-0201 arm only) 
 
 
X 
X 
 
X 
X 
 
X10 
 
Adverse events11 and concomitant medication16  
assessment 
 
X 
X18 
X18 
X 
X18 
X18 
 
X 
X 
Pharmacokinetic sampling 
 
 
 
X17 
 
 
 
 
 
 
Disease assessment(s) 
X1 
 
 
 
 
 
 
X12 
X13 
 
Biomarker blood sample 
 
X4 
 
 
 
 
 
X14 
X14 
 
Archival Tumor Tissue 
 
X15 
 
 
 
 
 
 
 
 
Tumor biopsy (optional) 
 
X4 
 
 
 
 
 
 
 
 


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Abbreviations: SCR = screening, ECOG = Eastern Cooperative Oncology Group, SFU = safety follow up visit; EOT = end of treatment visit; ET = 
early termination  
1 
Screening procedures will be performed within 14 days of enrollment/ randomization, except baseline tumor assessment, which can be 
evaluated within 21 days of enrollment/ randomization 
2 
Cycles 2 – n will follow the same assessment schedule 
3 
Safety follow-up visit will occur approximately 30 (+ 7) days after the last administration of RX-0201 or everolimus, whichever occurs later 
4 
Assessment can be performed within 5 days before Day 1 of each cycle 
5 
A serum pregnancy test must be negative for all females of childbearing potential 
6 
A urine pregnancy test must be negative for all females of childbearing potential before treatment begins. If a serum pregnancy test was done 
and determined negative within 72 hours of planned first dose a urine pregnancy test is not needed 
7 
See Appendix C for analytes  to be collected. If screening laboratory tests were performed within 72 hours of Cycle 1 Day 1, they do not need 
to be repeated on Cycle 1 Day 1. Samples to be taken before any RX-0201 or everolimus is administered 
8 
Everolimus (10 mg) will be taken at the clinic on Cycle 1 Day 1, and then at home every day thereafter 
9 
Subjects will bring all everolimus packaging (empty and full) to the clinic to determine drug compliance. For subjects receiving everolimus 
alone, compliance will be verified at least once per cycle when the subject returns to the site. 
10 RX-0201 compliance will be checked at the Early Termination if the subject was receiving RX-0201 at the time of early termination. 
11 All adverse events attributed to study drug(s) will be assessed until resolution or return to baseline 
12 Disease assessment will occur at the end of every 2 cycles 
13 Subjects first meeting criteria for complete response or partial response at the last on-treatment tumor assessment should have a follow-up 
tumor assessment at the End of treatment or Early Termination visit providing it is ≥ 3 weeks from the previous tumor assessment in order to 
confirm the response based on RECIST ver. 1.1 criteria 
14 Biomarker blood samples will be collected within 1 day of the disease assessment (approximately at the end of every 2 cycles and at EOT/ET 
if applicable) 
15 Tissue blocks or tissue sections from initial diagnosis or upon diagnosis of advanced metastatic disease will be available for submission to the 
central laboratory within approximately 4 weeks after initiation of study treatment; exceptions require written documentation of why a sample is 
not available and prior approval by the sponsor before randomization 
16 Cycles 1-16 only 
17 For subjects receiving RX-0201, one blood sample will be drawn prior to the end of infusion.  If the sample draw is inadvertently missed, it can 
be drawn on Day 15 in a subsequent cycle. 
18 For subjects receiving everolimus alone, the assessment may be completed by phone. 
 


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Appendix C.  Laboratory Analytes 
 
Chemistry  
Urinalysis 
Hematology 
Coagulation 
Sodium 
Specific gravity 
RBC 
PT or INR 
Potassium 
pH 
Hemoglobin 
PTT 
Chloride 
Hemoglobin 
Hematocrit 
Total protein  
Protein 
MCV  
Other Labs 
Albumin 
Glucose 
MCHC 
Urine HCG 
Calcium 
Bilirubin 
Platelets 
Serum HCG 
Phosphorus 
Ketones 
WBC 
HBV* 
Glucose 
WBC 
Differential 
HCV* 
BUN 
RBC 
• Eosinophils 
HIV* 
Serum Creatinine 
Epithelial cells 
• Basophils 
Uric acid 
Bacteria 
• Lymphocytes 
Total bilirubin 
• Neutrophils 
Amylase 
Lipase 
Alkaline phosphatase  
AST (SGOT) 
ALT (SGPT) 
GGT 
Creatine Kinase 
ALT = alanine amino transferase; AST aspartate amino transferase; BUN = blood, urea, nitrogen; GGT = 
gamma-glutamyl transferase; HBV = hepatitis B virus; HCV = Hepatitis C virus; HCG = human chorionic 
gonadotropin;  HIV = Human Immunodeficiency Virus; INR = international normalized ratio; MCV = mean 
corpuscular volume; MCHC = mean corpuscular hemoglobin concentration; PT = prothrombin time; PTT 
= partial thromboplastin time; RBC = red blood cells; WBC = white blood cells 
*If a subject’s HIV, HBV, or HCV status can be confirmed via medical record to be negative, new tests do 
not need to be performed. 
 


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Appendix D.  Pharmacy Guide 
 
RX-0201 
Packaging and Formulation 
RX-0201 was manufactured by Avecia Biotechnology in Milford, MA and packaged by 
Formatech in Andover, MA and distributed using Calent’s distribution processes (Mt. Laurel, NJ) 
clinical study drug distribution procedures.  RX-0201 will be supplied as a sterile lyophilized 
powder that will be reconstituted with sterile water for injection immediately prior to its 
administration by continuous infusion.  Each 10 ml glass vial will contain 438 mg of RX-0201. 
Labeling 
Each vial will be labeled with the product name, study number, Sponsor name, lot number, 
manufacturing date, storage conditions and Investigational use statement. 
Storage 
The study drug, RX-0201 must be stored between --30 to -15oC.  If the storage temperature is 
outside the range please contact Rexahn or its designee for instructions. 
Records of the actual storage conditions during the period of the study must be maintained (e.g., 
records of the date and time and initials of person checking, and the “working day” temperatures 
of the room used for storage of clinical study supplies, continuous temperature recordings, or 
regularly maintained temperature alarm systems used in conjunction with temperature 
recording). 
Preparation for Intravenous Administration 
For each cycle of RX-0201, a total of 2 infusion bags will be used, one 1000 ml infusion bag for 
each of the two 7-day treatment weeks.  Each infusion bag lasts approximately 7 days and will 
be prepared at the time of use, with a 7-day dose plus overage.  In order to conserve the drug 
product, it is recommended that only a 10% overage be prepared.  However, recognizing that 
individual site pharmacy policy may only allow full day doses to be administered, other overages 
(e.g. 1 day or ~14%) may be prepared when required. In each RX-0201 treatment cycle, the first 
bag will be prepared at the beginning of the infusion, Day 1, and the second bag will be 
prepared on Day 8.  The site staff will calculate the total weekly dose for each subject based 
upon their BSA calculation, using either the DuBois or Mosteller formulas.  The same formula for 
calculating BSA for a subject should be used throughout the study.  The calculation will be 
documented in the subject’s source records. If a subject’s prior 2 weight measurements have 
varied ≤ 10%, the site staff may use the previous BSA calculation to expedite the drug ordering 
and preparation process. 


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RX-0201 will be administered via continuous infusion with an ambulatory infusion pump.  If the 
pump fails, the subject will notify the site.  The pump will be replaced.  
The dose of infused RX-0201 in 1000 ml infusion bags will be prepared as follows on the 
day when administration is to begin: 
1. On Days 1 and 8 of each RX-0201 cycle, calculate the body surface area (BSA) for 
the subject using the DuBois or Mosteller formulas.  The body weight will be taken on 
the day of planned dosing.  This BSA will be recalculated for each drug 
administration. 
DuBois: BSA (m²) = 0.20247 x Height (m) 0.725 x Weight (kg) 0.425 
Mosteller: BSA (m2) = ( Height (cm) x Weight (kg) / 3600 )½  
• 
Calculate the total weekly dose for each subject based upon the subject’s BSA using 
the following formula which includes a 10% overage: 
Total Weekly RX-0201 Dose plus 10% (0.7 day) overage (mg) =  
BSA (m2) x 125 (or 200 or 250) mg/m2/day x 7 days x 1.10  
 
• 
Determine the number of RX-0201 vials needed for the dosing. 
• 
Allow RX-0201 vials to equilibrate to room temperature prior to use. Vials may be 
thawed at 2 to 8°C for up 24 hours and/or at room temperature for up to 2 hours prior 
to reconstitution. 
• 
Reconstitute each RX-0201 vial containing 438 mg by adding 6.6 ml of sterile water 
for injection to prepare a concentration of 66.4 mg/ml of RX-0201. Reconstituted vials 
should be stored at 2 to 8°C for no longer than 4 hours. 
• 
Calculate the volume (in ml) of drug to be added to the 1000 ml infusion bag 
containing normal saline for 7 days of dosing plus 10% overage using the following 
formula: 
Total volume of RX-0201 (ml) = Total Weekly RX-0201 Dose + overage (mg) calculated in 
Step 2 divided by 100 mg/ml 
 
RX-0201 in normal saline will be infused into the subject via an intravenous access device (such 
as a Port-a-Cath® or PICC line) using a volumetric infusion pump with an in-line 0.2-0.22 micron 
sterile (disposable) filter at a rate of 5.0 ml/hour.  The total volume administered over a 7-day 
period (168 hours) will be 840 ml.  If a 10% overage is prepared, the bag will contain 924 ml.   
Each bag will be prepared as follows on the day when administration is to begin: 


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• 
Commercially supplied saline bags: 
o Create a bag with a volume of 924 ml (10% overage) of normal saline.  Using 
a commercially supplied 1000 ml bag of normal saline remove the 
manufacturer’s overfill plus 76 ml to reduce the volume of the bag to 924 ml.  
o From the 924 ml bag, remove a volume of normal saline to equal the amount 
of RX-0201 diluted above in Step 5 above (Total Volume of RX-0201 + 
overage). 
• 
Saline bags produced using automated on-site pharmacy systems: 
o Create a bag with a volume equal to 924 ml (10% overage) less the amount 
of RX-0201 diluted above in Step 5 above (Total Volume of RX-0201 + 
overage). 
• 
Add the calculated volume of the reconstituted RX-0201 (100 mg/ml) to the infusion 
bag and mix completely (turn the bag upside down several times but do not shake 
vigorously).   
• 
Remove all air from the bag before use.  
When the subject returns to the site at the end of the infusion the volume and amount of RX-
0201 infused will be recorded into the subject’s medical record. 
Supply and Return of Drug 
At study initiation and as needed thereafter, RX-0201 will be shipped to a responsible person 
(e.g., a pharmacist) at the investigator’s institution, who will check the amount and condition of 
the drug and enter these data into the Proof of Receipt Form and Investigational Product 
Accountability Record.  The Proof of Receipt Form should then be sent to Rexahn or its 
designee and the original retained at the site.  At the end of the study, or as directed, all 
RX-0201 supplies will be destroyed at the site or returned to Rexahn or its designee.   
Investigational Product Accountability 
An Investigational Product Accountability Record for the investigational products as mandated 
by the protocol must be kept current and should contain: 
• 
the dates and quantities of investigational product received from Rexahn  
• 
lot number for product received 
• 
subject’s identification (subject number and initials) 
• 
date and quantity of investigational product dispensed (and remaining, if from individual 
subject drug units) 


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• 
the initials of the dispenser 
• 
dose preparation records 
• 
date and quantity of drug returned to the investigator/pharmacy, if appropriate 
Where applicable, describe whether the returned investigational product will need to be weighed 
or counted. 
The Return of Investigational Product for Destruction Form must be completed and included in 
the shipment of used and unused investigational product to Rexahn or its designee.  At the end 
of the study, the Final Investigational Product Reconciliation Statement must be completed and 
provided to Rexahn. 
These inventories must be made available for inspection by an authorized Rexahn 
representative and regulatory agency inspectors.  The investigator is responsible for the 
accountability of all used and unused clinical study supplies. 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
08 March 2017 
 
Page 77 of 81 
 
 
CONFIDENTIAL 
REXAHN PHARMACEUTICALS, INC. 
Appendix E.  RECIST ver. 1.1 
(Eisenhauer, E. A., et al., 2009) 
Definitions 
- 
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 must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be recorded) 
with a minimum size of 10 mm by CT scan (irrespective of scanner type) and 
MRI (no less than double the slice thickness and a minimum of 10mm); 10mm 
caliper measurement by clinical exam (when superficial); or 20 mm by chest 
X-ray (if clearly defined and surrounded by aerated lung). 
- 
Non-measurable Lesions - all other lesions, including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm with spiral CT 
scan), ie, leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of the skin or lung, 
and also abdominal masses/ abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. Lytic bone 
lesions, with an identifiable soft tissue component, evaluated by CT or MRI, 
can be considered as measurable lesions if the soft tissue component 
otherwise meets the definition of measurability previously described. Blastic 
bone lesions are non-measurable.  
• 
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 not more than 21 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 will only be considered measurable when they are superficial (eg, skin 
nodules and palpable lymph nodes) and ≥ 10 mm in diameter as assessed using 
calipers. For the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Methods of Measurement  
• 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. MRI is also acceptable in certain situations (e.g. for body 
scans but not for lung). CT and MRI should be performed with cuts of 5 mm or less in 
slice thickness contiguously. When CT scans have a slice thickness >5 mm, the 
minimum size should be twice the slice thickness. Spiral CT should be performed using a 
5 to 8 mm contiguous reconstruction algorithm.  This applies to tumors of the chest, 
abdomen and pelvis. Head and neck tumors and those of extremities usually require 
specific protocols. 
• 
Ultrasound should not be used to measure tumor lesions.   
• 
Cytology and histology can be used to differentiate between partial response and 
complete response in rare cases (eg, after treatment to differentiate between residual 
benign lesions and residual malignant lesions in tumor types such as germ cell tumors). 
 


Protocol Number:  RX-0201-P2-A-09 
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08 March 2017 
 
Page 78 of 81 
 
 
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Baseline Documentation of “Target” and “Non-Target” Lesions 
• 
All measurable lesions up to a maximum of two lesions per organ and five lesions in 
total, representative of all involved organs should be identified as target lesions and 
recorded and measured during screening.  
• 
It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  
• 
A sum of the diameters  (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. The 
baseline sum diameters will be used as reference by which to characterize any objective 
tumor regression in the measurable dimension of the disease. If lymph nodes are to be 
included in the sum, only the short axis will contribute.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. It is possible to record multiple nontarget 
lesions involving the same organ as a single item on the eCRF (e.g. “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”).  
 
Subsequent Documentation of “Target” and “Non-Target” Lesions 
• 
All target lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 
2mm). However, if target lesions or lymph nodes become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as 
being ‘too small to measure’, a default value of 5mm should be assigned 
• 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum. Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the ‘coalesced lesion’ 
• 
Finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent 
something other than tumor. This is particularly important when patient’s baseline lesions 
show PR or CR. When in doubt, subsequent timepoint should be evaluated. Lesion seen 
in anatomical region which was not imaged at baseline = new lesion 
 
Response Criteria 
Evaluation of Target Lesions  
* Complete Response (CR): 
Disappearance of all target lesions. Any pathological 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 of diameters. 


Protocol Number:  RX-0201-P2-A-09 
Product:  RX-0201 
08 March 2017 
 
Page 79 of 81 
 
 
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* Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum recorded since 
the treatment started (nadir). The sum must also demonstrate 
an absolute increase of at least 5 mm over nadir. 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease. 
 
Evaluation of Non-Target Lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker levels. Alll lymph nodes must be non-
pahological in size (<10 mm short axis). 
* Non-CR/ Non-PD:  
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker levels above normal limits. 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.Unequivocal 
progression of existing non-target lesions is defined as: (1) 
overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit 
discontinuation of therapy; or (2) in the absence of 
measurable disease, change in non-measurable disease is 
comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. Examples 
include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to 
widespread 
Not evaluable (NE) 
When no imaging/measurement is done at all at a particular 
time point, the patient is not evaluable (NE) at that time point. 
If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that 
time point, unless a convincing argument can be made that 
the contribution of the individual missing lesion(s) would not 
change the assigned time point response 
 
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 patient'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 


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08 March 2017 
 
Page 80 of 81 
 
 
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CR 
NE 
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 = Complete Response; PR = Partial Response; SD = Stable Disease; PD = Progressive Disease; 
NE = Not Evaluable 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment.  
• 
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 
• 
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, measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general not less than 6 – 8 weeks) that is defined in the 
study protocol.    
Overall Response First 
Timepoint 
Overall Response 
Subsequent Timepoint 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, OR PR 
CR 
SD 
SD provided minimum 
criteria for SD duration are 
met. Otherwise PD 
CR 
PD 
SD provided minimum 
criteria for SD duration are 
met. Otherwise PD 
CR 
NE 
SD provided minimum 
criteria for SD duration are 
met. Otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 


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Product:  RX-0201 
08 March 2017 
 
Page 81 of 81 
 
 
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PR 
PD 
SD provided minimum 
criteria for SD duration are 
met. Otherwise PD 
PR 
NE 
SD provided minimum 
criteria for SD duration are 
met. Otherwise NE 
NE 
NE 
NE 
 
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: 
Rexahn Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: RX-0201-P2-A-09 
Version: Final 1.0 (Dated 07DEC2018) 
Confidential/Proprietary Property of Rexahn Pharmaceuticals, Inc. 
Page 1 of 39 
Study Title: 
Sponsor 
Name of Test Drug: 
Protocol: 
Phase: 
Analysis Plan Version 
Analysis Plan Date 
Author 
STATISTICAL ANALYSIS PLAN 
A Multi-Center, Open-label, Phase 1b/2 Study to Evaluate the 
Safety and Efficacy of RX-0201 in Combination With 
Everolimus to Treat Subjects With Advanced Renal Cell 
Carcinoma (NCT02089334)
Rexahn Pharmaceuticals, Inc 
15245 Shady Grove Road, Suite 455 
Rockville, MD 20850 USA 
Telephone (240) 268-5300 
Fax (240) 268-5310 
RX-0201 
RX-0201-P2-A-09 
Phase 1b/2 
Version 1.0 
29 May, 2018 
JC Kuan, Ph.D. 
H2O Clinical, LLC. 
224 Schilling Circle, STE 1888 
Hunt Valley, MD 21031 


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Protocol: RX-0201-P2-A-09 
 
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APPROVAL SIGNATURES 
 
 
Author: 
 
JC Kuan, Ph.D. 
 
 
 
Biostatistician, Biostatistics 
 
 
 
H2O Clinical, LLC. 
 
 
 
 
_______________________________________________________ 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
 
Approved By:  
Christine Peterson, Ph.D. 
 
 
Senior Director Clinical Operations and Regulatory Affairs 
 
 
 
 
Rexahn Pharmaceuticals, Inc. 
 
 
 
 
_______________________________________________________ 
 
 
 
Signature 
 
 
 
 
 
 


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Protocol: RX-0201-P2-A-09 
 
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Version 
Version Data 
Reasons for Modification 
0.1 
August 8, 2015 
Issued by Cliff Meng based on Protocol Amendment 
#2 
0.2 
May 29, 2018 
JC Kuan modified the SAP based on Protocol 
Amendment #4 
0.3 
October 08, 2018 
JC Kuan modified the SAP based on the telecon with 
Rexahn on Sep 12, 2018. 
 
 
 
 
 
 
 


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1 
Table of Contents 
1 
Table of Contents ............................................................................................. 4 
2 
Abbreviations and Definitions ........................................................................... 7 
3 
Introduction ..................................................................................................... 8 
3.1 
Preface .......................................................................................................... 8 
3.2 
Purpose of the Analyses ................................................................................ 8 
4 
Study Objectives and Endpoints ........................................................................ 8 
4.1 
Study Objectives ............................................................................................ 8 
4.2 
Endpoints ...................................................................................................... 9 
4.3 
Derived variables ........................................................................................... 9 
5 
Study Methods ................................................................................................ 13 
5.1 
General Study Design and Plan .................................................................... 13 
5.2 
Equivalence or Non-Inferiority Studies ......................................................... 14 
5.3 
Inclusion-Exclusion Criteria and General Study Population Defined .............. 14 
5.3.1 
Inclusion Criteria ...................................................................................... 14 
5.3.2 
Exclusion Criteria ..................................................................................... 15 
5.4 
Subject Enrollment/ Randomization and Blinding/ Subject Replacement ...... 16 
5.5 
Study Variables ............................................................................................ 17 
5.5.1 
Definition of Dose-Limiting Toxicity ......................................................... 17 
5.5.2 
Dose Escalation and Definition of Maximum Tolerated Dose ..................... 17 
5.5.3 
Determination of MTD or the RX-0201 Recommended Stage 2 Starting 
Dose 
18 
6 
Sample Size .................................................................................................... 19 
7 
General Considerations ................................................................................... 19 
7.1 
Timing of Analyses ...................................................................................... 19 
7.2 
Analysis Population ..................................................................................... 19 
7.2.1 
Full Analysis Set ....................................................................................... 19 
7.2.2 
Per Protocol Analysis Set .......................................................................... 19 
7.2.3 
Safety Analysis Set .................................................................................... 20 
7.2.4 
Dose Limiting Toxicity Analysis Set .......................................................... 20 
7.2.5 
Pharmacokinetic Analysis Set .................................................................... 20 
7.2.6 
Missing Data ............................................................................................ 20 


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7.2.7 
Partial/Missing Dates for Study-Related Visits or Procedures .................... 20 
7.2.8 
Partial/Missing Dates for Adverse Events .................................................. 21 
7.3 
Interim Analyses and Data Monitoring ......................................................... 21 
7.3.1 
Purpose of Interim Analyses ..................................................................... 21 
7.3.2 
Planned Schedule of Interim Analyses ....................................................... 21 
7.3.3 
Scope of Dose Escalation .......................................................................... 22 
7.3.4 
Analysis Methods to Minimize Bias ........................................................... 22 
7.3.5 
Adjustment of Confidence Intervals and p-values ..................................... 22 
7.3.6 
Interim Analysis for Sample Size Adjustment ............................................ 23 
7.3.7 
Practical Measures to Minimize Bias .......................................................... 23 
7.3.8 
Documentation of Interim Analyses .......................................................... 23 
7.4 
Multi-center Studies .................................................................................... 23 
7.5 
Multiple Testing .......................................................................................... 23 
8 
Summary of Study Data .................................................................................. 23 
8.1 
Subject Disposition ...................................................................................... 23 
8.2 
Protocol Deviation ....................................................................................... 24 
8.3 
Demographic and Baseline Variables ........................................................... 24 
8.4 
Prior and Concomitant Medical Conditions .................................................. 24 
8.5 
Prior and Concomitant Medications / Non-Drug Treatments ........................ 25 
8.6 
Treatment Compliance ................................................................................ 25 
8.7 
Primary Safety Endpoint ............................................................................... 26 
8.8 
Secondary Safety Endpoint ........................................................................... 26 
8.9 
Extent of Exposure ...................................................................................... 26 
8.10 
Adverse Events ......................................................................................... 26 
8.11 
Death, Serious Adverse Events and other Significant Adverse Events ......... 28 
8.12 
Pregnancies .............................................................................................. 29 
8.13 
Clinical Laboratory Evaluations ................................................................. 29 
8.14 
Other Safety Measures .............................................................................. 29 
8.14.1 
ECOG Performance Status ...................................................................... 29 
8.14.2 
Vital Signs ............................................................................................. 30 
9 
Efficacy Analyses ............................................................................................ 30 


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9.1 
Primary Efficacy Analysis ............................................................................. 30 
9.1.1 
Progression-Free Survival ......................................................................... 30 
9.1.2 
Best Overall Response (per eCRF).............................................................. 31 
9.1.3 
Time to Response ..................................................................................... 32 
9.1.4 
Duration of Response ............................................................................... 32 
9.1.5 
Pharmacokinetics ..................................................................................... 32 
10 
Technical Details ......................................................................................... 33 
11 
Summary of Changes to the Protocol ........................................................... 33 
12 
References .................................................................................................. 34 
13 
Listing of Tables, Listings and Figures ......................................................... 35 
16 
Appendices ................................................................................................. 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 
Abbreviations and Definitions 
AE 
Adverse Event 
CR 
Complete Response (RECIST criteria) 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-Limiting Toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ITT 
Intent to Treat 
MTD 
Maximum Tolerated Dose 
NE 
Not evaluable (RECIST criteria) 
PD 
Progressive Disease (RECIST criteria) 
PFS 
Progression-Free Survival 
PR 
Partial Response (RECIST criteria) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease (RECIST criteria) 
SOC 
System Organ Class 
WHO Drug 
Word Health Organization Drug Dictionary Enhanced 


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3 
Introduction 
3.1 
Preface 
This document describes the data analysis specifications for Rexahn Pharmaceuticals protocol RX-
0201-P2-A-09 titled: “A Multicenter, Open-label, Phase 1b/2 Study to Evaluate the Safety and 
Efficacy of RX-0201 in Combination With Everolimus to Treat Subjects With Advanced Renal Cell 
Carcinoma”. This version of the statistical analysis plan dated April 3, 2018 was prepared in 
accordance with the protocol RX-0201-P2-A-09 Amendment 04 dated March 8, 2017. Other related 
documents are the electronic case report form (eCRF) data definition fields and data set definitions. 
3.2 
Purpose of the Analyses 
The purpose of this Statistical Analysis Plan (SAP) is to provide a framework in which answers to the 
protocol objectives may be achieved in a statistically rigorous fashion using methods identified prior to 
database lock. Any deviations from these methods must be documented in the final clinical study 
report. 
4 
Study Objectives and Endpoints 
4.1 
Study Objectives 
Primary objective:  
• 
To determine the maximum tolerated dose (MTD) of RX-0201, up to a target dose of 250 
mg/m2/day, when given in combination with everolimus (Stage 1) 
• 
To determine progression-free survival in subjects with advanced renal cell carcinoma treated 
with the combination of RX-0201 and everolimus versus everolimus alone (Stage 2)  
Secondary objective(s): 
• 
To assess the pharmacokinetics of RX-0201 in combination with everolimus (Stage 1) 
• 
 To evaluate parameters of clinical benefit of RX-0201 in combination with everolimus versus 
everolimus alone as measured by duration of response, time to response, and response rate 
(Stage 2)  
• 
To evaluate the safety and tolerability of RX-0201 in combination with everolimus versus 
everolimus alone (Stage 1 and Stage 2) 
Exploratory objective: 
• 
To investigate the effects of RX-0201 and everolimus on AKT pathway biomarkers, tumor 
apoptosis biomarkers and other biomarkers in blood or tumor samples (Stage 1 and Stage 2) 
• 
To further evaluate the peak plasma concentration of RX-0201 at the target dose (Stage 2) 


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4.2 
Endpoints 
Primary Endpoint:  
• 
The incidence of adverse events and clinical laboratory abnormalities defined as dose-limiting 
toxicities (Stage 1) 
• 
Progression-free survival at 4.5 months (Stage2) 
Secondary Endpoints:  
• 
Pharmacokinetic profile of RX-0201 (Stage 1) 
• 
Incidence of adverse events, changes in clinical laboratory tests and vital signs over time 
(Stage 1 and Stage 2) 
• 
Tumor response rate, duration of response, time to response and response rates (Stage 2) 
Exploratory Endpoint:  
• 
Blood levels of AKT pathway biomarkers, tumor apoptosis biomarkers or other biomarkers 
(Stage 1 and Stage 2) 
• 
Plasma concentration of RX-0201 at the end of infusion (Stage 2) 
4.3 
Derived variables 
Subject Age 
The subject’s age will be calculated as the number of years from the subject’s date of birth to his/her 
screening date: Age = ([Screening Date - Date of Birth] / 365.25). 
Baseline 
The baseline value for any variable will be 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 will be the value from the screening period measured 
closest to study day 1. 
Time from First Histopathological /Cytological Diagnosis  to Screening Visit 
Date of the first histopathological/cytological diagnosis will be captured in the EDC dataset. Date of 
screening visit will be captured in the Visit Date SAS dataset.    
Dose-Limiting Toxicity (DLT) 
The definition of DLT is described in Section 6.5of this SAP. Dose-limiting toxicity will be evaluated 
during Cycle 1 of treatment.For purposes of displaying DLTs on a per-subject and per-cohort basis, 


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the Electronic Data Capture (EDC) system will capture and identify whether or not a subject 
experiences a DLT in the AE dataset.        
Maximum Tolerated Dose (MTD) 
The determination of Maximum Tolerated Dose (MTD) is described in Section 6.4 of this SAP. 
Response Evaluation Criteria in Solid Tumors (RECIST) Criteria: Version 1.1 
RECIST v1.1 criteria are outlined in Appendix E of the protocol.  
Overall Response Rate (ORR, Investigator Assessment) 
The tables below provide time point overall responses for all possible combinations of tumor 
responses in subjects with target and non-target lesions, with or without new lesions, per RECIST 
v1.1. 
A summary of the overall response status calculation at each time point is presented in Table 1 for 
subjects who have measurable lesions at baseline, and in Table 2 for subjects who have only non-
measurable (therefore non-target) lesions at baseline. For data display and analysis purposes, the 
“BEST” overall response for each subject from all post-baseline time point overall responses will be 
used. The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence, or occurrence of intolerable toxicity, whatever comes first, taking, for 
target lesions, as reference for progressive disease, the smallest sum of diameters of target lesions 
recorded since the treatment started.  
When no imaging/measurement is done at all at a particular time point, the subject will not be 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing argument 
can be made that the contribution of the individual missing lesion(s) would not change the assigned 
time point response. Overall Response Rate (ORR) will be defined as the proportion of subjects with 
a best overall response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD).   
 
Table 1  
Time point response for subjects with target (+/- non-target) lesions 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR / Non-PD 
No 
PR 


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CR 
NE 
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 = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE 
= inevaluable 
 
 
Table 2  
Time point response for subjects with non-target disease 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR / Non-PD 
No 
Non-CR / Non-PD (1) 
Not all evaluated 
No 
NE 
PD 
Yes or No 
PD 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE 
= not evaluable 
(1) Non-CR / non-PD is preferred over ‘Stable Disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials. To assign this category 
when no lesions can be measured is not advised. 
 
Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed not less than 4 weeks after the initial criteria for 
response are first met. In the case of SD, measurements must have met the SD criteria at least once 


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after study entry at a minimum interval (in general not less than 6 – 8 weeks) that is defined in the 
study protocol. Best overall response thus can be interpreted as shown in the Table below 
(Eisenhauer et al, 2009).  
Table 3  
Best overall response when confirmation of CR and PR required 
Overall Response First 
Timepoint  
Overall Response 
Subsequent Timepoint  
BEST overall response  
CR  
CR  
CR  
CR  
PR  
SD, PD, OR PR  
CR  
SD  
SD provided minimum criteria 
for SD duration are met. 
Otherwise PD  
CR  
PD  
SD provided minimum criteria 
for SD duration are met. 
Otherwise PD  
CR  
NE  
SD provided minimum criteria 
for SD duration are met. 
Otherwise NE  
PR  
CR  
PR  
PR  
PR  
PR  
PR  
SD  
SD  
PR  
PD  
SD provided minimum criteria 
for SD duration are met. 
Otherwise PD  
PR  
NE  
SD provided minimum criteria 
for SD duration are met. 
Otherwise NE  
NE  
NE  
NE  
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE 
= not evaluable 
 
Appendix E of the protocol provides details on methods of measurements, documentation and 
evaluation of target / non-target lesions. 
Time to Response 
The Time to Response will be the time between initiation of treatment and first documentation of PR 
or CR. 
Duration of Response 
The duration of response will be the time from first documented response (CR or PR) until the earlier 
of either first documented tumor progression (PD) or death from any cause. Subjects achieving a CR 
or PR, who are alive without progression, are lost to follow up, or who have died without report of 


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progression as of the time of analysis will be censored at the date of last response assessment or last 
date on study, whichever is earliest.  
Progression-Free Survival (PFS) 
Progression-free survival will be defined as the time from date of initiation of treatment until the earlier 
of either first documented tumor progression (PD) or death from any cause. Subjects alive without 
progression or lost to follow-up at the time of analysis will be censored at the date of last response 
assessment. Progression free survival will be analyzed at 4.5 months (Stage 2).  
5 
Study Methods 
5.1 
General Study Design and Plan 
This is a 2-stage phase 1b/2, multi-center, open-label study to assess the safety and tolerability of 
RX-0201 in combination with everolimus versus everolimus alone to treat subjects with advanced 
renal cell carcinoma. Approximately 32 subjects will be recruited and enrolled into the study over 20 
centers in the US. 
Stage 1 is an open-label, dose-escalation phase 1b study of RX-0201 to identify a safe and tolerable 
dose of RX-0201 up to a target dose of 250 mg/m2/day when given in combination with everolimus. 
Approximately 9 subjects will be enrolled to receive the combination of everolimus and RX-0201 at 
increasing doses of RX-0201 to the MTD or up to a target dose of 250 mg/m2/day. The number of 
subjects enrolled into Stage 1 will vary depending upon the number of dose levels needed to 
determine the MTD, up to a target dose of 250 mg/m2/day.   
Stage 2 is an open-label, 2-arm phase 2 study of RX-0201 in combination with everolimus versus 
everolimus alone. Approximately 3 additional subjects will be treated with everolimus alone arm and 
up to 20 subjects in the everolimus/RX-0201 arm.    
Everolimus will be administered daily at 10 mg orally at approximately the same time each day 
consistently with or without food per the approved label instructions in Stage 1 and Stage 2.  
RX-0201 will be administered at a starting dose of 125 mg/m2/day, by a 24 hour continuous 
intravenous infusion for 14 days followed by 7 days of rest in each 21 day cycle. RX-0201 doses in 
Stage 1 will be escalated until a maximum tolerated dose (MTD) or a target dose of 250 mg/m2/day is 
reached. The MTD or the target dose will be tested further in Stage 2.  
For subjects assigned to receive RX-0201 and everolimus, a cycle will be defined as the period 
elapsing from the first day of RX-0201 administration through Day 21 of the cycle or to the recovery 


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from any adverse events sufficient that a new cycle of therapy can be administered (e.g., on Day 29 
or Day 36), whichever occurs later. Once a new cycle starts, the prior cycle is considered to be 
completed. For subjects assigned to the everolimus only arm, a cycle will be defined as the period 
elapsing from the first day of everolimus administration through Day 21 of the cycle or to the recovery 
from any adverse events sufficient that a new cycle of therapy can be administered, whichever occurs 
laterSubjects in Stage 1 and Stage 2 may receive up to 8 cycles of combined therapy until withdrawal 
of consent, pregnancy, substantial noncompliance with study procedures, intolerable adverse event, 
documented radiological disease progression or death, principal investigator judgment that it is in the 
best interest of the subject to stop treatment, or study discontinuation. Subjects, who the principal 
investigator feels are receiving benefit, may continue to receive additional cycles of therapy following 
discussions with the Sponsor. Subjects randomized to the everolimus only treatment arm will 
complete the study after 8 cycles but may continue to receive everolimus off-study. 
Each subject should complete all study procedures in approximately 8 months (i.e., screening period 
up to 14 days; treatment period up to eight 21-day cycles, safety follow-up approximately 30 days 
after the last dose of study medication). However, for subjects approved to receive additional 
treatment cycles, the duration may be longer than 8 months. The study duration is estimated at 
approximately 30 months. 
 
5.2 
 Equivalence or Non-Inferiority Studies 
No equivalence or non-inferiority test will be conducted in the analysis.  
5.3 
Inclusion-Exclusion Criteria and General Study Population Defined 
5.3.1 
Inclusion Criteria 
Disease Related 
• 
Documented histological or cytological diagnosis of renal cell cancer with a clear-cell 
component  
• 
Measurable or evaluable disease defined by Response Evaluation Criteria for Solid Tumors 
(RECIST) ver. 1.1  
• 
Must have received at least one course of therapy with a VEGFR-targeting tyrosine kinase 
inhibitor (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib) and progressed within 6 
months of planned first dose of study treatment.  
• 
Prior therapy with cytokines (i.e., IL-2, Interferon) and/or VEGF-ligand inhibitors (i.e., 
bevacizumab) are permitted  
• 
Prior vaccine therapy in the adjuvant setting is permitted  
• 
Tissue blocks or tissue sections from initial diagnosis or upon diagnosis of advanced 
metastatic disease will be available for submission to the central laboratory within 


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approximately 4 weeks after initiation of study treatment; exceptions (e.g., histology 
determined by fine needle aspirate or tissue is no longer available) require written 
documentation of why a sample is not available and prior approval by the sponsor before 
enrollment/ randomization  
• 
ECOG performance status of 0, 1 or 2  
• 
Life expectancy > 3 months  
Demographic 
• 
Males and females ≥ 18 years of age at screening  
Ethical 
• 
Before any study-specific procedures are performed, written informed consent must be 
obtained  
5.3.2 
Exclusion Criteria  
Disease Related  
• 
Disease-associated symptoms requiring immediate therapy or other interventions  
• 
Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery and stable for at least 3 months before planned first dose of 
study drug  
Laboratory  
• 
Absolute neutrophil count < 1.5 x 109/L  
• 
Platelet count < 100 x 109/L  
• 
Hemoglobin < 9 g/dL  
• 
Bilirubin > 1.5 X upper limit of normal (ULN)  
• 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 X ULN (OR > 5 X 
ULN in the presence of known liver metastases)  
• 
Serum creatinine > 1.5 X ULN OR estimated creatinine clearance ≤ 60 ml/min (Cockroft-
Gault)  
• 
Partial thromboplastin time (PTT) > 1.25 X ULN  
• 
Prothrombin time (PT) > 1.25 X ULN OR international normalization ratio (INR) > 1.4  
Medications  
• 
Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy 
within 4 weeks before planned first dose of study drug. Systemic treatment with radionuclides 
within 6 weeks before planned first dose of study drug. Subjects with clinically relevant 
ongoing complications from prior radiation therapy are not eligible  
• 
Prior treatment with everolimus, or any other specific or selective TORC1/PI3K/AKT inhibitor 
(e.g., temsirolimus)  
• 
Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitor) within 2 weeks before planned first dose of study drug  
• 
Receipt of any type of anticancer antibody (including investigational antibody) within 4 weeks 
before planned first dose of study drug  
• 
Taking strong inducers or inhibitors of CYP450s for subjects receiving everolimus  
• 
Chronic treatment with corticosteroids or other immunosuppressive agents  
• 
Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet 


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inhibitors  
• 
Subjects with a known hypersensitivity to everolimus or other rapamycins (sirolimus, 
temsirolimus) or to its excipients  
• 
Not recovered from toxicities related to any prior treatments, unless adverse events are 
clinically non-significant and/or stable on supportive therapy  
General 
• 
History of any medical, psychiatric, or social (e.g., addictive disorder) conditions, or laboratory 
abnormality that in the opinion of the investigator, may increase the risks associated with 
study participation or treatments that may interfere with the conduct of the study or the 
interpretation of study results  
• 
Major surgery within 2 months before planned first dose of study drug. Complete wound 
healing from major surgery must have occurred within 1 month before planned first dose of 
study drug and from minor surgery at least 10 days before planned first dose of study drug  
• 
Myocardial infarction within the previous 6 months before planned first dose of study drug  
• 
Active infection requiring parenteral antibiotics within 2 weeks before planned first dose of 
study drug  
• 
Diagnosis of another malignancy within 2 years before planned first dose of study drug, 
except for superficial skin cancers, or localized, low grade tumors;  
• 
Currently enrolled in and has not yet completed at least 30 days since ending other 
investigational device or drug study before planned first dose of study drug, or subject is 
currently receiving other investigational agent(s).  
• 
Prior or current history of hepatitis B, hepatitis C or human immunodeficiency virus  
• 
Pregnant, planning a pregnancy or breastfeeding during the study  
• 
Sexually active fertile subjects (male and female), must agree to use medically accepted 
methods of contraception during the course of the study and for 30 days after the last dose of 
study treatment. Female subjects must meet at least one of the following criteria:  
 
• 
be surgically sterile (i.e., have had bilateral tubal ligation, hysterectomy, or bilateral    
• 
oophorectomy at least 6 months before enrollment; appropriate documentation will be   
• 
required),  
• 
be post-menopausal for at least 12 months OR  
• 
if sexually active, be willing to use double-barrier contraception (e.g., condom with    
• 
spermicide), intrauterine device, steroidal contraceptive (oral, transdermal, implanted, 
or  
• 
injected) or other method, approved by the sponsor.  
• 
Unwilling or unable to comply with study requirements or not available for follow-up 
assessments  
• 
Any other major illnesses that in the investigator’s judgment substantially increases the risk 
associated with the subject’s participation in the study  
 
5.4 
Subject Enrollment/ Randomization and Blinding/ Subject Replacement 
Subjects in Stage 1 will be enrolled to receive the combination everolimus with escalating doses of 
RX-0201. Subjects in Stage 2 will no longer be randomized to 1 of 2 treatment arms (i.e., everolimus 
versus everolimus/RX-0201). All subjects in Stage 2will now be assigned to the everolimus/ RX-0201 
treatment arm. Subjects in Stage 1 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 


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replaced. Any replacement subject will be enrolled into the same dosing cohort as that for the subject 
who withdrew.  
Subjects in Stage 2 who are enrolled but not treated will be replaced.  
5.5 
Study Variables 
5.5.1 
Definition 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. Dose-limiting toxicities (DLT) will be evaluated during Cycle 1 of 
treatment. These DLTs will be graded and documented according the National Cancer Institute 
Common Terminology Criteria for Adverse Event (NCI CTCAE) (v4.03)A DLT will be defined as the 
occurrence of any of the following that are determined by the investigator to be related to RX-0201: 
• 
Grade 4 neutropenia (ANC < 0.5 x 109/L) with fever or lasting 3 days or longer  
 
• 
Any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with ≥ Grade 1 
hemorrhage  
 
• 
Any ≥ Grade 3 coagulation abnormality (defined by PT and/or INR and PTT values) 
associated with clinical hemorrhage ≥ Grade 1.  
 
• 
Nausea/vomiting ≥ Grade 3 despite maximal antiemetic therapy; diarrhea ≥ Grade 3 despite 
maximal anti-diarrheal therapy.  
 
• 
Grade 4 thrombocytopenia (platelet count < 25 x 109/L)  
 
• 
Any other non-hematological toxicity ≥ Grade 3 with the exception of alopecia  
5.5.2 
Dose Escalation and Definition of Maximum Tolerated Dose 
Initially 3 subjects will be enrolled to receive everolimus plus 125 mg/m2/day of RX-0201. Depending 
on whether there are any dose limiting toxicities (DLTs) attributed to RX-0201, the following dose-
escalation decisions and rules will be followed:  
 
Dose-escalation decisions: 
Dose Group 
 
Theoretical dose (mg/m2/da)  
Escalation 
 
1 
 
 
125 
 
 
 
- 
 
2 
 
 
200 
 
 
 
1.60 
 
3 
 
 
250 
 
 
 
1.25 
 
Dose-escalation rules: 


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• 
If 0 of the first 3 subjects experience DLT during the first 3 weeks of treatment, then the dose 
will be escalated to the next higher level in 3 subsequent subjects. 
• 
If 1 of the first 3 subjects experiences DLT at the current dose during the first 3 weeks of 
treatment, then 3 more subjects will be accrued at the same dose level. 
• 
If 0 of the 3 additional subjects experience DLT during the first 3 weeks of treatment, then the 
dose will be escalated to the next higher level in 3 subsequent subjects. 
• 
If ≥1 of the 3 additional subjects in a cohort experiences DLT in the first 3 weeks of treatment, 
the MTD has been exceeded and 3 more subjects will be treated at the next lower dose level 
(if only 3 subjects were previously treated at that prior dose level). 
• 
If ≥2 of 3 or ≥2 of 6 subjects experience DLT during the first 3 weeks of treatment, then the 
MTD has been exceeded and 3 more subjects will be treated at the next lower dose level (if 
only 3 subjects were previously treated at that prior dose level). 
• 
Each group of 3 subjects within a cohort must be observed for a minimum period of 3 weeks 
without DLT before subsequent subjects are enrolled at the next higher dose level. 
• 
Escalation to the next dose level of the study can occur upon review of the safety data from 
all ongoing and previous subjects and with the concurrence of the study sponsor and the 
principal investigators. 
In the event that attribution of causality of potential DLTs to study agent may be equivocal, 
discussions with the safety review committee will occur and additional subjects may be enrolled at 
that dose level. The decision to escalate to the next dose level will be based upon observation of 
DLTs during Cycle 1 from at least 3 subjects in the previous dose level. Reviews will be conducted by 
the safety review committee to monitor safety data on an ongoing basis throughout the study. In 
addition, the investigators and/or the Medical Monitor may prompt a meeting by the safety review 
committee at any time. Rexahn 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 during Stage 1. 
5.5.3 
Determination of MTD or the RX-0201 Recommended Stage 2 Starting Dose 
The establishment of the MTD or the safety of the target RX-0201 dose of 250 mg/m2/day will be 
based on a review of the overall safety data by the safety review committee.  The MTD is the highest 
starting dose level associated with first-cycle DLTs in < 33.3% of subjects.  Once the safety of the 
MTD of the target RX-0201 dose of 250 mg/m2/day is initially established, additional subjects (up to 
20 subjects total) will be enrolled to receive the target RX-0201 dose of 250 mg/m2/day in Stage 2. 
Selection of a recommended Stage 2 starting dose from within the tested dose ranges and schedules 
will be based on evaluation of available safety information with findings regarding compliance, and 
achievement of targeted pharmacokinetic values. 


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6 
Sample Size 
Sample size calculation for this study has been empirically set. Approximately 32 subjects will be 
recruited and enrolled into the study over 20 centers in the US. 
For Stage 1, approximately 9 subjects will be enrolled in to receive the combination of everolimus (10 
mg) and RX-0201 at increasing doses of RX-0201 to the MTD or up to a target dose of 250 
mg/m2/day. For Stage 2, approximately 3 additional subjects will be treated with everolimus alone arm 
and up to 20 subjects in the everolimus/RX-0201. 
7 
General Considerations 
The software used for all summary statistics and statistical analyses will be SAS Version 9.4 or later. 
Safety, Efficacy, and PK assessments will be summarized separately for Stage 1 and Stage 2. 
Additional summaries and analyses of pooled Phase 1 and 2 data may also be generated based on 
applicability of dosing regimens.  
Unless otherwise noted, data will be summarized in tabular format by increasing dose level of RX-
0201 for the combination of RX-0201 and Everolimus in Stage 1, by combination of RX-0201 and 
Everolimus in Stage 2, and by RX-0201 dose level for the combination of RX-0201 and Everolimus 
Stage 2. All groups combined (i.e., Total/Overall column) will also be presented when appropriate. All 
study data documented on the eCRFs will be included in the study data listings.  
7.1 
Timing of Analyses 
Analysis window is not defined in this study. 
7.2 
Analysis Population 
7.2.1 
Full Analysis Set 
The Full Analysis set includes all enrolled subjects with subjects analyzed according to the treatment 
assigned at enrollment/randomization. All efficacy endpoints will be analyzed using the Full Analysis 
set. 
7.2.2 
Per Protocol Analysis Set 
The Per-Protocol Analysis set includes all subjects without pre-specified major protocol deviations. 
Sensitivity analyses of some efficacy endpoints may be performed using the per-protocol analysis set. 


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7.2.3 
Safety Analysis Set 
The safety analysis set includes all subjects who receive at least one dose of study drug(s) with 
subjects analyzed according to the treatment received. All safety data will be analyzed in accordance 
with this analysis set. The safety analysis set will be defined as all subjects who receive at least 1 
dose of study drug. These subjects will be analyzed according to the treatment received. All safety 
data will be analyzed in the safety analysis set. 
7.2.4 
Dose Limiting Toxicity Analysis Set 
The dose limiting toxicity assessment set will include all evaluable subjects. An evaluable subject is 
any subject who experiences a dose limiting toxicity in the first 21 days of treatment or completes 2 
weeks of RX-0201 treatment in cycle 1.   
 
7.2.5 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set will include all enrolled subjects who undergo blood sampling 
during the study and have measurable concentrations of RX-0201 above the respective assays’ limit 
of quantification at any time point after dosing.Evaluable for Tumor Response Analysis Set (Stage 2 
only) 
The analysis of objective response includes all subjects in the Full Analysis Set (and per-protocol set 
if applicable) with a uni-dimensional measurable lesion at baseline (as per RECIST 1.1 with 
modifications). 
7.2.6 
Missing Data 
In general, data will be analyzed as received from the clinical database. Hence, except for some 
partial/missing dates (see below), missing values, including those caused by dropouts, will not be 
imputed.  Missing or partially missing dates in the following situations will be imputed for purposes of 
analysis: 
7.2.7 
Partial/Missing Dates for Study-Related Visits or Procedures 
It is anticipated that all study-related visit and procedure dates entered into the clinical study database 
will be complete (i.e. day, month, year are all recorded) and accurate. Any missing or partially missing 


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dates of this type will be queried before statistical analyses are performed. If the day, month, and/or 
year are still unknown, then the dates will be imputed as follows for purposes of analysis: 
• 
If the day of the visit or procedure date is missing, then take the previous visit and add the 
target number of days to the next visit according to the visit schedule.  
• 
If the month of the visit or procedure date is missing then take the previous visit and add the 
target number of months to the next visit according to the visit schedule. 
• 
If the year of the visit or procedure date is missing, then the year will be queried. If the year is 
unknown, no imputation of year will take place.  
Imputed dates will be flagged in the subject data listings. 
7.2.8 
Partial/Missing Dates for Adverse Events 
For any adverse event that has a missing or incomplete start date, a query will be issued to capture 
the full date. If only a partial date is reported for the start of an AE, a complete date will be estimated 
using the following algorithm: 
• 
If only the year is reported (i.e., missing the month and day): The date of the first dose of 
investigational product will be used as the start of the AE. 
• 
The year and month are reported (i.e., missing the day): The first day of the month will be 
imputed. 
• 
The month and day are reported (i.e., missing the year): only situations where the year is 
self-evident will be allowed.  
No imputation will be applied to an incomplete AE end date. The rationale will be that there should be 
a start date for all subject AEs but there may not be an end dates for AEs that are ongoing at the time 
the subject exits the study. 
7.3 
Interim Analyses and Data Monitoring 
7.3.1 
Purpose of Interim Analyses 
Other than the safety evaluation required to determine whether to proceed to Stage 2 of accrual, no 
planned formal interim analysis will be performed. 
If concerns arise during any data reviews, the sponsor may request additional specific safety data be 
collected and recommend modifying study conduct. 
7.3.2 
Planned Schedule of Interim Analyses 


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  As noted in Section 7.5.1, other than the safety evaluation required to determine whether to proceed 
to Stage 2 of accrual, no planned formal interim analysis will be performed. 
 
7.3.3 
Scope of Dose Escalation 
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. 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 during Stage 1.  
The establishment of the MTD or the safety of the target RX-0201 dose of 250 mg/m2/day will be 
based on a review of the overall safety data by the investigators, medical monitor and sponsor. The 
MTD is the highest starting dose level associated with first-cycle DLTs in < 33.3% of subjects. Once 
the safety of the target RX-0201 dose of 250 mg/m2/day is initially established, additional subjects 
(up to 20 subjects total) will be enrolled to receive RX-0201 at the target RX-0201 dose of 250 
mg/m2/day in Stage 2. Selection of a recommended Stage 2 starting dose from within the tested dose 
range will be based on evaluation of available safety information with findings regarding compliance. 
Stopping Rules 
The sponsor may also terminate the study at any time for reasons which may or may not be related to 
safety or study conduct. 
7.3.4 
Analysis Methods to Minimize Bias 
None. 
7.3.5 
Adjustment of Confidence Intervals and p-values 
Any statistical tests that are utilized will be two-sided, with a type 1 error rate of 5%. All confidence 
intervals will be two-sided, constructed at the 95% confidence level. Any inferential statistical tests 
conducted in this study will be considered exploratory in nature; therefore, no p-value adjustments for 
multiplicity analyses will be made. 


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Data will be summarized using the Safety Analysis Set with respect to enrollment and disposition 
summaries, demographics and baseline characteristics, concomitant medications, and safety 
measures. Summary (i.e. descriptive) statistics will include N, mean, standard deviation, median, 
range (minimum, maximum), values for continuous variables and frequencies, and percentages for 
categorical variables.  Time-to-event analyses will be summarized using Kaplan-Meier survival 
analysis and graphs.  95% confidence intervals for the estimated median times and percentiles will 
also be displayed if applicable.  
Missing or invalid data will be generally treated as missing, not imputed, unless otherwise stated (see 
Section 7.4).  
7.3.6 
Interim Analysis for Sample Size Adjustment 
Not applicable.   
7.3.7 
Practical Measures to Minimize Bias 
Not applicable.   
7.3.8 
Documentation of Interim Analyses 
Not applicable.   
7.4 
Multi-center Studies 
Up to 20 sites in the US will participate in this study. Sites that do not enroll subjects within 3 months 
of site initiation may be terminated. 
Data from all centers will be combined for the analysis purposes. 
7.5 
Multiple Testing 
Not applicable.   
8 
Summary of Study Data 
8.1 
Subject Disposition 
Subject enrollment by site and across all sites will be tabulated by dose group and all subjects.  


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The number of subjects discontinuing the study and the primary reason for discontinuation will be 
tabulated for descriptive purposes by dose group and overall. 
Screen failure subjects will be included only in the disposition table and subject enrollment listing 
indicating reason for failure.  
In addition, the number and percentage of subjects in each of the 4 analysis data sets (safety 
analysis set, full analysis set, per-protocol analysis set, and evaluable for tumor response analysis 
set,) will be summarized by treatment group. 
8.2 
Protocol Deviation 
A protocol deviation will be any noncompliance with the clinical trial protocol or Good Clinical Practice 
(GCP). The noncompliance may be either on the part of the subject, the investigator, or the study site 
staff. Protocol deviations will be identified and documented by Rexahn project management based on 
a review of data listings prior to database lock.  
The number and percentage of subjects with any major and minor deviations will be tabulated for 
descriptive purposes by dose group and overall. 
8.3 
Demographic and Baseline Variables 
A summary of age, gender, race, ethnicity, metastatic clear cell renal carcinoma diagnosis, tumor 
stage, current disease status, time (months) from first diagnosis of metastatic disease to screening 
visit, prior medical history, prior anti-cancer systemic therapy (related to study indication), prior anti-
cancer radiotherapy (related to study indication), prior anti-cancer surgery (related to study 
indication), vital signs at screening, and ECOG Performance Status will be presented using 
appropriate descriptive statistics by dose group. The categorical (discrete) variables will be 
summarized using counts and percentages. The continuous variables will be summarized using n, 
mean, median, standard deviation, and range (maximum, minimum). 
8.4 
Prior and Concomitant Medical Conditions 
The number and percentage of all subjects with any medical history will be summarized overall and 
for each body system. Body systems will be included as recorded on the eCRF. Percentages will be 
calculated based on number of subjects in the safety analysis set.  
Subjects’ medical history data including medical condition, start date and end date/ongoing will be 
presented in a listing. 


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8.5 
Prior and Concomitant Medications / Non-Drug Treatments 
For the purpose of this analysis, concomitant medications/therapies will be defined as those 
medications/ therapies taken after the first administration of study drug; medications/therapies taken 
within 14 days prior to the first administration of study drug will be defined as prior 
medications/therapies. These medications will be coded using World Health Organization Drug 
Dictionary Enhanced (WHO Drug, June, 2014).   The number and proportion of subjects in the safety 
analysis set using different prior/concomitant medications will be tabulated and summarized in a table 
by WHO Drug Anatomical-Therapeutic-Chemical (ATC) class and drug name for each dose group, 
and non-drug therapies will be mapped to preferred terms and related system organ classes (SOC) 
for each dose group. These data will also be presented in subject listings. 
8.6 
Treatment Compliance 
Time on treatment (date of first dose to date of discontinuation date recorded on the end of study 
eCRF page) for each dose group will be characterized using descriptive summary statistics (n, mean, 
median, standard deviation, and range (maximum, minimum)). 
RX-0201 compliance at each visit (%) = [Total Actual Volume Administered (mL) of RX-0201 / (Total 
reservoir volume of RX-0201)]*100  
Everolimus at each visit (%) = (Number of Doses Taken / Number of Expected Doses)*100       
A listing will be provided for the number and timing of prescribed dose reductions and dose 
interruptions. 
Safety Analyses 
The incidence of subjects with adverse events and clinical laboratory abnormalities, defined as dose 
limiting toxicities after 1 cycle of therapy, is one of the primary endpoints. The safety of RX-0201 will 
be evaluated through reporting using the grading system in the CTCAE version 4.03 for adverse 
events and laboratory abnormalities. This will be used to grade changes in vital signs, and laboratory 
assessments to include serum chemistry, hematology, coagulation tests and urinalysis. All statistical 
methods for safety data will be descriptive in nature.  
Dose Limiting Toxicities that occur during Cycle 1 will be tabulated by DLT criteria and RX-0201 dose 
level. Vital signs will be tabulated and presented as raw data and change from baseline at each time 
point. Laboratory safety data will be tabulated in shift tables based on laboratory-specific normal 
ranges. Adverse events will be tabulated by body system, intensity and relationship to study drug. 


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Vital signs, weight, and data will be summarized using appropriate descriptive statistics, by treatment 
group and time. 
All subjects who receive at least 1 dose of RX-0201 will be included in the final summaries and 
listings of safety data. All safety analyses will be performed by dose level, treatment cycle, and week, 
where appropriate. 
8.7 
Primary Safety Endpoint 
One of the primary safety endpoints is the incidence of adverse events and clinical laboratory 
abnormalities defined as dose-limiting toxicities (Stage 1).  
8.8 
Secondary Safety Endpoint 
Incidence of adverse events, changes in clinical laboratory tests and vital signs over time (Stage 1 
and Stage 2). 
8.9 
Extent of Exposure 
Duration of exposure will be defined as the total number of days a subject is exposed to study drug 
and will be presented as the total number of days from the first dosing date (Day 1) to the last dosing 
date (date of last dose minus the date of first dose + 1).  
The total cumulative dose will be defined as the sum of the received doses across all study days. The 
average daily dose and cumulative dose will be summarized by descriptive summary statistics. 
A summary of each subject’s exposure will be presented in a listing.  
8.10 Adverse Events 
All Adverse Events (AEs) will be listed as described on the eCRF.  
An adverse event will be 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 will 
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.  


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• 
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,) 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., 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.  
• 
A complication related to pregnancy or termination of a pregnancy (see Section 9.7.2 for 
additional information). 
None of the following events will be 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 sequela. 
Verbatim terms of AEs will be mapped to preferred terms and related system organ classes (SOC) 
using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1.The incidence rate of 
treatment emergent adverse events (TEAEs), defined as all adverse events reported as new or 


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worsened after the start of study drug, will be summarized by treatment group, system organ class, 
preferred term and maximum severity for all adverse events, serious adverse events, adverse events 
leading to discontinuation of study specified treatment, adverse events leading to discontinuation from 
the study and fatal adverse events using subjects in the safety population. In addition, summaries of 
exposure adjusted adverse event rates may also be presented. These summary tables will also be 
repeated for treatment related adverse events. 
Tables will summarize the number and percentage of subjects having an event in each system organ 
class and preferred term by dose group. The denominator used to calculate incidence percentages 
consists of subjects receiving at least one dose of RX-0201 in the combination of RX-0201 and 
Everolimus group.  
Further tables will summarize the number and percentage of subjects having adverse events, 
classified according to severity and the number and percentage of subjects with related events. The 
order of SOCs presented in tables will be according to the internationally agreed order of SOCs 
according to MedDRA. Within each SOC, the preferred terms will be shown in alphabetic order. 
Note: Subjects who have multiple events in the same SOC and/or preferred term will be counted only 
once at each level of summation (overall, by SOC, and by preferred term) in the tables. For 
summaries of AEs by severity, only the highest severity of AE will be counted at each level of 
summation (overall, by SOC, and by preferred term) in the tables. For summaries of related AEs, 
subjects with more than one related AE will be counted only once at each level of summation (overall, 
by SOC, and by preferred term) in the tables.   
8.11 Death, Serious Adverse Events and other Significant Adverse Events 
A listing of subjects who died on study will be presented.  
Tables will summarize the number and percentage of subjects having a serious adverse event in 
each SOC and preferred term. Further tables will summarize the number and percentage of subjects 
having serious adverse events judged to be related to RX-0201.  
The order of SOCs presented in tables will be according to the internationally agreed order of SOCs 
according to Medical Dictionary for Regulatory Affairs (MedDRA) version 21.0. Within each SOC, the 
preferred terms will be shown in alphabetic order. 
A listing of subjects reporting serious adverse events will be included. 
A listing of subjects and the adverse events leading to study discontinuation will be presented.   


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Separate listings will be presented for total adverse events, serious adverse events, adverse events 
related to treatment with RX-0201 and CTCAE Grade 3 and 4 adverse events. 
8.12 Pregnancies 
Pregnancy Test results will be presented in by-subject listings for further medical review.  
8.13 Clinical Laboratory Evaluations 
Abnormal laboratory values will be assessed according to NCI CTCAE v4.03 where possible. The 
criteria for “clinically significant” laboratory abnormalities include a laboratory abnormality that leads to 
a DLT or a laboratory abnormality that results in any treatment-emergent therapeutic intervention (i.e., 
concomitant medication or therapy), or any other laboratory abnormality judged by the investigator to 
be of other particular clinical relevance. 
.  
All relevant clinical laboratory tests will be classified as Low, Normal, and High, or Normal/Abnormal 
according to the normal ranges. This categorical data will be summarized in shift tables comparing 
the results at each scheduled post-baseline visit with those at the baseline visit.  
When there are multiple values within a visit for a particular laboratory variable, the worst value will be 
taken (worst being the smallest value for criteria below a certain threshold or the largest value for 
criteria above a certain threshold). If a subject has both a value below the threshold and a value 
above the threshold, the value furthest from the threshold will be chosen. 
Urinalysis data will be presented in subject listings only.  
All laboratory (hematology, coagulation, clinical chemistry, and urinalysis) parameters, values, units, 
normal range, flags collected (normal/abnormal) in the clinical database will be included in by-subject 
listings for further medical review. Laboratory values with associated CTCAE version 4 grades will 
have the associated grade displayed.   
8.14 Other Safety Measures 
8.14.1 ECOG Performance Status 
ECOG performance status results will be summarized descriptively using N frequency and 
percentage by dose group at each visit. 


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8.14.2 Vital Signs 
Resting vital signs, including pulse, blood pressure, respiration rate, temperature and weight, will be 
collected at screening, days 1, 8 and 15 of each cycle, end of treatment (or early termination), and 
safety follow-up visits. They will be summarized descriptively as will change from baseline results by 
treatment group and assessment time point. 
 
9 
Efficacy Analyses 
9.1 
Primary Efficacy Analysis 
Tumor assessment(s) will be performed by the investigator using RECIST Version 1.1 criteria with 
modifications (Appendix E of the protocol) at the end of every 2 cycles  
Subjects first meeting criteria for complete response or partial response at the last on-treatment tumor 
assessment should have a follow-up tumor assessment at the End of treatment or Early Termination 
visit providing it is ≥ 3 weeks from the previous tumor assessment.  
 The results will be available before the beginning of the next cycle. 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 
will be evaluated for tumor progression at the time symptoms occur. 
The efficacy endpoints analyzed for this study are tumor response (complete response (CR) plus 
partial response (PR) according to RECIST), progression-free survival (PFS), time to response and 
response duration (for responders only). Progression-free survival is defined as time from first dose to 
the earlier of either first documented disease progression or death from any cause. Time to response 
is defined as time from first dose to first PR or CR (that is subsequently confirmed). Duration of 
response will be defined as time from first PR or CR (that is subsequently confirmed) to the earlier of 
either first documented disease progression or death from any cause. 
9.1.1 
Progression-Free Survival 
 
Progression-free survival (PFS) will be defined as the date treatment starts to the date of first 
documented disease progression (PD) or death due to any cause, whichever comes first. Subjects 
alive without disease progression or lost to follow up at the time of analysis will be censored at the 
date of last response assessment. Table 1 below shows the censoring rules for progression-free 
survival.  


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The distribution of the progression-free survival will be estimated and graphed using Kaplan-Meier 
method. If applicable, estimates of the 25th percentile, median and 75th percentile and their 
respective 95% confidence intervals will be provided.  
Kaplan-Meier curves for RX-0201 in combination with everolimus and everolimus alone will be 
estimated separately but displayed on one graph as a visual comparison of the survival curves 
between treatment groups. The log-rank test will be performed to compare the survival curves at the 
0.05 significance level.   
Table 1         Censoring Rules for Progression-Free Survival 
Situation 
End Date 
Censored 
Documented PD during the study 
Date of the first assessment of the 
series of the tests that determined PD 
No 
Death during the study before PD 
Date of death 
No 
Discontinued due to PD, but no 
documented PD  
Date of observation of clinical 
progression (tumor timepoint 
response assessment CRF page) or 
date of discontinuation. 
No 
No baseline assessments  
Date of randomization  
Yes 
Treatment discontinuation for other 
than PD or death, and no post-
baseline tumor assessments 
Date of randomization 
Yes 
Treatment discontinuation for other 
than PD or death with post-baseline 
tumor assessments 
Date of last tumor assessment  
Yes 
Death or PD after two or more missed 
tumor assessments 
Date of last tumor assessment before 
missed tumor assessment 
Yes  
Subjects still on treatment without PD 
as of data cut-off 
Date of last tumor assessment  
Yes 
Only NE assessments after CR, PR, 
SD 
 
Date of last tumor assessment before 
NE assessment 
Yes 
Note1: During the study includes Stage 2 treatment phase and follow-up period. 
 
 
 
9.1.2 
Best Overall Response (per eCRF) 
Best overall response as assessed by the Investigator (with confirmation required for CR and PR) will 
be determined by RECIST criteria v1.1 per the eCRF and used in data display and analyses. The 
responses, listed from best to worst will be: complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD), and not evaluable (NE).  


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The number and percentage of subjects in each category of best response and best Overall 
Response Rate (CR + PR) will be summarized for RX-0201 in combination with everolimus, and 
groups combined. The corresponding 95% confidence intervals will be computed by treatment group 
using the Clopper-Pearson method for calculating the exact binomial intervals.  
9.1.3 
Time to Response 
Time to response is defined as time from first dose to first PR or CR (that is subsequently confirmed). 
The distribution of time to response will be estimated and graphed using Kaplan-Meier method. If 
applicable, estimates of the 25th percentile, median and 75th percentile and their respective 95% 
confidence intervals will be provided.  
Kaplan-Meier curves for RX-0201 in combination with everolimus will be estimated separately but 
displayed on one graph as a visual comparison of the survival curves between treatment groups. The 
log-rank test will be performed to compare the survival curves at the 0.05 significance level.   
9.1.4 
Duration of Response 
Duration of response (DoR) will be defined as the time from the first documented response (CR or 
PR) to either the first documented disease progression or death due to any cause whichever is first. 
Subjects achieving a CR or PR, who are alive without disease progression or are lost to follow up at 
the time of analysis, will be censored at the date of last response assessment. 
Only subjects who achieve a best response of CR or PR by the confirmed Investigator Assessment of 
Efficacy will be included in this analysis. The duration of response will be assessed on a subject-by-
subject basis and descriptively summarized by treatment group and overall.  
Kaplan-Meier curves for RX-0201 in combination with everolimus will be estimated if applicable. 
9.1.5 
Pharmacokinetics 
Pharmacokinetic parameters such as area under the time-concentration curve (AUC), maximum 
plasma concentration (Cmax), time to first maximum plasma concentration (Tmax), volume of 
distribution (Vd/F), terminal halflife (t1/2), and total body clearance (CL/F) will be estimated using 
standard non-compartmental methods and will be derived from blood plasma concentration versus 
time for RX-0201 for each subject.   


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RX-0201 concentrations in plasma will be listed by subject and time point. Concentrations by time 
data may be plotted for each subject. Pharmacokinetic parameters will be listed by subject and 
descriptively summarized by dose level. RX-0201 concentration time data will be summarized and 
plotted by dose group.   
For the calculation of summary statistics of the concentration values, values that are below the limit of 
quantitation (BLQ) of 1.00 ng/mL are treated as 0.00 prior to the first quantifiable concentration and 
as missing thereafter. 
10 Technical Details 
Statistical Analysis Software (SAS) version 9.4 or later will be used to analyze the data, create 
summary tables, subject data listings, and graphical representation of the data. 
All SAS programs will be validated via independent validation programs per H2O Clinical internal 
SOPs. 
11 Summary of Changes to the Protocol 
None. 
 
 


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12 References 
International Federation of Pharmaceutical Manufacturers and Associations.Medical Dictionary for 
Regulatory Activities (MedDRA).Version 10.1.Reston, Virginia, USA; 2008. 
WHO Collaborating Center for International Drug Monitoring. WHO Drug Dictionary.July 2008 edition. 
Uppsala, Sweden; 2008. 
SAS Institute Inc. SAS Version 9.1. Cary, NC, USA; 2002-2003. 
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., & Verweij, J.  
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European 
journal of cancer, 2009; 45: 228-247. 


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13 Listing of Tables, Listings and Figures 
 
 
FIGURE 
NUMBER 
FIGURE TITLE 
POPULATION FOR 
ANALYSIS 
1 
Waterfall Plot (maximum % reduction from baseline in tumor size 
– target lesions only) 
Evaluable for Tumor 
Response Analysis Set 
2 
Kaplan-Meier Plot – Progression Free Survival 
Evaluable for Tumor 
Response Analysis Set 
3 
Kaplan-Meier Plot – Time to Response 
Evaluable for Tumor 
Response Analysis Set 
4 
Kaplan-Meier Plot – Duration of Respons (if applicable) 
Evaluable for Tumor 
Response Analysis 
 
 
 
 
 
 
 
 
 
 
 


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16 
Appendices  
Appendix A.  Stage 1 Schedule of Assessments 
 
 Abbreviations: SCR = screening, ECOG = Eastern Cooperative Oncology Group, SFU = safety follow up visit; EOT = end of treatment visit; ET = 
early termination 


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1    Screening procedures will be performed within 14 days of enrollment/ randomization, except baseline tumor assessment, which can be 
evaluated within 21 days of enrollment/ randomization 
2    Cycles 2 – 8 will follow the same assessment schedule 
3    Safety follow-up visit will occur approximately 30 (+ 7) days after the last administration of RX-0201 or everolimus, whichever occurs later 
4    Assessment can be performed within 3 days before Day 1 of each cycle 
5    A serum pregnancy test must be negative for all females of childbearing potential 
6    A urine pregnancy test must be negative for all females of childbearing potential before treatment begins. If a serum pregnancy test was done 
and determined negative within 72 hours of planned first dose a urine pregnancy test is not needed 
7    Vital signs can be assessed up to 3 days before Day 1 and will be assessed whenever a PK sample is collected in Cycle 1 
8    See Appendix C for analytes to be collected. If screening laboratory tests were performed within 72 hours of Cycle 1 Day 1, they do not need 
to be repeated on Cycle 1 Day 1. Samples to be taken before any RX-0201 or everolimus is administered9    Everolimus will be taken at the clinic 
on Days 1, 2, 15, and 16 of Cycle 1, and Day 1 of all other cycles 
10  Subjects will bring all everolimus packaging (empty and full) to the clinic to determine drug compliance 
11  RX-0201 compliance will be checked at the Early Termination if the subject was receiving RX-0201 at the time of early termination. 
12  All adverse events attributed to study drug(s) will be assessed until resolution or return to baseline 
13  Blood will be collected for subjects enrolled in only Stage 1 at the following time points: 
•    Immediately prior to Cycle 1 infusion, then at 1 hour ± 5 minutes, 2 hours ± 5 minutes, 3 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours 
± 10 minutes, and 24 hours (± 1 hour) (ie, Day 2) after start of RX-0201 infusion . 
•    Immediately prior to the end of Cycle 1 infusion (ie, Day 15), then at 1 hour ± 5 minutes, 2 hours ± 5 minutes, 3 hours ± 10 minutes, 4 hours 
± 10 minutes, 6 hours ± 10 minutes, and 24 hours (± 1 hour) (ie, Day 16) after the RX-0201 infusion pump has been turned off 
14  Disease assessment will occur at the end of every 2 cycles 
15  Subjects first meeting criteria for complete response or partial response at the last on-treatment tumor assessment should have a follow-up 
tumor assessment at the End of treatment or Early Termination visit providing it is ≥ 3 weeks from the previous tumor assessment in order to 
confirm the response based on RECIST ver. 1.1 criteria 
16  Biomarker blood samples will be collected within 1 day of the disease assessment (approximately at the end of every 2 cycles and at EOT/ET 
if applicable) 
17  Tissue blocks or tissue sections from initial diagnosis or upon diagnosis of advanced metastatic disease will be available for submission to the 
central laboratory within approximately 4 weeks after initiation of study treatment; exceptions require written documentation of why a sample is not 
available and prior approval by the sponsor before enrollment 
 
 
 


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Appendix B.  Stage 2 Schedule of Assessments 
Abbreviations: SCR = screening, ECOG = Eastern Cooperative Oncology Group, SFU = safety follow up visit; EOT = end of treatment visit;  
ET = early termination 
 


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1    Screening procedures will be performed within 14 days of enrollment/ randomization, except baseline tumor assessment, which can be    
evaluated within 21 days of enrollment/ randomization 
2    Cycles 2 – 8 will follow the same assessment schedule 
3    Safety follow-up visit will occur approximately 30 (+ 7) days after the last administration of RX-0201 or everolimus, whichever occurs later 
4    Assessment can be performed within 3 days before Day 1 of each cycle 
5    A serum pregnancy test must be negative for all females of childbearing potential 
6    A urine pregnancy test must be negative for all females of childbearing potential before treatment begins. If a serum pregnancy test was done 
and determined negative within 72 hours of planned first dose a urine pregnancy test is not needed 
7    See Appendix C for analytes to be collected. If screening laboratory tests were performed within 72 hours of Cycle 1 Day 1, they do not need to 
be repeated on Cycle 1 Day 1. Samples to be taken before any RX-0201 or everolimus is administered 
8    Everolimus (10 mg) will be taken at the clinic on Cycle 1 Day 1, and then at home every day thereafter 
9    Subjects will bring all everolimus packaging (empty and full) to the clinic to determine drug compliance 
10  RX-0201 compliance will be checked at the Early Termination if the subject was receiving RX-0201 at the time of early termination. 
11  All adverse events attributed to study drug(s) will be assessed until resolution or return to baseline 
12  Disease assessment will occur at the end of every 2 cycles 
13  Subjects first meeting criteria for complete response or partial response at the last on-treatment tumor assessment should have a follow-up 
tumor assessment at the End of treatment or Early Termination visit providing it is ≥ 3 weeks from the previous tumor assessment in order to 
confirm the response based on RECIST ver. 1.1 criteria 
14  Biomarker blood samples will be collected within 1 day of the disease assessment (approximately at the end of every 2 cycles and at EOT/ET 
if applicable) 
15  Tissue blocks or tissue sections from initial diagnosis or upon diagnosis of advanced metastatic disease will be available for submission to the 
central laboratory within approximately 4 weeks after initiation of study treatment; exceptions require written documentation of why a sample is not 
available and prior approval by the sponsor before randomization