Conditions: Prostate Cancer
Keywords: Yeliva ABC294640 103193
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 69
Healthy volunteers: no

Brief summary:
This is a Phase II study of the investigational drug opaganib. Patients with metastatic castration resistant prostate cancer (mCRPC) who have experienced disease progression while receiving abiraterone or enzalutamide will receive Opaganib at either 250 mg or 500 mg by mouth twice a day continuously. Patients will continue on study drug until the development of progressive disease, intolerable toxicity, withdrawal of patient consent or other event as outlined in patient discontinuation.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: Opaganib intervention 2: Abiraterone intervention 3: Enzalutamide intervention 4: Opaganib
Intervention descriptions: intervention 1: 500mg of Opaganib orally twice a day continuously. intervention 2: IV as directed by SOC intervention 3: IV as directed by SOC intervention 4: 250mg of Opaganib orally twice a day continuously.

Protocol document:
Prot_SAP_000.pdf: 
CTO # 103193 
Protocol version 4.0 dated 06/08/2021 
 
 CONFIDENTIAL - 1 
A Phase II Study of the Addition of Opaganib to Androgen Antagonists in Patients with 
Prostate Cancer Progression on Enzalutamide or Abiraterone  
 
  
Study Drug:    
 
Opaganib 
 
 
 
 
Enzalutamide 
 
 
 
 
Abiraterone 
 
Coordinating Center: 
Medical University of South Carolina- 
 
 
 
 
Hollings Cancer Center  
 
Participating Sites:  
Medical University of South Carolina, Hollings Cancer Center 
 
 
 
 
Emory University 
 
 
 
 
Ralph H. Johnson VA Medical Center 
 
Sponsor-Investigator:  
Michael Lilly, M.D.  
 
 
 
 
 
 
 
 
 
Hollings Cancer Center 
 
 
 
 
Medical University of South Carolina 
86 Jonathan Lucas Street 
Charleston, SC 29425 
 
Co-Investigator: 
 
Omer Kucuk, MD 
 
 
 
 
Emory University 
 
 
 
 
 
 
201 Dowman Drive 
Atlanta, GA 30322 
 
Statistician 
 
 
Hong Li, PhD 
 
 
 
 
Hollings Cancer Center 
 
 
 
 
Medical University of South Carolina 
 
 
 
 
 
 
86 JonathanLucas Street MSC 955 
 
 
 
 
Charleston, SC 29425 
 
Coordinating Office: 
Sponsor-Investigator Support Unit  
Hollings Cancer Center  
 
 
 
 
86 Jonathan Lucas Street, Suite 373 
 
 
 
 
Charleston, SC 29425 
 
 
 
 
Phone:  843-792-0275 
 
 
 
 
Fax:  843-792-5123 
 
 
 
 


CTO # 103193 
Protocol version 4.0 dated 06/08/2021 
 
 CONFIDENTIAL - 2 
 
MUSC Study ID:  103193 
 
 
RedHill Study ID: ABC-107 
 
NCT#:  NCT04207255 
 
 
 
VERSION HISTORY: 
 
 
Version 1.0 dated 10/7/2019 
Version 1.1 dated 11/18/2019 
Version 1.2 dated 11/21/2019 
Version 1.3 dated 11/26/2019 
Version 1.4 dated 12/13/2019 
Version 1.5 dated 01/09/2020 
Version 1.6 dated 01/11/2020 
Version 1.7 dated 02/06/2020 
Version 2.0 dated 04/01/2020 
Version 3.2 dated 03/25/2021 
Version 4.0 dated 06/08/2021 
 
 
 
 


CTO # 103193 
Protocol version 4.0 dated 06/08/2021 
 
 CONFIDENTIAL - 3 
I have read the Protocol entitled  
“A Phase II Study of the Addition of Opaganib to Androgen Antagonists in Patients with 
Prostate Cancer Progression on Enzalutamide or Abiraterone” 
 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good 
Clinical Practice and applicable regulatory requirements and to inform all who assist me in the 
conduct of this study of their responsibilities and obligations. 
 
 
 
 
 
___________________________________ 
 
Principal investigator printed name 
 
 
 
 
___________________________________  
__________________ 
 
 
Principal investigator signature 
 
 
 
Date 
 
 
 
 
___________________________________ 
 
Participating Center Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol version 4.0 dated 06/08/2021 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................. 6 
DEFINITIONS OF TERMS USED ............................................................................................... 17 
1   BACKGROUND ...................................................................................................................... 20 
1.1   PROSTATE CANCER ........................................................................................................... 20 
1.2  OPAGANIB .......................................................................................................................... 21 
1.3   SUMMARY OF OPAGANIB PHASE I DATA. .................................................................... 22 
Phase I Study Design ............................................................................................................. 22 
Phase I Safety Data ................................................................................................................ 23 
Phase I Efficacy Data ............................................................................................................ 24 
Phase I Pharmacokinetic Data ............................................................................................. 24 
1.4   RATIONALE FOR USE OF OPAGANIB FOR TREATMENT OF PROSTATE CANCER ............. 26 
2   STUDY DESIGN ...................................................................................................................... 27 
2.1  STUDY DESIGN ............................................................................................................... 27 
2.2   OBJECTIVES .................................................................................................................. 27 
Primary Objectives ................................................................................................................ 27 
Secondary Objectives ............................................................................................................ 27 
3   STUDY PATIENTS ................................................................................................................. 27 
3.1   INCLUSION CRITERIA ................................................................................................ 28 
3.2   EXCLUSION CRITERIA ............................................................................................... 29 
3.3   SUBJECT RECRUITMENT ........................................................................................... 30 
3.4   INFORMED CONSENT PROCESS .............................................................................. 30 
3.5   PATIENT REGISTRATION .......................................................................................... 31 
4   TREATMENT PLAN ............................................................................................................... 31 
4.1   STUDY CALENDAR ....................................................................................................... 31 
4.2   STUDY TREATMENT .................................................................................................... 31 
4.3   DOSE MODIFICATIONS ............................................................................................... 32 
4.4   DEFINITION OF DOSE-LIMITING TOXICITY........................................................ 34 
4.6   CORRELATIVE STUDIES ............................................................................................ 35 
4.7   PHARMACOKINETICS ........................................................................................................ 35 
5   STUDY DRUGS ....................................................................................................................... 36 
5.1   OPAGANIB ...................................................................................................................... 36 
5.2  ABIRATERONE ............................................................................................................... 37 
5.3  ENZALUTAMIDE ........................................................................................................... 37 
6  SAFETY PLAN ......................................................................................................................... 37 
6.1   GENERAL PLAN TO MANAGE SAFETY .................................................................. 37 
6.2  SAFETY PLAN FOR PSYCHIATRIC SYMPTOMS FROM STUDY DRUG ........... 38 
7   CONCOMITANT AND EXCLUDED THERAPIES .............................................................. 38 
7.1   ANTINEOPLASTIC DRUGS ......................................................................................... 38 
7.2   CYP SUBSTRATE DRUGS, INHIBITORS, AND ACTIVATORS ............................ 38 
7.3   MINIMIZING NEUROPSYCHIATRIC ADVERSE EVENTS ..................................................... 38 
8   PATIENT DISCONTINUATION ............................................................................................ 39 


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8.1  PATIENTS RESUMING TREATMENT………………………………….………..…39 
9   STATISTICAL CONSIDERATIONS ...................................................................................... 40 
9.1   STATISTICAL ANALYSIS FOR PRIMARY OBJECTIVE ............................................. 40 
9.2   STATSTICAL ANALYSIS FOR SECONDARY OBJECTIVES ........................................ 40 
9.3. ANALYSIS POPULATIONS ........................................................................................... 41 
9.4   SAMPLE SIZE DETERMINATION ....................................................................................... 42 
9.5   INTERIM ANALYSES .......................................................................................................... 42 
10   ADVERSE EVENT REPORTING REQUIREMENTS ......................................................... 43 
10.1   PURPOSE .......................................................................................................................... 43 
10.2   DEFINITION OF ADVERSE EVENT ................................................................................... 44 
10.3   DEFINITION OF SERIOUS ADVERSE EVENT ................................................................... 44 
10.4   DEFINITION OF SEVERITY .............................................................................................. 45 
10.5   DEFINITION OF START DATE, STOP DATE, DURATION ................................................ 45 
10.6   ACTIONS TAKEN ............................................................................................................. 45 
10.7   DEFINITION OF RELATIONSHIP TO STUDY DRUG ......................................................... 46 
10.8   DEFINITION OF OUTCOME AT TIME OF LAST OBSERVATION ..................................... 47 
10.9   DOCUMENTATION AND ASSESSMENT OF ADVERSE EVENTS ........................................ 47 
10.10   EXPECTED AND UNEXPECTED ADVERSE EVENTS ...................................................... 48 
10.11   ADDITIONAL ADVERSE EVENT CONSIDERATIONS ..................................................... 48 
10.12   SERIOUS ADVERSE EVENT REPORTING ...................................................................... 49 
11   MONITORING ....................................................................................................................... 50 
11.1   PROTOCOL DEVIATIONS ................................................................................................. 50 
11.2   SAFETY REPORTING ........................................................................................................ 50 
11.3   DATA SAFETY MONITORING COMMITTEE (DSMC) .................................................... 50 
12   ADMINISTRATIVE STRUCTURE ...................................................................................... 50 
12.1   INVESTIGATOR REQUIREMENTS .................................................................................... 51 
12.2   STUDY INITIATION .......................................................................................................... 51 
12.3   STUDY COMPLETION ...................................................................................................... 52 
12.4   RECORD RETENTION ................................................................................................ 52 
12.5   INFORMED CONSENT ...................................................................................................... 52 
12.6   INSTITUTIONAL REVIEW BOARD APPROVAL ................................................................ 52 
12.7   QUALITY ASSURANCE ..................................................................................................... 53 
13   REFERENCES ....................................................................................................................... 54 
APPENDIX A: SCHEDULE OF INTERVENTION .................................................................... 58 
APPENDIX B: DEFINITION OF DISEASE CONTROL ............................................................ 60 
APPENDIX C:  LIST OF CYP SUBSTRATES AND INHIBITORS........................................... 61 
APPENDIX D:  ECOG PERFORMANCE STATUS SCALE ...................................................... 68 
APPENDIX E.  STUDY SCHEMATIC DIAGRAM .................................................................... 69 
 


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PROTOCOL SYNOPSIS  
TITLE 
A Phase II Study of the Addition of Opaganib to Androgen 
Antagonists in Patients with Prostate Cancer Progression on 
Enzalutamide or Abiraterone  
PHASE 
II 
STUDY 
RATIONALE 
Opaganib 
[3-(4-chlorophenyl)-adamantane-1-carboxylic 
acid 
(pyridin-4-
ylmethyl)amide, hydrochloride salt] is an orally available inhibitor of the enzyme 
sphingosine kinase-2 (SK2).  SK2 is an innovative molecular target for anti-
cancer therapy because of its critical role in sphingolipid metabolism, which is 
known to regulate tumor cell death and proliferation. Preclinical studies 
demonstrate that opaganib inhibits signaling through the RAS/RAF/MEK/ERK 
and RAS/PI3K/AKT pathways, promotes tumor cell killing, and inhibits host 
inflammation in several tumor models.  
 
Dysregulation of androgen receptor- (AR)- and MYC-dependent signaling is 
characteristic of castration-resistant prostate cancer (CRPC), and confers 
resistance to many forms of therapy.  Opaganib decreases MYC and AR protein 
and mRNA expression in prostate cancer cell lines, and inhibits the growth of 
prostate cancer cells with amplified or splice variant AR genes as a single agent, 
or synergistically with docetaxel.  We hypothesize that opaganib will have 
therapeutic activity in patients with metastatic CRPC (mCRPC) . 


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STUDY DESIGN 
This is a Phase II efficacy study of opaganib in patients with metastatic 
castration-resistant prostate cancer that is progressing during treatment with 
androgen signaling blockers abiraterone or enzalutamide.  An initial “run in” 
cohort (cohort 1) of 6 patients with mCRPC  will be enrolled, 3 failing treatment 
with abiraterone (cohort 1a) and 3 failing treatment with enzalutamide (cohort 
1b).  These subjects will receive opaganib 250 mg po BID, along with 
continuation of prior abiraterone or enzalutamide, to document tolerability in 
this new patient population, and to document the effects of opaganib on blood 
PSA levels.  Provided that there is no untoward toxicity in these patients, 2 
additional cohorts of patients with worsening disease during abiraterone (cohort 
2) or enzalutamide (cohort 3) treatment will be enrolled.  They will receive 
opaganib 500 mg po bid continuously.  In addition they will continue previous 
androgen blocking agents (abiraterone or enzalutamide, and gonadotropin 
releasing hormone GnRH receptor agonist/antagonist).  Treatment will continue 
until there is 1) unacceptable toxicity (gr 3 or 4 toxicity that does not resolve to 
grade 1 or less by 28 days), 2) institution of new additional prostate cancer 
therapy, 3) withdrawal of consent, 4) any condition that, in the opinion of the 
treating physician, renders continued opaganib treatment to be not in the 
patient’s best interest, 5) lack of compliance with study procedures by the 
patient, or 6) lack of disease control by study-specified parameters.  


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OBJECTIVES –  
Primary Objectives 
• To measure the proportion of patients with disease control during opaganib 
(plus abiraterone or enzalutamide) therapy, using a composite metric based 
on PSA, bone scan, and RECIST measurements per Prostate Cancer 
Working Group 3 (PCWG3) criteria.  For purposes of this study, disease 
control is defined as stable disease or better after four cycles (16 weeks) of 
treatment.  
Secondary Objectives 
• To estimate the radiographic progression-free survival (rPFS), PSA 
progression-free survival (PSA-PFS) times in patients treated with 
opaganib (plus abiraterone or enzalutamide). 
• To document the PSA response rate, RECIST response rate, and change in 
QOL (FACT-P) in mCRPC patients treated with opaganib (plus abiraterone 
or enzalutamide) after four cycles of treatment 
• To determine the effects opaganib on regression or progression of mCRPC 
clones with amplified AR or MYC, identified by serial ctDNA-based 
genomic profiling. 
• To assess safety of opaganib in mCRPC patients, in combination with 
abiraterone or enzalutamide, GnRHR agonist/antagonist 
• To monitor changes in numbers or activity of immune cells and myeloid-
derived suppressor cells during opaganib therapy (with continued ADT). 
NUMBER OF 
PATIENTS 
Up to 60 patients 


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PATIENT 
ELIGIBILITY 
CRITERIA 
Inclusion criteria 
1. Patient must have mCRPC.  Each patient must have: 
a. Tissue diagnosis documented by pathology report, or clinic note 
attesting to same. 
b. Radiographically-demonstrated metastases 
c. Patients may have adenocarcinoma, or ductal carcinoma, or 
combinations of these entities 
2. Voluntary, signed and dated, institutional review board (IRB)-approved 
informed consent form in accordance with regulatory and institutional 
guidelines. 
3. Documented progression during treatment with enzalutamide or abiraterone, as 
determined by the enrolling investigator 
4. Testosterone level documented to be less than 50ng/dL 
5. 18 years of age or older. 
6. ECOG performance status of 0-2. 
7.  Acceptable liver function: 
a. Bilirubin ≤ 1.5 times upper limit of normal (CTCAE Grade 1 
baseline) 
b. AST (SGOT) & ALT (SGPT) < 3 x ULN (CTCAE Grade 1 baseline) 
c. Subjects with Gilbert’s syndrome may be included if the total 
bilirubin is < 3x ULN and the direct bilirubin is within normal limits 
8.  Acceptable kidney function: 
a. Serum creatinine ≤ 1.5 X ULN (CTCAE Grade 1 baseline) 
9.  Acceptable hematologic status: 
a. Absolute neutrophil count > 1000 cells/mm3, 
b. Platelet count > 75,000 (plt/mm3) (CTCAE Grade 1 baseline) 
c. Hemoglobin > 9.0 g/dL. 
10.  Acceptable blood sugar control: 
a. Fasting blood glucose of <165mg/dL or random blood glucose of < 
200mg/dL 
11.  Urinalysis: No clinically significant abnormalities. 
12.  International normalized ratio (INR) ≤ 1.7 for patients not on anti-
coagulation meds 
13. Well-controlled blood pressure as determined by the treating investigator.   
14. Patients requiring narcotic analgesics must be on stable doses for at least 2 
weeks prior to study entry.   
Exclusion criteria 
1. New York Heart Association Class III or IV, cardiac disease, 


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myocardial infarction within the past 6 months, unstable arrhythmia, or 
evidence of ischemia on ECG.  
2. Underlying psychiatric disorder requiring hospitalization within the last 
two years. 
3. Clinically significant neurological disorder (Parkinson’s disease, 
dementia, multiple sclerosis), as determined by the enrolling 
investigator 
4. Active, uncontrolled bacterial, viral or fungal infection, requiring 
systemic therapy. 
5. Treatment with local or systemic radiation therapy, surgery, or 
investigational therapy within 28 days prior to registration  
6. Unwillingness or inability to comply with procedures required in this 
protocol. 
7. Serious nonmalignant disease that could compromise protocol 
objectives in the opinion of the Investigator. 
8. Patients who are receiving coumadin, apixaban or rivaroxaban 
 
Patients who are receiving other drugs that are sensitive substrates of 
CYP450 1A2, 3A4, 2B6, 2C8, 2C9, 2C19 or 2D6, P-gP, BCRP, and 
OATP1B1, or strong inhibitors or inducers of all major CYP450 
isozymes that cannot be stopped at least 7 days or 5 half-lives 
(whichever is longer) before starting treatment with opaganib may be 
treated on this study with careful monitoring for toxic effects or loss of 
efficacy of the relevant drug.  A list of commonly used drugs that are 
sensitive substrates of CYP450 1A2, 3A4, 2B6, 2C8, 2C9, 2C19 or 
2D6, P-gP, BCRP, and OATP1B1, or strong inhibitors or inducers of all 
major CYP450 isozymes with the half-life of each drug identified, is 
included as an Appendix C. 
9. Patients who are currently participating in any other clinical trial of an 
investigational product. 
10. Other primary malignancy requiring systemic treatment within past 5 
years except carcinoma in situ of the cervix or urinary bladder or non-
melanoma skin cancer. 
11. Any other mental incapacitation or psychiatric illness that would 
preclude study participation, as determined by the enrolling 
investigator.   
12. Prisoners or patients who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness must not be enrolled into this study. 


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13. Patients that have had chemotherapy for castration resistant prostate 
cancer (patients can have had chemotherapy for castration sensitive PC) 
• Exception: Patients who had prior chemo for CRPC are eligible 
if they have a PS=0-1 and life expectancy of more than 6 
months. 


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TEST ARTICLE 
ADMINISTRATION 
Opaganib will be administered at the dose of 250 mg (cohorts 1a and 1b) or 500 
mg (cohorts 2 and 3) orally twice a day (approximately 12 hours apart) 
continuously.  Opaganib will be dosed after a light to moderate meal.  A cycle 
will be defined as 28 days.   
PRESTUDY 
ASSESSMENTS 
 
Screening Period 
• Informed consent 
• Eligibility determination 
Baseline Period  
Within 14 days prior to Cycle 1 Day 1 
• Complete medical history  
• Concomitant medication assessment 
• Baseline Review of Systems and adverse event (AE) documentation 
• Physical examination, to include neurologic exam and mini-mental state 
examination 
• Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) 
and weight 
• ECOG Performance Status  
• FACT-P Quality of Life questionnaire 
• 12-lead electrocardiogram  
• Serum chemistry 
• Coagulation parameters 
• CBC with differential 
• Urinalysis 
• Urine protein + urine creatinine 
• PSA, CEA, LDH level 
 
Within 28 days prior to Cycle 1 Day 1 
• 
Radiographic tumor measurements.  Investigator’s choice of CT scans of 
chest/abdomen/pelvis with contrast or MRI scan of abdomen/pelvis with or 
without contrast;  technetium bone scan for all patients.  Optional:  fluciclovine 
PET scan 
 
Within 56 days of Cycle 1 Day 1 (with no interval new therapy) 
• 
Guardant 360 genomic profile 


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TREATMENT 
ASSESSMENTS 
Patients will be monitored every 28 days.  The patient assessments include: 
• Review of concomitant medications, including narcotic usage. 
• Adverse Event monitoring (patient diary, review of systems). 
• ECOG Performance Status.  
• Physical exam to include neurologic exam  
• Weight.  
• Vital signs (temperature, blood pressure, pulse rate, and respiratory rate). 
• Serum chemistry.  
• Coagulation parameters 
• CBC with differential. 
• Urinalysis 
• Urine protein + urine creatinine 
 
Period assessments (see schedule of interventions, Appendix A) will also 
include the following: 
• Coagulation parameters 
• Mini-mental Status Exam 
• PSA 
• LDH 
• CEA (if initially elevated) 
 
• Radiological assessment will be performed after completion of 4 cycles 
(112 days) of drug treatment, and then every 2 cycles (56 days) until 
criteria for study withdrawal are met. If a response is noted, a follow-up 
radiographic assessment may be performed at 4 weeks to confirm 
response.  Choice of radiologic studies will be at the discretion of the 
treating physician, but should include studies similar to those baseline 
studies that showed metastases. 
 
• Guardant 360 genomic profile will be repeated after 112 days of 
treatment, and at the off-study visit (if more than 56 days later). 


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INVESTIGATIVE 
SITES  
This study will be conducted at the Medical University of South Carolina, 
Hollings Cancer Center, Charleston, SC 29425; Ralph H. Johnson VA Medical 
Center, Charleston, SC 29401; Emory University, Atlanta, GA.  


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STATISTICAL 
ANALYSIS  
Primary endpoint analysis: 
We will estimate the proportion of patients with disease control during opaganib 
(plus abiraterone or enzalutamide) therapy, using a composite metric based on 
PSA, bone scan, and RECIST measurements per PCWG3 criteria (see the 
definitions in Appendix B).  The primary measurement will be determined after 
four cycles (day 113) of treatment, or at withdrawal from the study. The 95% 
confidence interval for the proportion of disease control will be presented. A 
one-sided exact binomial test will be performed based on a null hypothesized 
proportion of 0.1 with a significance level of 0.05. 
 
Secondary endpoint analysis: 
• Kaplan-Meier estimates of the time-to-event (i.e., rPFS or PSA-PFS) 
will be constructed using a competing-risks approach which treats 
death due to cause unrelated to prostate cancer as a competing event.  
Median time to progression will be estimated and the corresponding 
95% confidence intervals constructed using Greenwood’s variance 
estimate (Collett, 1994). 
• Both PSA response rate and overall response rate will be estimated 
with the 95% confidence interval. The change in QOL will be 
summarized graphically and numerically, and tested based on two-
sided paired t-test. 
• The relationship between changes in marker levels (copy number for 
AR, MYC amplified clones based on Guardant 360 genomic profile) 
and patient response for regression or progression of mCRPC clones 
will be assessed graphically.  Scatterplots of percent change in target 
lesions versus change in marker levels will be constructed.  Variable 
transformations will be considered as needed, and Pearson or 
Spearman correlation coefficients will be constructed as appropriate.  
Based on two-sided Pearson or Spearman correlation coefficients test 
with alpha = 0.05, the sample size of 27 provides a 77% power to 
detect a correlation of 0.5 versus a null correlation of 0. 


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• The safety analysis will be conducted using descriptive statistics of 
the incidence of adverse events (AEs) and serious adverse events 
(SAEs), all events of death, and any study specific issue of concern.  
Adverse events will be coded by body system, and summary tables 
with incidence rates of AEs will be generated.  Descriptive statistics 
of AEs will be reported for all patients, patients who discontinue due 
to AEs, and patients with related AEs.  Severity, duration, 
investigator attributed relationship to treatment, and outcomes of 
AEs will be reported.  AE and SAE reporting criteria are outlined in 
section 10. 
• The numbers or activity of immune cells and myeloid-derived 
suppressor cells (measured at baseline and certain time points) will 
be summarized graphically. The mean of the difference of cell counts 
between time points will be described with the 95% confidence 
interval. The changes in cell counts will be analyzed using a paired t-
test to see if the change is significant. Equivalent non-parametric 
tests (e.g., Wilcoxon rank-sum test) will be used as appropriate. 


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DURATION OF 
STUDY  
Approximately 30 months, assuming 4 months for study activation, and an 
enrollment rate of 4 subjects per month, among all sites. 
 
 
DEFINITIONS OF TERMS USED 
OPAGANIB 
3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-
ylmethyl)amide, hydrochloride salt 
ADT 
 
 
androgen depleting therapy 
AE 
 
       
adverse event 
AKT 
 
 
protein kinase B 
ALT 
 
 
alanine aminotransferase 
API 
 
 
active pharmaceutical ingredient 
AR 
 
 
androgen receptor 
AST 
 
 
aspartate aminotransferase 
AUC 
 
 
area under the drug concentration over time curve 
BID 
 
 
twice per day 
BUN 
 
 
blood urea nitrogen 
CBC 
 
 
complete blood count, a blood test consisting of hemoglobin, hematocrit, 
 
 
 
white blood count, platelet count, mean corpuscular volume, mean  
 
 
 
corpuscular hemoglobin concentration, mean corpuscular hemoglobin 
CEA 
 
 
carcinoembryonic antigen 
CI 
 
 
combination index 
CMP 
 
 
complete metabolic panel, a blood test that includes plasma concentrations 
 
 
 
of sodium, potassium, chloride, bicarbonate, blood urea nitrogen,  
 
 
 
creatinine, aspartate aminotransferase, alkaline phosphatase, calcium,  
 
 
 
albumin, total bilirubin,  alanine aminotransferase, glucose 
c-Myc  
 
myelocytomatosis oncogene 
CR 
 
 
complete response 
CRF 
 
 
Case Report Form 
CT 
 
 
computer-assisted tomography 
CTCAE 
 
Common Toxicity Criteria adverse event 
CTRC  
 
Clinical and Translation Research Center 
CV 
 
 
cardiovascular 
CYP 
 
 
cytochrome P450 
DLT 
 
 
dose limiting toxicity 
DMS 
 
 
N,N-dimethylsphingosine 
DSMC  
 
Data Safety Monitoring Committee 
ECG 
 
 
electrocardiogram 
ECOG  
 
Eastern Cooperative Oncology Group 
EDC   
 
electronic data capture system 
EGF 
 
 
epidermal growth factor 
ERK 
 
 
extracellular signal-related kinase 
FDA 
 
 
Food and Drug Administration 
GI 
 
 
gastrointestinal 


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GLP 
 
 
Good Laboratory Practice 
GnRH  
 
gonadotropin releasing hormone 
HADS  
 
Hospital Anxiety and Depression Scale 
HCC 
 
 
Hollings Cancer Center, MUSC 
HED 
 
 
human equivalent dose 
hERG  
 
human ether-a-go-go related gene 
HIV 
 
 
human immunodeficiency virus 
HNSTD 
 
highest nonseverely toxic dose 
ICH 
 
 
International Conference on Harmonization 
IC50 
 
 
concentration that inhibits by 50% 
IL-1β  
 
interleukin 1-beta 
IL-6 
 
 
interleukin 6 
iNOS  
 
inducible nitric oxide synthase 
IRB 
 
 
Institutional Review Board 
LC/MS  
 
liquid chromatography with mass-spectrometry detection 
LDH 
 
 
lactate dehydrogenase 
mCRPC 
 
metastatic castration-resistant prostate cancer 
MDSC  
 
myeloid-derived suppressor cells 
MEK  
 
mitogen-activated protein kinase/ERK kinase 
MTD  
 
maximum tolerated dose 
MMSE  
 
Mini-Mental State Exam 
MTOR  
 
mammalian target of rapamycin 
MRI 
 
 
magnetic resonance imaging 
NCI 
 
 
National Cancer Institute 
NFκB  
 
nuclear factor kappa-B 
NOAEL 
 
no adverse effect level 
p 
 
 
probability factor 
PBMC  
 
Peripheral Blood Mononuclear Cells  
PCWG3 
 
Prostate Cancer Working Group 3 
PD  
 
 
pharmacodynamics(s) 
PDGF  
 
platelet-derived growth factor 
PI 
 
 
Principal Investigator 
PI3K 
 
 
phophatidylinositide 3-kinase 
PK 
 
 
pharmacokinetic(s) 
PR 
 
 
partial response 
PSA 
 
 
prostate-specific antigen 
PT 
 
 
prothrombin 
PTT 
 
 
prothrombin time 
Raf 
 
 
rapidly accelerated fibrosarcoma oncogene 
Ras 
 
 
rat sarcoma oncogene 
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
S1P 
 
 
sphingosine 1-phosphate 
SAE 
 
 
serious adverse event 
s.c. 
 
 
subcutaneous 
SD 
 
 
stable disease 
SEM 
 
 
standard error of the mean 


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SIS Unit 
 
Sponsor-Investigator Support Unit 
SK 
 
 
sphingosine kinase 
SK1 
 
 
sphingosine kinase-1 
SK2 
 
 
sphingosine kinase-2 
TNFα  
 
tumor necrosis factor-alpha 
TUNEL 
 
terminal deoxynucleotidyl transferase dUTP nick end labeling 
ULN 
 
 
upper limit of normal 
VEGF  
 
vascular endothelial growth factor 
W 
 
 
week 
WBC  
 
white blood cells 
 
 


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 CONFIDENTIAL - 20 
1   BACKGROUND 
1.1   PROSTATE CANCER 
Localized prostate cancer is usually treated with radiation or surgery, though in many cases 
watchful waiting is considered appropriate.  Patients with high grade tumors and extraprostatic 
extension have poorer prognoses and may receive additional treatment as part of initial therapy. 
Some patients have metastatic disease at diagnosis, and others, despite adequate initial treatment, 
develop metastatic disease over a period of time which may be greater than a decade. 
 
The first, and most classic, therapy for advanced prostate cancer is androgen-depleting treatment 
(ADT) to reduce signaling through the androgen receptor (AR).  Such interventions include 
treatments to deplete AR ligands such as testosterone, e.g., orchiectomy, GnRHR 
agonists/antagonists, 17-lyase inhibitors, estrogen agonists, and treatments that prevent the 
association of AR and its androgen ligands, i.e., anti-androgens (Antonarakis et al 2015).  
However, resistance usually develops to these therapies, accompanied by continued signaling 
through the androgen receptor (AR).  Resistance to antiandrogen therapy is often associated with 
presence of AR-V7 splice variant (Antonarakis et al, 2014; Antonarakis et al, 2017), mutations in 
the AR ligand-binding domain, or amplification of AR, MYC, and other genes.  Androgen 
blockade has been associated multiple toxicities, including loss of muscle mass (Pezaro et al, 
2013), increased body fat, insulin resistance, cognitive decline, and loss of sexual function.  In 
patients with preexisting cardiac disease, androgen blockade has been associated with increased 
all-cause mortality (Ziehr et al, 2015).  
 
Classic cytotoxic agents such as docetaxel, cabazitaxel, platinum analogs, and mitoxantrone have 
been shown to have reproducible anti-tumor effects in prostate cancer patients, with 
improvement in overall survival in some cases.  However, as prostate cancer is usually a disease 
of older men, coexistence of major comorbidities is common and often precludes use of 
cytotoxic agents in patients who have failed initial, less toxic therapy.   
  
Few effective prostate cancer treatments that are not androgen axis antagonists or cytotoxic 
agents are available.  Sipuleucel-T autologous cellular immunotherapy produces as modest 
improvement in overall survival, as does radium-223 treatment.  However neither agent reliably 
produces shrinkage of soft tissue masses, or reductions in PSA level, suggesting that there is 
little direct anti-cancer effect.  Rare patients with increased antigenic load (high microsatellite 
instability, high tumor mutational burden, biallelic silencing of CDK12 [each <5% of metastatic 
prostate cancer]) may respond to checkpoint antibodies. 
 
Many kinase inhibitors have been evaluated for use in prostate cancer management, but none are 
FDA-approved.  Several problems have been identified.  First, prostate cancer patients often 
tolerate multi-targeted kinase inhibitors poorly, with severe fatigue and non-hematologic grade 3 
and 4 toxicities.  This results in many patients tolerating only half or less of a “typical” full dose 
of inhibitor.  Possibly this results from years of lack of testosterone, and general ill health.   


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Second, assessment of response to kinase inhibitors is often difficult.  The lack of RECIST-
evaluable lesions (present only in about 20% of subjects with metastatic prostate cancer) makes 
evaluation of any therapy difficult.  However some kinase inhibitors have been shown to 
artifactually elevate PSA levels, obscuring potential anti-tumor effects.  The hyperacute increase 
in PSA usually happens within a few days of the start of treatment, resulting in an apparent 
increase in the PSA velocity.  When the kinase inhibitor is stopped the PSA level may drop 
abruptly as well.  This phenomenon has been described for patients treated with CEP-701, 
imatinib, and sorafenib (Collins, et al., 2007; Dahut, et al., 2008).  We have also observed this in 
prostate cancer patients treated with trametinib (M. Lilly, unpublished 2018).  Third, there are 
few examples of prostate cancer patients where a mutant kinase plays a dominant, driver role in 
prostate carcinogenesis.  While lung cancer, melanoma, and many hematologic malignancies 
have activated kinases as drivers, prostate cancer usually results from deficiencies of tumor 
suppressors or DNA repair mechanisms.  Constitutively-active BRAF and PIK3CA mutants occur 
in 3% and 8% of PCa subjects respectively, but other active kinase mutants are rare.  While 
kinase inhibitors targeting non-mutant kinases (eg, CDK4/6 inhibitors) have been clinically 
useful, it is difficult to predict a priori whether a patient will benefit from this kind of treatment.  
Empiric clinical trials are usually required. 
 
1.2  OPAGANIB 
Opaganib (formerly ABC294640) is a selective inhibitor of sphingosine kinase 2 (SK2), which 
converts sphingosine to sphingosine-1-phosphate (S1P) (Figure 1).   
 
Sphingomyelin, an essential component of cellular membranes and which serves as a precursor 
for important cellular lipid messengers, is converted by sphingomyelinase to ceramide.  
Ceramidase catalyzes the conversion of ceramide to sphingosine, which is subsequently 
converted to S1P by sphingosine kinases.  Ceramide and sphingosine are pro-apoptotic in tumor 
cells but do not perturb quiescent normal cells, but S1P is associated with tumor cell 
proliferation, angiogenesis and inflammation as well as anti-apoptotic activity.  The balance 
between sphingosine and S1P, therefore, appears to play an important role in the survival and 


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 CONFIDENTIAL - 22 
progression of tumor cells.  This balance has been referred to as the “rheostat” by several authors 
(Cuvillier et al, 1996; Pyne and Pyne, 2010). 
 
SK2 is distinguished from sphingosine kinase 1 (SK1) by its primarily nuclear rather than 
cytosolic location (Neubauer et al, 2016;  Ogretmen 2018).  Despite catalyzing the same 
reaction, SK2 inhibition has different effects than SK1 inhibition (ibid). In several models, 
inhibition of SK2 has a greater anticancer effect than inhibition of SK1 (Gao et al, 2012). In 
addition to SK2 inhibition, opaganib also inhibits dihydroceramide desaturase, which may be an 
additional mechanism for its anticancer activity (Venant et al, 2015).   
 
Opaganib is an orally-available selective SK2 inhibitor with several mechanisms of action of 
relevance to prostate cancer.  First, it attenuates signaling through the Ras/Raf/MEK/ERK and 
Ras/PI3K/AKT pathways (Gao, et al., 2012)  Second, it suppresses the activation of NFκB by 
TNFα, inhibiting TNFα-driven inflammation.(Maines, et al., 2008)  Third, opaganib appears to 
target MYC protein for proteasomal degradation [Voelkel-Johnson, et al; unpublished data 2018] 
through its direct effects on SK2.  Fourth, through its effects on diydroceramide desaturase 
opaganib reduces AR protein and mRNA.   Fifth, opaganib decreased the immunosuppressive 
potential of MDSCs [unpublished data].   
 
Opaganib has demonstrated anticancer activity in multiple preclinical models of common 
tumors, including activity in ER positive (Antoon et al, 2010) and triple negative breast (Antoon 
et al, 2012), non-small cell lung (Dai et al, 2018), ovarian (White et al, 2013), pancreatic 
(Beljanski et al, 2011; Lewis et al, 2016) and prostate (Gestaut et al, 2014; Schrecengost et al, 
2015; Venant et al, 2016) cancer.  In addition, opaganib has been shown in vitro to potentiate the 
activity of several common chemotherapeutic agents including doxorubicin (Leili et al, 2018) 
and 5-fluorouracil and cisplatin (Xun et al, 2015).  Based on preclinical data, overexpression of 
SK2 has been suggested as a marker for opaganib sensitivity (Guan et al, 2016), but to date no 
clinical correlative markers of opaganib activity have been studied. 
 
1.3   SUMMARY OF OPAGANIB PHASE I DATA.  
To the best of our knowledge, opaganib is the only SK2 inhibitor in clinical trials, and thus is a 
unique, first-in-class compound testing the impact of a novel mechanism on cancer treatment.  A 
first-in-human phase 1 study in advanced solid tumor patients (Britten et al, 2017; 
NCT01488513), a food effect study in healthy volunteers, and a phase 1 study in advanced 
myeloma patients (data on file, RedHill Biopharma) have been completed.  A phase 2 study in 
advanced cholangiocarcinoma is under way (NCT03377179).  The recommended phase 2 dose 
has been defined and clinical activity has been seen in both patient studies. 
Phase I Study Design 
The first-in-human phase I trial employed a 3+3 design.  Opaganib was administered orally 
as 250 mg gelatin capsules on a continuous schedule, with 28 days constituting a Cycle.  
Tumors were re-imaged every two cycles (8 weeks), and patients were allowed to continue 


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Protocol version 4.0 dated 06/08/2021 
 
 CONFIDENTIAL - 23 
receiving the drug if there is no disease progression (by RECIST criteria).  Primary 
endpoints were:  identification of the Maximum Tolerated Dose (MTD); determination of 
the Dose Limiting Toxicities (DLT); and evaluation of safety.  Secondary endpoints were:  
determination of pharmacokinetics; evaluation of pharmacodynamics effects; and 
assessment of antitumor activity.   
Phase I Safety Data 
Twenty-one patients were treated in the trial, as outlined in Table 1.   Three patients (one at 
250 mg bid, and two at 500 mg bid) were unable to complete Cycle 1 due to complications 
from their disease, and were replaced.   
 
The first patient on study at 250 mg qd developed dose-limiting grade 4 hyperglycemia in 
the setting of rapidly progressing pancreas cancer; no additional patients experienced drug-
related hyperglycemia.  Among the four patients enrolled at 750 mg bid, one ovarian 
cancer patient had dose-limiting grade 3 nausea and vomiting, and two patients were 
unable to complete cycle 1 due to drug-related toxicities (one with grade 2 dysarthria which 
recurred with grade 2 non-cardiac chest discomfort and grade 2 choking sensation when 
drug was restarted at 500 mg bid; the other with grade 2 acute kidney injury, grade 3 
nausea, and grade 2 agitation).  The 750 mg bid dose level was declared not tolerable, and 
the 500 mg dose level was expanded.   
 
One patient at the expanded 500 mg dose level was dose reduced at Cycle 3 due to grade 3 
hallucinations, muscle spasms, and paresthesias:  this patient discontinued when spasticity 
recurred at 250 mg bid.  The other five patients at 500 mg bid tolerated the drug well, and 
the 500 mg bid dose level was established as the recommended phase II dose. 
 
Table 1.  Dose Escalation Summary 
 
Cohort 
 
Dose Level 
Number of Patients 
(Evaluable for DLTa) 
 
DLT 
1 
250 mg po qd 
6 (6) 
Grade 4 hyperglycemia (1 patient) 
2 
250 mg po bid 
4 (3b) 
None 
3 
500 mg po bid 
4 (3c) 
None 
4 
750 mg po bid 
4 (2d) 
Grade 3 nausea/vomiting (1 patient) 
5 
500 mg po bid 
3 (3) 
None 
 
 
 
Treatment has generally been well tolerated. The main adverse reactions noted have been 
psychiatric:  mood changes, hallucinations, anxiety.  These reactions have generally occurred at 
either 500 mg bid or 750 mg bid and resolved either with dose reduction or discontinuation of 


CTO # 103193 
Protocol version 4.0 dated 06/08/2021 
 
 CONFIDENTIAL - 24 
treatment.  After the food effect study demonstrated that bioavailability was similar with or 
without food and that absorption was more gradual after food, patients were instructed to take 
medication after eating; prior to that, dosing was while fasting.  Virtually all patients who had 
psychiatric reactions were also on narcotic analgesics, often given irregularly on an as-needed 
basis.  With the change to dosing after eating and better regulation of analgesic dosing, 
psychiatric reactions have become much less common and milder.  Patients who are not on 
narcotic analgesics have generally tolerated 750 mg bid. 
 
Phase I Efficacy Data 
Among the 15 patients evaluable for anti-tumor activity across all dose levels, one (7%) heavily 
pretreated cholangiocarcinoma patient developed a partial response after 8 cycles at 250 mg qd, 
and continued on study for a total of 18 cycles before developing progressive disease.  Six 
patients (40%) had a best response of stable disease:  one metastatic urothelial carcinoma patient 
(at 250 mg qd) ultimately developed progressive disease after 12 courses; one cholangio-
carcinoma patient (at 500 mg bid) came off study in course 3 for toxicity; and four patients (1 at 
250 mg qd, 2 at 250 mg bid, and 1 at 500 mg bid) came off study for progressive disease at the 
second disease evaluation (prior to cycle 4).  The remaining eight (53%) patients had progressive 
disease as their best response.  No patients with prostate cancer were entered into the phase 1 
study. 
 
 Phase I Pharmacokinetic Data 
Pharmacokinetic profiling was conducted on Days 1 and 28 of Cycle 1; pharmacokinetic data for 
opaganib is shown in Figure 2.  Following oral administration of the drug, plasma concentrations 
of opaganib typically peak at 1-2 hours, and then declined with a half-time of clearance of 
approximately 5-15 hours.  The Cmax levels of opaganib were comparable at Day 1 and Day 28 at 
all dose levels; however, the AUC0-T values at Day 28 were greater than those at Day 1 for the 
500 mg bid and 750 mg 
bid cohorts, suggesting a 
possibility of 
accumulation at higher 
doses.  As shown in 
Figure 2, the Cmax 
(combining data for Day 1 
with Day 28, as well as 
250 mg qd with 250 mg 
bid) was approximately 
linear with dose between 
250 and 500 mg (2.7 ± 0.3 
and 5.2 ± 1.1 μg/mL, 
respectively); however, 
there was no statistical 
Cmax
250
500
750
0
4
8
12
16
ABC294640  Dose (mg)
ABC294640 Cmax (µg/mL)
Day 1 AUC0-T
250
500
750
0
20
40
60
80
100
ABC294640  Dose (mg)
ABC294640 AUC (µg*h/mL)
Figure 2.  PK of opaganib in humans. 
Plasma opaganib (ABC294640) level in 
plasma samples from patients getting 
250 (, Δ), 500 (●, ○) or 750 mg (∎, 
□) of opaganib. Panel A.  The Cmax
level for each PK profile is shown with 
values from Day 1 (filled symbols) and 
Day 28 (open symbols).  Dotted line = 
the Cmax predicted for antitumor activity 
in mouse tumors. Panel B.  Day 1 
AUC0-T values.  Panel C.  Day 28 
AUC0-T
Day 28 AUC0-T
250 QD
250 BID
500 BID
750 BID
0
20
40
60
80
100
ABC294640  Dose (mg)
ABC294640 AUC (µg*h/mL)
B
A
C


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further increase at 750 mg (5.6 ± 0.6 μg/mL).  Doses of opaganib that provide therapeutic 
efficacy in mouse xenograft models provide a Cmax of approximately 3.5 μg/mL (French, et al., 
2010), a drug level that was achieved by 33%, 75% and 100% of patients treated with 250, 500 
and 750 mg of opaganib, respectively.  Cmax and AUC0-T values at Day 1 suggest an 
approximately linear increase between the 250 and 500 mg doses; however, further increases in 
drug exposure were not obtained at the 750 mg dose level.  AUC0-T data for Day 28 show a 
similar linear increase between doses of 250 and 500 mg, with the possibility of further increase 
suggested by the single data point obtained for the 750 mg dose. 
 
Phase I Pharmacodynamic Data 
The target of opaganib, SK2, catalyzes phosphorylation of sphingosine to S1P.  In cancer 
patients, plasma S1P was employed as a biomarker for inhibition of SK2.  Plasma samples were 
assessed for sphingolipid 
profiles by LC-MS/MS in 
the Lipidomics Core at 
MUSC.  Opaganib 
treatment of human 
patients resulted in rapid 
decreases in plasma S1P 
levels very similar to 
changes observed in mice.  
In general, plasma S1P 
levels reached a minimum 
at approximately 12 hours 
after opaganib treatment 
and typically recovered to 
baseline by 24 hours 
(Figure 3).  Combining 
data from Days 1 and 28, 
as well as combining 250 mg qd with 250 mg bid, the maximum S1P decreases for patients 
receiving 250, 500 and 750 mg of opaganib were 51±6% (n=10), 46±9% (n=5) and 54±14% 
(n=2), respectively.  The kinetics and magnitude of reduction of dihydro-S1P in the plasma 
virtually paralleled the data for S1P, consistent with the known ability of SK2 to phosphorylate 
either sphingosine or dihydrosphingosine (sphinganine).  In contrast, plasma samples from the 
250 and 500 mg treatment groups contained elevated levels of dihydroC16-ceramide, which 
reached a maximum at 8-12 hr and then returned to baseline at 24 hr.  It is noteworthy that the 
changes in S1P and dihydroS1P were not dose-related in these patients, suggesting that the 
pharmacodynamic maximal effect is achieved by the 250 mg dose of opaganib.  Our findings 
demonstrated safety and an initial assessment of pharmacokinetic and pharmacodynamic profiles 
in treated patients.  
 
Figure 3:  Effects of opaganib 
treatment on plasma sphingolipid 
levels.  S1P (Panel A), dihydroS1P 
(Panel B) and dihydroC16-ceramide 
(Panel C) were measured in plasma 
samples from patients treated with 250 
(), 500 (●) or 750 mg (∎) of opaganib.  
Values = mean ± SEM for the treatment 
groups after normalization to time=0 for 
individual patients.
A 
A 
B 
C 


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1.4   RATIONALE FOR USE OF OPAGANIB FOR TREATMENT OF PROSTATE 
CANCER 
Preclinical data support the utility of opaganib in prostate cancer (Schrecengost et al, 2015): 
• Downregulation of MYC and AR expression and activity; MYC, AR are overexpressed in 
many prostate cancers; 
• In vitro activity against CRPC cell lines; 
• In vitro activity against AR splice variant cell lines; 
• In vivo activity in a mouse xenograft prostate cancer model, LNCaP, at a dose well below 
the equivalent dose tolerated by patients (Schrecengost, et al., 2015).  There is also 
antitumor activity in MycCAP tumors in syngeneic FVB mice, both as a single agent and 
in combination with enzalutamide (unpublished data, M. Lilly, 2019). 
 
 
Two additional studies have demonstrated the effects of opaganib on prostate cancer (Gestaut, et 
al., 2014; Venant, et al, 2015).  Data demonstrating key activities of opaganib in prostate cancer 
are shown in Fig. 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Myeloid derived suppressor cells (MDSC) have been linked to prostate cancer progression 
(Lopez-Bujanda et al, 2017; Santegoets et al, 2014).  In a myeloma model, SK2 knockout 
inhibited production of MDSC and growth of myeloma (Kang et al, 2018). In a murine model, 
opaganib inhibits the function of MDSC, enhancing activity of T cells (Mehrotra, preliminary 
Figure 4. Opaganib (ABC) abrogates 
multiple proliferative pathways in 
LNCaP PCa cells. A: Cells were 
treated with 10 μM, 20 μM ABC or 
vehicle for 24 or 48 hr, and cell lysates 
were immunoblotted as indicated. B: 
Cells were cultured in androgen-
depleted media ± ABC, and mRNA for 
MYC, CDK1, and ODC were analyzed 
by qRT-PCR. C: Cells were treated as in 
B and mRNA for AR, PSA, TMPRSS2, 
and FKBP5 were analyzed by qRT-
PCR. D: Cells were plated at low 
density and treated with 10 μM ABC, 
100 nM PF543 or vehicle for 2 weeks.  
Cell colonies with fixed, stained with 
crystal violet and colonies with 50 or 
greater cells were counted. **p < 0.01 
compared to DMSO. E: Cells were 
treated with 10 nM PF543, 100 nM 
PF543, 1 μM PF543 or vehicle for 
72 hr, and lysates were 
immunoblotted as indicated. From 


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unpublished data, 2019).  Thus, opaganib may inhibit growth of prostate cancer through multiple 
mechanisms and act at least additively with hormone blocking therapy. 
 
2   STUDY DESIGN 
2.1  STUDY DESIGN 
This is a Phase II efficacy study of opaganib in patients with metastatic castration-resistant 
prostate cancer who have experienced disease progression while receiving abiraterone or 
enzalutamide.   Patients will receive opaganib continuously while continuing abiraterone or 
enzalutamide, and will continue on therapy until the development of progressive disease, 
intolerable toxicity, withdrawal of patient consent or other event as outlined in patient 
discontinuation Section 8. 
 
2.2   OBJECTIVES 
Primary Objectives 
• 
To measure the proportion of patients with disease control during opaganib (plus abiraterone or 
enzalutamide) therapy, using a composite metric based on PSA, bone scan, and RECIST 
measurements per PCWG3 criteria (Appendix B; Scher, et al., 2016).  For purposes of this study, 
disease control is defined as stable disease or better after four cycles (16 weeks) of treatment. A 
cycle will be 28 days of therapy. 
 
Secondary Objectives 
• To estimate the overall survival (OS), radiographic progression-free survival (rPFS), and 
PSA progression-free survival (PSA-PFS) times in patients treated with opaganib (plus 
abiraterone or enzalutamide). 
• To document the PSA response rate, RECIST response rate, and change in QOL (FACT-
P) and pain score (Likert Pain Score) in mCRPC patients treated with opaganib (plus 
abiraterone or enzalutamide) after four cycles of treatment 
• To determine the effects opaganib on regression or progression of mCRPC clones with 
amplified AR or MYC, identified by serial ctDNA-based genomic profiling. 
• To assess safety of opaganib in mCRPC patients, in combination with abiraterone or 
enzalutamide, GnRHR agonist/antagonist (this is the primary objective for the run-in 
cohort) 
• To monitor changes in numbers or activity of immune cells and myeloid-derived 
suppressor cells during opaganib therapy (with continued ADT). 
 
3   STUDY PATIENTS 
Patients with metastastic castration-resistant prostate cancer (mCRPC) who have shown 
disease progression while being treated with abiraterone (cohort 1a or 2) or enzalutamide 
(cohort 1b or 3) are eligible for this trial.  Potential study patients will be screened 
according to the Inclusion, Exclusion Criteria.  Each of the following criteria must be met 


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 CONFIDENTIAL - 28 
in order for a patient to be considered eligible for enrollment. Study-specific evaluations 
may be performed only after written informed consent has been obtained. 
 
3.1   INCLUSION CRITERIA 
1.  Patient must have mCRPC.  Each patient must have: 
• Tissue diagnosis documented by pathology report, or clinic note attesting to same. 
• Radiographically-demonstrated metastases 
• Patients must have adenocarcinoma, or ductal carcinoma, or combinations of these 
two entities 
 
2.  Voluntary, signed and dated, institutional review board (IRB)-approved informed consent 
form in accordance with regulatory and institutional guidelines. 
 
3.  Documented progression during treatment with enzalutamide or abiraterone, as determined by the 
enrolling investigator. 
 
4.  Testosterone level documented to be less than 50ng/dL 
 
5.  18 years of age or older. 
 
6.  ECOG performance status of 0-2. 
 
7.  Acceptable liver function: 
• 
Bilirubin ≤ 1.5 times upper limit of normal (CTCAE Grade 1 baseline) 
• 
AST (SGOT) & ALT (SGPT) < 3 x ULN  (CTCAE Grade 1 baseline) 
• 
Subjects with Gilbert’s syndrome may be included if the total bilirubin is < 3x ULN and the 
direct bilirubin is within normal limits 
 
8.  Acceptable kidney function indicated by serum creatinine ≤ 1.5 X ULN (CTCAE Grade 1 
baseline) 
 
9.  Acceptable hematologic status: 
• 
Absolute neutrophil count > 1000 cells/mm3, 
• 
Platelet count > 75,000 (plt/mm3)  (CTCAE Grade 1 baseline) 
• 
Hemoglobin > 9.0 g/dL. 
 
10.  Fasting blood glucose of <165mg/dL or random blood glucose of < 200mg/dL 
 
11.  Urinalysis:  no clinically significant abnormalities 


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12.  International normalized ratio (INR) ≤1.7 for patients not on anti-coagulation meds 
 
13.  Well-controlled blood pressure as determined by the treating investigator 
 
14.    Patients requiring narcotic analgesics must be on stable doses for at least 2 weeks prior to 
study entry.   
 
3.2   EXCLUSION CRITERIA 
1.  New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the 
past 6 months, unstable arrhythmia, or evidence of ischemia on ECG.  
 
2.  Underlying psychiatric disorder requiring hospitalization within the last two years. 
 
3.  Clinically significant neurological disorder (Parkinson’s disease, dementia, multiple 
sclerosis), as determined by the enrolling investigator. 
 
4.  Active, uncontrolled bacterial, viral or fungal infection, requiring systemic therapy. 
 
5.  Treatment with radiation therapy, surgery, or investigational therapy within 28 days prior to 
registration. 
  
6.  Unwillingness or inability to comply with procedures required in this protocol. 
 
7.  Serious nonmalignant disease that could compromise protocol objectives in the opinion of the 
Investigator. 
 
8.  Patients who are receiving coumadin, apixaban or rivaroxaban.  Patients who are receiving 
other drugs that are sensitive substrates of CYP450 1A2, 3A4, 2B6, 2C8, 2C9, 2C19 or 2D6, P-
gP, BCRP, and OATP1B1,or strong inhibitors or inducers of all major CYP450 isozymes that 
cannot be stopped at least 7 days or 5 half-lives (whichever is longer) before starting treatment 
with opaganib may be treated on this study with careful monitoring for toxic effects or loss of 
efficacy of the relevant drug.  A list of commonly used drugs that are sensitive substrates of 
CYP450 1A2, 3A4, 2B6, 2C8, 2C9, 2C19 or 2D6, P-gP, BCRP, and OATP1B1, or strong 
inhibitors or inducers of all major CYP450 isozymes with the half-life of each drug identified, is 
included as an Appendix C. 
 
9.  Patients who are currently participating in any other clinical trial of an investigational 
product. 


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10.  Other primary malignancy requiring systemic treatment within past 5 years except 
carcinoma in situ of the cervix or urinary bladder or non-melanoma skin cancer. 
 
11.  Any other mental incapacitation or psychiatric illness that would preclude study 
participation, as determined by the enrolling investigator.   
 
12. Prisoners or patients who are compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled 
into this study. 
 
13. Patients that have had chemotherapy for castration resistant prostate cancer (patients can 
have had chemotherapy for castration sensitive PC) 
• Exception: Patients who had prior chemo for CRPC are eligible if they have a PS=0-1 
and life expectancy of more than 6 months. 
 
3.3   SUBJECT RECRUITMENT 
This study will take place at the MUSC and up to two other cancer centers (to be determined). 
• 
Subjects will be identified by the designated IRB-approved study team or will be referred by 
colleagues who care for the patient populations under study. 
• 
Designated IRB-approved study research team personnel may screen records to identify potential 
subjects. Records and/or areas that may be reviewed include pathology/surgical reports, and 
pharmacy records. 
• 
Potential subjects will only be approached for the study after they have been informed of the 
study by someone involved with their clinical care. 
• 
Potential subjects who have previously agreed to be contacted for research may be approached by 
the study team. 
 
3.4   INFORMED CONSENT PROCESS 
• Subjects who are interested in participating will be interviewed in clinic. They will be 
given time to read the consent in private setting and ask questions. A designated IRB 
approved member of the study will explain the nature of the study, the benefits and 
risks. Informed consent will be obtained by designated IRB approved research 
members in clinic. Consent will be documented by obtaining the subject’s signature 
on the approved consent form, and documenting the consent process through a 
progress note in the participant’s clinical or research record.  
• Consent may be obtained the same day the patient is presented with the trial.  
 


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3.5   PATIENT REGISTRATION 
The Hollings Cancer Center’s Sponsor-Investigator Support Unit (SIS Unit) will provide patient 
registration services for the study.  The SIS Unit will conduct a patient eligibility audit review of 
all eligibility source documents prior to patient registration.  These procedures are outlined in the 
MUSC 103193 Operations Manual.  After obtaining signed informed consent and completion of 
required baseline assessments, eligible subjects will be registered.  A unique subject number will 
be assigned to each patient.  The SIS Unit will issue a patient registration confirmation email to 
the enrolling study team at the time of registration which will include the patient’s study ID 
number.   
 
4   TREATMENT PLAN 
4.1   STUDY CALENDAR 
Patients will be evaluated according to the Study Calendar (Appendix  A). The CTCAE 5.0 
manual will be used to assess adverse events.  All study dates will be +/- 5 days.  
 
The visit at which a response assessment shows disease progression, or shows lack of 
disease control, or a decision is made to discontinue treatment for other reasons, such as 
toxicity, will be considered the End of Treatment visit.   
 
Patients completing their treatment should return for Post-30 day visit per Study Calendar 
(Appendix  A). Patients who have an ongoing Grade ≥ 3 or serious adverse event that is at 
least possibly related to treatment will be contacted by the investigator or designee 
approximately every week until the event is resolved to baseline or determined to be 
irreversible.  
 
Patients will be followed for survival by clinic visit, review of medical record, and/or 
telephone call every 3 months from treatment discontinuation date for a maximum of 30 
months after the last patient has been registered to the trial or until at least 80% of patients 
treated on study in both arms have died, whichever comes first. 
 
4.2   STUDY TREATMENT 
Opaganib will be given at 250 mg (cohorts 1a, 1b) or 500 mg (cohorts 2, 3) orally twice a day 
(approximately 12 hours apart) continuously.  A cycle will be defined as 28 days.  The dose will 
be given after a light to moderate meal.   
 
It will be important to assess patient compliance for the administration of opaganib.  Patients will 
be provided a drug diary at the beginning of each cycle, i.e. when additional drug is dispensed to 
the patient.  Patients will be instructed to complete the drug diary and record their daily 
administration of drug during the morning and afternoon/evening timeframes.  Any missed or 
modified doses should be documented along with the reason for the modification.  Patients will 
be instructed to return their container(s) of opaganib at each clinic visit so that the delegated 


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research team can conduct a pill count to assess patient compliance.  The research team has the 
ability to withdraw a patient from the study if that patient demonstrates repeated protocol 
noncompliance. 
  
4.3   DOSE MODIFICATIONS 
Individual patients may continue to receive therapy at the same dose provided they do not 
experience unacceptable toxicity or disease progression. All grade 1 toxicities and adverse 
events, and tolerable unrelated grade 2 adverse events, can be treated according to standard 
clinical practice guidelines. Toxicity is an adverse event judged by the investigator to be 
possibly, probably or definitely related to study medication. 
 
• See Table 2 for the Dose Modification Plan for patients experiencing opaganib-
related toxicities 
• See Table 3 for the Dose Modification Plan for patients experiencing Grade 3 or 
4 adverse events not related to opaganib  
• Patients who experience opaganib related neurologic and/or psychiatric toxicities will 
be managed according to Table 2 (grade 2) or Table 3 (grade ≥ 3).   
 
For cohorts 1a and 1b, if one of the first three patients in either cohort develops a dose-limiting 
toxicity (DLT, as described in Section 4.4, below), the cohort is to be expanded to six patients.  
If no patient among the first three in cohort 1a or 1b develops a DLT, proceed to cohort 2 or 3, 
respectively.  Similarly, if one patient among the first 3 of cohort 1a or 1b has developed a DLT 
but no additional patient among the second three develops a DLT, proceed to cohort 2 or 3, 
respectively. 
 
If a second patient in either cohort 1a or 1b develops a DLT, accrual to that cohort will be 
discontinued and no patients will be accrued in cohort 2 or 3, respectively. 
 
Stopping rules for cohorts 2 and 3 are shown in Table 5, below. 
Patients who develop intolerable grade 2 or ≥ grade 3 OPAGANIB-related toxicity at 250 mg bid 
will not be permitted further dose reduction, and may be withdrawn from study for toxicity. 
 
Patients who develop grade 4 toxicity which does not resolve to ≤ grade 2 within 48 hours by 
standard measures, such as antiemetics for vomiting, or electrolyte replacement/modification 
therapy for electrolyte imbalances, are to permanently discontinue study medication. 
 
If the treating investigator determines that the patient needs to discontinue Abiraterone or 
Enzalutamide due to toxicity, the patient may continue on Opaganib alone.  
 


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Table 2.  Dose Modification Plan for Opaganib Related Toxicities  
NCI 
CTC 
5.0 
Criteria 
Opaganib Dose Modification Instructions 
Any intolerable grade 
2 toxicity (includes 
neurologic/psychiatric 
toxicity) 
The investigator should consult the study sponsor regarding 
opaganib-related grade 2 toxicities that are considered intolerable 
by the patient or physician.   A dose reduction may occur with 
prior consultation with and approval by the study sponsor. 
Grade 3 hematologic, 
renal or hepatic 
toxicity  
1. Hold study drug.  
2. Assess patient weekly.  
3. If the toxicity improves to ≤ baseline within 28 days, restart study drug 
and reduce dose to 250mg BID.  
4. If the toxicity recurs at the same grade discontinue study drug.  If the 
dose is held longer than 3 weeks discontinue from study.   
5. Omitted doses are not made up  
 
Grade 3 other non-
hematologic, toxicity 
(includes 
neurologic/psychiatric 
toxicity)  
1. Hold study drug.  
2. Assess patient weekly. 
3. If the toxicity improves to ≤ baseline within 28 days, restart study drug 
and reduce dose to 250mg BID  
4. If the toxicity recurs at the same grade discontinue study drug.  If the 
dose is held longer than 4 weeks, discontinue from study.   
   5.  Omitted doses are not made up. 
 
Any grade 4 toxicity 
(includes 
neurologic/psychiatric 
toxicity) 
For most related grade 4 adverse events of any duration, permanent 
discontinuation of study drug is required. Exceptions to this criteria include: 
• 
clinically insignificant laboratory abnormalities that resolve within two 
days on optimum treatment 
• 
emesis  
 


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Table 3.  Dose Modification Plan for Adverse Events NOT related to Opaganib  
NCI 
CTC 
5.0 
Criter
ia 
Opaganib Dose Modification Instructions 
≥Grade 3  
1. Hold study drug until resolution or improvement to not more than one 
grade above baseline. 
2. If AE improves to within one grade of baseline level within 4 weeks, 
restart study drug at the same dose.  A dose reduction may occur with 
prior consultation with and approval by the study sponsor. 
3. If the AE does not resolve to within one grade of baseline level within 
4 weeks, consult the study sponsor. 
 
Omitted doses are not made up. 
 
 
4.4   DEFINITION OF DOSE-LIMITING TOXICITY 
The DLT period for this study is 28 days. Safety will be reviewed and confirmed centrally by the 
safety review committee before the next dose assignment. A DLT is defined as an event 
considered at least possibly related to opaganib or its combination with abiraterone or 
enzalutamide and meeting one of the following criteria: 
a) Grade 4 thrombocytopenia of any duration  
b) Grade 3 thrombocytopenia with significant hemorrhage of any duration 
c) Grade 4 neutropenia greater than 5 days  
d) Febrile neutropenia 
e) Grade ≥3 non-hematologic toxicity of any duration, except: 
• 
Grade 3 nausea, vomiting, or diarrhea and grade 4 vomiting or diarrhea in the 
absence of maximal medical therapy that resolves in 72 hrs 
• 
Grade 3 fatigue lasting <5 d 
• 
Grade 3 HTN that can be controlled with medical therapy 
• 
An increase of indirect (unconjugated) bilirubin indicative of Gilbert’s syndrome 
• 
Serum lipase and/or serum amylase CTCAE Grade 3 ≤ 7 consecutive days without 
clinical signs or symptoms of pancreatitis 
• 
Neuropsychiatric events (e.g., depression, anxiety) which resolve to ≤grade 1 by 
modification of concomitant medications, e.g., narcotic pain medication regimen 
• 
Electrolyte imbalances which resolve within 3 days with routine therapy, e.g., 
modification of electrolyte and/or fluid administration 
f) Grade 3 non-hematological toxicity that delays administration of either study drug for 
more than 2 weeks   


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g) ALT/AST >3xULN with bilirubin >2xULN without another explanation (e.g., 
cholestasis)    
h) Patients who are not able to tolerate at least 80% of the planned dose over the first 28 
days due to toxicity, i.e., adverse events possibly, probably or definitely related to 
treatment, even if these toxicities are not otherwise listed as DLTs. 
 
4.5     ADDITIONAL MEDICATIONS 
Patients should continue ongoing gonadotropin releasing hormone receptor agonists or 
antagonists for the duration of the study to maintain the testosterone level at <50ng/dL. 
 
Men with the potential to father children must use effective contraceptive methods during the 
study.  The female partner of male subject must be either not of childbearing potential (defined 
as postmenopausal for ≥ 1 year or surgically sterile) or practicing two forms of contraception.  A 
sexually active male participants must agree to use a physical barrier method (male latex rubber 
condom with or without spermicide). 
 
4.6   CORRELATIVE STUDIES 
Samples will be processed and stored locally in Dr. Mehrotra’s lab in HO503.  The trial will be 
carried out at MUSC and one other cancer center (to be determined).  Correlative studies will be 
done and will be exchanged between participating institutions.  Samples may be stored for future 
use. 
 
4.7   PHARMACOKINETICS 
PKs for this study are optional. Pharmacokinetics will be collected for 12 patients (6 from cohort 2 and 6 
from cohort 3). 
 
Table 4: PK collection 
Daya 
Time (relative to 
dosing), hd 
Abiraterone 
PK Assay 
Enzalutamide 
PK Assayc 
Opaganib 
PK Assay 
Screening 
(Day -7 
thru 0) 
0b 
X 
X 
 
1 
X 
X 
 
2 
X 
X 
 
4 
X 
X 
 
Day 29 
(Day 25 - 
Day 33) 
0 
X 
X 
X 
1 
X 
X 
X 
2 
X 
X 
X 
4 
X 
X 
X 
a. Relative to start of opaganib.  To be drawn on one day of the range shown; day 0 = day before 
start of opaganib. 
b. Within the hour before dosing 
c. At times of enzalutamide sampling, also get blood for N-desmethyl enzalutamide 
d. One and two hours post dose: +/- 20 minutes. Four hours post dose: +/- 30 minutes 
 
Following are the volumes of blood (and tubes) required for each of the PK assays: 
• 
Abiraterone – 3mL of blood in EDTA K2 tube 


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• 
Enzalutamide – 2mL of blood in EDTA K2 tube 
• 
Opaganib – 3 mL of blood in K3 EDTA tube 
 
See study lab manual for specimen storage and shipping information. 
 
 
5   STUDY DRUGS 
 
5.1   OPAGANIB 
Opaganib is an orally available inhibitor of the enzyme sphingosine kinase 2.  Opaganib 
will be provided by RedHill Biopharma. The current FDA status of opaganib is “under 
review”.  
 
Formulation 
Opaganib is available in 250 mg and 375 mg capsules.  Capsules contain the milled active 
pharmaceutical ingredient (API) opaganib along with the excipients microcrystalline 
cellulose, USP/NF (Avicel® PH102, FMC) (FMC biopolymer) and colloidal silicon 
dioxide, NF (Cab-O-Sil® M5P).  Opaganib is a white to off-white powder and for clinical 
use it is encapsulated in white opaque hard gelatin capsules. 
 
Dosage and Administration.   
The study drug will be administered orally at 250mg or 500mg every 12 hours (+/- 2 
hours), after a light to moderate meal.  A dose modification plan is also provided in Section 
4.3.   
 
Storage. 
Storage conditions: Store at room temperature, 15-30°C (59-86°F) in a secure, locked area, 
properly labeled and segregated from other materials.  This storage area should only be 
accessible to authorized individuals. 
 
Labeling. 
The test article will be labeled with the sponsor name and address, description of contents and 
storage conditions, and will contain the statement “Investigational Product: To be used in a 
clinical investigation only.” 
 
Test Article Accountability. 
The Investigator must maintain adequate records showing the receipt, dispensing, return, or 
other disposition of the test article including the date, quantity, batch or code number and 
identification of subjects (patient number and initials) who receive the test article. The 
Investigator will not supply the test article to any person except those named as 
subinvestigators and submitted to the local regulatory authority, designated staff and 
patients in this study. The Investigator will not dispense the test article from any sites other 


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than those submitted to the local regulatory authority. The test article will not be relabeled 
or reassigned for use by other patients.   
 
Upon completion of the study, unused supplies of the opaganib test article will be returned 
to RedHill Biopharma or destroyed as directed. 
 
5.2  ABIRATERONE 
Abiraterone will be provided by the patient or third party from clinical grade material 
marketed as Zytiga® or Yonsa®, or from the marketed generic material.  The patient will 
continue to take the dose used before study enrollment, for the duration of the study.  
Abiraterone will be taken alone, without other drugs or food, at least 1hr prior to, or 2hr 
after a meal.  The patient will also take prednisone 5mg (or methylprednisolone 4mg, if 
using Yonsa) PO Q AM with breakfast. 
 
5.3  ENZALUTAMIDE 
Enzalutamide will be provided by the patient or third party from clinical grade material 
marketed as Xtandi®.  The patient will continue to take the dose used before study 
enrollment, for the duration of the study.  Enzalutamide capsules will be taken all together, 
or singly in rapid succession, within one hour 
 
6  SAFETY PLAN 
6.1   GENERAL PLAN TO MANAGE SAFETY 
A number of measures will be taken to ensure the safety of patients participating in this 
trial.  These measures will be addressed through exclusion criteria and routine monitoring 
as outlined below.  In addition, an early stopping monitoring plan is outlined in Section 9. 
 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study.  Safety evaluations 
will consist of medical interviews, recording of adverse events, physical examinations 
(including neurologic examination, as well as mini-mental state exam), blood pressure, and 
laboratory measurements (performed by local laboratories).  Patients will be evaluated for 
adverse events (all grades), serious adverse events, and adverse events requiring study drug 
interruption or discontinuation at each study visit for the duration of their participation in 
the study.  Patients discontinued from the treatment phase of the study for any reason will 
be evaluated within 30–42 days after last dose of study drug.   Patients who have an 
ongoing treatment-related Grade > 3 or serious adverse event at the time of discontinuation 
from study treatment will continue to be followed as per Section 4. 
 
If the female partner of a male subject becomes pregnant despite precautions, she should be 
apprised of the potential risk of fetal morbidity or loss. 
 


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Serious adverse events will be reported as outlined in section 10.12.    
 
6.2  SAFETY PLAN FOR PSYCHIATRIC SYMPTOMS FROM STUDY DRUG 
Patients will be evaluated at each study clinic visit by a medical oncologist for psychiatric 
or neurological symptoms potentially related to opaganib. In addition, mini-mental status 
examination (MMSE) will be conducted at various time points within the study.    Patients 
exhibiting symptoms of psychiatric or neurological impairment on physical exam or a 
clinically significant decrease in MMSE score in the opinion of the investigator that does 
not resolve with interruption or discontinuation of opaganib will be referred to specialty 
psychiatric or neurological care as deemed appropriate. 
 
7   CONCOMITANT AND EXCLUDED THERAPIES 
All supportive care measures consistent with optimal patient care will be given throughout 
the study.  
 
7.1   ANTINEOPLASTIC DRUGS 
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, including 
chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy, is not 
permitted while participating in this study. Use of concurrent investigational agents is not 
permitted.  
 
7.2   CYP SUBSTRATE DRUGS, INHIBITORS, AND ACTIVATORS 
Patients may not receive coumadin, apixaban or rivaroxaban while on the study.  Patients 
requiring anticoagulation may receive anticoagulants which will not be affected by CYP 
inhibition, i.e., standard or low molecular weight heparin or dabigatran.  
 
When possible, avoid drugs with narrow therapeutic indices and that are CYP isoenzyme 
substrates.   Patients who are receiving drugs that are CYP substrates or must start receiving such 
drugs while on study should be monitored for toxicities associated with these concomitant 
medication(s), as exposure to these medications could be increased by opaganib. A list of 
commonly used drugs that are sensitive substrates of CYP450 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 
3A4, P-gP, BCRP, and OATP1B1 (with the half-life of each drug identified) is included as 
Appendix C.  It is also shown is shown in a table from Indiana University Department of 
Medicine Clinical Pharmacology Division, at:  
http://www.medicine.iupui.edu/clinpharm/ddis/clinical-table/ 
 
7.3   MINIMIZING NEUROPSYCHIATRIC ADVERSE EVENTS 
Neuropsychiatric adverse events, including anxiety and hallucinations, were noted in initial 
clinical studies of opaganib.  Administering opaganib after eating results in more gradual 
absorption with minimal change in bioavailability.  This appeared to decrease the incidence and 
severity of neuropsychiatric adverse events.   


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In addition, there appears to be an interaction between narcotic analgesics and opaganib with 
respect to neuropsychiatric adverse events.  Many patients entered into this study are likely to 
require narcotic analgesics for treatment of pain from bone metastases.  The adverse events may 
be avoided or minimized if patients are on nonnarcotic analgesics in addition to stable doses of 
narcotic analgesic rather than PRN doses.  Keeping patients on relatively stable doses of 
narcotics may minimize the fluctuation of narcotic blood levels.  In a previous study, switching 
patients from PRN to standing doses of analgesics appeared to ameliorate neuropsychiatric 
adverse events. 
 
8   PATIENT DISCONTINUATION 
Patients may discontinue study treatment at any time.  Any patient who discontinues 
treatment will be asked to return to the study center to undergo end of treatment 
assessments as outlined within Study Calendar (Appendix A).  The primary reason for 
discontinuation should be recorded.  Reasons for discontinuation of a patient by the 
investigator include, but are not limited to, the following:   
 
Subjects who meet the following criteria should be discontinued from study treatment:  
• Documented disease progression (loss of disease control) per Appendix B 
• Clinically significant deterioration of the patient’s condition  
• Patient noncompliance 
• Adverse events requiring treatment discontinuation, regardless of relationship to study 
medication 
• Investigator determination that it is not in the patient’s best interest to continue      
participation 
• Withdrawal of consent by patient  
 
8.1   PATIENTS RESUMING STUDY TREATMENT 
Patients that have had a delay in their study treatment of no more than 8 weeks for any reason 
can re-initiate treatment provided that: 
• 
The patient has not experienced radiographic or clinical progression 
• 
PSA has not increased more than 25% from the PSA level at the time of treatment interruption 
• 
The patient has not received any new anticancer treatment in the interim. 
 
Patients that discontinue study treatment due to PSA progression can resume study treatment if 
the following conditions are met: 
• The patient’s PSA has dropped back down below what would have been considered 
disease progression 
• No more than 8 weeks have passed since the patient discontinued study treatment 
• The patient did not / does not show any other signs of disease progression (clinical or 
radiographic) 
• No other therapies were initiated since the patient discontinued study treatment 
 


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If a patient meets all the above criteria and is resuming study treatment, they will continue as if 
there has been a treatment delay and will re-initiate therapy at the next corresponding visit on the 
study calendar (see appendix A). 
 
9   STATISTICAL CONSIDERATIONS 
 
Proportion of patients achieving various efficacy endpoints and times to efficacy events will be 
calculated from the patients in cohorts 2 and 3.  Safety endpoints will be calculated based on all 
patients, with subgroup analysis for cohorts 2 and 3. 
 
9.1   STATISTICAL ANALYSIS FOR PRIMARY OBJECTIVE 
We will estimate the proportion of patients with disease control during opaganib (plus 
abiraterone or enzalutamide) therapy, using a composite metric based on PSA, bone scan, and 
RECIST measurements per PCWG3 criteria (see the definitions in Appendix B).  The primary 
measurement will be determined after four cycles (day 113) of treatment. The 95% confidence 
interval for the proportion of disease control will be presented. A one-sided exact binomial test 
will be performed based on a null hypothesized proportion of 0.1 with a significance level of 
0.05. 
 
9.2   STATSTICAL ANALYSIS FOR SECONDARY OBJECTIVES 
Estimate the radiographic progression-free survival (rPFS), PSA progression-free survival 
(PFS) times in patients treated with opaganib (plus abiraterone or enzalutamide).  
rPFS is defined as the length of time from initiation of study treatment until documented disease 
progression per mRECIST or per PCWG3 criteria for disease progression on bone scans (see 
Appendix B).  Patients who have not radiographic progression by the end of the follow-up will 
have their rPFS values censored. PSA-PFS is defined as the length of time from initiation of 
study treatment until documented PSA progression per PCWG3 criteria.  These criteria specify 
an increase in PSA of >25% above the baseline (if no PSA response) or nadir (if PSA response) 
value, as an indicator of PSA progression.  A PSA value felt to indicate progressive disease must 
be confirmed with a repeated elevated value at least 1 month later.  Patients who have not PSA 
progression by the end of the follow-up will have their PSA-PFS values censored. Kaplan-Meier 
estimates of the time-to-event (i.e., rPFS or PSA-PFS) will be constructed using a competing-
risks approach which treats death due to causes unrelated to prostate cancer as a competing 
event.  Median time to progression will be estimated and the corresponding 95% confidence 
intervals constructed using Greenwood’s variance estimate (Collett, 1994).  
 
Document the PSA response rate, overall response rate, and change in QOL (FACT-P) in 
mCRPC patients treated with opaganib (plus abiraterone or enzalutamide) 16 weeks after the 
start of treatment 
PSA response rate is the proportion of patients demonstrating a 25% or greater reduction in PSA 
level compared with the baseline value, at any point during therapy with opaganib (with 
abiraterone or enzalutamide).  This response definition is consistent with the recommendations 
of the PCWG3 (Scher, et al., 2016). Overall response rate is the proportion of patients 


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demonstrating a complete or partial response of RECIST-evaluable lesions at any point during 
therapy with opaganib (with abiraterone or enzalutamide).  The definitions of response are well-
standardized (Eisenhauer et al, 2009). Both PSA response rate and overall response rate will be 
estimated with the 95% confidence interval. The change in QOL will be summarized graphically 
and numerically, and tested based on two-sided paired t-test. 
 
Determine the effects opaganib on regression or progression of mCRPC clones with amplified 
AR or MYC, identified by serial ctDNA-based genomic profiling. 
The relationship between changes in marker levels (copy number for AR, MYC amplified clones 
based on Guardant 360 genomic profile) and patient response for regression or progression of 
mCRPC clones will be assessed graphically.  Scatterplots of percent change in target lesions 
versus change in marker levels will be constructed.  Variable transformations will be considered 
as needed, and Pearson or Spearman correlation coefficients will be constructed as appropriate.  
Based on two-sided Pearson or Spearman correlation coefficients test with alpha = 0.05, the 
sample size of 27 provides a 77% power to detect a correlation of 0.5 versus a null correlation of 
0. 
 
Assess safety of opaganib in mCRPC patients, in combination with abiraterone or 
enzalutamide, GnRHR agonist/antagonist 
The safety analysis will be conducted using descriptive statistics of the incidence of adverse 
events (AEs) and serious adverse events (SAEs), all events of death, and any study specific issue 
of concern.  Adverse events will be coded by body system, and summary tables with incidence 
rates of AEs will be generated.  Descriptive statistics of AEs will be reported for all patients, 
patients who discontinue due to AEs, and patients with related AEs.  Severity, duration, 
investigator attributed relationship to treatment, and outcomes of AEs will be reported.  AE and 
SAE reporting criteria are outlined in section 10. 
 
Monitor changes in numbers or activity of immune cells and myeloid-derived suppressor 
cells during opaganib therapy (with continued ADT).The numbers or activity of immune 
cells and myeloid-derived suppressor cells (measured at baseline and certain time points) 
will be summarized graphically. The mean of the difference of cell counts between time 
points will be described with the 95% confidence interval. The changes in cell counts will 
be analyzed using a paired t-test to see if the change is significant. Equivalent non-
parametric tests (e.g., Wilcoxon rank-sum test) will be used as appropriate. 
 
9.3. ANALYSIS POPULATIONS 
 
Patients with disease progression while receiving abiraterone will constitute cohort 1a and 2 
(maximum of 6 and 27 patients, respectively) while those worsening during enzalutamide 
treatment will be enrolled into cohort 1b and 3 (maximum of 6 and 46 patients, respectively).   
 
Intent to treat population set 


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Patients who drop out prior to receiving their first dose of opaganib will be replaced.  
Those who have received at least one dose of opaganib will contribute to the intent-to-treat 
(ITT) analysis.  Patients in the ITT population who withdraw prior to response evaluation 
at 16 weeks will be treated as non-responders in the ITT analysis.   
 
Analyses for the efficacy endpoints will be performed on patients who are assigned to 
receive opaganib 500 mg bid along with their antiandrogen.  Efficacy results from the 
patients in cohorts 1a and 1b will be described but will not be included in the calculations 
for either the primary or secondary efficacy endpoints. 
 
Safety population set 
The safety population is defined as all patients who receive at least one dose of study drug. 
Safety analyses will be performed for the entire safety population (i.e., patients in all 
cohorts), and subgroup analyses will be performed for cohort 2 and 3.    
 
9.4   SAMPLE SIZE DETERMINATION  
The primary endpoint is a binary indicator of disease control for patients in cohort 2 and 3. Each 
cohort will be analyzed independently. A maximum of 27 subjects will be enrolled in cohorts 2 
and 46 subjects in cohort 3. With a null hypothesized disease control of 0.1 and sample size of 27 
evaluable patients, the power to detect the difference of 0.2 (i.e., alternative proportion of 0.3) is 
86.4% based on one-sided exact binomial test with alpha = 0.05 (type I error rate).  
 
9.5   INTERIM ANALYSES 
Futility monitoring 
This trial employs a Simon minimax two-stage design (Simon, 1989) for each cohort. The null 
hypothesis is that the true response rate is 0.1, and the alternative hypothesis is that the true 
response rate is 0.3. An interim analysis for futility will be performed when a total number of 20 
patients is evaluable for disease control according to a multiparameter index (See Appendix B). 
If there are one or fewer responses for disease control in the first 20 patients, then accrual to that 
cohort will be halted for futility. At the end of trial, we reject the null hypothesis if there are 6 or 
more responses for disease control among 27 evaluable patients.  When the true response rate is 
0.1, the expected sample size for this trial is 24.3 and the probability of early stopping is 39.2% 
 
Safety monitoring 
We have incorporated safety stopping rules into our design to ensure patient safety (Table 5).  
We will stop the trial early if there is significant toxicity, defined as an unacceptable adverse 
event rate of grade 3 or 4 adverse events, or serious adverse events deemed probably, or 
definitely related to study drug. We consider an acceptable level to be 15% (null hypothesis H0) 
and an unacceptable rate to be 30% (alternative hypothesis H1).  We will use a likelihood ratio 
test that allows stopping for strong evidence that the grade 3-4 toxicity/related SAE rate is 30% 
vs. 15%. Specifically, the stopping threshold is determined by a likelihood ratio value of 10 or 
greater favoring the alternative adverse event rate of 30%. Given our sample size of 27 and based 


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on 10,000 simulations, this likelihood-based stopping rule yields a 53.04% chance of early 
termination if the true grade 3-4 adverse event/SAE rate is 30% and only a 4.14% chance of 
early stopping if the true rate is 15%. 
 
Table 5: Safety stopping rules for each cohort 2 and 3. 
Total number of 
patients treated 
Number of patients with grade 3 
or 4 AE, or  SAE possibly, 
probably, or definitely related to 
study medication, or who 
discontinued study drug due to 
toxicitya 
Observed 
toxicity rate 
Likelihood ratio favoring 
H1 versus H0 
<= 6 
4 
≥0.67 
≥10.9 
7-10 
5 
≥0.50 
≥12.1 
11-15 
6 
≥0.40 
≥11.2 
16-20 
7 
≥0.35 
≥10.3 
21-24 
8 
≥0.33 
≥11.5 
25-27 
9 
≥0.33 
≥15.5 
 
a. Any adverse event considered possibly, probably or definitely related to study drug, regardless of grade.  
 
10   ADVERSE EVENT REPORTING REQUIREMENTS 
The local investigator is responsible for ensuring that all AEs and SAEs that are observed 
or reported during the study are collected and reported to the EDC and to the IRB as 
appropriate.   
 
The study period during which all AEs and SAEs must be reported begins after initiation of 
study treatment and ends 30 days following the last administration of study treatment. After 
this period, investigators should only report SAEs that are attributed to prior study 
treatment.  
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the study, and actions taken.  
 
10.1   PURPOSE 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 


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future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during a trial. Additionally, certain adverse events must be reported in an expedited 
manner to allow for monitoring of patient safety and care. The following guidelines prescribe 
routine and expedited adverse event reporting for this protocol.  
 
Throughout the study, the Investigator will be required to provide appropriate information 
concerning any findings that suggest significant hazards, contraindications, side effects, or 
precautions pertinent to the safety of the drug under investigation.  
 
Note:  All deaths on study require expedited reporting if they occur during opaganib treatment or 
within 30 days of the final dose.  Deaths will be reported to the IRB and DSMC of record.  
Attribution to treatment or other cause must be provided. 
 
10.2   DEFINITION OF ADVERSE EVENT 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign, symptom, or disease temporally associated with the 
subject’s receipt of study medication, whether or not considered related to the subject’s 
participation in the research.  All adverse events should be recorded and described in the 
EDC.  Adverse events also include Grade 3 or 4 abnormal laboratory test results that are 
clinically significant.  
 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency, duration or severity, or a change in the quality, of the disease or condition.  Only 
grade 3 or 4 abnormal lab values that were not noted during the Screening Phase should be 
recorded; however, any clinical consequences of the abnormality, regardless of grade, should be 
reported as AEs.  Hospitalization for elective surgery or routine clinical procedures that are not 
the result of an AE (e.g., surgical insertion of central line) need not be considered AEs and 
should not be recorded as an AE.  Progression of cancer also will not be considered an AE. 
 
10.3   DEFINITION OF SERIOUS ADVERSE EVENT 
An SAE is defined by regulatory agencies as one that suggests a significant hazard or side effect, 
regardless of the investigator or sponsor’s opinion on the relationship to investigational product.  
This includes, but may not be limited to, any event that (at any dose): 
• Is fatal 
• Is life threatening (places the subject at immediate risk of death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Is a persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• A hospitalization meeting the regulatory requirement for the “serious” criteria is 
any inpatient hospital admission that includes a minimum of an overnight stay in 
a health care facility. 


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Any event that does not exactly meet this definition yet, in the investigator’s opinion represents a 
significant hazard can be assigned the “other significant hazard” regulatory reporting serious 
criteria. 
 
Additionally, important medical events that may not be immediately life threatening or result in 
death or hospitalization but that may jeopardize the subject or require intervention to prevent 
one of the outcomes listed above, or result in urgent investigation, may be considered serious.  
Examples include allergic bronchospasm, convulsions, and blood dyscrasias. 
 
10.4   DEFINITION OF SEVERITY 
Adverse events will be graded according to the revised NCI Common Toxicity Criteria.  If 
toxicities are not defined by the NCI Common Toxicity Criteria v. 5.0, the intensity of each 
adverse event should be graded as either Mild (grade 1), Moderate (grade 2), Severe (grade 3), or 
life-threatening (grade 4) by the Investigator.   
 
GRADE 1 
MILD:  Sign or symptom noticeable, but does not interfere with normal daily 
activities. 
GRADE 2 
MODERATE:  Sign or symptom sufficient to interfere with normal daily 
activities. 
GRADE 3 
SEVERE:  Sign or symptom is incapacitating, with inability to perform daily 
activities. 
GRADE 4 
LIFE-THREATENING:  sign or symptom poses immediate risk of death to this 
patient. 
 
10.5   DEFINITION OF START DATE, STOP DATE, DURATION 
The definitions of AE start/stop dates and duration will be as follows: 
 
Start Date 
The date at which the AE is first noted 
Stop Date 
The date at which the AE is known to be resolved. If it is 
not known to have stopped, then indicate “ongoing.” 
 
10.6   ACTIONS TAKEN 
Action(s) taken may consist of the following: 
 
None: 
No actions taken 


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Dose permanently 
stopped: 
Test article was permanently discontinued because of the AE 
Dose modified: 
Test article was given at a lower dose, at a longer interval between 
doses, or was temporarily withheld  
because of the AE 
Corrective treatment: 
Specified medication (to be listed on the concomitant medication 
chart) has been used as a countermeasure 
Others: 
Other actions, such as an operative procedure were required 
because of the AE 
 
10.7   DEFINITION OF RELATIONSHIP TO STUDY DRUG 
The categories for classifying the Investigator’s opinion regarding the relationship of an AE to 
the study drug are listed below. 
 
Definitely related: 
An adverse event occurring in a plausible time relationship to drug 
administration, and which cannot be explained by concurrent 
disease or other drugs or chemicals.  The response to withdrawal of 
the drug should be clinically plausible.  The event must be definite 
pharmacologically or phenomenologically, using a satisfactory re-
challenge procedure if necessary and feasible. 
Probably related: 
An adverse event with a reasonable time sequence to 
administration, and which cannot be explained by 
concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on 
withdrawal.  Re-challenge information is not required to 
fulfill this definition.  (Note: there are important 
exceptions when an adverse event does not disappear 
upon discontinuation of the drug, yet drug-relatedness 
clearly exists, (e.g. bone marrow suppression, fixed-drug 
eruptions, and tardive dyskinesias) 
Possibly related: 
An adverse event with a reasonable time sequence to administration 
of the drug, but which could also be explained by concurrent disease 
or other drugs or chemicals.  Information on drug withdrawal may 
be lacking or unclear. 


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Not related: 
An adverse event with a temporal relationship to drug 
administration which makes a causal relationship improbable, and in 
which other drugs, chemicals or underlying diseases provide 
plausible explanations. 
 
10.8   DEFINITION OF OUTCOME AT TIME OF LAST OBSERVATION 
The outcome at the time of last observation will be classified as: 
• Resolved 
• Resolved with Sequelae 
• Ongoing 
• Death 
 
Death should only be entered as the outcome for an AE when the patient’s death is probably or 
definitely related to the AE (Note: the causal relationship of the AE to the test article is not to be 
considered in making this decision). If more than one AE is possibly related to the patient's 
death, the outcome of death should be indicated for each such AE. 
 
10.9   DOCUMENTATION AND ASSESSMENT OF ADVERSE EVENTS 
The Investigator will monitor and/or ask about or evaluate AEs using non leading questions at 
each visit or evaluation. The occurrence of all AEs will be documented in the eCRF with the 
following information, where appropriate: 
• AE name or term 
• When the AE first occurred (start date) 
• When the AE stopped (stop date), (or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness  
• Actions taken 
• Outcome 
• Investigator opinion regarding the relationship of AE to the study drug(s) 
 
Adverse events should be documented from the day 1 of study treatment until 30 days after 
the discontinuation of study treatment. After this period, investigators should only report 
SAEs that are attributed to prior study treatment. The AEs must be documented as soon and 
as completely as possible in the EDC. Follow-up information must be entered as soon as 
available. The causality assessment must be assigned by the Investigator.  
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 


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duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the study, and actions taken.  
 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior investigational agent 
exposure. If the investigator should become aware of the development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a female subject who 
participated in the study, this should be reported as an SAE. 
 
10.10   EXPECTED AND UNEXPECTED ADVERSE EVENTS 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the current Investigator Brochure (IB). 
This includes adverse events for which the specificity or severity is not consistent with the 
description in the IB. (For example, under this definition, hepatic necrosis would be 
unexpected if the IB only referred to elevated hepatic enzymes or hepatitis.) 
 
10.11   ADDITIONAL ADVERSE EVENT CONSIDERATIONS 
Diagnosis vs. Signs and Symptoms  
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the time 
of reporting, it is acceptable to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information.  
 
Deaths  
All deaths that occur during the protocol-specified AE reporting period, regardless of 
attribution, will be reported to the appropriate parties. When recording a death, the event or 
condition that caused or contributed to the fatal outcome should be reported as the single 
medical concept. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death”.  
 
Death due to disease progression will not be considered a serious adverse event 
 
Preexisting Medical Conditions  
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only if 
the frequency, severity, or character of the condition worsens during the study. When 


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reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”).  
 
Hospitalizations for Medical or Surgical Procedures  
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. If a subject is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the procedure 
itself, should be reported as the SAE. For example, if a subject is hospitalized to undergo 
coronary bypass surgery, record the heart condition that necessitated the bypass as the 
SAE.  
 
10.12   SERIOUS ADVERSE EVENT REPORTING 
The Investigator must report all SAEs promptly to Dr. Michael Lilly (via the SIS Unit, 
HCC/MUSC) and RedHill Biopharma (via redhill107_safety@mwbconsulting.com) 
within 24 hours of first becoming aware of the event. This report will be accomplished by 
completing a study-specific SAE form available in the REDCap system.  The submitted report 
will be transmitted simultaneously and immediately to RedHill Biopharma and MUSC. 
 
For all possibly related and unexpected SAEs, sites will complete a Medwatch 3500A form 
and submit to MUSC via REDCap. 
 
MUSC will be responsible for submission of SAE reports to the FDA, either on a routine basis or 
as expedited reports, as required by FDA regulations.  
 
At the time of first notification of an SAE, the following information should be provided by the 
site, if available: 
• 
Patient’s study number and initials 
• 
Treatment regimen including date of first & last dose of test article, as applicable 
• 
Protocol description (and number, if assigned) 
• 
Adverse event term and grade 
• 
Date of occurrence of the event 
• 
A brief description of the event, severity, outcome to date and any actions taken 
• 
The seriousness criteria(on) that were met 
• 
Concomitant medication at onset of the event 
• 
Relevant past history information 
• 
Relevant laboratory test findings 
• 
Investigator’s assessment of the relationship to test article  
 
Any missing or additional relevant information concerning the SAE should be provided in a 
written follow-up report. 
 


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It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity 
to require the subject’s removal from treatment. If the subject is permanently withdrawn from the 
study due to an SAE, this information must be included in either the initial or follow-up SAE 
Report Form. 
 
The Investigator is required to comply with applicable regulations regarding the notification of 
his/her IRB or Ethics Committee.  A copy of any SAE submissions to the IRB should also be 
submitted to MUSC. 
 
11   MONITORING 
The SIS Unit (Hollings Cancer Center CTO) will be responsible for the monitoring of study 
patient data and records.  Each patient case will have their eligibility criteria audited prior to 
patient registration. The eligibility reviews will be conducted by the SIS Unit.   The procedure 
for submitting registration documents for eligibility review is outlined in the operations manual 
for this study. 
 
11.1   PROTOCOL DEVIATIONS 
A Protocol Deviation is any variance from the protocol involving a subject or subjects that is not 
approved by the IRB prior to its initiation or implementation, and occurs when a member of the 
study team departs from the IRB-approved protocol in any way without the investigator first 
obtaining IRB approval.  Any protocol deviation will be reported by the site within 10 days of 
notification.  The procedure for submitting protocol deviations is outlined in the operations 
manual for this study. 
11.2   SAFETY REPORTING 
All toxicities, serious and non-serious, that meet the AE reporting criteria will be reported in the 
EDC.  In addition, Serious Adverse Events have special reporting requirements.  
 
11.3   DATA SAFETY MONITORING COMMITTEE (DSMC) 
The Hollings Cancer Center DSMC will have oversight of the protocol. The DSMC will meet at 
a minimum on a semi-annual to discuss this investigator-initiated trial.  
 
In addition, all protocol deviations and SAEs as defined above will be reviewed by the DSMC at 
monthly meetings. As new protocol deviations or serious adverse events are reported, the SIS 
Unit will review these reports for form completion and follow up if more information is 
warranted. The SIS Unit will forward the event report to the DSMC so that the information can 
be reviewed at the next available meeting. During the DSMC review, the DSMC can make 
recommendations for any further study action.  
 
12   ADMINISTRATIVE STRUCTURE 
This trial will be a multi-institution, investigator-initiated study.  Potential sites will be 
identified by Dr. Michael Lilly as the lead Principal Investigator.   


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12.1   INVESTIGATOR REQUIREMENTS 
Dr. Michael Lilly will be responsible for selecting qualified investigators, providing them 
with the information they need to conduct an investigation properly, ensuring proper 
monitoring of the investigation, ensuring that the investigation is conducted in accordance 
with the general investigational plan and protocol, and ensuring that FDA and all 
participating investigators are promptly informed of significant new adverse effects or risks 
with respect to the drug. 
 
12.2   STUDY INITIATION 
Centers participating in this study cannot begin enrollment until an initiation letter has been 
issued from the SIS Unit. Each center is required to participate in an initiation conference 
call. 
 
Before the start of this study and the shipment of opaganib to a participating center, the 
following documents must be on file at the SIS Unit. Participating centers will be 
responsible for submitting the initiation documents to the SIS Unit.   
 
These documents are required to be submitted by each participating center:   
1. U.S. Food and Drug Administration (FDA) Form 1572, signed by the Principal 
Investigator at the participating center. 
2. The names of any sub-investigators at the participating center must appear on this form.  
Investigators must also complete all regulatory documentation as required by local 
regulations. This includes any required human subjects training required by the site’s 
local IRB. 
3. Current curricula vitae and documentation of professional licensure of the Principal 
Investigator and co-Investigators listed on the 1572. 
4. Resumes and human subject protections documentation (e.g. NIH, CITI) for all research 
personnel (e.g. study coordinators, data managers and other research personnel).  
5. A signed and dated investigator brochure acceptance form.  
6. A signed and dated protocol signature page. 
7. Written documentation of IRB approval of protocol (identified by title, protocol version 
and date of approval) for each site. 
8. IRB approved study informed consent and HIPAA consent form. HIPAA consent 
language can be included within the study informed consent. Please note that all informed 
consent forms should be reviewed and approved by the Sis Unit prior to submission to 
the site’s designated IRB. 
9. A signed Confidentiality Agreement.  


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10. A signed Clinical Trial Agreement for each site.  
11. Laboratory certifications (CAP, CLIAs) and laboratory reference value ranges for each 
laboratory listed on the site’s 1572. 
12. Any other site specific forms as specified in the investigator-initiated multicenter manual.  
12.3   STUDY COMPLETION 
The following data and materials are required by MUSC before a study can be considered 
complete or terminated: 
1. Copies of protocol amendments and IRB approval/notification, if appropriate. 
2. Copies of the IRB final report, documentation of submission to the IRB.  
3. A summary of the study prepared by the Principal Investigator (Study report, manuscript 
and/or abstract). 
4. All regulatory documents (e.g., updated curriculum vitae for each Principal Investigator, 
updated U.S. FDA Form 1572 for each site). 
12.4   RECORD RETENTION 
The Sponsor-Investigator must ensure maintenance of all study records per applicable federal 
regulations and institutional requirements set forth in MUSC HRPP 5.2. 
 
12.5   INFORMED CONSENT 
The principles of informed consent are described by Federal Regulatory Guidelines 
(Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection 
from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 
45 CFR 46). They must be followed to comply with FDA regulations for the conduct and 
monitoring of clinical investigations. 
 
Informed consent will be obtained by personnel who are qualified by education, training 
and experience to perform the task.  The Sponsor-Investigator will not use the services of 
study personnel for whom sanctions have been invoked where there has been scientific 
misconduct or fraud.   
 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks and other critical issues regarding clinical studies in which they volunteer to participate.  
The approved consent form will adhere to the ethical principles that have their origin in the 
Declaration of Helsinki. 
 
12.6   INSTITUTIONAL REVIEW BOARD APPROVAL 
This protocol, the informed consent document, and relevant supporting information must 
be submitted to the IRB for review and must be approved before the study is initiated.  In 
addition, any advertising materials, if applicable, must be approved by the IRB.  The study 


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will be conducted in accordance with U.S. FDA, applicable national and local health 
authority, and IRB requirements. 
 
The Principal Investigator at each site is responsible for keeping his/her IRB apprised of 
the progress of the study and of any changes made to the protocol as deemed appropriate, 
but in any case the IRB must be updated at least once a year.  The Principal Investigator 
must also keep the IRB informed of any significant adverse events. 
 
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected.  This generally refers to serious adverse 
events that are not already identified in the Investigator Brochure and that are considered 
possibly or probably related to the study drug by the investigator.  Some IRBs may have 
other specific adverse event requirements to which investigators are expected to adhere.  If 
a center’s IRB does not require the review of all external adverse events, a written policy or 
statement outlining the IRB’s reporting requirements must be provided to the SIS Unit. 
 
12.7   QUALITY ASSURANCE 
Steps to assure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the 
Investigator and associated personnel prior to the study, remote monitoring visits by and 
ongoing data quality reviews of the EDC. Data will be reviewed for accuracy and 
completeness and any discrepancies will be resolved with the Investigator or designees as 
appropriate. 
 
 
 
 
 


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Oncogenes by the Selective sphingosine kinase-2 Inhibitor ABC294640 Hinders Prostate Cancer 
Progression.  Mol Cancer Res 2015; 13(12):1591-601. 
 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989 
Mar;10(1):1-10.  
 
Venant H, Rahmaniyan M, Jones EE, Lu P, Lilly MB, Garrett-Mayer E, Drake RR, Kraveka JM, 
Smith CD, Voelkel-Johnson C.The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the 
Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and 
In Vivo. Mol Cancer Ther.  2015; 12:2744-52. 
 
White MD, Chan L, Antoon JW, Beckman BS.  Targeting ovarian cancer and chemoresistance 
through selective inhibition of sphingosine kinase-2 with ABC294640.  Anticancer 
Res. 2013;33(9):3573-9. 
 
Xun C, Chen MB, Qi L, Tie-Ning Z, Peng X, Ning L, Zhi-Xiao C, Li-Wei W 
Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in 
vitro and in vivo.J Exp Clin Cancer Res. 2015 4; 34:94. 
 
Ziehr DR, Chen M-H, Zhang D, Braccioforte MH, Moran BJ, Mahal BA, Hyatt A, Basaria SS, 
Beard CJ, Beckman JA, Choueiri TK, D’Amico AV, Hoffman KE, Hu JC, Martin NE, Sweeney 
CJ, Trinh Q-D, Nguyen PL. Association of androgen-deprivation therapy with excess cardiac-
specific mortality in men with prostate cancer.  BJU Int 2015;116:358-65. 
 


CTO # 103193 
Protocol version 4.0 dated 06/08/2021 
 
 CONFIDENTIAL - 58 
 
 
APPENDIX A: SCHEDULE OF INTERVENTION 
 
Procedurej 
Screeninga 
Day 
1g 
Day 
29 
Day 
57 
Day 
85 
Day 
113d 
Day 141 and every 
28 days post Day 
113 
Day 169 and 
every 56 days post 
Day 113 
End 
Rxm 
Off-
Studye, 
l, m 
Informed consent 
x 
  
  
  
  
  
  
  
  
  
Vital signs, weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
Performance status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
Focused history & physical 
exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
FACT-P 
x 
x 
 
 
 
x 
 
 
x 
 
Likert pain score, pain med 
use 
x 
x 
 
 x 
 
x 
 
 
x 
 
Pill count 
 
 
x 
x 
x 
x 
x 
x 
x 
 
Mini-mental status exam 
x 
x 
 
x 
 
x 
 
 
x 
 
Adverse event assessment 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
12-Lead ECG 
x 
 
 
 
 
 
 
 
 
 
CBC + differential 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
CMP 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
PSA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
LDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
CEA  
x 
x 
xi 
xi 
xi 
xi 
xi 
xi 
xi 
  
PT, PTT, INR 
x 
x 
 
 
 
x 
 
 
x 
  
Plasma magnesium 
x 
x 
 
 
 
x 
 
 
x 
  
Urinalysis + Urine Protein + 
Urine Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
Research blood samples for 
Dr. S. Mehrotra’s labh 
x 
  
  
x 
 
x 
  
  
x 
  
Guardant 360 genomic 
profilek 
x 
  
  
  
  
x 
  
  
x 
  
Radiographic Assessment b 
x 
 
  
 
 
x 
  
x 
x 
  


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Protocol version 4.0 dated 06/08/2021 
 
 CONFIDENTIAL - 59 
Tumor response 
assessmentf, n 
  
 
  
 
  
x 
  
x 
x 
  
Abiraterone/prednisone or 
enzalutamidec 
 
x  
  
  
Opaganib 
  
x 
  
  
Pharmacokineticso 
x 
 
x 
 
 
 
 
 
 
 
Procedure 
Screeninga 
Day 
1g 
Day 
29 
Day 
57 
Day 
85 
Day 
113d 
Day 141 and every 
28 days post Day 
113 
Day 169 and 
every 56 days post 
Day 113 
End 
Rxm 
Off-
Studye, 
l, m 
Items highlighted yellow are considered research specific procedures 
 
a. 
Procedures done at screening do not need to be repeated at week 1 unless there is more than 21 days (28 days for imaging 
studies) between screening and the start of treatment. 
b. 
Radiographic tumor measurements.  Investigator’s choice of CT scans of chest/abdomen/pelvis with contrast, MRI scan of 
abdomen/pelvis with or without contrast, fluciclovine PET scan, technetium bone scan. Abdomen, pelvis CT imaging should 
be done with contrast unless there is a contraindication (allergy, renal insufficiency). MRI may be substituted for abdominal, 
pelvic CT if the physician wishes. The same imaging modality should be used throughout the study. 
c. 
Subject should continue their previous dose of abiraterone (plus prednisone) or enzalutamide throughout the study unless 
new toxicity from those agents develops. 
d. 
Subjects who show disease control at day 113 should continue on protocol treatment, with clinical assessments every 4 
weeks, and radiographic assessment every 56 days. 
e. 
Approximately 30 days after the last dose of opaganib, can be done via phone call 
f. 
Tumor response should be assessed at day 113, and if there is disease control, every 56 days thereafter. 
g. 
All times are +/- 5 days. 
h. 
Research sample = 1 x up to 10 mL EDTA blood delivered to Dr. Shikar Mehrotra’s lab. 
i. 
Only if elevated at screening or Day 1. 
j. 
Deviations from standard of care procedures will not be considered protocol deviations 
k. 
When feasible, Guardant 360 genomic profile will be obtained as standard of care procedure 
l. 
Patients will be followed for survival by clinic visit, review of medical record, and/or telephone call every 3 months from 
treatment discontinuation date for a maximum of 30 months after the last patient has been registered to the trial or until at 
least 80% of patients treated on study in both arms have died, whichever comes first. 
m. Patients that come off study for PSA progression can re-initiate study therapy if their PSA comes back down below what 
would be considered progression within two months of treatment discontinuation – see section 8.1 for specific criteria for 
treatment re-initiation. Patients should still complete all End Rx procedures per the study calendar. 
n. 
Patients are also assessed for PSA disease control at these time points; however, it is up to the treating investigator to 
determine whether they think the patient’s PSA is progressing prior to Day 113. 
o. 
PKs are optional – the patient must elect to participate 
 
 
 
 
 
 


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Protocol version 4.0 dated 06/08/2021 
 
 CONFIDENTIAL - 60 
 
 
APPENDIX B: DEFINITION OF DISEASE CONTROL 
      
Parameter 
Disease Control 
Not Disease Control 
PSA level 
Less than a 25% increase in 
PSA level above baseline level (if 
no PSA decrease) or nadir level 
(if there is a PSA decrease) 
25% or more increase in PSA 
level above baseline (if no PSA 
decrease) or nadir level (if there 
is a PSA decrease).  The absolute 
level of PSA increase must be at 
least 2ng/mL. 
RECIST-evaluable 
lesions 
• 
Complete disappearance 
of lesion;  
• 
Less than a 30% increase 
in the shortest diameter 
(lymph nodes) or longest 
diameter (all other 
lesions) 
30% or more increase in the 
shortest diameter (lymph nodes) 
or longest diameter (all other 
lesions) 
Bone scan 
• 
One or no new lesions 
compared with baseline 
scan 
• 
Two or more new lesions 
compared with baseline 
scan, but without two 
additional lesions on 
followup scan in 8 weeks 
Two or more new lesions 
compared with baseline scan, 
confirmed with another scan 
showing two additional lesions in 
8 weeks (2+2) 
 
 
Patients with disease control at an assessment point must demonstrate at least one of the 
findings in each category (PSA, RECIST, bone scan) under the disease control category.  If 
the findings in the “not disease control” column are found for any category, the patient will 
have failed to show disease control, and should be removed from study.  Criteria for 
disease control are from PCWG3 (Scher, et al., 2016). 


CTO # 103193 
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 CONFIDENTIAL - 61 
 
 
APPENDIX C:  LIST OF CYP SUBSTRATES AND INHIBITORS 
List of commonly used drugs that are sensitive substrates of  CYP450 1A2, 3A4, 2B6, 2C8, 2C9, 
2C19 or 2D6, or strong inhibitors or inducers of all major CYP450 isozymes 
 
This table was developed using information published on the University of Indiana, School of 
Medicine, Department of Medicine, Division of Clinical Pharmacology website 
http://www.medicine.iupui.edu/clinpharm/ddis/table.asp. This list in not inclusive; therefore, 
please refer to the FDA-approved package insert to review drug interactions for medications 
not listed in this appendix.  
 
In determining the half-life, where a time range was provided, the upper end of the range was 
used to provide the largest margin of safety.  Additionally, for a few drugs, half-lives were 
provided for "fast" and "slow" metabolizers.  In those cases, the longer value is given below. 
 
Drug 
Half-life 
(hr) 
5 x half-life 
(hr) 
Reference 
alprazolam 
12 
60 
Goodman & Gilman 11th edition 
amiodarone 
600 
3000 
Goodman & Gilman 11th edition 
amitriptyline 
21 
105 
Goodman & Gilman 11th edition 
amlodipine 
39 
195 
Goodman & Gilman 11th edition 
aripiprazole 
47 
235 
Goodman & Gilman 11th edition 
astemizole 
24 
120 
http://en.wikipedia.org/wiki/ 
Astemizole (accessed 09/03/2010) 
atorvastatin 
19.5 
97.5 
Goodman & Gilman 11th edition 
bupropion 
11 
55 
Goodman & Gilman 11th edition 
buspirone 
2.4 
12 
Goodman & Gilman 11th edition 
carbamazepine 
15 
75 
Goodman & Gilman 11th edition 
celecoxib 
11.2 
56 
Goodman & Gilman 11th edition 
chlorpheniramine 
20 
100 
Goodman & Gilman 11th edition 
cimetidine 
2 
10 
Goodman & Gilman 11th edition 
cisapride 
10 
50 
http://en.wikipedia.org/wiki/ Cisapride 
(accessed 09/03/2010) 
clarithromycin 
3.3 
16.5 
Goodman & Gilman 11th edition 


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clomipramine 
50 
250 
http://en.wikipedia.org/wiki/ 
Clomipramine (accessed 09/03/2010) 
clopidogrel 
8 
40 
http://en.wikipedia.org/wiki/ 
Clopidogrel (accessed 09/03/2010) 
clozapine 
12 
60 
Goodman & Gilman 11th edition 
codeine  
2.9 
14.5 
Goodman & Gilman 11th edition 
cyclobenzamideprine 18 
90 
http://en.wikipedia.org/wiki/ 
Cyclobenzamideprine (accessed 
09/03/2010) 
cyclophosphamide 
7.5 
37.5 
Goodman & Gilman 11th edition 
cyclosporine 
10.7 
53.5 
Goodman & Gilman 11th edition 
dabrafenib 
8 
40 
http://online.lexi.com 
Dabrafenib (accessed 1/6/20) 
desipramine 
23 
115 
http://en.wikipedia.org/wiki/ 
Desipramine (accessed 09/03/2010) 
dextromethorphan 
29.5 
147.5 
Goodman & Gilman 11th edition 
diazepam 
43 
215 
Goodman & Gilman 11th edition 
diclofenac 
1.1 
5.5 
Goodman & Gilman 11th edition 
diltiazem 
4.4 
22 
Goodman & Gilman 11th edition 
doxepin 
18 
90 
Goodman & Gilman 11th edition 
duloxetine 
12.1 
60.5 
http://en.wikipedia.org/wiki/ 
Duloxetine (accessed 09/03/2010) 
efavirenz 
76 
380 
http://online.lexi.com 
Efavirenz (accessed 1/6/20) 
erythromycin 
1.6 
8 
Goodman & Gilman 11th edition 
felodipine 
14 
70 
Goodman & Gilman 11th edition 
flecainide 
11 
55 
Goodman & Gilman 11th edition 
fluconazole 
32 
160 
Goodman & Gilman 11th edition 
fluoxetine 
53 
265 
Goodman & Gilman 11th edition 
fluvastatin 
2.5 
12.5 
http://en.wikipedia.org/wiki/ 
Fluvastatin (accessed 09/03/2010) 


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 CONFIDENTIAL - 63 
fluvoxamine 
15.6 
78 
http://en.wikipedia.org/wiki/ 
Fluvoxamine (accessed 09/03/2010) 
glipizide 
3.4 
17 
Goodman & Gilman 11th edition 
haloperidol 
18 
90 
Goodman & Gilman 11th edition 
ibuprofen 
2 
10 
Goodman & Gilman 11th edition 
ifosfamide 
15 
75 
http://online.lexi.com 
Ifosfamide (accessed 1/6/20) 
imatinib 
40 
200 
http://en.wikipedia.org/wiki/ Imatinib 
(accessed 09/03/2010) 
imipramine 
16 
80 
Goodman & Gilman 11th edition 
indinavir 
1.8 
9 
http://en.wikipedia.org/wiki/Indinavir 
(accessed 09/03/2010) 
indomethacin 
2.4 
12 
Goodman & Gilman 11th edition 
irbesartan 
13 
65 
Goodman & Gilman 11th edition 
isoniazid 
3.1 
15.5 
Goodman & Gilman 11th edition 
itraconazole 
21 
105 
Goodman & Gilman 11th edition 
ketoconazole 
3.3 
16.5 
Goodman & Gilman 11th edition 
lansoprazole 
0.9 
4.5 
Goodman & Gilman 11th edition 
losartan 
5.4 
27 
Goodman & Gilman 11th edition 
lovastatin 
4 
20 
Goodman & Gilman 11th edition 
meperidine 
4 
20 
http://online.lexi.com 
Meperidine (accessed 1/6/20) 
methadone 
27 
135 
Goodman & Gilman 11th edition 
mexiletine 
12 
60 
http://en.wikipedia.org/wiki/Mexiletin
e (accessed 09/03/2010) 
mibefradil 
25 
125 
http://www.drugs.com/mmx/ 
mibefradil-dihydrochloride.html 
(accessed 09/03/2010) 
midazolam 
1.9 
9.5 
Goodman & Gilman 11th edition 
nambutone 
23 
115 
http://www.drugbank.ca/drugs/DB004
61 (accessed 09/03/2010) 
naproxen 
14 
70 
Goodman & Gilman 11th edition 


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nefazodone 
4 
20 
http://en.wikipedia.org/wiki/ 
Nefazodone (accessed 09/03/2010) 
nelfinavir 
5 
25 
Goodman & Gilman 11th edition 
nevirapine 
45 
225 
http://online.lexi.com 
Nevirapine (accessed 1/6/20) 
nifedipine 
1.8 
9 
Goodman & Gilman 11th edition 
nisoldipine 
12 
60 
http://en.wikipedia.org/wiki/ 
Nisoldipine (accessed 09/03/2010) 
nitrendipine 
24 
120 
http://adisonline.com/drugs/Abstract/1
987/33020/Nitrendipine__A_Review_
of_its_Pharmacodynamic_and.3.aspx 
(accessed 09/03/2010) 
olanzapine 
33.1 
165.5 
Goodman & Gilman 11th edition 
olodaterol 
7.5 
37.5 
http://online.lexi.com 
Olodaterol (accessed 1/6/20) 
omeprazole 
1.2 
6 
http://en.wikipedia.org/wiki/ 
Omeprazole (accessed 09/03/2010) 
ondansetron 
3.5 
17.5 
Goodman & Gilman 11th edition 
paclitaxel 
20 
100 
http://online.lexi.com 
Paclitaxel (accessed 1/6/20) 
pantoprazole 
1 
5 
http://en.wikipedia.org/wiki/ 
Pantoprazole (accessed 09/03/2010) 
paroxetine 
17 
85 
Goodman & Gilman 11th edition 
phenobarbital 
99 
495 
Goodman & Gilman 11th edition 
phenobarbitone 
120 
600 
http://www.webhealthcentre.com/drug
ix/Phenobarbitone_di0110.aspx 
(accessed 09/03/2010) 
phenytoin 
24 
120 
Goodman & Gilman 11th edition 
pimozide 
72 
360 
http://en.wikipedia.org/wiki/ Pimozide 
(accessed 09/03/2010) 
pioglitazone 
11 
55 
Goodman & Gilman 11th edition 
piroxicam 
86 
430 
http://en.wikipedia.org/wiki/ 
Piroxicam (accessed 09/03/2010) 


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 CONFIDENTIAL - 65 
ponatinib 
24 
120 
http://online.lexi.com 
Pontini (accessed 1/6/20) 
progesterone 
55.1 
275.5 
http://en.wikipedia.org/wiki/ 
Progesterone (accessed 09/03/2010) 
propafenone 
10 
50 
http://en.wikipedia.org/wiki/ 
Propafenone (accessed 09/03/2010) 
quinidine 
6.2 
31 
Goodman & Gilman 11th edition 
quinine 
18 
90 
Goodman & Gilman 11th edition 
rabeprazole 
1.5 
7.5 
http://en.wikipedia.org/wiki/ 
Rabeprazole (accessed 09/03/2010) 
repaglinide 
1 
5 
http://online.lexi.com 
Repaglinide (accessed 1/6/20) 
rifabutin 
62 
310 
http://en.wikipedia.org/wiki/ Rifabutin 
(accessed 09/03/2010) 
rifampin 
3.5 
17.5 
Goodman & Gilman 11th edition 
riluzole 
14 
70 
Goodman & Gilman 11th edition 
risperidone 
3.2 
16 
Goodman & Gilman 11th edition 
ritonavir 
5 
25 
Goodman & Gilman 11th edition 
rosiglitazone 
4 
20 
Goodman & Gilman 11th edition 
saquinavir 
15 
75 
http://en.wikipedia.org/wiki/ 
Saquinavir (accessed 09/03/2010) 
secobarbital 
40 
200 
http://en.wikipedia.org/wiki/ 
Secobarbital (accessed 09/03/2010) 
selegiline 
10 
50 
http://online.lexi.com 
Selegiline (accessed 1/6/20) 
selexipag 
2.5 
12.5 
http://online.lexi.com 
Selexipag (accessed 1/6/20) 
sildenafil 
2.4 
12 
Goodman & Gilman 11th edition 
simvastatin 
3 
15 
Goodman & Gilman 11th edition 
S-metoprolol 
3.2 
16 
Goodman & Gilman 11th edition 
sorafenib 
48 
240 
http://online.lexi.com 
Sorafenib (accessed 1/6/20) 
sulfamethoxazole 
10.1 
50.5 
Goodman & Gilman 11th edition 


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 CONFIDENTIAL - 66 
tacrine 
4 
20 
http://en.wikipedia.org/wiki/ Tacrine 
(accessed 09/03/2010) 
tacrolimus (FK506) 
12 
60 
Goodman & Gilman 11th edition 
tamoxifen 
264 
1320 
Goodman & Gilman 11th edition 
telithromycin 
23 
115 
Goodman & Gilman 11th edition 
theophylline 
9 
45 
Goodman & Gilman 11th edition 
thioridazine 
20 
100 
http://en.wikipedia.org/wiki/ 
Thioridazine (accessed 09/03/2010) 
ticlopidine 
120 
600 
http://en.wikipedia.org/wiki/ 
Ticlopidine (accessed 09/03/2010) 
timolol 
2.7 
13.5 
Goodman & Gilman 11th edition 
tizanidine 
2.5 
12.5 
http://en.wikipedia.org/wiki/ 
Tizanidine (accessed 09/03/2010) 
tolbutamide 
5.9 
29.5 
Goodman & Gilman 11th edition 
torsemide 
8 
40 
http://en.wikipedia.org/wiki/ 
Torsemide (accessed 09/03/2010) 
tramadol 
7.5 
37.5 
Goodman & Gilman 11th edition 
trazodone 
5.9 
29.5 
Goodman & Gilman 11th edition 
triazolam 
5.5 
27.5 
http://en.wikipedia.org/wiki/ 
Triazolam (accessed 09/03/2010) 
troglitazone 
34 
170 
http://en.wikipedia.org/wiki/ 
Troglitazone (accessed 09/03/2010) 
troleandomycin 
4.2 
21 
Roger G. Finch, 2003 
http://books.google.com/books?id=PQ
W4kz6rQDEC&printsec=frontcover&
dq=inauthor:%22Roger+G.+Finch%2
2&hl=en&ei=3lqGTNLJIcT48Aau652
eAg&sa=X&oi=book_result&ct=resul
t&resnum=2&ved=0CDIQ6AEwAQ#
v=onepage&q&f=false 
velpatasvir 
15 
75 
http://online.lexi.com 
Velpatasvir (accessed 1/6/20) 
venlafaxine 
4.9 
24.5 
Goodman & Gilman 11th edition 
verapamil 
4 
20 
Goodman & Gilman 11th edition 


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vincristine 
22.6 
113 
Goodman & Gilman 11th edition 
warfarin 
37 
185 
Goodman & Gilman 11th edition 
zileuton 
2.5 
12.5 
http://en.wikipedia.org/wiki/ Zileuton 
(accessed 09/03/2010) 
zolmitriptan 
3 
15 
http://en.wikipedia.org/wiki/ 
Zolmitriptan (accessed 09/03/2010) 
 
 
 
 
 


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 CONFIDENTIAL - 68 
APPENDIX D:  ECOG PERFORMANCE STATUS SCALE 
 
Grade 
Description 
0 
Fully active, able to carry on all predisease 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 
housework or office work 
2 
Ambulatory and capable of all selfcare but unable to carry out 
any work activities.  Up and about >50% of waking hours 
3 
Capable of only limited selfcare, confined to a bed or chair 
>50% of waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.   
Totally confined to bed or chair 
5 
Dead 
 
 
 
 


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 CONFIDENTIAL - 69 
 APPENDIX E.  STUDY SCHEMATIC DIAGRAM 
 
 

ICF_001.pdf: 
Page 1 of 22 
Version Date: 07/01/2021 
IRB APPROVED 
AS MODIFIED 
Jul 02, 2021 
 
 
 
Medical University of South Carolina 
CONSENT TO BE A RESEARCH SUBJECT 
 
TITLE: 
A Phase II Study of the Addition of Opaganib to Androgen Antagonists in 
Patients with Prostate Cancer Progression on Enzalutamide or Abiraterone   
 
PROTOCOL NO.: 
103193 
 
WIRB® Protocol #20200552 
 
Pro95537 
 
SPONSOR: 
Medical University of South Carolina 
 
INVESTIGATOR: 
Michael Lilly, MD 
 
86 Jonathan Lucas Street 
  
Charleston, South Carolina 29425 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
843-792-9007 (24 hours) 
 
 
SUMMARY 
You are being asked to volunteer for a research study. Research studies are voluntary and include only people 
who choose to take part.  You are being asked to take part in this study because you have prostate cancer. 
 
The overall goal of this study is to look at the safety and effectiveness of the investigational drug opaganib in 
participants with metastatic castration-resistant prostate cancer (mCRPC). It is an investigational drug because it 
has not been approved by the Food and Drug Administration (FDA) for treatment of cancer.  This combination 
of drugs has not previously been studied in humans.  Participation in this study will require you to complete 
seven study visits over the first 3 months and if you show disease control at that time you will continue to be 
seen every 4 weeks for as long as you are on study. During these visits, you will be asked to provide blood and 
urine samples, undergo radiographic scans or imaging procedures and complete surveys about your quality of 
life or any pain you may be experiencing. After you come off of the study you will enter a follow-up period for 
up to 3 years where study team members will follow your care by clinic visit, phone contact and/or medical 
record review every three months to collect information on the status of your cancer. 
 
If opaganib is proven effective, you may benefit from participating in this study, but that cannot be guaranteed. 
The greatest risks of this study include symptoms of gastrointestinal discomfort, complications from blood 
draws and loss of confidentiality. Participating in this study might make it so you cannot receive other 
treatments with demonstrated survival advantage and side effects from the investigational drug could prevent 


Page 2 of 22 
Version Date: 07/01/2021 
IRB APPROVED 
AS MODIFIED 
Jul 02, 2021 
 
 
 
you from getting these treatments in the future. You do not have to participate in this study to have your 
condition treated.  
 
If you choose not to participate in this study, you will continue to see your regular doctor and receive treatment 
for your prostate cancer.  
 
A. PURPOSE OF THE RESEARCH  
Please read this consent form carefully and take your time making your decision.  You may discuss your 
decision with your friends and family.  You can also discuss it with your health care team.  Ask the study doctor 
or study staff to explain any words or information that you do not clearly understand.   
 
The purpose of this study is to look at the safety and effectiveness of the investigational drug opaganib in 
participants with metastatic prostate cancer.  The study drug, opaganib has been studied in a clinical trial to find 
the most tolerated dose level.  The results of this clinical trial and other lab studies have indicated that opaganib 
may be effective at slowing tumor growth.  You are being asked to participate in this study because you have 
prostate cancer that has progressed (gotten worse) on your current therapy. 
 
This study is sponsored by MUSC with funding from a grant from the National Institutes of Health (NIH) to 
conduct this study.  The investigator in charge of this study is Dr. Michael Lilly.  Dr. Lilly will receive payment 
to support activities required to conduct and manage this study.  No one on the research team will receive a 
direct payment or an increase in salary for conducting the study 
 
This study will be conducted at MUSC and up to two other cancer centers. About 60 participants will 
participate in this clinical study, with up to 20 participants being enrolled at MUSC. 
 
B. PROCEDURES 
Before you begin the study: 
If you agree to be in the study, you will need to have the following exams, tests and procedures to find out if 
you are eligible.  These exams, tests and procedures are part of regular cancer care and may be done even if you 
do not join this study.  If you have had some of them recently, they may not need to be repeated.  This will be 
up to the study doctor.  It may take about 2 hours to complete all of the tests below:  
 
 History and physical exam.  The study doctor will ask you what medications you are taking  
 Vitals and weight 
 About 2 teaspoons of blood will be taken to look at your blood counts, the health of your tissue, kidneys 
and liver, to look at your prostate health and your electrolyte balance.  Electrolytes are minerals in your 
blood that help maintain your body’s blood chemistry, muscle action and other bodily functions.  
 A urine sample will be collected 
 Radiographic scans or imaging using Computed Tomography (CT) scan (a series of images taken with 
x-rays), positron emission tomography (PET) scan or magnetic resonance imaging (MRI) of the chest, 


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pelvis and abdomen and a bone scan. These scans will give a detailed picture of the areas of the body 
taken from different angles.  The procedures for these are described below. 
 
The CT scanner is a doughnut-shaped machine. During the procedure, a technologist will take you into 
the CT scan room where you will lie down on the participant table (usually on your back) inside of the 
CT machine. You should get comfortable because it is very important not to move during certain parts 
of the test. During this scan, you will be asked to hold your breath so that the pictures will not be 
blurred. The machine will make some noise, and the table will move during the scan. You may also 
receive signals from the technologist or from the machine about your breathing. If you have any 
discomfort during the test or after the injection, be sure to tell the technologist.  
 
During an MRI you will be placed on a narrow bed and then slid into a small tunnel approximately 6 
feet in length and 25 inches in diameter. You will hear a loud machine-like noise. 
 
Before or during the CT or MRI, you may be given an injection of a contrast liquid in your vein to allow 
the radiologist to obtain clearer images of your organs. 
 
A PET Scan is a diagnostic tool used to detect cancer and find out the cancer’s stage (a way of 
describing where the cancer is located, if or where it has spread, and whether it is affecting the functions 
of other organs in the body). Before the scan, you’ll get tracers through a vein in your arm, through a 
solution you drink, or in a gas you inhale.  Your body needs time to absorb the tracers, so you’ll wait 
about an hour before the scan begins.  Next, you’ll undergo the scan, which can last anywhere from 30 
to 45 minutes. This involves lying on a narrow table attached to a PET machine, which looks like a giant 
letter “O.” The table glides slowly into the machine so that the scan can be conducted. You’ll need to lie 
still during the scan. The technician will let you know when you need to remain still. You may be asked 
to hold your breath for several seconds. You’ll hear buzzing and clicking noises during the test. 
 
During a bone scan the doctor will inject (through an IV in your vein) radioactive substance. A short 
time later, a machine measures how much radiation has been taken into the bones. The test does not hurt 
but you may have to stay in a certain position to get a good picture. 
 
You will also have the following research procedures during the screening part of the study.  These will only be 
done if you agree to be on the study and you sign this informed consent document: 
 
 About 4 teaspoons of blood will be taken to look at how well you blood is clotting, phosphorous levels 
and other tumor markers produced by cancer cells in the body and for research purposes.  
 Questionnaires looking at your quality of life and how you are feeling. 
 Questionnaire to look at any pain you might be experiencing.  
 
If the exams, tests and procedures show that you can be in the study, you will be registered to the study and will 
begin study participation. 


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During the study: 
The study is divided into intervals called “cycles.”  These cycles are made up of 28 days.  During these cycles, 
you will be given opaganib. There will be no changes to your scheduled abiraterone or enzalutamide treatment 
as a result of this study. You will continue to see your regular doctor and will continue your other therapy as 
they have prescribed.  If the treating investigator determines that you need to discontinue Abiraterone or 
Enzalutamide due to toxicity, you may continue on Opaganib alone. 
 
Dose Assignment of Opaganib: 
There are two dose levels of opaganib that are described below. If you are in one of the first groups of subjects 
to get the study drug, you will be assigned to dose level 1, which is the starting dose level.  If the starting dose 
level does not cause significant side effects, the study sponsor may increase the dose to dose level 2.  All 
participants receive the active drug. If the investigator decides that the dose level is not well tolerated by the 
participants, the dose level could decrease for the whole study or the study could stop completely. 
 
Dose Level 
Opaganib 
1 
250mg twice a day 
2 
500mg twice a day 
 
The opaganib should be taken twice a day about 12 hours apart after a light meal. You will be asked to write on 
a study drug diary or form to help keep track of when you take the tablets as well as any symptoms or side 
effects that you may have.  You will fill out this diary form each day.  
 
If you forget and miss a dose, you should take the dose as soon as possible.  If the next dose is due in less than 8 
hours, you should skip the missed dose and take the next dose as scheduled. You should write any missed or 
skipped doses in your drug diary. 
 
If you vomit after taking the medication, you should not take another dose at that time. At your next scheduled 
dose, take your normal dose. Write your symptom of vomiting on the study drug diary and discuss this 
information with the study doctor.   
 
Day 1: 
After you are registered to the study you will come into clinic for your Day 1 study visit and to receive your 
study medication. You will have the following standard of care exams, tests and procedures.  If you have had 
some of them recently, they may not need to be repeated.  This will be up to the study doctor.  It may take about 
2 hours to complete all of the tests below:  
 
 History and physical exam.  The study doctor will ask you what medications you are taking  
 Vitals and weight 
 About 2 teaspoons of blood will be taken to look at your blood counts, the health of your kidneys and 
liver and your electrolyte balance.  Electrolytes are minerals in your blood that help maintain your 
body’s blood chemistry, muscle action and other bodily functions.   
 A urine sample will be collected 


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You will also have the following research procedures: 
 
 About 2 teaspoons of blood will be taken to look at how well you blood is clotting, the health of your 
tissues and prostate, phosphorous levels and other tumor markers produced by cancer cells in the body.   
 Questionnaires looking at your quality of life and how you are feeling. 
 Questionnaire to look at any pain you might be experiencing.  
 
Day 29: 
You will have the following standard of care exams, tests and procedures. You will need to bring your pill 
bottle(s) and drug diary to this visit. It may take about 2 hours to complete all of the tests below:  
 
 History and physical exam.  The study doctor will ask you what medications you are taking  
 Vitals and weight 
 About 1 teaspoon of blood will be taken to look at your blood counts, the health of your kidneys and 
liver and your electrolyte balance.  Electrolytes are minerals in your blood that help maintain your 
body’s blood chemistry, muscle action and other bodily functions.   
 A urine sample will be collected 
 
You will also have the following research procedures: 
 
 About 1 teaspoon of blood will be taken to look at the health of your tissue and prostate. 
 The study doctor will ask about any side effects you may be experiencing as well as review your study 
drug diary and any remaining pills. 
 
Day 57: 
You will have the following standard of care exams, tests and procedures. You will need to bring your pill 
bottle(s) and drug diary to this visit. It may take about 2 hours to complete all of the tests below:  
 
 History and physical exam.  The study doctor will ask you what medications you are taking  
 Vitals and weight 
 About 1 teaspoon of blood will be taken to look at your blood counts, the health of your kidneys and 
liver and your electrolyte balance.  Electrolytes are minerals in your blood that help maintain your 
body’s blood chemistry, muscle action and other bodily functions.     
 A urine sample will be collected 
 
You will also have the following research procedures: 
 
 The study doctor will ask about any side effects you may be experiencing as well as review your study 
drug diary and any remaining pills. 


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 About 3 teaspoons of blood will be taken to look at the health of your tissue, prostate and for research 
purposes.  
 Questionnaire to look at your mental status.  
 
Day 85: 
You will have the following standard of care exams, tests and procedures. You will need to bring your pill 
bottle(s) and drug diary to this visit. It may take about 2 hours to complete all of the tests below:  
 
 History and physical exam.  The study doctor will ask you what medications you are taking  
 Vitals and weight 
 About 2 teaspoons of blood will be taken to look at your blood counts, the health of your kidneys and 
liver, to look at your prostate health and your electrolyte balance.  Electrolytes are minerals in your 
blood that help maintain your body’s blood chemistry, muscle action and other bodily functions.   
 A urine sample will be collected 
 
You will also have the following research procedures: 
 
 About 1 teaspoon of blood will be taken to look at the health of your tissues and other tumor markers 
produced by cancer cells in the body. 
 The study doctor will ask about any side effects you may be experiencing as well as review your study 
drug diary and any remaining pills. 
 
Day 113: 
You will have the following standard of care exams, tests and procedures. You will need to bring your pill 
bottle(s) and drug diary to this visit. It may take about 2 hours to complete all of the tests below:  
 
 History and physical exam.  The study doctor will ask you what medications you are taking  
 Vitals and weight 
 About 1 teaspoons of blood will be taken to look at your blood counts, the health of your kidneys and 
liver and your electrolyte balance.  Electrolytes are minerals in your blood that help maintain your 
body’s blood chemistry, muscle action and other bodily functions. 
 A urine sample will be collected 
 The investigator will obtain the results of your radiographic scans or imaging using CT scan, PET scan 
or MRI of the chest, pelvis and abdomen and bone scan. 
 
You will also have the following research procedures: 
 
 The study doctor will ask about any side effects you may be experiencing as well as review your study 
drug diary and any remaining pills. 


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 About 4 teaspoons of blood will be taken to look at how well you blood is clotting, phosphorous levels, 
the health of your tissue and prostate and other tumor markers produced by cancer cells in the body and 
for research purposes.   
 Tumor response assessment. 
 Questionnaires looking at your quality of life and how you are feeling. 
 Questionnaire to look at any pain you might be experiencing.  
 Questionnaire to look at your mental status.  
 
Every 28 days: 
After Day 113 you will come in every 28 days for the following standard of care exams, tests and procedures. 
You will need to bring your pill bottle(s) and drug diary to this visit. It may take about 2 hours to complete all 
of the tests below:  
 
 History and physical exam.  The study doctor will ask you what medications you are taking  
 Vitals and weight 
 About 2 teaspoons of blood will be taken to look at your blood counts, the health of your kidneys and 
liver and your electrolyte balance.  Electrolytes are minerals in your blood that help maintain your 
body’s blood chemistry, muscle action and other bodily functions.   
 A urine sample will be collected 
 
You will also have the following research procedures: 
 
 About 2 teaspoons of blood will be taken to look at the health of your tissue and prostate. 
 The study doctor will ask about any side effects you may be experiencing as well as review your study 
drug diary and any remaining pills. 
 
Every 56 days: 
After day 113 every 56 days you will have some additional tests and procedures. You will need to bring your 
pill bottle(s) and drug diary to this visit. It may take about 2 hours to complete all of the tests below:  
 
 About 1 additional teaspoon of blood will be taken to look at your prostate health.  
 The investigator will obtain the results of your radiographic scans or imaging using CT scan, PET scan 
or MRI of the chest, pelvis and abdomen and bone scan. 
 
You will also have the following additional research procedure: 
 
 Tumor response assessment. 
 


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End of Treatment: 
You will have the following standard of care exams, tests and procedures completed as a part of your end of 
treatment visit. You will need to bring your pill bottle(s) and drug diary to this visit. It may take about 2 hours 
to complete all of the tests below:  
 
 History and physical exam.  The study doctor will ask you what medications you are taking  
 Vitals and weight 
 About 2 teaspoons of blood will be taken to look at your blood counts, the health of your tissue, kidneys 
and liver, to look at your prostate health and your electrolyte balance.  Electrolytes are minerals in your 
blood that help maintain your body’s blood chemistry, muscle action and other bodily functions.   
 The investigator will obtain the results of your radiographic scans or imaging using CT scan, PET scan 
or MRI of the chest, pelvis and abdomen and bone scan. 
 A urine sample will be collected 
 
You will also have the following research procedures: 
 
 The study doctor will ask about any side effects you may be experiencing as well as review your study 
drug diary and any remaining pills. 
 About 4 teaspoons of blood will be taken to look at how well you blood is clotting, phosphorous levels, 
the health of your tissue and other tumor markers produced by cancer cells in the body and for research 
purposes.  
 Tumor response assessment. 
 Questionnaires looking at your quality of life and how you are feeling. 
 Questionnaire to look at any pain you might be experiencing.  
 Questionnaire to look at your mental status.  
 
30 days post treatment: 
About 30 days after you stop taking the study drug you will meet with the study doctor to discuss any side 
effects you may be experiencing.  
 
After the Study: 
After you complete the end of study visit, you will enter a follow up period.  The study team will follow your 
care by clinic visit, review of medical record and/or telephone call every 3 months for up to 3 years after the last 
participant is enrolled to the study.  
 
Optional Blood Sample Collections for Additional Research: 
Up to 12 patients on the study will have blood samples collected for the researchers to learn more about the 
level of study drug in your body over a given period of time, and how the study drug interacts with other 
medications you are taking.  These collections are optional and will not affect your participation in the study 
should you choose to not have these samples collected. 


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If you do agree to the sample collections, the following amounts of blood will be collected: 
 
Up to 3 teaspoons of blood will be collected within 7 days of starting treatment, about 1 teaspoon per hour over 
4 hours. 
Up to 5 teaspoons of blood will be collected on study Day 29, about 1 ¼   teaspoons per hour over 4 hours. 
Please discuss with your study doctor any questions you may have about the optional sample collections.  After 
you have made a decision on whether to participate, please initial one of the lines below: 
 
_________ YES, I agree to the optional blood sample collections for additional research. 
 
_________ NO, I do NOT agree to the optional blood sample collections for additional research. 
 
Withdrawal 
You are free to withdraw from this study at any time. If you decide to withdraw from this study you should 
notify the research team by speaking with them in clinic, by phone and/or in writing immediately. The research 
team may also end your participation in this study if you do not follow instructions, miss scheduled visits, your 
safety and welfare are at risk, or the study sponsor decides to stop the study. 
 
If you experience any of the side effects listed in the Risks and Discomforts section or if you become ill during 
the research, you may need to be withdrawn from the study, even if you would like to continue. The research 
team will make the decision and let you know if it is not possible for you to continue. The decision may be 
made to protect your safety and welfare, or because it is part of the research plan that people who develop 
certain conditions may not continue to participate. 
 
If you withdraw or are removed from the study, the researcher may ask you to return to the clinic for a final 
close‐out visit or evaluation. 
 
C. DURATION 
Participation in the study will take about 7 visits over a period of about 3 months then you will continue to be 
seen every 4 weeks until your disease progresses or you discontinue treatment. Once you come off study you 
will be in follow up for up to 3 years. During this time the study team will follow your care by clinic visit, 
phone contact and/or medical record review every three months to collect information on the status of your 
cancer. 
 
D. RISKS AND DISCOMFORTS 
While on this study, you are at risk for the side effects listed below.  Not everyone will get these side effects.  
You may have none or several.  Most people do not experience all of the side effects listed. A side effect may 
get worse while on study drug, or more side effects may develop as the longer you stay on study.  This depends 
on your general health and the amount of the study drug you receive (the dose). 


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Many side effects are inconvenient but not damaging to your health.   
 
They are almost always reversible and usually go away shortly after study drug is complete.  However, some 
side effects are serious medical conditions that may cause your death or cause your condition to deteriorate.  
The study doctor will closely monitor and treat/prevent the side effects you might have through the study 
period.  Other drugs and procedures may be given to make side effects less serious and less uncomfortable.  
There may be side effects which are unknown at this time. 
 
Opaganib 
Common adverse events occurring in greater than or equal to 10% of subjects:  
• Nausea 
• Fatigue 
• Vomiting 
• Diarrhea 
• Muscle spasms 
• Hot flashes 
• Acute kidney injury 
 
Less common adverse events occurring in less than 10% of subjects: 
• Urinary retention or inability to completely empty the bladder 
• Ringing in the ears 
• A fungal infection in the mouth and throat called thrush 
• Rapid heart rate 
• Sweating 
• A feeling of unusual tightness, stiffness or pull in the muscles 
• Acid reflux or gastroesophageal reflux disease (GERD) 
• Rash 
• Pain, including pain the pelvic area 
• Numbness 
• Lower extremity weakness 
• High blood pressure 
• Increase in lipid levels or fat particles in the blood 
• Increase in blood glucose levels 
• Hearing impaired 
• Generalized muscle weakness 
• Excess gas 
• Fingernail changes 


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• Shortness of breath 
• Dry mouth 
• Choking sensation 
• Chest discomfort 
• Changes in liver function tests (AST, ALT and bilirubin) 
• Loss of appetite 
• Anemia or reduction in hemoglobin in the blood that may cause shortness of breath and tiredness 
• Abnormal reflexes 
• Abdominal discomfort 
 
Neuropsychiatric Effects 
These are side effects that affect your nervous system or have psychiatric effects. 
 
Common adverse events occurring in greater than or equal to 10% of subjects:  
• General change in mood and mood swings 
• Vision changes including visual disturbances and blurred vision 
• Dizziness 
• Changes in taste 
• Feeling of sleepiness or drowsiness 
 
Less common adverse events occurring in less than 10% of subjects: 
• Anxiety 
• Agitation 
• Damage to the nerves that causes weakness, numbness and pain in the hands and feet 
• Abnormal reflexes 
• Difficulty speaking 
• Hallucinations 
• Memory loss 
• Feeling of pins and needles in the legs and arms 
• Pain, burning or tingling of the skin when touching part of the body 
• Headache 
 
Reproductive Risks 
You should not father a child while on this study as the treatment may indirectly affect an unborn child. If you 
are sexually active and are at risk of causing a pregnancy, you and your female partner(s) must use a method to 
avoid pregnancy that works well or you must not have sex.  Examples of acceptable methods of birth control 
includes: birth control pills, patch, IUD, condom, sponge, diaphragm with spermicide, or avoiding sexual 
activity that could cause you to become pregnant. 
 


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Unless you cannot have children because of surgery or other medical reasons, you must be using an effective 
form of birth control before you start the study, during the study and up to 12 weeks after discontinuing the 
study.  There may be risk to a fetus or nursing child which are unknown at this time. 
 
Procedure Risks 
CT scan - There is always a slight risk from being exposed to any radiation, including the low levels of x-rays 
used for a CT scan.  
 
However, the risk from the x-rays is usually very low compared with the potential usefulness of the test to 
manage your treatment. In rare cases, you may have an allergic reaction to the contrast material given. If you 
are taking metformin (or similar drugs by mouth to treat high blood sugar), such treatment will be stopped for 2-
3 days around the time a scan is planned in order to avoid kidney side effects. The radiologist doing these tests 
will explain the risks and ask you to sign a separate consent form. 
 
PET scan - There is a chance that you may experience discomfort, pain, or swelling at the site where the 
radiotracer FDG is injected. You could have an allergic reaction but this has been rarely observed. The amount 
of radiation put into your body is small and the radiation from the radiotracer will be gone from your body in a 
few hours. 
 
MRI scan – Because the MRI machine acts like a large magnet, it could move iron-containing objects in the 
MRI room during your examination, which in the process could possibly harm you. Precautions will be taken to 
prevent such an event from happening; loose metal objects, like pocket knives or key chains, are not allowed in 
the MRI room. If you have a piece of metal in your body, such as a fragment in your eye, aneurysm clips, ear 
implants, spinal nerve stimulators, or a pacemaker, you will not be allowed into the MRI room and cannot have 
an MRI. Having an MRI can cause some discomfort for you. You may feel claustrophobic (fear of being 
enclosed in a small space) in the scanner. The scan can be loud and temporary hearing loss has been reported 
from this loud noise. You will be asked to wear ear plugs to make you more comfortable. At times during the 
test, you may be asked not to swallow for a while, which can be uncomfortable. 
 
Bone Scan - In this study, you will be exposed to some radiation from the bone scans. The amount of radiation 
you will get is like the amount from other x-ray exams routinely used in medicine. Public policy is to keep 
exposure levels as low as possible. 
 
Contrast dye may be used with some procedures, which has a small possibility of a severe allergic reaction and 
may also cause kidney problems, especially if you are dehydrated or have poor kidney function. 
 
ECG Risk 
Electrocardiogram (ECG) - You may experience a minor discomfort, similar to removing a bandage, when the 
electrodes are removed from your skin. You may have slight redness or inflammation due to the adhesive used 
to attach the electrodes to the skin that will go away on its own. 


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Blood Draw Risks   
The risks of drawing blood include temporary discomfort from the needle stick, bruising and infection. Fainting 
could occur. 
 
Loss of confidentiality 
There is a risk of loss of confidentiality since medical records will be reviewed during this study.  MUSC and 
its study team members will take every effort to ensure that your information is kept confidential during this 
study.   
 
Unknown risks 
The experimental study drug may have unknown side effects. The researchers will let you know if they learn 
anything that might make you change your mind about participating in the study. 
 
E. MEDICAL RECORDS AND CERTIFICATE OF CONFIDENTIALITY  
This research is covered by a Certificate of Confidentiality from the Federal government. This means that the 
researchers may not disclose information or biospecimens that may identify you, even by a court subpoena, in 
any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, nor can the 
information or biospecimens be used as evidence, unless you have consented to this disclosure.  Information or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not connected with the 
research except if you have consented to the disclosure, including for your medical treatment; or if it is used for 
other scientific research, as allowed by federal regulations protecting research subjects.  
 
A Certificate of Confidentiality does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. If you are an MUSC participant you have an MUSC medical record.  If you 
have never been an MUSC participant, a MUSC medical record will be created for the purposes of this study. 
Results of research tests or procedures will be included in your MUSC medical record. All information within 
your medical record can be viewed by individuals authorized to access the record. We will make every effort to 
keep confidential all research information in the medical record that identify you to the extent allowed by law; 
however, there is the possibility that your research information will be disclosed. 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, state, or local 
law. Examples of required disclosure include: child abuse and neglect, or harm to self or others 
 
Finally, a Certificate may not be used to withhold information from the Federal government needed for auditing 
or evaluating Federally funded projects or information needed by the FDA. 
 
F. BENEFITS 
If you agree to take part in this study, there may or may not be direct medical benefit to you.  Your participation 
in this study may provide important information regarding the study drug and that may lead to future clinical 
studies.  Other participants with cancer may benefit in the future. 


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G. COSTS 
You and/or your insurance company will be billed for all routine clinic visits and all standard laboratory tests 
(e.g. routine blood counts and blood chemistry tests). Some health plans will not pay these costs for people 
taking part in studies. Check with your insurance company to find out what they will pay for, as if they refuse to 
pay you will be held financially responsible. 
 
The study drug opaganib will be provided by the study and will not be charged to you.  The following 
procedures are not considered standard of care and will be paid for by the sponsor: 
 
• Blood tests to look at how well your blood is clotting, phosphorous levels, the health of your prostate 
and tissue and to look at other tumor markers produced by cancer cells in the body 
• Blood collected for research purposes  
• Research questionnaires about quality of life and pain 
 
Please ask Dr. Michael Lilly if you would like to know more about which tests and studies are being done 
solely for research purposes. 
 
H. PAYMENT TO PARTICIPANTS 
In return for your time and effort, once you are enrolled on the study you will be paid $75 cash for each study 
visit you complete; not to exceed a total of $750.00 during your time on study.  
 
Payment for study visits will be made using a pre-paid debit card, called a ClinCard. It works like a bank debit 
card and you may use the card to purchase goods or services everywhere Debit MasterCard is accepted. You 
will be given a ClinCard at the beginning of the study.  Each time you receive payment for participation in this 
study, the money will be added to the card, as outlined in the payment schedule above.  Details of the debit card 
system are explained on an additional sheet. 
 
You may receive payment by other options besides the ClinCard.  Payments that you receive from MUSC for 
participating in a research study are considered taxable income per IRS regulations.  Payment types may also 
include, but are not limited to: checks, cash, gift certificates/cards, personal property, and other items of value.  
If the total amount of payment you receive from MUSC reaches or exceeds $600.00 in a calendar year, you will 
be issued a Form 1099. 
 
I. ALTERNATIVES 
If you choose not to participate in this study, you will continue to see your regular doctor and receive treatment 
for your prostate cancer. Standard therapy for prostate cancer include other forms of androgen deprivation, 
radiation therapy or chemotherapy standard of care. 
 


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If you decide that you don’t want any more active treatment, one of your options is called “comfort care.”  
Comfort care includes pain medication and other support.  It aims to maintain your comfort and dignity rather 
than cure disease.  Usually this care can be provided at home.  
 
If you think you might prefer comfort care, please discuss this with your family, friends and your doctor. 
 
J. SIGNIFICANT NEW FINDINGS 
If there are significant new findings during the course of the study, you will be notified.  
 
K. DATA SHARING 
Information about you (including your identifiable private information and/or any identifiable biospecimens) 
may have all of your identifiers removed and used for future research studies or distributed to other researchers 
for future research without additional informed consent from you. 
 
L. DISCLOSURE OF RESULTS 
Research results, including individual research results, will not be disclosed to you. 
 
M. AUTHORIZATION TO USE AND DISCLOSE (RELEASE) MEDICAL INFORMATION 
As part of this research study, your study doctor and his/her research team will keep records of your 
participation in this study. 
 
The health information MUSC may use or disclose (release) for this research study includes information in your 
medical record, results of physical exams, medical history, lab tests or certain health information indicating or 
relating to your condition.  
 
Your study doctor and his/her research team will use and disclose (release) your health information to conduct 
this study. The health information listed above may be used by and/or disclosed (released) to the following, as 
applicable: 
 
• 
The sponsor of the study including its agents such as data repositories or contract research 
organizations monitoring the study; 
• 
Other institutions and investigators participating in the study; 
• 
Data Safety Monitoring Boards; 
• 
Accrediting agencies; 
• 
Clinical staff not involved in the study whom may become involved if it is relevant; 
• 
Parents of minor children if less than 16 years old.  Parents of children 16 years old or older require 
authorization from the child; or 
• 
Health insurer or payer in order to secure payment for covered treatment; 


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• 
Federal and state agencies and MUSC committees having authority over the study such as: 
o The Institutional Review Board (IRB) overseeing this study;  Committees with quality 
improvement responsibilities;  Office of Human Research Protections; Food and Drug 
Administration;  National Institutes of Health or Other governmental offices, such as a 
public health agency or as required by law. 
 
Those persons who receive your health information may not be required by Federal privacy laws (such as the 
Privacy Rule) to protect it and may share your information with others without your permission, if permitted by 
laws governing them.   You do not have to sign this consent form.  If you choose not to sign, it will not affect 
your treatment, payment or enrollment in any health plan or affect your eligibility for benefits.  However, you 
will not be allowed to be a participant in this research study. 
 
You will be given a copy of this consent form.  Your authorization will expire at the conclusion of this study or, 
if you are participating in a study designed for the development of a drug or device, your authorization will 
remain in effect until the drug or device is approved by the FDA or until the company’s application to study the 
drug/device is withdrawn.   You have the right to withdraw your agreement at any time.  You can do this by 
giving written notice to your study doctor.  If you withdraw your agreement, you will not be allowed to 
continue participation in this research study.  However, the information that has already been collected will still 
be used and released as described above.  You have the right to review your health information that is created 
during your participation in this study.  After the study is completed, you may request this information. 
 
Your health information will be used or disclosed when required by law.   
 
Your health information may be shared with a public health authority that is authorized by law to collect or 
receive such information for the purpose of preventing or controlling disease, injury or disability and for 
conducting public health surveillance, investigations or interventions.  No publication or public presentation 
about the research study will reveal your identity without another signed authorization from you.   
 
If you have questions or concerns about this Authorization or your privacy rights, please contact MUSC’s 
Privacy Officer at (843) 792-8740. 
 
Regulations require that you be given a copy of the MUSC Notice of Privacy Practices (NPP) describing the 
practices of MUSC regarding your health information. One can be found at the end of this form. 
 


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In addition to the main study, you have the option of participating in the optional portions of this study. Your 
protected health information may be used or shared with others outside of MUSC for this research as well. 
Please initial below if we may use/disclose your protected health information for the optional research portion/s 
of this study. 
 
 ____Yes, you may use my protected health information for the optional research portions of this study. 
 ____No, you may not use my protected health information for the optional research portions of this study. 
 
N. STUDENT PARTICIPATION 
Your participation or discontinuance will not constitute an element of your academic performance, nor will it 
be a part of your academic record at this Institution. 
 
O. EMPLOYEE PARTICIPATION 
Your participation or discontinuance will not constitute an element of your job performance or evaluation, 
nor will it be a part of your personnel record at this Institution. 
 
P. CLINICAL TRIALS.GOV  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time. 
 
Q. COLLECTION OF SPECIMENS 
As part of this study, we would like to store the specimens collected from you for future research on prostate 
cancer. This future research may be conducted by Dr. Lilly or by other researchers who obtain IRB approval for 
their research. This research may involve genetic studies. This research will not include whole genome 
sequencing.  The specimens will be coded/anonymized. This will protect your confidentiality and anonymity; it 
will also have other consequences: 
 
1. Results of any future research will not be given to you or your doctor. 
2. Even though your name and other personal identifiers will not be connected to the sample, other 
information about you might still be connected. For instance, information about your race, ethnicity, sex, 
your medical history, and so forth might be available to investigators studying your specimen. Such 
information might be important for research or public health. It is possible that this information 
(including genetic information) might come to be associated with your racial or ethnic group. 
3. The specimens obtained from you in this research may help in the development of a future commercial 
product. There are no plans to provide financial compensation to you should this occur. 
 
You may request at any time that your research samples be removed from storage and not be used for future 
research.  


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If you decide you want your samples removed, you may contact Dr. Michael Lilly via written communication at 
the following address: 
 
Hollings Cancer Center 
Medical University of South Carolina 
86 Jonathan Lucas Street 
Charleston, SC 29425 
 
Once the request is received, and if your samples have not already been used for other research, they will be 
destroyed. If you do not make such a request, your specimens will be stored indefinitely or until completely 
used. 
 
R. FUTURE CONTACT 
The researcher in charge of this study might like to contact you in the future about other research opportunities. 
Please initial by your choice below:  
 
____Yes, I agree to be contacted 
____No, I do not agree to be contacted 
 
Results of this research will be used for the purposes described in this study. This information may be 
published, but you will not be identified. Information that is obtained concerning this research that can be 
identified with you will remain confidential to the extent possible within State and Federal law. The sponsor and 
the Food and Drug Administration (FDA) will receive copies of the research records. The investigators 
associated with this study, employees of the sponsor, the FDA, and the MUSC Institutional Review Board for 
Human Research will have access to identifying information. All records in South Carolina are subject to 
subpoena by a court of law. 
 
In the event of a study related injury, you should immediately go to the emergency room of the Medical 
University Hospital, or in case of an emergency go to the nearest hospital, and tell the physician on call that you 
are in a research study. They will call your study doctor who will make arrangements for your treatment. If the 
study sponsor does not pay for your treatment, the Medical University Hospital and the physicians who render 
treatment to you will bill your insurance company. If your insurance company denies coverage or insurance is 
not available, you will be responsible for payment for all services rendered to you. If you are injured as a result 
of this study, you do not give up your right to pursue a claim through the legal system. 
 
Your participation in this study is voluntary. You may refuse to take part in or stop taking part in this study at 
any time. You should call the investigator in charge of this study if you decide to do this. The data collected on 
you to this point remains part of the study database and may not be removed. Your decision not to take part or 
to stop taking part in the study will have no penalty and will not affect your current or future medical care or 
any benefits to which you are otherwise entitled. 


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The investigators and/or the sponsor may stop your participation in this study at any time if they decide it is in 
your best interest. They may also do this if you do not follow the investigator’s instructions. 
 
Volunteers Statement 
 
I have been given a chance to ask questions about this research study. These questions have been answered to 
my satisfaction. If I have any more questions about my participation in this study or study related injury, I may 
contact Dr. Michael Lilly at (843) 792-0592 or (843) 792-9007 (24 hours). I may contact the Medical 
University of SC Participant and Family Care Liaison (843) 792-5555 concerning medical treatment. 
 
If I have any questions, problems, or concerns, desire further information or wish to offer input, I may contact 
the Medical University of SC Institutional Review Board for Human Research IRB Manager or the Office of 
Research Integrity Director at (843) 792-4148. This includes any questions about my rights as a research subject 
in this study. 
 
This research is being overseen by an Institutional Review Board (“IRB”). An IRB is a group of people who 
perform independent review of research studies. You may talk to them at (800) 562-4789, help@wirb.com if:  
 
o You have questions, concerns, or complaints that are not being answered by the research team. 
o You are not getting answers from the research team. 
o You cannot reach the research team. 
o You want to talk to someone else about the research. 
o You have questions about your rights as a research subject. 
 
I agree to participate in this study. I have been given a copy of this form for my own records. 
 
 
 
 
Signature of Person Obtaining Consent 
Date 
*Name of Participant 
 
 
 
 
Signature of Participant 
Date 


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NOTICE OF PRIVACY PRACTICES 
MUSC Organized Health Care Arrangement (OHCA) 
 
 
 
The Medical University of South Carolina and its affiliates (including but not limited to the Medical University Hospital 
Authority, MUSC Physicians, and MUSC Physicians Primary Care) participate in a clinically integrated health care 
setting.  As a result of this clinical integration, these organizations function as an Organized Health Care Arrangement 
(OHCA) as defined by the Health Insurance Portability and Accountability Act (HIPAA).  For purposes of this notice, 
the members of the MUSC OHCA are collectively referred to in this document as “MUSC.”  We collect or receive this 
information about your past, present or future health condition to provide health care to you, to receive 
payment for this health care, or to operate the hospital and/or clinics. 
 
HOW WE MAY USE AND RELEASE YOUR PROTECTED HEALTH INFORMATION (PHI) 
A.   The following uses do NOT require your authorization, except where required by SC law: 
1.  For treatment.  Your PHI may be discussed by caregivers to determine your plan of care.  For example, the 
physicians, nurses, medical students and other health care personnel may share PHI in order to coordinate the services 
you may need. 
2.  To obtain payment.  We may use and disclose PHI to obtain payment for our services from you, an insurance 
company or a third party.  For example, we may use the information to send a claim to your insurance company. 
3.  For health care operations.  We may use and disclose PHI for hospital and/or clinic operations.  For example, we 
may use the information to review our treatment and services and to evaluate the performance of our staff in caring for 
you.  
4.  For public health activities.  We report to public health authorities, as required by law, information regarding births, 
deaths, various diseases, reactions to medications and medical products. 
5.  Victims of abuse, neglect, domestic violence.  Your PHI may be released, as required by law, to the South Carolina 
Department of Social Services when cases of abuse and neglect are suspected. 
6.  Health oversight activities.  We will release information for federal or state audits, civil, administrative or criminal 
investigations, inspections, licensure or disciplinary actions, as required by law. 
7.  Judicial and administrative proceedings.  Your PHI may be released in response to a subpoena or court order. 
8.  Law enforcement or national security purposes.  Your PHI may be released as part of an investigation by law 
enforcement. 
9.  Uses and disclosures about participants who have died.  We provide coroners, medical examiners and funeral 
directors necessary information related to an individual’s death. 
10.  For purposes of organ donation.  As required by law, we will notify organ procurement organizations to assist them 
in organ, eye or tissue donation and transplants. 
11.  Research.  We may use your PHI if the Institutional Review Board (IRB) for research reviews, approves and 
establishes safeguards to ensure privacy. 
12.  To avoid harm.  In order to avoid a serious threat to the health or safety of a person or the public, we may release 
limited information to law enforcement personnel or persons able to prevent or lessen such harm. 
THIS NOTICE DESCRIBES HOW MEDICAL INFORMATION ABOUT YOU MAY BE USED AND DISCLOSED AND HOW 
YOU CAN GET ACCESSS TO THIS INFORMATION.  PLEASE REVIEW IT CAREFULLY. 


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13.  For workers compensation purposes.  We may release your PHI to comply with workers compensation laws. 
14.  Marketing.  We may send you information on the latest treatment, support groups and other resources affecting your 
health. 
15.  Fundraising activities.  We may use your PHI to communicate with you to raise funds to support health care 
services and educational programs we provide to the community.  You have the right to opt out of receiving fundraising 
communications with each solicitation. 
16.  Appointment reminders and health-related benefits and services.  We may contact you with a reminder that you 
have an appointment. 
B.  You may object to the following uses of PHI: 
1.  Hospital directories.  Unless you object, we may include your name, location, general condition and religious 
affiliation in our participant directory for use by clergy and visitors who ask for you by name. 
2.  Information shared with family, friends or others.  Unless you object, we may release your PHI to a family member, 
friend, or other person involved with your care or the payment for your care. 
3.  Health plan.  You have the right to request that we not disclose certain PHI to your health plan for health services or 
items when you pay for those services or items in full. 
C.  Your prior written authorization is required (to release your PHI) in the following situations: 
You may revoke your authorization by submitting a written notice to the privacy contact identified below.  If we have a 
written authorization to release your PHI, it may occur before we receive your revocation 
1.  Any uses or disclosures beyond treatment, payment or healthcare operations and not specified in parts A & B above. 
2.  Psychotherapy notes. 
3.  Any circumstance where we seek to sell your information. 
 
WHAT RIGHTS YOU HAVE REGARDING YOUR PHI 
Although your health record is the physical property of MUSC, the information belongs to you, and you have the following 
rights with respect to your PHI: 
A.  The Right to Request Limits on How We Use and Release Your PHI.  You have the right to ask that we limit how 
we use and release your PHI.  We will consider your request, but we are not always legally required to accept it.  If we 
accept your request, we will put any limits in writing and abide by them except in emergency situations.  Your request 
must be in writing and state (1) the information you want to limit; (2) whether you want to limit our use, disclosure or both; 
(3) to whom you want the limits to apply, for example, disclosures to your spouse; and (4) an expiration date. 
B. The Right to Choose How We Communicate PHI with You.  You have the right to request that we communicate with 
you about PHI in a certain way or at a certain location (for example, sending information to your work address rather than 
your home address).  You must make your request in writing and specify how and where you wish to be contacted.  We 
will accommodate reasonable requests. 
C.  The Right to See and Get Copies of Your PHI.  You have the right to inspect and receive a copy of your PHI 
(including an electronic copy), which is contained in a designated record set that may be used to make decisions about 
your care.  You must submit your request in writing.  If you request a copy of this information, we may charge a fee for 
copying, mailing or other costs associated with your request.  We may deny your request to inspect and receive a copy in 
certain very limited circumstances.  If you are denied access to PHI, you may request that the denial be reviewed. 
D.  The Right to Get a List of Instances of When and to Whom We Have Disclosed Your PHI.  This list may not 
include uses such as those made for treatment, payment, or health care operations, directly to you, to your family, or in 
our facility directory as described above in this Notice of Privacy Practices.  This list also may not include uses for which a 
signed authorization has been received or disclosures made more than six years prior to the date of your request. 
E.  The Right to Amend Your PHI.  If you believe there is a mistake in your PHI or that a piece of important information is 
missing, you have the right to request that we amend the existing information or add the missing information.  You must 
provide the request and your reason for the request in writing.  We may deny your request in writing if the PHI is correct 
and complete or if it originated in another facility’s record. 
F.  The Right to Receive a Paper or Electronic Copy of This Notice:  You may ask us to give you a copy of this Notice 


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at any time.  For the above requests (and to receive forms) please contact:  Health Information Services (Medical 
Records), Attention:  Release of Information / 169 Ashley Avenue / MSC 369 / Charleston, SC  29425.   The phone 
number is (843) 792-3881. 
G.  The Right to Revoke an Authorization.  If you choose to sign an authorization to release your PHI, you can later 
revoke that authorization in writing.  This revocation will stop any future release of your health information except as 
allowed or required by law.   
H.  The Right to be Notified of a Breach.  If there is a breach of your unsecured PHI, we will notify you of the breach in 
writing. 
 
HEALTH INFORMATION EXCHANGES 
MUSC, along with other health care providers belongs to health information exchanges.   These information exchanges 
are used in the diagnosis and treatment of participants. As a member of these exchanges, MUSC shares certain 
participant health information with other health care providers. Should you require treatment at another location that is a 
part of one of these exchanges, that provider may gather historical health information to assist with your treatment.  You 
have the option of saying that this cannot be done. If you choose not to take part in these alliances, please contact the 
MUSC Privacy Office at 792-4037. 
 
HOW TO COMPLAIN ABOUT OUR PRIVACY PRACTICES 
If you think your privacy rights may have been violated, or you disagree with a decision we made about access to your 
PHI, you may file a complaint with the office listed in the next section of this Notice.  Please be assured that you will not 
be penalized and there will be no retaliation for voicing a concern or filing a complaint.  We are committed to the 
delivery of quality health care in a confidential and private environment. 
 
PERSON TO CONTACT FOR INFORMATION ABOUT THIS NOTICE OR TO COMPLAIN ABOUT OUR PRIVACY 
PRACTICES 
If you have any questions about this Notice or any complaints about our privacy practices please call the Privacy Officer 
(843) 792-4037, the Privacy Hotline (800) 296-0269, or contact in writing:  HIPAA Privacy Officer / 169 Ashley Avenue / 
MSC 332 / Charleston SC 29425.  You also may send a written complaint to the Office of Civil Rights.  The address will 
be provided at your request. 
 
CHANGES TO THIS NOTCE 
We reserve the right to change the terms of this Notice at any time.  We also reserve the right to make the revised or 
changed Notice effective for existing as well as future PHI.  This Notice will always contain the effective date.  You may 
view this notice and any revisions to it at: http://www.musc.edu/privacy. 
 
EFFECTIVE DATE OF THIS NOTICE 
This Notice went into effect on April 14, 2003. 
 
Revised September 2013.