Clinical trial NCT04525131
Conditions: Bladder Cancer
Keywords: Newly diagnosed or recurrent bladder tumors
Sponsor: CicloMed LLC
Start date: 2020-11-25; Completion date: 2023-06-30
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II, single center open label to determine safety, dose tolerance, PK and PD of the recommended Phase 2 dose (RP2D) of CPX-POM administered in patients with any newly diagnosed or recurrent bladder tumors.

Detailed description:
This will be an open-label study to determine the safety, dose tolerance, pharmacokinetics, and pharmacodynamics of CPX-POM in patients with newly diagnosed or recurrent, untreated or intravesical treatment completed \>6 months before the current diagnosis, resectable tumors. Approximately 12 patients will be enrolled and treated with 900 mg/m2 CPX-POM administered IV over 20 minutes once per day for 5 days followed by TURBT on Day 5 after the fifth dose. TURBT will be performed 2 to 6 hours following drug administration on Day 5.

Pretreatment bladder tumor tissues will be obtained at the time of in-office cystoscopy by cold cup biopsy within 4 weeks of TURBT. Posttreatment bladder tumor tissues will be obtained at TURBT. Bladder tumor tissues will undergo pathological evaluation at each site.

Prior to administration of the first CPX-POM dose on Day 1, pre-dose blood (plasma) and urine (clean catch) samples will be collected. At the time of TURBT on Day 5, one 3-mL blood (plasma) sample and a urine specimen will be collected for measurement of CPX-POM concentrations.

Patients will be followed for at least 30 days after the last dose of CPX-POM for safety

Arms: arm 1: IV over 20 minutes once per day
Interventions: intervention 1: CPX-POM
Intervention descriptions: intervention 1: CPX-POM

Protocol documents:
Prot_000.pdf: 
 
CicloMed LLC 
 
CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
A Window of Opportunity Study to Characterize the Safety, 
Dose Tolerance, Pharmacokinetics, and Pharmacodynamics of 
CPX-POM in Patients with Newly Diagnosed or Recurrent 
Bladder Tumors 
 
 
Sponsor: 
CicloMed LLC  
4520 Main Street 
Suite 1500 
Kansas City, MO 64111 
 
 
IND No.: 
132545 
 
 
Indication: 
Non-Muscle Invasive Bladder Cancer 
 
 
Protocol ID: 
CPX-POM-002 
 
 
Protocol Versions/Dates: 
Original Protocol Version 1.0 /13 July 2020 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or under control 
of CicloMed LLC, and is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Institutional Review Board or Independent 
Ethics Committee. The information is only to be used by you in connection with authorized clinical studies 
of the investigational drug described in the protocol. You will not disclose any of the information to others 
without written authorization from CicloMed LLC, except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 


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SPONSOR SIGNATURE PAGE 
 
CicloMed LLC  
4520 Main Street 
Suite 1500 
Kansas City, MO 64111 
 
A Window of Opportunity Study to Characterize the Safety, Dose Tolerance, 
Pharmacokinetics, and Pharmacodynamics of CPX-POM in Patients with Newly Diagnosed 
or Recurrent Bladder Tumors 
Version 1.0, 13 July 2020 
This protocol has been approved by CicloMed LLC.  The following signatures document this 
approval. 
 
 
 
 
 
7-14-2020 
William McCulloch, MB, FRCP, FFPM 
Medical Consultant 
CicloMed LLC 
 
(Date) 
 
 
 
 
 
 
 
14 July 2020 
Scott J Weir, PharmD, PhD 
Chief Scientific Officer [Acting] 
CicloMed LLC 
 
(Date) 
 


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INVESTIGATOR PROTOCOL AGREEMENT 
A Window of Opportunity Study to Characterize the Safety, Dose Tolerance, 
Pharmacokinetics, and Pharmacodynamics of CPX-POM in Patients with Newly Diagnosed 
or Recurrent Bladder Tumors 
Version 1.0, 13 July 2020. 
 
By my signature, I  
• Confirm that my staff and I have carefully read and understand this protocol and the 
Investigator’s Brochure (IB) and are thoroughly familiar with the appropriate use of 
the investigational drug described herein.   
• Agree to comply with the conduct and terms of the study specified herein and with 
any other study procedures provided by the Sponsor, CicloMed LLC.   
• Agree to comply with United States (US) Food and Drug Administration (FDA) 
regulations, the International Conference on Harmonization (ICH) Good Clinical 
Practices (GCP) guidelines, the Declaration of Helsinki, and all applicable rules, 
regulations, and federal, state, and local laws relating to the conduct of clinical studies 
and the protection of human subjects.  
• Agree not to implement changes to the protocol without agreement from the Sponsor 
and prior written approval (where required) from the Institutional Review Board 
(IRB), except when necessary to eliminate an immediate hazard to the subjects.  
• Agree to onsite monitoring of the case report forms (CRFs) and source documents by 
the Sponsor or designee and to audit by the Sponsor or designee and appropriate 
regulatory authorities, including, but not limited to, the FDA and IRB inspectors. 
• Agree to supervise the conduct of the study and maintain responsibility for training 
and supervising all personnel who have been delegated responsibilities under my 
leadership.  The protocol and other important study materials will be available to 
study staff throughout the conduct of the study. 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Print Name 
 
 
 


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TABLE OF CONTENTS 
 
1. 
PROTOCOL SUMMARY ............................................................................................................................. 6 
1.1. 
Synopsis ............................................................................................................................................ 6 
1.2. 
Study Diagram .................................................................................................................................. 8 
1.3. 
Schedule of Assessments ................................................................................................................ 10 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................ 14 
2. 
INTRODUCTION ....................................................................................................................................... 16 
2.1. 
Background on CPX-POM ............................................................................................................. 16 
2.2. 
Background on Bladder Cancer and Rationale for the Study .......................................................... 18 
3. 
OBJECTIVES .............................................................................................................................................. 21 
4. 
STUDY DESIGN ........................................................................................................................................ 22 
4.1. 
Overall Design ................................................................................................................................ 22 
4.2. 
Rationale for Study Design ............................................................................................................. 22 
4.3. 
Dose Selection ................................................................................................................................ 22 
4.4. 
End of Study Definition .................................................................................................................. 22 
5. 
STUDY POPULATION .............................................................................................................................. 24 
5.1. 
Inclusion Criteria ............................................................................................................................ 24 
5.2. 
Exclusion Criteria ........................................................................................................................... 25 
5.3. 
Meals and Dietary Considerations .................................................................................................. 27 
5.4. 
Screen Failures ................................................................................................................................ 27 
6. 
TREATMENTS ........................................................................................................................................... 28 
6.1. 
Investigational Product ................................................................................................................... 28 
6.1.1. 
Description of Investigational Product .......................................................................... 28 
6.1.2. 
Packaging and Labeling ................................................................................................ 28 
6.1.3. 
Storage and Handling .................................................................................................... 28 
6.1.4. 
Dosage and Administration ........................................................................................... 28 
6.1.5. 
Dose Modifications ....................................................................................................... 28 
6.1.6. 
Compliance ................................................................................................................... 29 
6.1.7. 
Accountability ............................................................................................................... 29 
6.2. 
Prior and Concomitant Medications ................................................................................................ 29 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL .................................................................................................... 31 
7.1. 
Discontinuation of Study Treatment ............................................................................................... 31 
7.2. 
Patient Discontinuation/Withdrawal from the Study ...................................................................... 31 
7.3. 
Lost to Follow Up ........................................................................................................................... 31 
8. 
STUDY ASSESSMENTS ........................................................................................................................... 33 
8.1. 
Safety Assessments ......................................................................................................................... 33 
8.1.1. 
Adverse Events and Serious Adverse Events ................................................................ 33 
8.1.2. 
Pregnancy ...................................................................................................................... 38 
8.1.3. 
Other Safety and Screening Assessments ..................................................................... 39 
8.2. 
Pharmacokinetic Assessments ........................................................................................................ 42 
8.3. 
Pharmacodynamic Assessments ...................................................................................................... 43 
9. 
STATISTICAL CONSIDERATIONS ......................................................................................................... 44 
9.1. 
Number of Patients.......................................................................................................................... 44 
9.2. 
Analysis Sets ................................................................................................................................... 44 
9.2.1. 
Safety ............................................................................................................................ 44 
9.2.2. 
Pharmacokinetics .......................................................................................................... 44 
9.3. 
Data Handling Conventions ............................................................................................................ 44 
9.4. 
Demographic Data and Baseline Characteristics ............................................................................ 44 
9.5. 
Safety Analysis ............................................................................................................................... 44 
9.5.1. 
Adverse Events ............................................................................................................. 44 
9.5.2. 
Laboratory Evaluations ................................................................................................. 45 
9.5.3. 
Other Safety Evaluations ............................................................................................... 45 


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9.6. 
Pharmacokinetic Analysis ............................................................................................................... 45 
9.7. 
Pharmacodynamic Analyses ........................................................................................................... 45 
9.8. 
Interim Analyses ............................................................................................................................. 46 
10. REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .................................... 47 
10.1. 
Regulatory and Ethical Considerations ........................................................................................... 47 
10.1.1. 
Institutional Review Board/Ethics Committee .............................................................. 47 
10.1.2. 
Ethical Conduct of the Study ........................................................................................ 47 
10.1.3. 
Informed Consent .......................................................................................................... 48 
10.1.4. 
Confidentiality .............................................................................................................. 48 
10.2. 
Study Oversight .............................................................................................................................. 49 
10.2.1. 
Data Quality Assurance ................................................................................................. 49 
10.2.2. 
Source Documents ........................................................................................................ 49 
10.2.3. 
Study and Site Closure .................................................................................................. 49 
10.2.4. 
Reporting of Results and Publications .......................................................................... 50 
10.2.5. 
Study Files and Retention of Records ........................................................................... 51 
10.2.6. 
Case Report Forms ........................................................................................................ 52 
10.2.7. 
Inspections .................................................................................................................... 52 
10.2.8. 
Protocol Compliance ..................................................................................................... 52 
10.2.9. 
Study Discontinuation ................................................................................................... 52 
11. REFERENCES ............................................................................................................................................ 53 
 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments ............................................................................................... 11 
Table 2. 
Eastern Cooperative Oncology Group Performance Status ........................................... 40 
Table 3. 
Listing of Required Screening and Safety Laboratory Parameters ................................ 42 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Study Design ................................................................................................................... 9 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
 
CicloMed LLC 
4520 Main Street 
Suite 1500 
Kansas City, MO 64111 
 
 
 
Study Title:  
A Window of Opportunity Study to Characterize the Safety, Dose Tolerance, 
Pharmacokinetics, and Pharmacodynamics of CPX-POM in Patients with 
Newly Diagnosed or Recurrent Bladder Tumors 
IND Number: 
132545 
Study Centers 
Planned: 
One center in the United States 
Objectives: 
The primary objective is: 
• 
To characterize the safety and dose tolerance of CPX-POM 
administered as 900 mg/m2 by 20-minute intravenous (IV) infusion 
once daily for 5 days to patients with newly diagnosed or recurrent 
bladder tumors who will be scheduled to undergo transurethral 
resection of a bladder tumor (TURBT) 
The secondary objectives are: 
• 
To determine the number of patients with treatment-related adverse 
events (AEs) 
• 
To elucidate mechanisms of CPX-POM action on bladder tumor tissues 
employing an unbiased approach, using ribonucleic acid sequencing 
(whole transcriptome shotgun sequencing, RNA-seq) and chromatin 
immunoprecipitation-DNA sequencing (ChIP-seq) 
• 
To determine the change in bladder tumor tissue cell proliferation, 
Notch and Wnt cell signaling pathways, as well as bladder tumor tissue 
CD8+ tumor-infiltrating lymphocytes (TIL) via immunohistochemistry 
• 
To determine bladder tumor tissue-to-plasma and tissue-to-urine 
ciclopirox (CPX) concentration ratios 


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Study Design: 
This will be an open-label study to determine the safety, dose tolerance, 
pharmacokinetics, and pharmacodynamics of CPX-POM in patients with newly 
diagnosed or recurrent, untreated or intravesical treatment completed 
>6 months before the current diagnosis, resectable tumors.  Approximately 
12 patients will be enrolled and treated with 900 mg/m2 CPX-POM 
administered IV over 20 minutes once per day for 5 days followed by TURBT 
on Day 5 after the fifth dose.  TURBT will be performed 2 to 6 hours following 
drug administration on Day 5.  
Pretreatment bladder tumor tissues will be obtained at the time of in-office 
cystoscopy by cold cup biopsy within 4 weeks of TURBT.  Posttreatment 
bladder tumor tissues will be obtained at TURBT.  Bladder tumor tissues will 
undergo pathological evaluation at each site.  
Prior to administration of the first CPX-POM dose on Day 1, pre-dose blood 
(plasma) and urine (clean catch) samples will be collected.  At the time of 
TURBT on Day 5, one 3-mL blood (plasma) sample and a urine specimen will 
be collected for measurement of CPX-POM concentrations.  
Patients will be followed for at least 30 days after the last dose of CPX-POM 
for safety. 
Number of 
Patients 
Planned: 
Approximately 12 patients will be enrolled. 
Target 
Population: 
The target population for this study is patients with newly diagnosed bladder 
tumors, inclusive of recurrent disease, who are treatment-naïve or had treatment 
completed >6 months before screening, and will be scheduled to undergo 
TURBT 
Duration of 
Study: 
Patients will be in this study for approximately 9 weeks:  up to a 28-day 
screening period, a 5-day treatment period, and a 30-day follow-up period.  
Diagnosis and 
Main Eligibility 
Criteria: 
Patients eligible for enrollment will be adults who are likely to have a new 
bladder tumor based on clinical presentation or who are at high risk for tumor 
recurrence based on previous history, which is subsequently confirmed 
cystoscopically and will be scheduled to undergo TURBT.  Patients must be 
treatment-naïve or had treatment completed >6 months before screening, and 
have an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2. 
Test Product, 
Dose, and Mode 
of 
Administration: 
Patients will begin treatment with CPX-POM on a Monday, 4 days before the 
date of scheduled TURBT on a Friday.  Patients will receive CPX-POM 
900 mg/m2 by 20-minute IV infusion once daily for 5 days followed by 
TURBT after the last dose on Day 5.  
Reference 
Therapy, Dose, 
and Mode of 
Administration: 
Not applicable. 
Criteria for 
Evaluation: 
Safety and Dose Tolerance: 
Safety and tolerability will be based on an assessment of AEs, physical 
examinations, vital signs, electrocardiograms (ECGs), clinical laboratory tests, 
ophthalmologic assessments, and concomitant medications.   


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Pharmacokinetics and Pharmacodynamics  
Bladder cancer tissue will be obtained at the time of in-office biopsy during 
cystoscopy and at TURBT and will be evaluated by the departments of 
pathology at the clinical sites.  Bladder tumor tissues will be analyzed using 
RNA-seq and ChIP-seq to elucidate mechanisms of CPX-POM action.  To 
determine the change in bladder tumor tissue cell proliferation, Notch and Wnt 
cell signaling pathways, as well as bladder tumor tissue CD8+ TILs, 
immunohistochemistry will be performed on paraffin-embedded slides. 
Concentrations of CPX-POM, CPX, and ciclopirox glucuronide (CPX-G) in 
urine, plasma, and tumor tissue collected at the time of TURBT on Days 1 
and 5 will be determined by Good Laboratory Practices (GLP)-validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) methods.  Urine 
β-glucuronidase activity will be determined in the urine specimens collected on 
Days 1 and 5 by enzyme linked immunosorbent assay (ELISA).  
Statistical 
Methods: 
Safety and Dose Tolerance: 
Safety data will be presented in by-patient listings.  Categorical safety 
endpoints will be summarized by frequency of events/abnormalities for each 
dose group and overall.  Continuous safety endpoints will be summarized using 
descriptive statistics (number of subjects [n], mean, standard deviation, median, 
first quartile [Q1], third quartile [Q3], minimum, maximum) for each dose 
group and overall.   
Pharmacokinetics and Pharmacodynamics: 
By-patient listings of the results of bladder tumor tissues RNA-seq and 
ChIP-seq analyses will be provided.  By-patient listings of 
immunohistochemical analysis of pre-treatment and TURBT bladder tumor 
tissues will be provided.  
By-patient listings of concentrations of CPX in tumor, plasma, and urine will 
be provided.  Bladder tumor tissue-to-plasma and tissue-to-urine CPX 
concentration ratios will be presented for each patient.  
By-patient listings of urine β-glucuronidase activity will be provided.  
 
This study will be conducted in accordance with the guidelines of current GCPs including 
archiving of essential documents.  
1.2. 
Study Diagram 
The study design is illustrated in Figure 1. 
 


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Figure 1. 
Study Design 
 
 
Abbreviations: D = day, PK = pharmacokinetics; TURBT = transurethral resection of bladder tumor; V = visit. 
 
Study Day:
D -28 
to -1
D35 ±3
Baseline safety assessments, PK samples,  and CPX-POM dosing
Safety follow-up visit 
V1
Study Visit:
D1
V2
V6
Screening eligibility assessments
D2
V5
D3 D4 D5
V3
V4
Safety assessments, CPX-POM dosing
Safety assessments, CPX-POM dosing, PK samples, TURBT
Safety assessments, CPX-POM dosing
Safety assessments, CPX-POM dosing
No dosing or study visits
V7
informed Consent
In-office cystoscopy/ cold cup biopsy 
D -28 
to -1


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1.3. 
Schedule of Assessments 
The schedule of assessments is shown in Table 1. 
 


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Table 1. 
Schedule of Assessments 
Study Procedure 
Screening 
Period 
Treatment Period 
Follow-up 
Period / ET 1 
Study Days: 
D -28 to  
D -1 
D1 
D2 
D3 
D4 
D5 
D35 
Study Visits: 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Informed consent 
X 
 
 
 
 
 
 
Cystoscopy / cold cup biopsy 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Pregnancy test 2 
X 
X 
 
 
 
 
X 
MUGA or ECHO 
X 
 
 
 
 
 
 
Chest X-ray or CT scan 
X 
 
 
 
 
 
 
Obtain tumor tissue sample 3 
X 
 
 
 
 
X 
 
Hematology 4 
X 
X 
 
X 
 
X 
X 
Clinical chemistry 5 
X 
X 
 
X 
 
X 
X 
Urinalysis 6 
X 
X 
 
X 
 
 
X 
Full physical exam 7 
X 
 
 
 
 
 
X 
Assess for physical 
symptoms/toxicities 7 
 
X 
X 
X 
X 
X 
 
Vital signs 8 
X 
X 
X 
X 
X 
X 
X 
ECG 9 
X 
X 
 
 
 
X 
X 
Adverse events 10 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 11 
X 
X 
X 
X 
X 
X 
X 
PK blood sample 12 
 
X 
 
 
 
X 
 
PK urine sample 13 
 
X 
 
 
 
X 
 
Body surface area 14 
 
X 
 
 
 
 
 
CPX-POM infusions 15 
 
X 
X 
X 
X 
X 
 
TURBT 16 
 
 
 
 
 
X 
 


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Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; 
BSA = body surface area; BUN = blood urea nitrogen; CPX-G = ciclopirox glucuronide; CPX-POM = ciclopirox phosphoryloxymethyl ester; 
CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EDTA = ethylenediamine tetraacetic acid; 
eGFR = estimated glomerular filtration rate; ELISA = enzyme linked immunosorbent assay; ET = early termination; GGT = gamma glutamyl transferase; 
IV = intravenous; LC-MS/MS = liquid chromatography-tandem mass spectrometry; MUGA = multi-gated acquisition; PD = pharmacodynamic; 
PK = pharmacokinetic; PT = prothrombin time; QTc = corrected QT interval; RBC = red blood cell; RC = radical cystectomy; SAE = serious adverse event; 
TURBT = transurethral resection of a bladder tumor; V = visit; WBC = white blood cell.   
1. Safety follow-up assessments will be performed within 30 days (±3 days) after the last dose of CPX-POM.  Or, in the event that a patient 
discontinues from the study prematurely, the site will make every effort to perform the assessments listed for this study visit.  
2. Pregnancy tests will be required only for women of childbearing potential at Screening and before dosing on Day 1.  Urine or serum pregnancy tests 
are acceptable.  
3. Pre-treatment bladder tumor tissue sample will be obtained during in-office cystoscopy by cold cup biopsy within 4 weeks of TURBT.  Post-
treatment bladder tissue sample will be obtained at surgical resection (TURBT) on Day 5. 
4. Hematology will include measurement of hemoglobin, hematocrit, platelets, RBC, reticulocytes, and WBC with differential.   
5. Clinical chemistry will include measurement of potassium, sodium, chloride, glucose, BUN, creatinine, creatinine clearance, ALT, AST, GGT, 
alkaline phosphatase; indirect bilirubin, direct bilirubin, total bilirubin, total protein, albumin, calcium, bicarbonate, magnesium, phosphate, lipase, 
and amylase.   
6. Urinalysis will include color, turbidity, pH, specific gravity, glucose, ketones, nitrites, bilirubin, urobilirubin, protein, RBCs, WBCs, epithelial cells, 
casts, crystals, and bacteria, and eGFR at Screening only. 
7. A full physical examination will be conducted at Screening and at Visit 7/Follow-up.  At each other study visit, patients will be assessed for 
continued dosing and any possible physical symptoms/toxicities and a physical examination may be performed, if indicated.  Body weight should 
be measured at each study visit.  Height should be measured at Screening.  
8. Vital signs will be measured before any blood draws scheduled for the same time point.  Vital signs will include blood pressure, respiratory rate, 
pulse, oxygen saturation, and temperature.    
9. At Screening, 12-lead ECGs will be performed in triplicate, with each measurement separated by 2 minutes.  The average of the 3 screening ECGs 
will be used to calculate QTc interval to determine study eligibility.  Thereafter, single 12-lead ECGs will be performed for all patients prior to drug 
administration on Days 1 and 5 and at the Final Study visit.   
10. All AEs and SAEs will be collected from the signing of the informed consent form through the time of TURBT.  Starting at TURBT, only AEs 
related to CPX-POM treatment should be recorded; AEs related to the TURBT will not need to be recorded.  
11. All concomitant medications will be recorded from the time of Screening up to the time of TURBT. Starting at TURBT, only medications 
associated with an AE related to CPX-POM treatment need to be recorded; routine medications and medications associated with the TURBT 
procedure do not need to be recorded.   
12. Single blood (plasma) samples will be taken on Day 1 prior to CPX-POM administration and on Day 5 at the time of TURBT.  Concentrations of 
CPX-POM, CPX, and CPX-G will be determined in these samples by LC-MS/MS.  The date and time of sample collection will be recorded.  


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13. A clean catch urine sample will be collected on Day 1 prior to CPX-POM administration.  A second urine specimen will be collected on Day 5 at 
the time of TURBT.  Concentrations CPX-POM, CPX, and CPX-G will be determined in these samples by LC-MS/MS.  Urine β-glucuronidase 
activity will also be determined in these samples by ELISA.  
14. BSA will be calculated by the site personnel using the Dubois method of calculation using screening (Visit 1) height and baseline (Visits 2) weight 
measurements.   
15. CPX-POM infusions will be administered as 900 mg/m2 20-minute IV infusion once daily for 5 days. Patients will be observed for at least 1 hour 
after completion of each infusion of CPX-POM.  
16. TURBT will be performed within 2 to 6 hours after the last dose of CPX-POM has been administered on Day 5.  
 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AUC 
area under the concentration-time curve 
BSA 
body surface area 
ChIP-seq 
chromatin immunoprecipitation-DNA sequencing 
CNS 
central nervous system 
CPX 
ciclopirox 
CPX-G 
ciclopirox glucuronide 
CPX-O 
ciclopirox olamine 
CPX-POM 
ciclopirox phosphoryloxymethyl ester (ciclopirox prodrug) 
CRF 
case report form(s) 
CRO 
contract research organization  
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
ECHO 
echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
estimated glomerular filtration rate 
FDA 
(United States) Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IRB 
institutional review board 
IV 
intravenous 
MIBC 
muscle invasive bladder cancer 
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition 
n 
number of subjects 
NCI 
National Cancer Institute 
NMIBC 
nonmuscle invasive bladder cancer 
NOAEL 
no observed adverse effect level 


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NYHA 
New York Heart Association 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia’s formula 
RC 
radical cystectomy 
RNA 
ribonucleic acid 
RNA-seq 
RNA-sequencing or whole transcriptome shotgun sequencing (use of next-
generation sequencing to reveal the presence and quantity of RNA in a 
biological sample) 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SOC 
system organ class 
TIL 
tumor infiltrating lymphocyte 
TURBT 
transurethral resection of a bladder tumor 
ULN 
upper limit of the normal range 


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2. 
INTRODUCTION 
2.1. 
Background on CPX-POM 
Fosciclopirox (CPX-POM) is a prodrug of ciclopirox (CPX).  CPX is a synthetic antifungal 
agent approved for topical dermatologic use in the treatment of a broad spectrum of fungal 
organisms (Gupta, 2001).  CPX and ciclopirox olamine (CPX-O) are contained in a number 
of marketed topical drug products.  CPX also exerts antibacterial activity against many 
Gram-positive and Gram-negative bacteria (Abrams et al, 1991).  CPX is a hydroxypyridone 
that is structurally unrelated to other antifungal agents and has a unique and complex mode 
of action.  CPX is thought to act through the chelation of polyvalent metal cations, such as 
iron and aluminum, resulting in the inhibition of the metal-dependent enzyme systems (e.g., 
cytochromes, catalase, peroxidase), thus disrupting cellular activities, such as inhibiting 
degradation of peroxides within the fungal cells (Gupta and Plott, 2004) and mitochondrial 
electron transport processes and energy production (Sakurai et al, 1978; Gupta et al, 1994).  
It is also thought that CPX affects the cytoplasmic membranes, inhibiting transport of 
essential elements in the fungal cell, disrupting the synthesis of DNA, ribonucleic acid 
(RNA), and protein (Gupta and Plott, 2004).  In addition, CPX may have anti-inflammatory 
activity as demonstrated by its ability to inhibit the synthesis of prostaglandins and 
leukotrienes in human polymorphonuclear cells (Abrams et al, 1991) and to inhibit the 
formation of 5-lipoxygenase and ciclo-oxygenase (Bohn and Kraemer, 2000; Hanel et al, 
1991).   
CPX has demonstrated in vivo and/or in vitro anticancer activity in at least 17 types of solid 
tumor and hematologic cancers (CPX-POM Investigators Brochure, 2017).  CPX modulates 
iron-dependent enzymes and signaling pathways resulting in inhibition of cell growth, 
proliferation, and survival.  CPX has been demonstrated to chelate intracellular iron in 
human cancer cells (Kwong et al, 2015; Eberhard et al, 2009; Sidarovich et al, 2015), which 
plays an important role in cancer cell death resulting from exposure to CPX (Clement et al, 
2002; Szüts and Krude, 2004; Eberhard et al, 2009; Sidarovich et al, 2015).  CPX exposure 
altered expression of 54 proteins in stem cells, including those associated with nucleotide 
binding, biosynthetic processes, gene expression, regulation of transcription, cell cycle 
processes, RNA and messenger RNA (mRNA) processing, and embryonic development 
(Dihazi et al, 2011). 
CicloMed is aware of 2 published reports of CPX-O administered orally to humans (Minden 
et al, 2014; Kellner et al, 1981).  Following oral administration of CPX-O to patients with 
refractory hematologic malignancies, evidence of pharmacodynamic (PD) activity was 
observed (Minden et al, 2014; Song et al, 2011).  Administration by the oral route of 
administration, however, is not feasible because of dose-limiting gastrointestinal toxicity and 
poor oral bioavailability due to high first pass effect (Minden et al, 2014).   


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Scientists at the University of Kansas synthesized the phosphoryloxymethyl ester of CPX, 
CPX-POM to enable parenteral administration of CPX.  In contrast to CPX and CPX-O, 
CPX-POM has high water solubility and is readily formulated for parenteral administration.   
Pharmacokinetic (PK) studies in laboratory animals showed that CPX-POM is rapidly and 
completely metabolized to its active metabolite, CPX, which then disappears from plasma 
following systemic administration of CPX-POM.  Following systemic administration of 
CPX-POM, the dose is eliminated from the body via renal clearance of CPX and the inactive 
glucuronide metabolite of CPX (CPX-G).   
In rats, intravenous (IV) CPX-POM administered for 28 consecutive days did not cause 
mortality or changes in body weight, food consumption, ophthalmology, hematology, 
coagulation, clinical chemistry, urinalysis, or organ weights.  There were no test item-related 
findings grossly or microscopically at the highest dose level tested (50 mg/kg/day).  Test 
item-related transient clinical signs, including slight to moderate decreased activity, increased 
respiration, eating-like behavior, and slight to moderate incoordination were noted 
immediately after dosing at 50 mg/kg/day.  The no observed adverse effect level (NOAEL) 
in rats was 25 mg/kg/day in males and 50 mg/kg/day in females.  
In dogs, CPX-POM administered for 28 consecutive days did not cause mortality or changes 
in body weight, food consumption, electrocardiogram (ECG) parameters, hematology, 
coagulation, clinical chemistry, urinalysis, or organ weights.  There were no test item-related 
findings grossly or microscopically at dose levels up to 30 mg/kg/day.  Test item-related 
transient clinical signs such as salivation, fecal changes, aggression, shaking, and tremors 
were noted after dosing at the highest dose level tested on the study (30 mg/kg/day).  
Convulsion was apparent in one dog on a single occasion.  Test-item related ophthalmic 
changes were noted in 3/10 dogs treated with 30 mg/kg/day.  Thus, the NOAEL in dogs was 
determined to be 10 mg/kg/day and the highest non-serious toxic dose (HNSTD) in the dog 
was determined to be 30 mg/kg.   
The first study of CPX-POM in patients (Study CPX-POM-001) has been initiated.  A total 
of 19 patients with a histologically- or cytologically-confirmed solid tumor refractory to 
standard therapy were enrolled in the Dose Escalation cohorts, 6 males and 13 females 
ranging in age from 20 to 86 years.  The starting dose of CPX-POM was 30 mg/m2 
administered once per day on Days 1 to 5 of each 21-day cycle.  Doses were escalated per 
protocol up to 1200 mg/m2.  The number of cycles of CPX-POM administered ranged from 
1 to 6 per patient (mean = 2.5 cycles).  The maximum tolerated dose (MTD) was determined 
to be 900 mg/m2, which was administered to a total of 6 patients.  The safety, dose tolerance, 
PK, and PD of IV CPX-POM, administered at the MTD over 20 minutes are currently being 
characterized in an expansion cohort of 12 patients with muscle invasive bladder cancer 
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CPX-POM was well tolerated up to the MTD of 900 mg/m2.  At the MTD, all of the related 
adverse events (AEs) were Grade 1 in severity.  Nausea and vomiting were the most 
frequently reported treatment-emergent adverse events (TEAEs), reported by 6 and 8 
patients, respectively, and were more common in the higher dose cohorts.  The primary dose 
limiting toxicity was central nervous system (CNS)-related side effects, in particular a drug-
related serious adverse event (SAE) of Grade 3 confusion in the 1200 mg/m2 cohort, which 
was considered a dose limiting toxicity, and 4 AEs of Grade 1 confusion in the 600 and 
900 mg/m2 cohorts (i.e., 2 reports in each cohort).  In the Nervous System system organ class 
(SOC), amnesia, dizziness, headache, and somnolence were also reported by 2 patients each.  
One patient in the 30 mg/m2 dose cohort died during the study as a result of an SAE of 
pneumonia, which started on Study Day 28 and was considered not related to CPX-POM 
treatment.   
During the Study CPX-POM-001 Dose Escalation Cohorts, CPX-POM injections were 
completed over a 10-minute period.  During the present study, injections will be completed 
over a 20-minute period.  Slowing the speed of CPX-POM injection may reduce the 
frequency and severity of CNS-related side effects such as confusion and infusion-related 
reactions.  
There was no evidence of corrected QT interval (QTc) prolongation or other ECG 
abnormalities in any patient receiving CPX-POM doses up to 1200 mg/m2.   
CPX-POM was rapidly and completely metabolized to CPX.  Plasma CPX-POM 
concentrations were observed in patients, however, concentrations declined rapidly, falling 
below the lower limits of the assay within 2 hours.  CPX-POM was not detected in urine. 
Analysis of PK data showed that systemic exposure to CPX increased proportionately with 
increasing dose.  The apparent elimination half-life of CPX typically ranged from 2 to 6 
hours across the dose range studied.  There was relatively low overall variability (<30%) in 
systemic clearance among individual patients.  There was no indication of accumulation over 
the 5 days of CPX-POM dosing (mean area under the concentration-time curve at steady 
state (AUCss)/initial area under the concentration-time curve (AUCi) = 1.03).  At the MTD, 
approximately 8.5% of the CPX-POM dose was excreted as CPX.  The mean urine 
concentrations of CPX over 24 hours were >200 µM at the MTD.  
2.2. 
Background on Bladder Cancer and Rationale for the Study 
The purpose of this study is to characterize the safety and mechanisms of action of CPX-
POM in patients with newly diagnosed or recurrent, untreated or intravesical treatment 
completed >6 months before the current diagnosis, resectable bladder tumors.  
Bladder cancer is the sixth most common solid tumor in the United States with an estimated 
80, 479 new cases and 17,670 deaths in 2019 (American Cancer Society, 2019).  In 2016, 
there were an estimated 699,450 people living with this disease in the United States (Siegel et 
al, 2019).  The disease has a high risk of recurrence as well as progression, thus requiring 


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life-long surveillance, making bladder cancer one of the most expensive cancers to treat on a 
per-patient-lifetime-basis (Botteman et al, 2003; Yeung et al, 2014).  While the overall 5-year 
survival rate for bladder cancer is 77%, in those with advanced disease, this rate can be as 
low as 4% (NCI SEER Cancer Stat Facts, 2019).  
Bladder cancer is defined as two diseases, each with different treatment approaches as well 
as outcomes.  Seventy percent or more of newly diagnosed patients have non-muscle 
invasive bladder cancer (NMIBC) which is generally considered less life-threatening than 
muscle invasive bladder cancer (MIBC) (Heney, 1992).  However, in spite of endoscopic 
resection followed by intravesical immunotherapy (Bacillus Calmette-Guérin [BCG]) or 
chemotherapy (e.g., mitomycin C, gemcitabine), 60 to 70% of those with NMIBC will recur 
and 20 to 30% will progress to MIBC (Aldoursari and Kassouf, 2010), where the gold 
standard treatment is radical cystectomy (RC) coupled with cisplatin-based chemotherapy in 
either neoadjuvant or adjuvant settings (Milan-Rodriguez et al, 2000).  It is estimated, 
however, that as many as 40 to 50% of MIBC patients are ineligible for cisplatin 
chemotherapy due to impaired renal function (Dash et al, 2006).  Patients with impaired 
performance status (Eastern Cooperative Oncology Group [ECOG] >1), heart failure (New 
York Heart Association [NYHA] class ≥III), grade ≥2 hearing loss, and/or grade ≥2 
neuropathy are also ineligible for cisplatin-based chemotherapy.  Given the poor complete 
response rate associated with neoadjuvant carboplatin and gemcitabine (Peyton et al, 2018), 
cisplatin-ineligible MIBC patients go straight to RC or enroll in clinical trials. 
CPX, the active metabolite of CPX-POM, has been shown to be active against both MIBC 
and NMIBC in vitro.  In vivo, CPX-POM treatment of mice with established bladder tumors 
induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) resulted in robust antitumor 
activity.  More importantly, CPX has been shown to have inhibitory activity against the 
Notch signaling pathway. Notch overexpression is associated with bladder cancer cell growth 
and survival.  Inhibition of Notch may be an important target for the control of bladder 
cancers.  Finally, currently available agents are administered topically by intravesical 
administration.  Approximately 50% of NMIBC cases will recur within 12 months and 25% 
will progress to MIBC.  CPX-POM affords an opportunity to develop a targeted, 
systemically administered therapy for NMIBC patients who are at risk of progressing to 
MIBC as well as a neoadjuvant treatment for MIBC in cisplatin-ineligible patients. 
CPX-POM potentially has several major advantages over CPX and CPX-O in the context of 
treatment for bladder cancer: 1) CPX-POM represents a composition of matter patentable 
invention; 2) CPX-POM possesses much improved physical and chemical properties that 
enable injectable formulation development; 3) by developing an injectable formulation of 
CPX-POM, CicloMed hopes to avoid the dose-limiting gastrointestinal toxicities and poor 
oral bioavailability observed following oral CPX-O administration; 4) CPX-POM is rapidly 
metabolized to CPX, which is eliminated in the urine as a glucuronide conjugate; 5) elevated 
beta-glucuronidase activity in the urine of bladder cancer patients has the potential to 


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hydrolyze the conjugate back to CPX and thereby affords the potential to target CPX to the 
bladder epithelium; and 6) CPX-POM administered systemically has the potential to deliver 
drug to the entire urinary tract (i.e., to treat upper urinary tract disease), as opposed to agents 
delivered by bladder instillation. 
The Investigator’s Brochure provides further details of the nonclinical studies and published 
clinical evaluations of CPX-POM (CPX-POM Investigator’s Brochure, 2019).  
  


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3. 
OBJECTIVES 
The primary objective is: 
• To characterize the safety and dose tolerance of CPX-POM administered as 
900 mg/m2 IV by 20-minute IV infusion once daily for 5 days to patients with newly 
diagnosed or recurrent bladder tumors who will be scheduled to undergo transurethral 
resection of a bladder tumor (TURBT) 
The secondary objectives are: 
• To determine the number of patients with treatment-related AEs 
• To elucidate mechanisms of CPX-POM action on bladder tumor tissues employing an 
unbiased approach, using ribonucleic acid sequencing (whole transcriptome shotgun 
sequencing, RNA-seq) and chromatin immunoprecipitation-DNA sequencing 
(ChIP-seq) 
• To determine the change in bladder tumor tissue cell proliferation, Notch and Wnt 
cell signaling pathways, as well as bladder tumor tissue CD8+ tumor-infiltrating 
lymphocytes (TIL) via immunohistochemistry 
• To determine bladder tumor tissue-to-plasma and tissue-to-urine CPX concentration 
ratios 
The exploratory objective is: 
• To determine urine ß-glucuronidase activity 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This will be an open-label study to determine the safety, dose tolerance, PK, and PD of 
CPX-POM in patients with newly diagnosed or recurrent, untreated or intravesical treatment 
completed >6 months before the current diagnosis, resectable tumors.  Approximately 
12 patients will be enrolled and treated with 900 mg/m2 CPX-POM administered IV over 
20 minutes once per day for 5 days followed by TURBT on Day 5 after the fifth dose.  
TURBT will be performed 2 to 6 hours following drug administration on Day 5.  
Pretreatment bladder tumor tissues will be obtained at the time of in-office cystoscopy by 
cold cup biopsy within 4 weeks of TURBT.  Posttreatment bladder tumor tissues will be 
obtained at TURBT.  Bladder tumor tissues will undergo pathological evaluation at each site.  
Prior to administration of the first CPX-POM dose on Day 1, pre-dose blood (plasma) and 
urine (clean catch) samples will be collected.  At the time of TURBT on Day 5, one 3-mL 
blood (plasma) sample and a urine specimen will be collected for measurement of CPX-POM 
concentrations.  
Patients will be followed for at least 30 days after the last dose of CPX-POM for safety. 
4.2. 
Rationale for Study Design 
The primary purpose of this study is to evaluate safety and dose tolerance as well as 
investigate the mechanisms of action of CPX-POM in patients with newly diagnosed or 
recurrent, untreated or intravesical treatment completed >6 months before the current 
diagnosis, resectable tumors, after administration of the recommended phase 2 dose (RP2D) 
to the target patient population.  The patient population selected will have pre-dose tumor 
samples obtained by in-office cystoscopy available and will be scheduled for TURBT, and 
therefore will not need to undergo additional, study-specific, invasive procedures.  
4.3. 
Dose Selection 
The dose planned for administration to patients in this study is the MTD and RP2D that was 
determined during Study CPX-POM-001:  900 mg/m2 once daily by 20 minute IV infusion 
for 5 days. 
4.4. 
End of Study Definition 
A patient is considered to have completed the study if he/she has completed 5 days of dosing 
with CPX-POM and has undergone TURBT from which tissue, blood, and urine samples are 
collected.  Patients will also complete a Day 35 Follow-Up Visit.  


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The end of the study is defined as the date of the last procedure for the last patient in the 
study.   


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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
1. Patient is male or female aged ≥18 years. 
2. Patient provided signed and dated informed consent prior to initiation of any study 
procedures. 
3. Patient is likely to have a new bladder tumor based on clinical presentation or is at 
high risk for tumor recurrence based on previous history. 
4. Patient has a cystoscopically confirmed bladder tumor and will be scheduled to 
undergo TURBT. 
5. Patient has not received prior treatment for bladder cancer or completed their last 
intravesical therapy >6 months before screening.  
6. Patient has an ECOG performance status of 0 (fully active, able to carry out all pre-
disease activities without restriction) or 1 (unable to perform physically strenuous 
activity but ambulatory and able to carry out work of a light or sedentary nature). 
7. Patient has a predicted life expectancy of ≥3 months. 
8. Patient has adequate renal function (creatinine ≤1.5 × the upper limit of the normal 
range (ULN) or an estimated glomerular filtration rate (eGFR) of 
>30 mL/min/1.73 m2). 
9. Patient has adequate hepatic function, as evidenced by a total bilirubin ≤1.5 × ULN, 
aspartate aminotransferase (AST) ≤3 × ULN and /or alanine aminotransferase (ALT) 
≤3 × ULN 
10. Patient has adequate bone marrow function, as evidenced by hemoglobin ≥9.0 g/dL in 
the absence of transfusion within the previous 72 hours, platelet count 
≥100×109cells/L, and absolute neutrophil count (ANC) ≥1.5×109 cells/L. 
11. Patient has no significant ischemic heart disease or myocardial infarction within 
6 months before the first dose of CPX-POM and currently has adequate cardiac 
function, as evidenced by a left ventricular ejection fraction of >50% as assessed by 
multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and 
corrected QT interval by Fridericia’s correction formula (QTcF) <450 msec for males 
and <470 msec for females.  The eligibility of patients with ventricular pacemakers 
for whom the QT interval may not be accurately measurable will be determined on a 
case-by-case basis by the Sponsor in consultation with the Medical Monitor. 


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12. Patient and his/her partner agree to use adequate contraception after providing written 
informed consent through 3 months after the last dose of CPX-POM, as follows: 
a. For women:  Negative pregnancy test during Screening and at Day 1 of each 
treatment cycle and compliant with a medically-approved contraceptive 
regimen during and for 3 months after the treatment period or documented to 
be surgically sterile or postmenopausal. 
b. For men:  Compliant with a medically-approved contraceptive regimen during 
and for 3 months after the treatment period or documented to be surgically 
sterile.  Men whose sexual partners are of child-bearing potential must agree 
to use 2 methods of contraception prior to study entry, during the study, and 
for 3 months after the treatment period. 
13. Patient is willing and able to participate in the study and comply with all study 
requirements. 
5.2. 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria are not to be enrolled in this study. 
1. Patients received prior intravesical therapy for bladder cancer within ≤6 months of the 
current diagnosis. 
2. Patients must not have had any of the following within 6 months before study drug 
administration:  
a. Myocardial infarction 
b. Severe/unstable angina 
c. Symptomatic congestive heart failure 
d. Cerebrovascular accident or transient ischemic attack, or 
e. Pulmonary embolism 
3. Ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 grade 2. 
4. Evidence of NYHA functional class III or IV heart disease. 
5. Uncontrolled hypertension (>150/100 mmHg despite optimal medical therapy). 


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6. Patient has an uncontrolled or severe intercurrent medical condition.  The decision to 
exclude a patient from the study for an uncontrolled or severe intercurrent medical 
condition will be made by the Principal Investigator.  Examples could include 
epilepsy, resistant infection, or any other neurological disease that would make 
clinical assessment difficult. 
7. Patient underwent major surgery or radiation therapy within 4 weeks before the first 
dose of CPX-POM or received an investigational drug or device within 4 weeks or 
5 half-lives of that agent (whichever is shorter) before the first dose of CPX-POM.  A 
minimum of 10 days between termination of the investigational drug and 
administration of CPX-POM is required.  
8. If female, patient is pregnant or breast-feeding. 
9. Patient has evidence of a serious active infection (e.g., infection requiring treatment 
with IV antibiotics). 
10. Patient has a known, active Hepatitis A infection.  
11. Patient has known human immunodeficiency virus (HIV) or Hepatitis B, or C 
infection, as such patients may be at increased risk for toxicity due to concomitant 
treatment and disease-related symptoms may preclude accurate assessment of the 
safety of CPX-POM. 
12. Patient has an important medical illness or abnormal laboratory finding that, in the 
Investigator’s opinion, would increase the risk of participating in this study. 
13. Patient is taking warfarin.  
14. Patients may not have another malignancy that could interfere with the evaluation of 
safety or efficacy of the study drug.  Patients with a prior malignancy will be allowed 
without approval in the following circumstances: 
a. Not currently active and diagnosed at least 3 years prior to the date of 
registration. 
b. Non-invasive diseases such as low risk cervical cancer or any cancer in situ. 
c. Localized (early stage) cancer treated with curative intent (without evidence 
of recurrence and intent for further therapy), and in which no chemotherapy 
was indicated.(e.g., low/intermediate risk prostate cancer, etc.). 
d. NMIBC for which treatment was completed >6 months before the current 
diagnosis. 
15. Patient has known allergy or hypersensitivity to any component of CPX-POM. 
16. Patient is taking any iron replacement therapy administered IV, intramuscularly, or 
orally due to the potential for loss of anticancer activity due to drug and/or 
metabolites chelating iron. 


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5.3. 
Meals and Dietary Considerations 
There are no meal or dietary restrictions.  
5.4. 
Screen Failures 
Patients who fail inclusion and/or exclusion criteria may not be rescreened for the study. 


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6. 
TREATMENTS 
6.1. 
Investigational Product 
6.1.1. 
Description of Investigational Product 
Fosciclopirox or ciclopirox prodrug (CPX-POM), sodium ((6-cyclohexyl-4-methyl-2-
oxopyridin-1(2H)-yl) oxy) methyl phosphate, is the phosphoryloxymethyl ester of CPX.  
CPX-POM will be provided as a sterile liquid formulation for IV administration. 
6.1.2. 
Packaging and Labeling 
CPX-POM will be packaged in plastic, 10-mL vials containing CPX-POM 50 mg/mL 
solution.  Vials will be labeled according to applicable regulatory requirements.   
6.1.3. 
Storage and Handling 
CPX-POM vials must be stored under refrigerated conditions at 2 to 8 ºC.   
Only patients enrolled in the study may receive CPX-POM and only authorized site staff may 
supply or administer CPX-POM.  All CPX-POM must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
6.1.4. 
Dosage and Administration 
At baseline, the body surface area (BSA) will be calculated by the Dubois method using 
Screening height and baseline weight measurements.  The baseline BSA is to be used to 
determine the patient’s study drug dose.   
Dubois Formula:  BSA= 0.007184 x W0.425 x H0.725 
CPX-POM will be administered as an IV infusion once daily on Days 1-5 of the study. 
CPX-POM will be added to a 100-mL piggyback bag of 0.9% sodium chloride solution and 
infused over a 20-minute period.  The dose administered will be 900 mg/m2. 
6.1.5. 
Dose Modifications 
Dose modifications are discouraged.  However, if a patient develops an SAE that the 
Investigator believes may be mitigated by a dose modification, the Medical Monitor should 
be contacted to discuss the possibility of a dose modification. 


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6.1.6. 
Compliance 
Administration of CPX-POM will be performed by site personnel.  Compliance will be 
assessed by inspection of drug accountability records at the study site.  
6.1.7. 
Accountability 
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused investigational medicinal product, placebos, and 
comparators.  This includes acknowledgment of receipt of each shipment of investigational 
product (quantity and condition), patient dispensing records, and returned or destroyed study 
product.  Dispensing records will document quantities received from CicloMed and 
quantities administered to patients, including lot number, date dispensed/administered, 
patient identifier number, and the initials of the person dispensing/administering the 
medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
CicloMed requirements.  Drug may be returned or destroyed on an ongoing basis during the 
study, if appropriate.  At the end of the study, following final drug inventory reconciliation 
by the monitor, the study site will dispose of and/or destroy all unused investigational 
medicinal product supplies, including empty containers, according to these procedures.  If the 
site cannot meet CicloMed’s requirements for disposal, arrangements will be made between 
the site and CicloMed or its representative for destruction or return of unused investigational 
medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by 
the study monitor over the course of the study.   
Further guidance and information for the final disposition of unused investigational product 
is provided in the Study Procedures Manual. 
6.2. 
Prior and Concomitant Medications 
Medications taken within 30 days before baseline (Study Visit 2) must be recorded as prior 
medications.   
Prohibited concomitant medications include any anti-cancer agents, steroids, any iron 
replacement therapy, warfarin, or any drug known to have significant nephrotoxicity.  A 
minimum of 10 days between termination of the prohibited concomitant medications or a 
duration of five elimination half-lives will be required prior to administration of IV 
CPX-POM to eligible patients.  Concomitant radiation therapy is also prohibited. 


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Note that anti-emetics such as ondansetron or granisetron are allowed if used with caution 
and attention to the approved labelling.   
All concomitant medications will be recorded from the time of Screening up to the time of 
TURBT.  Routine medications associated with the cystectomy procedure do not need to be 
recorded.  Starting at the time of TURBT, only medications associated with an AE related to 
CPX-POM treatment need to be recorded.   
 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PATIENT DISCONTINUATION/WITHDRAWAL  
7.1. 
Discontinuation of Study Treatment 
In the event of discontinuation of CPX-POM, every effort should be made to complete the 
assessments that are scheduled for the Follow-up/Early Termination visit.  See the Schedule 
of Assessments (Table 1) for data to be collected at the time of early termination. 
7.2. 
Patient Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.  The patient will be withdrawn before any CPX-POM treatment is 
administered if the in-office cystoscopy fails to confirm bladder tumor. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
If a patient withdraws prematurely from the trial for any reason, study staff should make 
every effort to complete the full set of evaluations scheduled for the Follow-up/Early 
Termination visit.  See the Schedule of Assessments (Table 1) for data to be collected at the 
time of early termination. 
7.3. 
Lost to Follow Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study. 
• Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 


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necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods).  These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  


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8. 
STUDY ASSESSMENTS 
8.1. 
Safety Assessments 
8.1.1. 
Adverse Events and Serious Adverse Events 
8.1.1.1. 
Definitions 
Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
AEs also include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure (e.g., such as venipuncture, biopsy) during or after Screening (before the 
administration of study investigational medicinal product). 
• Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study investigational medicinal product phase of a human clinical 
trial, will also be considered an AE. 
• Complications and termination of pregnancy (see Section 8.1.2 for additional 
information) 
• All AEs that occur from the study screening visit onwards and throughout the duration of 
the study, including the follow-up off study medication period should be recorded as an 
AE. 
An AE does not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; the condition that leads to the procedure is an AE. 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected before 
the screening visit that do not worsen.  
• If progression of underlying malignancy is clearly consistent with the suspected 
progression of the underlying cancer as defined by the Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1, or with clinical symptoms (clinical progression), it should 
not be reported as an AE/SAE.  Similarly, hospitalization due exclusively to the 
progression of underlying malignancy should NOT be reported as an SAE. 


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• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions). 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 
an AE.  It is considered to be pre-existing and should be documented on the medical 
history case report form (CRF). 
• Uncomplicated pregnancy. 
• An induced elective abortion to terminate a pregnancy without medical reason. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs, symptoms, and/or clinical sequelae 
resulting from lack of efficacy may be reported as AE or SAE if they fulfill the definition 
of an AE or SAE. 
Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
An SAE is defined as any untoward medial occurrence that, at any dose: 
• Results in death 
• Is life-threatening.  The term 'life-threatening' in the definition of 'serious' refers to an 
event in which the patient was at risk of death at the time of the event. It does not refer to 
an event, which hypothetically might have caused death, if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  In general, 
hospitalization signifies that the patient has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered 
serious.  Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• Results in persistent disability/incapacity.  The term disability means a substantial 
disruption of a person’s ability to conduct normal life functions.  This definition is not 
intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 


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• Is a congenital anomaly/birth defect in the offspring of a subject who received 
investigational medicinal product. 
• Other situations.  Medical or scientific judgment should be exercised in deciding whether 
SAE reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition. These events should usually be 
considered serious.  Examples of important medical events include invasive or malignant 
cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
8.1.1.2. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information  
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) 
through the Follow-up visit (28 +/- 5 days after the last dose of study drug).   
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the CRF not the AE section. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a patient has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the Sponsor. 
8.1.1.3. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.1.1.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification (within 24 hours from the first time a site team member is made aware of 
the event) by the investigator to the Sponsor of a SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of patients and the safety of a study 
intervention under clinical investigation are met.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 


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Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB, if appropriate according 
to local requirements. 
8.1.1.5. 
Reporting Procedures 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.  The investigator will then record all relevant AE/SAE information in the 
CRF. 
It is not acceptable for the investigator to send photocopies of the patient’s medical records in 
lieu of completion of the AE/SAE CRF page.  There may be instances when copies of 
medical records for certain cases are requested by CicloMed or its designee.  In this case, all 
patient identifiers, with the exception of the patient number, will be redacted on the copies of 
the medical records before submission. 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
All SAEs will be recorded and reported to the Sponsor or their designee within 24 hours from 
the time any site team member is made aware of the event.  The investigator will submit any 
updated SAE data to the Sponsor within 24 hours of it being available.  If any part of the 
source providing details of the event is not available, the Investigator will submit the SAE 
with as much information as he/she has at the time of the reporting requirements. 
Contacts and procedures for SAE reporting can be found in the Study Procedures Manual.   
8.1.1.6. 
Assessment of Causality 
The investigator is obligated to assess the relationship between CPX-POM and each 
occurrence of each AE/SAE as follows:  
• There is a "reasonable possibility" of a relationship between the CPX-POM and the AE.  
This conveys that there are facts, evidence, and/or arguments to suggest a causal 
relationship, rather than a relationship cannot be ruled out. 


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• There is not a “reasonable possibility” of a relationship between CPX-POM and the AE. 
The investigator will use clinical judgment to determine the relationship.  Alternative causes, 
such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration will be considered and 
investigated.  The investigator will also consult the Investigator’s Brochure (IB) in his/her 
assessment. 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor or contract research organization 
(CRO). However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the Sponsor or 
CRO.  The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.  
The relationship to study procedures (e.g., invasive procedures such as venepuncture or 
biopsy) should also be assessed using the following considerations: 
• There is a reasonable possibility that the AE occurred as a result of protocol-mandated 
procedures such as venipuncture or biopsy. 
• There is not a reasonable possibility that the AE occurred as a result of a protocol-
mandated procedure.   
8.1.1.7. 
Assessment of Intensity 
The investigator will make an assessment of intensity (Grade) for each AE and SAE reported 
during the study, using as a guide the NCI CTCAE, as provided in the Study Procedures 
Manual.   
8.1.1.8. 
Follow-up of Adverse Events and Serious Adverse Events 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by CicloMed or its 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 


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If a patient dies during participation in the study or during a recognized follow-up period, the 
investigator will provide CicloMed or its designee with a copy of any post-mortem findings 
including histopathology.   
New or updated information will be recorded in the originally completed CRF. 
The investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt 
of the information.  Contacts for SAE reporting can be found in the Study Procedures 
Manual. 
8.1.2. 
Pregnancy 
Pregnancies in female patients and female partners of male patients will be recorded from 
after the start of study intervention until 30 days after the last dose.  All pregnancies must be 
followed to conclusion to determine outcomes for both mother and baby.   
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  A spontaneous 
abortion is always considered to be an SAE and will be reported as such.  Any post-study 
pregnancy-related SAE considered reasonably related to the study intervention by the 
investigator will be reported to the Sponsor as described in Sections 8.1.1.4 and 8.1.1.5.  
While the investigator is not obligated to actively seek this information in former study 
patients, he or she may learn of an SAE through spontaneous reporting.  
8.1.2.1. 
Male Patients with Partners who Become Pregnant 
The investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study. This applies only to 
male patients who receive CPX-POM. 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy.  The female 
partner will also be followed to determine the outcome of the pregnancy.  Information on the 
status of the mother and child will be forwarded to the Sponsor.  Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date.  Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.  
8.1.2.2. 
Female Patients who Become Pregnant  
The investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this study.  Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a patient's pregnancy. The 


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patient will be followed to determine the outcome of the pregnancy.  The investigator will 
collect follow-up information on the patient and the neonate and the information will be 
forwarded to the Sponsor.  Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.  Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
Any female patient who becomes pregnant while participating in the study will discontinue 
CPX-POM and be withdrawn from the study.  
8.1.3. 
Other Safety and Screening Assessments 
8.1.3.1. 
In-Office Cystoscopy and Cold Cup Biopsy 
Patients will sign the informed consent prior to undergoing the in-office cystoscopy and cold 
cup biopsy procedures.  These procedures will be performed according to the standard of 
care at the study site.  Confirmed bladder tumor is required for continued study participation.  
In the unlikely event that a bladder tumor is not confirmed at the in-office cystoscopy, the 
patient will be withdrawn from the study.  Tumor tissue will be provided for study evaluation 
as described in Section 8.3. 
8.1.3.2. 
Cardiac Evaluation 
Patients will undergo a cardiac evaluation at Screening using MUGA or ECHO to evaluate 
their eligibility to participate in the study. 
Patients will also undergo a chest X-ray or computed tomography (CT) scan to confirm 
normal cardiac appearance/heart size at Screening.  
8.1.3.3. 
Eastern Cooperative Oncology Group Performance Status 
Patients will be evaluated for ECOG performance status at Screening and Follow-Up to 
evaluate their eligibility to participate in the study.  The ECOG performance status grades 
and criteria are shown in Table 2. 


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Table 2. 
Eastern Cooperative Oncology Group Performance Status  
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655. 
 
8.1.3.4. 
Physical Examinations 
A complete physical examination will be conducted at Screening and Follow-up.  At each 
other study visit, patients will be assessed for continued dosing and any possible 
symptoms/toxicities and a physical examination may be performed, if indicated (see 
Schedules of Assessments, Table 1).  Body weight should be measured at each study visit.  
Height should be measured at Screening. 
8.1.3.5. 
Vital Signs 
Vital signs will include blood pressure, respiratory rate, pulse, oxygen saturation, and 
temperature and will be measured at the times and days shown in the Schedules of 
Assessments (Table 1).   
Vital signs will be measured before any blood draws or injections scheduled for the same 
time point.   


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8.1.3.6. 
Electrocardiograms 
At Screening, 12-lead ECGs will be performed in triplicate, with each measurement 
separated by 2 minutes.  The average of the 3 screening ECGs will be used to calculate QTc 
and QTcF (Fridericia’s formula):  
 
to determine study eligibility.  Thereafter, single 12-lead ECGs will be performed at the dates 
and times indicated in the Schedules of Assessments (Table 1).   
8.1.3.7. 
Clinical Laboratory Assessments 
All protocol-required laboratory assessments, including hematology (including complete 
blood count), clinical chemistry (including comprehensive metabolic panel), and urinalysis 
must be conducted in accordance with the Study Procedures Manual and the Schedules of 
Assessments (Table 1). 
Abnormal laboratory tests that are clinically significant should also be recorded as AEs on 
the CRF, or as medical history if noted during Screening. 
A listing of clinical laboratory tests to be performed is provided in Table 3.   


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Table 3. 
Listing of Required Screening and Safety Laboratory Parameters 
Laboratory 
Assessments 
Parameters 
Hematology 
(CBC with 
differential) 
• 
Hemoglobin 
• 
Hematocrit  
• 
Platelet count 
• 
RBC count 
• 
Reticulocytes 
WBC Count with Differential 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Clinical 
Chemistry 
(including CMP) 
• 
Potassium 
• 
Sodium 
• 
Chloride 
• 
Glucose  
• 
BUN 
• 
Creatinine  
• 
Creatinine 
clearance 
• 
ALT 
• 
AST 
• 
GGT 
• 
Alkaline 
phosphatase 
• 
Direct bilirubin 
• 
Indirect bilirubin 
• 
Total bilirubin 
• 
Total protein  
• 
Albumin 
• 
Calcium 
• 
Bicarbonate  
• 
Magnesium 
• 
Phosphate 
• 
Lipase 
• 
Amylase 
Routine 
Urinalysis 
• 
Color 
• 
Turbidity 
• 
pH 
• 
Specific gravity 
• 
Glucose 
• 
Ketones 
• 
Nitrites 
• 
Bilirubin 
• 
Urobilirubin 
• 
Protein 
• 
RBCs 
• 
WBCs 
• 
Epithelial cells 
• 
Casts 
• 
Crystals 
• 
Bacteria 
• 
eGFR (Screening 
only) 
Other  
Serum or urine hCG pregnancy test (for women of child bearing potential) 
Abbreviations:  ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = 
aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CMP = 
comprehensive metabolic panel; eGFR = estimated glomerular filtration rate; GGT = gamma 
glutamyltransferase; hCG = human chorionic gonadotropin; MCH = mean corpuscular hemoglobin;  
MCV = mean corpuscular volume; PT = prothrombin time; RBC = red blood cell; WBC = white blood cell. 
 
8.2. 
Pharmacokinetic Assessments 
As shown in the Study Procedures Manual and the Schedule of Assessments (Table 1), a 
single blood (plasma) sample and a single clean-catch urine sample will be collected on 
Day 1 prior to drug administration.  At the time of TURBT on Day 5, a single blood (plasma) 
and urine sample will be collected.  Tissue, plasma, and urine concentrations of CPX-POM, 
CPX, and CPX-G will be determined employing Good Laboratory Practices (GLP)-validated 
liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods.  Urine 
β-glucuronidase activity will be determined in the urine samples collected on Days 1 and 5 
by enzyme linked immunosorbent assay (ELISA). 


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The actual date and time of each tissue, blood, and urine sample collection, and the date and 
time of the previous dose of CPX-POM will be recorded.  Processing, storage, and shipping 
procedures are provided in the Study Procedures Manual. 
8.3. 
Pharmacodynamic Assessments 
Bladder tumor tissues obtained at diagnosis and TURBT will be evaluated by RNA-seq and 
ChIP-seq analyses to elucidate mechanisms of CPX-POM action on bladder tumor tissues.  
Immunohistochemical analysis of prepared paraffin-embedded bladder tumor slides will be 
performed to determine cell proliferation, Notch and Wnt cell signaling pathways, as well as 
bladder tumor tissue CD8+ TIL. 
 


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9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis plan will be developed and finalized before database lock and will 
describe the finalized plans for analysis of study data.  This section is a summary of the 
planned statistical analyses at the time of protocol development. 
9.1. 
Number of Patients 
The estimated number of patients is 12.   
9.2. 
Analysis Sets 
9.2.1. 
Safety 
The Safety Set will consist of all patients who receive at least 1 dose of study drug.  All 
safety and PD data will be analyzed using the safety set.  
9.2.2. 
Pharmacokinetics 
The Pharmacokinetic Set will consist of all patients for whom a tissue, plasma, and/or urine 
sample is obtained and analyzed for determination of plasma drug and metabolites 
concentration. 
9.3. 
Data Handling Conventions 
9.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods. 
9.5. 
Safety Analysis 
Safety data will be presented in by-patient listings.  Categorical safety endpoints will be 
summarized by frequency of events/abnormalities for each dose group and overall.  
Continuous safety endpoints will be summarized using descriptive statistics (n, mean, 
standard deviation, median, first quartile [Q1], third quartile [Q3], minimum, maximum) for 
each dose group and overall. 
9.5.1. 
Adverse Events 
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). SOC, High-Level Group Term (HLGT), High-Level Term (HLT), 
Preferred Term, and Lower-Level Term (LLT) will be attached to the clinical database. 


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AEs will be summarized on the basis of the date of onset for the event.  A treatment-
emergent AE will be defined as any AE that begins on or after the date of first dose of 
CPX-POM.  
Summaries (number and percentage of patients) of treatment-emergent AEs (by SOC, and 
Preferred Term) will be provided by dose group/cohort and overall. 
9.5.2. 
Laboratory Evaluations 
Summaries of clinical laboratory data will be provided using descriptive statistics.  No 
inferential statistics will be provided.  Quantitative values and change from baseline in 
quantitative values will be summarized by dose group.  Listings of all laboratory results and 
reference ranges will be provided.   
Graded laboratory abnormalities will be defined using the grading scheme based on NCI 
CTCAE (4.03).  The incidence of treatment-emergent laboratory abnormalities, defined as 
values that increase at least one toxicity grade from baseline at any time post baseline up to 
and including the date of last dose of study drug, will be summarized by treatment group.  If 
baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) will be 
considered treatment emergent. 
9.5.3. 
Other Safety Evaluations 
Physical examination, ECG, and vital signs data will be summarized by dose group and 
overall.  Concomitant medications will be coded using the World Health Organization Drug 
Dictionary and listed by dose group.   
9.6. 
Pharmacokinetic Analysis 
Tissue, plasma, and urine concentrations of CPX-POM and its metabolites will be 
determined by GLP-validated liquid chromatography tandem mass spectroscopy LC-MS/MS 
assays and results will be presented in by-patient listings.  
Bladder tumor tissue-to-plasma and tissue-to-urine CPX concentration ratios will be 
calculated for each patient. 
Urine β–glucuronidase activity, expressed as units of activity per milliliter of urine as well as 
units of activity per milligram of urine creatinine, will be measured for each patient and 
listed.  
9.7. 
Pharmacodynamic Analyses 
Bladder tumor tissues will be analyzed using RNA-seq and ChIP-seq to elucidate 
mechanisms of CPX-POM action.  To determine the change in bladder tumor tissue cell 


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proliferation, Notch and Wnt cell signaling pathways, as well as bladder tumor tissue CD8+ 
TIL, immunohistochemistry will be performed on paraffin-embedded slides.   
 
9.8. 
Interim Analyses 
No formal interim analysis is planned.   


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10. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
10.1. 
Regulatory and Ethical Considerations 
10.1.1. 
Institutional Review Board/Ethics Committee 
IRBs must be constituted according to the applicable state and federal requirements of each 
participating location including International Council on Harmonisation (ICH) Good Clinical 
Practice (GCP). 
It is the responsibility of each investigational site to submit the protocol, IB, patient ICF, 
patient recruitment materials (if applicable), and other documentation as required by the IRB 
to their IRB for review and approval.  A copy of the written approval must be provided to the 
sponsor or CRO.  The documentation should clearly mention the approval/favorable opinion 
of the protocol, the patient ICF, and patient recruitment materials (if applicable), including 
respective version dates.  The written approval and a list of the voting members, their titles or 
occupations, and their institutional affiliations must be obtained from the IRB(s) and 
provided to the sponsor or CRO prior to the release of clinical study supplies to the 
investigational site and commencement of the study.  If any member of the IRB has direct 
participation in this trial, written notification regarding his or her abstinence from voting 
must also be obtained. 
Sites must adhere to all requirements stipulated by their respective IRB.  This includes 
notification to the IRB regarding: protocol amendments, updates to the patient informed 
consent, recruitment materials intended for viewing by patients, IND safety reports, serious 
and unexpected AEs, reports and updates regarding the ongoing review of the trial at 
intervals specified by the respective IRB, and submission of final study reports and 
summaries to IRB. 
It is the responsibility of each investigational site to submit information to the appropriate 
IRB for annual review and annual re-approval. 
10.1.2. 
Ethical Conduct of the Study 
This study will be conducted according to the protocol, Code of Federal Regulations 
(21 CFR Parts 50, 54, 56, and 312), the Declaration of Helsinki, and ICH GCP.  Each 
investigator will conduct the trial according to applicable local or regional regulatory 
requirements. 


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10.1.3. 
Informed Consent 
Prior to any study procedures being performed, patients and the person conducting the 
consent discussion will be required to sign and date the IRB-approved ICF, and each patient 
will be given a copy.  In addition, this information should be recorded in the patient’s 
medical record (i.e., source document). 
The written consent document will embody the elements of informed consent as described in 
the Declaration of Helsinki, the Code of Federal Regulations (21 CFR Part 50.25), the ICH 
GCP guidelines, and in accordance with any local regulations.  The investigator is 
responsible for the preparation, content, and IRB approval of the informed consent.  The ICF 
must be approved by the site-designated IRB and be acceptable to the sponsor or CRO. 
The ICF must be written in a language fully comprehensible to the prospective patient.  The 
investigator or designee shall give the patient adequate opportunity to read the ICF before it 
is signed and dated.  Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB.  Patients must be given ample 
opportunity to inquire about details of the study. 
10.1.4. 
Confidentiality 
The investigator must assure that patients’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties.  
Patients will be assigned a unique identifier by the sponsor.  Any patient records or datasets 
that are transferred to the sponsor will contain the identifier only; patient names or any 
information which would make the patient identifiable will not be transferred.  
NOTE:  The investigator must keep a screening log showing codes, names, and addresses for 
all patients screened and for all patients enrolled in the trial. 
The patient must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the patient.  
The patient must be informed that his/her medical records may be examined by clinical 
quality assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
The investigator agrees that all information received from CicloMed, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and 
any other study information, remain the sole and exclusive property of CicloMed during the 
conduct of the study and thereafter.  This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by 
law) without prior written consent from CicloMed.  The investigator further agrees to take all 


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reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
10.2. 
Study Oversight 
10.2.1. 
Data Quality Assurance 
All patient data relating to the study will be recorded in a printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data).  The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
10.2.2. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
Definitions of what constitutes source data can be found in the Study Procedures Manual. 
10.2.3. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed on a 
rolling basis upon database lock for each site individually or as the Sponsor determines.  


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A study site is considered closed when all required documents, study supplies, and 
investigational product have been collected and/or destroyed, and a study-site closure visit 
has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but 
are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of patients by the investigator 
• Discontinuation of further CPX-POM development 
10.2.4. 
Reporting of Results and Publications 
CicloMed will fulfill its commitment to publicly disclose the results of this study through 
posting the results on the www.clinicaltrials.gov web site.   
A clinical study report will be prepared and provided to the regulatory agency(ies).  
CicloMed will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report 
may be prepared in certain cases. 
Any investigator will submit any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. The investigator will comply with CicloMed’s request to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in 
order to obtain patent protection if deemed necessary. 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.  
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In this 
case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 


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10.2.5. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following two categories: (1) investigator’s 
study file, and (2) patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB, and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
The required source data includes at least the following information for each patient: 
• patient identification (name, date of birth, gender); 
• documentation that patient meets eligibility criteria, i.e., history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria); 
• participation in trial (including trial number); 
• trial discussed and date of informed consent; 
• dates of all visits; 
• documentation that protocol specific procedures were performed; 
• results of efficacy parameters, as required by the protocol; 
• start and end date (including dose regimen) of trial medication; 
• record of all AEs and other safety parameters (start and end date, and preferably 
including causality and intensity); 
• concomitant medication (including start and end date, dose if relevant; dose changes 
should be motivated); 
• date of trial completion and reason for early discontinuation, if applicable. 
All clinical study documents must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (i.e., United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH 
region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been 
notified. Investigators may be required to retain documents longer if required by applicable 
regulatory requirements, by local regulations, or by an agreement with CicloMed. The 
investigator must notify CicloMed before destroying any clinical study records. 
Should the investigator wish to assign the study records to another party or move them to 
another location, CicloMed must be notified in advance (i.e. in the case of a Principal 


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Investigator moving to a new location, retiring, etc.).  If a study site is assigned to another 
investigator for archival oversight or if the files are to be moved, this change will be noted in 
a memo, the Sponsor will be contacted, and the IRB will be notified depending on the IRB 
requirements. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and 
CicloMed to store these in sealed containers outside of the site so that they can be returned 
sealed to the investigator in case of a regulatory audit.  When source documents are required 
for the continued care of the patient, appropriate copies should be made for storage outside of 
the site. 
Biological samples at the conclusion of this study may be retained in storage by the sponsor 
for a period up to 2 years for purposes of this study. 
10.2.6. 
Case Report Forms 
For each patient enrolled, a CRF must be completed and signed by the Principal Investigator 
or sub-investigator (as appropriate) within a reasonable time period after data collection.  
This also applies to records for those patients who fail to complete the study (even during a 
screening period if a CRF was initiated).  If a patient withdraws from the study, the reason 
must be noted on the CRF.  If a patient is withdrawn from the study because of a 
treatment-limiting AE, thorough efforts should be made to clearly document the outcome. 
10.2.7. 
Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from CicloMed or its representatives, to IRBs, 
or to regulatory authority or health authority inspectors. 
10.2.8. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2.9. 
Study Discontinuation 
Both the sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange discontinuation procedures and notify the 
appropriate regulatory authority(ies) and IRBs.  In terminating the study, CicloMed and the 
investigator will assure that adequate consideration is given to the protection of the patients’ 
interests. 


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11. 
REFERENCES 
Abrams BB, Hanel H. Hoehler T. Ciclopirox olamine: a hydroxypyridone antifungal agent. 
Clin Dermatol. 1991;9(4):471-477. 
American Cancer Society. Cancer Facts & Figures 2019. Atlanta: American Cancer Society; 
2019.  
American Society of Clinical Oncology, Cancer.net Bladder Cancer Statistics web page. 
2019. Available at: https://www.cancer.net/cancer-types/bladder-cancer/statistics. Accessed 
24 April 2019.  
Bohn M, Kraemer KT. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% 
in the treatment of onychomyosis. J Am Acad Dermatol. 2000;43(4):S57-S69. 
Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, Pruthi R, Quale DZ, 
Ritch CR, Seigne JD, Skinner EC, Smith ND, McKiernan JM. Diagnosis and Treatment of 
Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196(4):1021-
1029. 
Clement PMJ, Hanauske-Abel HM, Wolff EC, Kleinman HK, Park MH. The antifungal drug 
ciclopirox inhibits deoxyhpusine and proline hydroxylation, endothelial cell growth and 
angiogenesis in vitro. Int J Cancer. 2002;100:491-498.  
ClinicalTrials.gov web site. Available at: https://clinicaltrials.gov/. Accessed May 18, 2017.  
CPX-POM Investigator’s Brochure. CicloMed LLC. 2019. 
Dihazi H, Dihazi GH, Jahn O, Meyer S, Nolte J, Asif AR, Mueller GA, Engel W. 
Multipotent adult germline stem cells and embryonic stem cells functional proteomics 
revealed an important role of eukaryotic initiation factor 5A (Eif5a) in stem cell 
differentiation. J Proteome Res. 2011;10:1962-1973. 
Eberhard Y, McDermott SP, Wang X, Gronda M, Venugopal A, Wood TE, Hurren R, Datti 
A, Batey RA, Wrana J, Antholine WE, Dick JE, Schimmer AD. Chelation of intracellular 
iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and 
myeloma cells. Blood. 2009;114(14):3064-3073. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shakar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45:228-247.  
[FDA] Food and Drug Administration. Guidance for Industry – S9 Nonclinical Evaluation 
for Anticancer Pharmaceuticals. March 2010. Available at: 


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https://www.fda.gov/downloads/Drugs/Guidances/ucm085389.pdf. Accessed September 18, 
2017.  
Gupta AK. Ciclopirox: an overview. Int J Dermatol. 2001;40(5):305-310. 
Gupta AK, Plott T. Ciclopirox: a broad-spectrum antifungal with antibacterial and anti-
inflammatory properties. Int J Dermatol. 2004; 43(Suppl 1):3-8.  
Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part 1. J Am Acad 
Dermatol. 1994;30(5 Pt 1):677-698. 
Hanel H, Smith-Kurtz E, Pastowsky S. Therapy of seborrheic eczema with an antifungal 
agent with an antiphlogistic effect. Mycoses. 1991;34(Suppl 1):91-93. 
Kellner HM, Arnold C, Christ OE, Eckert HG, Herok J, Hornke I, Rupp W. Investigations on 
the pharmacokinetics and biotransformation of the antimycotic ciclopiroxolamine in animals 
and humans after topical and systemic application. Anzneim-Forsch/Drug Res. 1981; 31(II). 
No. 8a:1337-1353.  
Kwong W-L, Lok C-N, Tse C-W, Wong E L-M, Che C-M. Anti-cancer iron(ii) complexes of 
pentadentate n-donor ligands: cytotoxicity, transcriptomics analyses, and mechanisms of 
action. Chem Eur J. 2015;21:3062–3072. 
Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase 1 cancer clinical trials. 
JNCI. 2009;101(10):708-720.  
Logan C, Brown M, Hayne D. Intravesical therapies for bladder cancer - indications and 
limitations. BJU Int. 2012;110(Suppl 4):12–21. 
Minden MD, Hogge DE, Weir SJ, Kasper J, Webster DA, Patton L, Jitkova Y, Hurren R, 
Gronda M, Goard CA, Rajewski LG, Haslam JL, Heppert KE, Schorno K, Chang H, 
Brandwein JM, Gupta V, Schuh AC, Trudel S, Yee KW, Reed GA, Schimmer AD. Oral 
ciclopirox olamine displays biological activity in a phase 1 study in patients with advanced 
hematologic malignancies. Am J Hematol. 2014; 89(4):363-368.  
Oken M, Creech R, Tormey D, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. 
Sakurai K, Sakeguchi T, Yamaguchi H, Iwata K. Mode of action of 6-cyclohexyl-1-hydroxy-
4-methyl-2(1H)-pyridone ethanolamine salt (Hoe296). Chemotherapy.1978;24(2):68-76. 
Sidarovich V, Adami V, Gatto P, Greco V, Tebaldi T, Tonini GP, Quattrone A. Translational 
downregulation of hsp90 expression by iron chelators in neuroblastoma cells. Mol 
Pharmacol. 2015;87(3):513-524. 


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Song S, Christova T, Perusini S, Alizadeh S, Bao RY, Miller BW, Hurren R, Jitkova Y, 
Gronda M, Isaac M, Joseph B, Subramanian R, Aman A, Chan A, Hogge DE, Weir SJ, 
Kaspar J, Schimmer AD, Al-awar R, Wrana JL, Altisano L. WNT inhibitor screen reveals 
iron dependence of β-catenin signaling in cancers. Cancer Res. 2011;71:7628-7639.  
Szüts D, Krude T. Cell cycle arrest at the initiation step of human chromosomal DNA 
replication causes DNA damage. J Cell Sci. 2004;117(Pt 21):4897-4908.  
Yeung C, Dinh T, Lee J. The health economics of bladder cancer: an updated review of the 
published literature. PharmacoEconomics. 2014;32:1093–1104. 
 

SAP_001.pdf: 
 
 
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CONFIDENTIAL 
 
 
 
 
Statistical Analysis Plan 
 
CicloMed LLC 
CPX-POM-002 
 
A Window of Opportunity Study to Characterize the Safety, Dose Tolerance, 
Pharmacokinetics and Pharmacodynamics of CPX-POM in Patients with Newly Diagnosed 
or Recurrent Bladder Tumors 
Version 1.0: July 13, 2020 
 
 
 
Sponsor:  
 
 
 
Analysis Plan Version: 1.0 
 
Analysis Plan Date: 17 May 2021 
 
Analysis Plan Author:
 
 


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CONFIDENTIAL 
Approval 
 
Upon review of this document the undersigned approves the Statistical Analysis Plan. The 
analysis methods and data presentation are acceptable. 
 
 
Signature 
Date 
 
CicloMed 
 
___________ 
 
 
CicloMed 
 
 
____________ 
 
 
___
Catal
t Clinica
 
 
______________ 
 
 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ....................................................................................................... 4 
1. 
INTRODUCTION .................................................................................................................. 5 
2. 
STUDY OBJECTIVES .......................................................................................................... 5 
2.1 PRIMARY OBJECTIVE .......................................................................................................... 5 
2.2 SECONDARY OBJECTIVES ................................................................................................... 5 
2.2 EXPLORATORY OBJECTIVE ................................................................................................. 5 
3. 
STUDY DESIGN AND PLAN .............................................................................................. 6 
4. 
DETERMINATION OF SAMPLE SIZE ............................................................................ 6 
5. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................... 6 
5.1 MISSING OR INCOMPLETE DATES ........................................................................................ 6 
6. 
ANALYSIS SETS ................................................................................................................... 7 
7. 
STUDY POPULATION......................................................................................................... 8 
7.1 
PATIENT DISPOSITION .................................................................................................... 8 
7.2 
PROTOCOL DEVIATIONS ................................................................................................ 8 
7.3 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ..................................................... 8 
7.4 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................... 8 
8. 
EFFECTIVENESS ANALYSES ........................................................................................... 9 
9. 
SAFETY ANALYSES ............................................................................................................ 9 
9.1 
BASELINE VALUES ......................................................................................................... 9 
9.2 
HANDLING OF DROPOUTS OR MISSING DATA ............................................................... 9 
9.3 
EXTENT OF EXPOSURE ................................................................................................... 9 
9.4 
ADVERSE EVENTS .......................................................................................................... 9 
9.5 
CLINICAL LABORATORY EVALUATION ....................................................................... 10 
9.6 
VITAL SIGNS ................................................................................................................ 10 
9.7 
PHYSICAL EXAMINATION ............................................................................................ 10 
9.8 
ELECTROCARDIOGRAM ................................................................................................ 11 
9.9 
OTHER SAFETY MEASUREMENTS ................................................................................ 11 
9.10 STUDY PROCEDURES ................................................................................................... 11 
10. PHARMACOKINETIC ANALYSES ................................................................................ 11 
11. PHARMACODYNAMIC ANALYSES .............................................................................. 11 
12. REFERENCES ..................................................................................................................... 12 
13. SOFTWARE ......................................................................................................................... 12 
14. SAP REVISIONS ................................................................................................................. 12 


 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index  
BSA 
Body Surface Area 
ChIP 
Chromatin Immunoprecipitation  
CI 
Confidence Interval 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ICH 
International Conference on Harmonization 
IQR 
Interquartile Range 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
NCI 
National Cancer Institute 
NCS 
Not Clinically Significant 
PS 
Pharmacokinetic Set 
PT 
Preferred Term 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase II Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-Emergent Adverse Event 
TIL 
Tumor-infiltrating Lymphocytes 
TLFs 
Tables, Listings, and Figures 
TURBT 
Transurethral Resection of Bladder Tumor 
WHO 
World Health Organization 


 
 
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1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of CicloMed LLC Protocol CPX-POM-002 [A Window of 
Opportunity Study to Characterize the Safety, Dose Tolerance, Pharmacokinetics, and 
Pharmacodynamics of CPX-POM in Patients with Newly Diagnosed or Recurrent Bladder 
Tumors]. The purpose of this plan is to provide specific guidelines from which the statistical 
analyses will proceed. Any deviations from this plan will be documented in the clinical study 
report (CSR). 
2. STUDY OBJECTIVES 
The primary purpose of this study is to evaluate safety and dose tolerance as well as investigate 
the mechanisms of action of CPX-POM in patients with newly diagnosed or recurrent, untreated 
or intravesical treatment completed >6 months before the current diagnosis, resectable bladder 
tumors, after administration of the recommended phase 2 dose (RP2D) to the target patient 
population. The patient population selected will have pre-dose tumor samples obtained by in-
office cystoscopy available and will be scheduled for transurethral resection of a bladder tumor 
(TURBT), and therefore will not need to undergo additional, study-specific, invasive procedures. 
2.1 Primary Objective 
The primary objective of the study is to characterize the safety and dose tolerance of CPX-POM 
administered as 900 mg/m2 IV by 20-minute IV infusion once daily for 5 days to patients with newly 
diagnosed or recurrent bladder tumors who will be scheduled to undergo TURBT. 
2.2 Secondary Objectives 
The secondary objectives of the study are: 
x To determine the number of patients with treatment-related AEs 
x To elucidate mechanisms of CPX-POM action on bladder tumor tissues emplying an 
unbiased approach, using ribonucleic acid sequencing (whole transcriptome shotgun 
sequencing, RNA-seq) and chromatin immunoprecipitation-DNA sequencing (ChIP-seq) 
x To determine the change in bladder tumor tissue cell proliferation, Notch and Wnt cell 
signaling pathways, as well as bladder tumor tissue CD8+ tumor-infiltrating lymphocytes 
(TIL) via immunohistochemistry 
x To determine bladder tumor tissue-to-plasma and tissue-to-urine CPX concentration 
ratios 
2.2 Exploratory Objective 
The exploratory objective of the study is to determine urine β-glucuronidase activity. 
 


 
 
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CONFIDENTIAL 
3. STUDY DESIGN AND PLAN 
This will be an open-label study to determine the safety, dose tolerance, pharmacokinetics, and 
pharmacodynamics of CPX-POM in patients with newly diagnosed or recurrent, untreated or 
intravesical treatment completed >6 months before the current diagnosis, resectable tumors. 
Approximately 12 patients will be enrolled and treated with 900 mg/m2 CPX-POM administered 
IV over 20 minutes once per day for 5 days followed by TURBT on Day 5 after the fifth dose. 
TURBT will be performed 2 to 6 hours following drug administration on Day 5. 
 
Pretreatment bladder tumor tissues will be obtained at the time of in-office cystoscopy by cold 
cup biopsy within 4 weeks of TURBT. Posttreatment bladder tumor tissues will be obtained at 
TURBT. Bladder tumor tissues will undergo pathological evaluation at each site. 
 
Prior to administration of the first CPX-POM dose on Day 1, pre-dose blood (plasma) and urine 
(clean catch) samples will be collected. At the time of TURBT on Day 5, one 3-mL blood 
(plasma) sample and a urine specimen will be collected for measurement of CPX-POM 
concentrations. The full schedule of assessments can be found in Table 1 of the protocol. 
 
Patients will be followed for at least 30 days after the last dose of CPX-POM for safety. 
4. DETERMINATION OF SAMPLE SIZE 
There were no formal sample size calculations conducted for this study as there are no formal 
statistical analyses planned. The estimated number of patients for this study is 12. 
5. GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Conference on Harmonisation (ICH) numbering convention will be used for all 
TLFs. Continuous variables will be summarized with sample size (n), mean, standard deviation 
(SD), median, interquartile range (IQR), minimums, and maximums. Other summaries (e.g., 
quartiles, 5%, 95% intervals, CV or %CV) may be used as appropriate.  Mean, median, and 
IQRvalues will be formatted to one more decimal place than the measured value. SD will be 
formatted to two more decimal places than the measured value. Minimum and Maximum values 
will be presented to the same number of decimal places as the measured value.  Categorical 
variables will be summarized by counts and by percentage of patients in corresponding 
categories.  
 
All analyses and tabulations will be performed using SAS£ Version 9.4 or higher. Tables, 
listings, and figures will be provided in PDF format.  
 
5.1 Missing or incomplete dates 
The most conservative approach will be systematically considered. If the AE onset date is 
missing / incomplete, it is assumed to have occurred during the study treatment phase (i.e., 


 
 
CicloMed LLC 
 
Statistical Analysis Plan 
CPX-POM-002 
 
17MAY2021 
 
 
CONFIDENTIAL 
considered a TEAE) except if the partial onset date or other data such as the stop date, indicates 
differently. Similarly, a medication with partial start and stop dates could be considered as both a 
prior and concomitant treatment. 
 
The following algorithms will be applied to missing and incomplete start and stop dates: 
 
Start Dates 
x If the day portion of the start date is missing, then the start date will be estimated to be 
equal to the date of first dose of study drug, provided the start month and year are the 
same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the missing day portion will be estimated as ‘01’. 
x If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first dose of study drug, provided the start year is the 
same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the event will be assumed to start on the first day 
of the given year (e.g., ??-???-2021 is estimated as 01-JAN-2021). 
x If the start date is completely missing and the stop date is either after the dose of study 
drug or completely missing, the start date will be estimated to be the day of study drug 
dosing. Otherwise, the start date will be estimated to be the first day of the same year as 
the stop date. All other non-AE and non-concomitant medication day calculations where 
only partial dates are available will be handled as follows: the first day of the month will 
be used in the calculations if the day part of a start date is missing while January 1 will be 
employed if both the month and day parts of a start date are missing. 
 
Stop Dates 
x If only the day of resolution is unknown, the day will be assumed to the last of the month 
(e.g., ??-JAN-2021 will be treated as 31-JAN-2021).  
x If both the day and month of resolution are unknown, the event will be assumed to have 
ceased on the last known date on the study or the last day of the year (e.g., ??-???-2021 
will be treated as 31-DEC-2021), whichever occurs earlier.  
x If the stop date is completely missing or the event is continuing, the event will be 
assumed to be after first dose of study drug and will be imputed using the last known date 
on the study. 
 
6. ANALYSIS SETS 
The following analysis sets will be used:  
 
x Safety Set (SS) will consist of all patients who receive at least 1 dose of study drug. All 
safety and pharmacodynamic (PD) data will be analyzed using the safety set. 
 
x Pharmacokinetic Set (PS) will consist of all patients for whom a tissue, plasma, and/or 
urine sample is obtained and analyzed for determintation of plasma drug and metabolites 
concentration. 


 
 
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Statistical Analysis Plan 
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CONFIDENTIAL 
7. STUDY POPULATION 
7.1 Patient Disposition 
Patient disposition information will be summarized for all patients by treatment group (only 900 
mg/m2 CPX-POM). Summaries will include: the number of patients screened, the number of 
patients in each analysis set, the number of patients completing the study, the number of patients 
completing 5 days of dosing with CPX-POM and who undergo TURBT from which tissue, 
blood, and urine samples were collected, the number of patients who completed the Day 35 
Follow-up Visit, the number of patients who died and the primary cause of death, the number of 
patients who had an autopsy, and the primary reason for discontinuation. 
7.2 Protocol Deviations 
Major protocol deviations that could potentially affect the efficacy or safety conclusions of the 
study will be identified prior to database lock.      
 
Major protocol deviations will be summarized by deviation category and listed.  
7.3 Demographics and Baseline Characteristics 
Demographics including age, sex at birth, ethnicity, race and childbearing potential will be listed 
and summarized.  Descriptive statistics will be presented for age. Frequency counts and 
percentages will be presented for sex, ethnicity, race, ECOG status and childbearing potential. 
 
Baseline characteristics of height (measured at screening), weight (measured at Visit 1), BSA, 
and whether bladder tumor is newly diagnosed or recurrent will be summarized with descriptive 
statistics. BSA will be calculated by the site personnel using the Dubois method using screening 
height and baseline weight measurements. 
 
Medical history will be mapped to preferred terms and system organ classes using the Medical 
Dictionary for Regulatory Activities (MedDRA) (version 23.1). Overall summaries will be 
provided by system organ class and preferred terms ordered by descending incidence of system 
organ class and preferred term within each system organ class. Medical history will also be 
listed. 
7.4 Prior and Concomitant Medications 
Prior and concomitant medication verbatim terms will be mapped to Anatomical Therapeutic 
Chemical (ATC) class and Preferred Names using the World Health Organization (WHO) Drug 
Dictionary Enhanced (version B3/September 2020). 
 
Concomitant medications are defined as medications that started on or after the treatment start 
date or were ongoing at the date of treatment start. Prior medications are defined as medications 
that started and stopped prior to the date of treatment start. Medications taken within 30 days 


 
 
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Statistical Analysis Plan 
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17MAY2021 
 
 
CONFIDENTIAL 
before baseline (Study Visit 2) must be recorded as a prior medication. Prior and concomitant 
medications will be listed. 
8. EFFECTIVENESS ANALYSES 
The primary objective of this study is to characterize the safety and dose tolerance of CPX-POM, 
there are no planned efficacy analyses.  Pharmacokinetic and pharmacodynamic analyses of 
bladder tumor tissue, plasma and urine samples will be reported separately. 
9. SAFETY ANALYSES 
All safety analyses will be based on the SS population. Data will be presented using descriptive 
statistics and no formal hypothesis testing will be implemented. 
9.1 Baseline Values 
Baseline is be defined as the measurement taken at baseline safety assessment Visit #2 (Study 
Day 1).  If that measurement is not available, baseline is defined as the last non-missing 
measurement recorded prior to CPX-POM administration.  
9.2 Handling of Dropouts or Missing Data 
No imputations will be made for missing values. Summaries will be based on observed data 
only. 
9.3 Extent of Exposure 
CPX-POM exposure will be summarized by visit and overall. Descriptive statistics for study 
drug administration will be presented for total dose administered and volume infused. Frequency 
counts and percentages will be presented for number of patients administered CPX-POM, 
number of infusions interrupted and the reason for interruption. CPX-POM adiminstration data 
will also be listed.  
9.4 Adverse Events 
All adverse event summaries will be restricted to Treatment Emergent Adverse Events (TEAE), 
which are defined as those AEs that occurred after first CPX-POM dosing and those existing 
AEs that worsened during the study. This will not include AEs that are due to the operative 
TURBT procedure. If it cannot be determined whether the AE is treatment emergent due to 
incomplete or missing data, then it will be considered treatment emergent. Verbatim terms will 
be mapped to preferred terms and system organ classes using the Medical Dictionary for 
Regulatory Activities (MedDRA) (version 23.1).  
 
Summaries that are displayed by system organ class and preferred terms will be ordered by 
descending order of incidence of system organ class and preferred term within each system organ 
class.  The following summaries will be provided: 
 


 
 
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Statistical Analysis Plan 
CPX-POM-002 
 
17MAY2021 
 
 
CONFIDENTIAL 
x Overall summary of AEs 
x TEAEs by system organ class and preferred term   
x TEAEs by system organ class, preferred term, and highest intensity   
x Related TEAEs by system organ class and preferred term 
x Serious TEAEs by system organ class and preferred term  
x Serious Related TEAEs by system organ class and preferred term 
x TEAEs leading to study discontinuation by system organ class and preferred term 
x TEAEs resulting in death 
 
Related events will be any event having the causality field marked as “Related” or missing on the 
Adverse Event eCRF page. Intensity (Grade) of AEs will be based on the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) (5.0). 
 
All AEs will be provided in a listing. 
9.5 Clinical Laboratory Evaluation 
Laboratory parameters (clinical chemistry, hematology, urinalysis) will be summarized using 
descriptive statistics at baseline and at each post-baseline time point. Changes from baseline will 
also be summarized.  
 
Graded laboratory abnormalities will be defined using the grading scheme based on NCI CTCAE 
(5.0). The incidence of treatment-emergent laboratory abnormalities, defined as values that 
increase at least one toxicity grade from baseline at any time post baseline up to and including 
the date of last dose of study drug, will be summarized by Grade. If baseline data are missing, 
then any graded abnormality (i.e., at least a Grade 1) will be considered treatment emergent. 
 
All laboratory parameters and pregnancy test results will be provided in listings.  
9.6 Vital Signs 
Vital signs (blood pressure, respiratory rate, heart rate, oxygen saturation and temperature) will 
be summarized using descriptive statistics at baseline and at each post-baseline time point. 
Changes from baseline will also be summarized. 
 
All vital signs data will be provided in listings. 
9.7 Physical Examination 
Physical examination results, including weight, will be listed. This listing will include data from 
each full physical exam (Screening and Follow-up/End of Treatment visits) and also assessments 
for physical symptoms/toxicities (recorded at each visit during the treatment period).  


 
 
CicloMed LLC 
 
Statistical Analysis Plan 
CPX-POM-002 
 
17MAY2021 
 
 
CONFIDENTIAL 
9.8 Electrocardiogram 
Overall interpretation results for ECG will be summarized using shift tables (Normal, Abnormal 
NCS, Abnormal CS) comparing baseline to follow-up. Descriptive statistics at baseline and at 
each post-baseline time point as well as changes from baseline will be summarized for each ECG 
parameter.   
 
All ECG results will be listed. 
9.9 Other Safety Measurements 
The following safety measurements collected will also be provided in listings: 
 
x Echocardiogram 
x Chest X-Ray or CT Scan 
x Pregnancy Test Results 
9.10 Study Procedures 
The details of the following procedures will be provided in listings: 
 
x Cytoscopy/Biopsy Procedures 
x Transurethral Resection of Bladder Tumor (TURBT) 
10. PHARMACOKINETIC ANALYSES 
Tissue, plasma, and urine concentrations of CPX-POM and its metabolites will be determined by 
GLP-validated liquid chromatography with tandem mass spectrometry LC-MS/MS assays and 
results will be presented in by-patient listings. 
 
Bladder tumor tissue-to-plasma and tissue-to-urine CPX concentration ratios will be calculated 
for each patient and listed. 
 
Urine β–glucuronidase activity, expressed as units of activity per milliliter of urine as well as 
units of activity per milligram of urine creatinine, will be measured for each patient and listed. 
 
These results will be reported separately. 
11. PHARMACODYNAMIC ANALYSES 
Bladder tumor tissues will be analyzed using single cell sequencing to elucidate mechanisms of 
CPX-POM action. To determine the change in bladder tumor tissue cell proliferation, Notch and 
Wnt cell signaling pathways, as well as bladder tumor tissue CD8+ TIL, immunohistochemistry 
will be performed on paraffin-embedded slides. 
 
These results will be reported separately. 


 
 
CicloMed LLC 
 
Statistical Analysis Plan 
CPX-POM-002 
 
17MAY2021 
 
 
CONFIDENTIAL 
12. REFERENCES 
 
13. SOFTWARE 
SAS Software Version 9.4. SAS Institute Inc., Cary, NC, USA. 
 
14. SAP REVISIONS 
Revision Date 
(dd month, yyyy) 
Section 
Summary of Revision 
Reason for Revision