Conditions: Familial Adenomatous Polyposis
Keywords: Familial Adenomatous Polyposis Eflornithine Sulindac
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 171
Healthy volunteers: no

Brief summary:
The purpose of this randomized, double-blind, Phase III trial is to determine if the combination of eflornithine plus sulindac is superior to sulindac or eflornithine as single agents in delaying time to the first occurrence of any FAP-related event. This includes: 1) FAP related disease progression indicating the need for excisional intervention involving the colon, rectum, pouch, duodenum and/or 2) clinically important events which includes progression to more advanced duodenal polyposis, cancer or death.

Detailed description:

Arms:
arm 1: Eflornithine 750 mg and Sulindac 150 mg arm 2: Eflornithine 750 mg and Placebo arm 3: Sulindac 150 mg and Placebo

Interventions: intervention 1: Eflornithine intervention 2: Eflornithine Placebo intervention 3: Sulindac 150 MG intervention 4: Sulindac placebo
Intervention descriptions: intervention 1: Eflornithine \[250 mg tablet, three tablets (750 mg) orally once a day\] intervention 2: Eflornithine placebo \[three tablets orally once a day\] intervention 3: Sulindac \[one tablet orally once a day\] intervention 4: Sulindac placebo \[one tablet orally once a day\]

Protocol document:
Prot_000.pdf: 
IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP - CPP-1X (Eflornithine HCl)/Sulindac 
CPP FAP-310 Ver 5.2, 17January2019 
Cover Page 
 
 
A DOUBLE-BLIND, RANDOMIZED, PHASE III TRIAL OF THE 
SAFETY AND EFFICACY OF CPP-1X / SULINDAC 
COMPARED WITH CPP-1X, SULINDAC AS SINGLE AGENTS 
IN PATIENTS WITH FAMILIAL ADENOMATOUS POLYPOSIS 
(FAP) 
CPP FAP-310 
CPP-1X (Eflornithine HCl) 
 
EudraCT Number: 2012-000427-41xE 
NCT Number: 01483144 
 
Date: 17January2019 
Version: 5.2 
 
 
Sponsored by  
Cancer Prevention Pharmaceuticals, Inc. 
1760 E. River Road, Suite 250 
Tucson, AZ 85718 
 
 
Confidentiality Statement 
The information contained herein is the proprietary property of Cancer Prevention 
Pharmaceuticals, Inc. and any unauthorized disclosure of such information without prior written 
authorization of Cancer Prevention Pharmaceuticals, Inc. is expressly prohibited. 
 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
1 
TABLE OF CONTENTS 
1. 
GENERAL INFORMATION ..............................................................................................6 
 
Protocol Title .....................................................................................................................6 
 
Sponsor and Study Monitor ...............................................................................................6 
 
Other Medical and/or Technical Departments ..................................................................7 
 
Signature Authority for Protocol and Protocol Amendments ...........................................7 
 
Clinical Investigators and Study Leadership .....................................................................7 
 
Study Schema ....................................................................................................................9 
2. 
BACKGROUND INFORMATION ..................................................................................10 
 
Natural History, Current Surgical and Endoscopic Treatment ........................................10 
 
Pharmacologic Clinical Trials in FAP Patients ...............................................................10 
 
Sulindac Alone ..........................................................................................................11 
 
Celecoxib Alone ........................................................................................................11 
 
NSAIDs Plus Eflornithine Combination ...................................................................12 
 
Eflornithine Alone ....................................................................................................12 
 
Sulindac and Eflornithine; Colorectal Polyp Chemoprevention .....................................13 
 
Biology Of Eflornithine ...................................................................................................13 
 
Rationale for Eflornithine Dose .......................................................................................14 
 
Rationale for Sulindac Dose ............................................................................................15 
 
Summary of Known and Potential Risks .........................................................................16 
 
Cardiac Risk ..............................................................................................................16 
 
Ototoxicity Risk ........................................................................................................16 
 
Sulindac Black Box Warning ....................................................................................17 
3. 
TRIAL OBJECTIVES AND PURPOSE ...........................................................................17 
 
Rationale ..........................................................................................................................17 
 
Rationale for Treatment Duration Extension up to 48 Months .......................................19 
 
Purpose ............................................................................................................................21 
4. 
INVESTIGATIONAL PLAN ............................................................................................22 
 
Study Population .............................................................................................................22 
 
Treatment .........................................................................................................................22 
 
Randomization .................................................................................................................23 
 
Primary Outcome .............................................................................................................23 
 
Secondary Outcomes .......................................................................................................23 
 
Population Pharmacokinetics for CPP-1X/Sulindac .......................................................24 
 
Polyamine Analysis .........................................................................................................24 
 
Pharmacogenetic and Genetic Analysis ..........................................................................24 
 
Quality of Life .................................................................................................................25 
5. 
STUDY DRUG INFORMATION .....................................................................................26 
 
CPP-1X [Eflornithine HCl] .............................................................................................26 
 
Eflornithine Clinical Pharmacology .........................................................................26 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
2 
 
CPP-1X (Eflornithine) Pharmacokinetics .................................................................27 
 
Sulindac ...........................................................................................................................27 
 
Sulindac Clinical Pharmacology ...............................................................................28 
 
Sulindac Pharmacokinetics .......................................................................................29 
6. 
SUBJECT RECRUITMENT, INCLUSION AND EXCLUSION CRITERIA .................30 
 
Patient Characteristics for Eligibility, Inclusion Criteria ................................................30 
 
Exclusion Criteria ............................................................................................................32 
 
Replacements and Screen Failures ..................................................................................33 
7. 
RANDOMIZATION AND STRATIFICATION ..............................................................33 
8. 
SPECIFIC TREATMENT PLAN AND SUBJECT MANAGEMENT ............................34 
 
Subject Assessments and Treatment Schedule ................................................................34 
 
Patient Accrual Logistics .................................................................................................38 
 
Initial Visit – Determining Potential Eligibility........................................................38 
 
Subsequent Screening for Eligibility ........................................................................38 
 
Final Eligibility and Potential Screen Failures .........................................................38 
 
Drug Administration .................................................................................................39 
 
Initial 24-Month Treatment Intervention Assessments .............................................39 
 
Initial 24 Month Treatment Intervention Early Termination (+ 2 weeks) ................40 
 
Initial 24 Month Treatment Intervention Follow-Up (30-days post end of treatment 
visit +/- 1 week) Off Study .......................................................................................41 
 
Initial 24 Month Treatment Intervention Follow-Up (Months 2-6, each month +/- 1 
week) Off Study ........................................................................................................41 
 
Treatment Extension Intervention (Months 25 - 48) ................................................42 
 Treatment Extension - End of Treatment/Early Termination (+/- 2 weeks) .............43 
 Treatment Extension Follow-Up (30-days post end of treatment visit +/- 1 week) Off 
Study .........................................................................................................................43 
 Termination of Treatment Extension Procedures .....................................................43 
 Treatment Compliance ..............................................................................................44 
 Definition of FAP-Related Events or Serious and Unexpected Toxicity .................44 
 
Study Blinding Information and Criteria for Protocol Treatment Removal ....................45 
 
Blinding and Unblinding...........................................................................................45 
 
Protocol Treatment Withdrawal (Off-Study Treatment) ..........................................46 
 
Protocol Withdrawal (Off-Study) .............................................................................46 
9. 
DISEASE ASSESSMENT AND SAMPLE COLLECTION ............................................46 
 
Baseline Endoscopy .........................................................................................................46 
 
Follow-up Endoscopies ...................................................................................................47 
 
Imaging Submission ........................................................................................................47 
 
Population Pharmacokinetic Sampling ............................................................................48 
 
Polyamine Sample Collection (Normal Mucosa Biopsy, Random Urine Sample) .........49 
 
Pharmacogenomic and Genetic Testing Sample Collection ...........................................49 
 


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3 
10. 
QUALITY OF LIFE AND DIETARY ASSESSMENTS .................................................50 
 Assessment of Quality of Life and Subject Preferences .................................................50 
 Dietary Assessment .........................................................................................................51 
11. 
ASSESSMENT OF SAFETY ............................................................................................51 
 Cardiac Risk ....................................................................................................................51 
 Ototoxicity Risk ...............................................................................................................51 
 Gastrointestinal Risk .......................................................................................................51 
 Safety Parameters ............................................................................................................52 
 Adverse Events ................................................................................................................52 
 Serious Adverse Events ...................................................................................................53 
 Reporting of AEs, SAEs, Serious and Unexpected Adverse Experiences ......................53 
 Reporting of Pregnancy ...................................................................................................54 
 Concomitant Medications ................................................................................................54 
12. 
STATISTICAL CONSIDERATIONS...............................................................................56 
 Primary Efficacy Objective and Analysis .......................................................................56 
 Secondary Efficacy Outcome and Analysis ....................................................................57 
 Other Secondary Outcomes .............................................................................................58 
 Sample Size Determination .............................................................................................59 
 Power Calculation Assumptions ...............................................................................59 
 Hazard Rates .............................................................................................................59 
 Populations for Analysis ..................................................................................................60 
 Intent-to-Treat (ITT) Population ...............................................................................60 
 Safety Population ......................................................................................................60 
 Per Protocol Population ............................................................................................61 
 Other Populations......................................................................................................61 
 Other Statistical Methods ................................................................................................61 
 Demographic and Baseline Characteristics ..............................................................61 
 Patient Disposition and Treatment Summaries .........................................................61 
 Categorical or Continuous-Valued Secondary Outcome and Safety Data ...............62 
 Subgroup Analyses ...................................................................................................62 
 Health Related Quality of Life (HRQoL) .................................................................62 
 Dietary Assessment ...................................................................................................63 
 General Procedures for Handling of Missing Data .........................................................63 
 Interim Monitoring and the Data Monitoring Committee ...............................................64 
 Pharmacokinetic Analysis for Eflornithine and Sulindac ...............................................65 
13. 
STUDY MANAGEMENT AND REPORTING PROCEDURES ....................................66 
 Data Monitoring ..............................................................................................................66 
 Patient Tablet Dispensing Record ...................................................................................66 
 Investigator Documentation ............................................................................................66 
 Protocol Amendments .....................................................................................................67 


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4 
 Access to Source Data and Documents ...........................................................................67 
 Investigational Agent Records and Accountability .........................................................67 
 Data Handling and Record Retention ..............................................................................68 
 Protocol Deviations .........................................................................................................68 
 Study Termination ...........................................................................................................68 
 Use of Data and Publication ............................................................................................68 
14. 
HUMAN SUBJECTS ........................................................................................................69 
 Ethical Conduct ...............................................................................................................69 
 Informed Consent ............................................................................................................69 
 Confidentiality .................................................................................................................69 
15. 
LISTING OF ABBREVIATIONS .....................................................................................70 
16. 
REFERENCES ..................................................................................................................72 
 
APPENDIX A 
SPIGELMAN’S SCORE AND STAGE ..........................................................78 
APPENDIX B 
INSIGHT RECTUM/POUCH ASSESSMENT AND STAGE95 .....................79 
APPENDIX C 
NEW YORK HEART ASSOCIATION CLASSIFICATION TABLE ...........80 
APPENDIX D 
DESMOID STAGING SYSTEM9 ...................................................................81 
APPENDIX E 
EVENT RATE SUMMARY TABLE ..............................................................82 
 
 
 
LIST OF TABLES 
Table 1 - Composition of CPP-1X (Eflornithine HCl), 250 mg Tablets ........................................ 26 
Table 2 - Composition of Sulindac 150 mg Tablets ....................................................................... 28 
Table 3 - FAP Study Schedule (Initial 24 Months of Treatment) ................................................... 34 
Table 4 - FAP Study Schedule (Treatment Extension to a Maximum of 48 Months) .................... 36 
Table 5 - Study Medication Schedule1 ............................................................................................ 39 
Table 6 – Pharmacokinetic Sample Number, Sampling Times and EKG collection ..................... 48 
 


IND 103,678 
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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
5 
INVESTIGATOR PROTOCOL AGREEMENT  
CPP FAP-310 
A DOUBLE-BLIND, RANDOMIZED, PHASE III TRIAL OF THE SAFETY AND EFFICACY OF CPP-
1X/SULINDAC COMPARED WITH CPP-1X, SULINDAC AS SINGLE AGENTS IN PATIENTS WITH 
FAMILIAL ADENOMATOUS POLYPOSIS (FAP)  
By signing below, I agree: 
1. 
That my staff and I have read, understand and will adhere to the protocol as written and agree 
that any changes to the protocol will be agreed to and approved by Cancer Prevention 
Pharmaceuticals, except to eliminate an immediate hazard to the patients.  Prior to instituting 
changes, I will obtain approval from the Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB)/Research Ethics Board (REB); 
2. 
To abide by all obligations stated on the FDA Form 1572 and other documents required by 
regulation; 
3. 
To conduct this study in accordance with the current International Conference on 
Harmonization (ICH) guidance, the Good Clinical Practices (GCP) guidance the US FDA 
regulations, EMA regulations, Health Canada regulations, local competent authority 
regulations, and local IRB/IEC/REB and legal requirements; 
4. 
To obtain IRB/IEC/REB approval of the protocol, any amendments to the protocol, and 
periodic re-approval as required, and to keep the IRB/IEC/REB informed of adverse events 
and periodically report the status of the study to them; 
5. 
To ensure that each patient enrolled into the trial, or legally authorized representative has 
read and understands the current patient information, and has signed the Informed Consent 
form; 
6. 
To ensure that I and all persons assisting me with the study are adequately informed and 
trained about the investigational drug and of their study related duties and functions as 
described in the protocol; 
7. 
To make prompt reports of Serious Adverse Events (SAEs) and deaths as defined in the 
protocol, the FDA regulations, EMA regulations, local competent authority regulations, and 
Health Canada regulations; 
8. 
To prepare and maintain adequate and accurate case histories to document all observations 
and other data pertinent to the study on each individual enrolled in the clinical trial. 
Investigator Signature:  ________________________________________  ________________ 
 
 
Date 
Investigator Name (Print):  _____________________________________ 
Institution:  __________________________________________________ 
 
__________________________________________________ 
 
__________________________________________________ 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
6 
1. 
GENERAL INFORMATION 
 
Protocol Title 
A Double-Blind, Randomized, Phase III Trial of the Safety and Efficacy of CPP-1X/Sulindac 
Compared with CPP-1X, Sulindac as Single Agents in Patients with Familial Adenomatous 
Polyposis (FAP)  
 
Sponsor and Study Monitor 
Cancer Prevention Pharmaceuticals, Inc. 
1760 E. River Road, Suite 250 
Tucson, AZ 85718 
Phone: +1 (520) 908-7774 
Fax: +1 (520) 232-2191 
 
Study Coordinator and Medical Monitor 
Alfred M. Cohen, M.D., F.A.C.S., F.A.S.C.R.S. 
Chief Medical Officer 
Cancer Prevention Pharmaceuticals, Inc. 
Email: acohen@canprevent.com 
Phone (Main): +1 (520) 908-7774 
Phone (Cell): +1 (520) 400-0116 
 
Legal Representative EU 
Cancer Prevent Pharma Ltd  
 
Andrew B. Hadlington, Wessex Pharma Services Ltd 
Tower 42, Level 30 
 
 
 
19 Webster Road, Winchester, 
International Finance Center 25 
 
Hants SO22 5NT 
London ECN2 1HQ United Kingdom 
Phone/Fax: 
+44 1962 843331 
Mobile: 
+44 7796 394475 
 
 
 
SAE Reporting, Reporting Contact Numbers 
SAE reporting to occur through the electronic data capture system or via paper CRF submission. 
Chiltern Drug Safety contact information: 
Phone: 1 (919) 462-8867 (US/Canada); 001 (919) 462-8867 (EU) 
Fax: 1 (919) 468-2288 (US/Canada); 001 (919) 468-2288 (EU) 
Email: dsafety@chiltern.com 
 
CPP Phone Contact Information: 
Monday – Friday (8:00 am – 5:00 pm MST), Phone: +1 (520) 908-7774; Fax: +1 (520) 232-2191 
 
Alternative CPP Contact Numbers: 
Alfred Cohen, M.D., cell: +1 (520) 400-0116 or Kathryn Grenier, cell: +1 (520) 444-5869 
 


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Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
7 
 
Other Medical and/or Technical Departments 
Biostatistician 
Bruce Levin, Ph.D. 
Professor, Department of Biostatistics,  
Mailman School of Public Health, Columbia University 
722 West 168th Street, Room 626a  
New York, NY 10032 
Bioanalysis Laboratories 
Metabolon Inc., 617 Davis Drive, Ste. 400, Durham NC, 27713, USA, will perform the testing for 
the polyamine samples collected. 
Molecular MD Inc., 1341 SW Custer Drive, Portland OR, 97219, USA, will perform the testing for 
the pharmacogenomic samples collected 
inVentiv Health Clinique, Inc., 2500 rue Einstein Street, Québec City, Québec G1P 0A2, Canada, 
will perform the bioanalysis for the pharmacokinetic samples collected. 
 
Signature Authority for Protocol and Protocol Amendments 
Alfred M. Cohen, M.D., F.A.C.S., F.A.S.C.R.S. 
Chief Medical Officer 
 
Clinical Investigators and Study Leadership 
Study Co-Principal Investigators 
Carol Burke, M.D. and James Church M.D., F.A.C.S., F.A.S.C.R.S 
Jewell Samadder, M.D. 
Ernest T. Hawk, M.D, M.P.H. 
Prof. Dr. Med Gabriella Möslein 
Clinical Investigators and Sites 
Patrick M. Lynch, J.D., M.D. 
Professor, Dept. of Gastroenterology, Hepatology, 
Nutrition, Division of Internal Medicine 
University of Texas, M.D. Anderson Cancer 
Center 
1515 Holcombe Boulevard,  
Houston, TX 77030 USA 
Carol Burke, M.D. 
Department of Gastroenterology and Hepatology 
James Church, M.D., FACS, FASCRS 
Department of Colorectal Surgery 
Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH 44195 USA 
Dr. Alex Henderson, Prof. Sir John Burn  
Institute of Genetic Medicine 
International Centre for Life 
Central Parkway 
Newcastle Upon Tyne and Wear 
NEI 3BZ United Kingdom 
Paul E. Wise, M.D. 
Washington University in St. Louis 
School of Medicine 
Section of Colon and Rectal Surgery 
CB 8109, 660 S. Euclid Ave 
St Louis, MO 63110 USA
Ramona Lim, M.D., Sapna Syngal, M.D., MPH 
Dana Farber Cancer Institute 
450 Brookline Avenue  
Boston, MA 02215 USA 
Priyanka Kanth, M.D. 
Huntsman Cancer Institute  
2000 Circle of Hope,  
Salt Lake City, UT 84112 USA 
Frank A. Sinicrope, M.D. 
Dept. of Gastroenterology and Hepatology 
Mayo Clinic 
200 First Street, S.W.  
Rochester, MN 55905 USA 
Elena Stoffel, M.D., MPH 
University of Michigan 
Comprehensive Cancer Center 
1500 East Medical Center Drive 
Ann Arbor, MI 48109 USA 


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Steve Gallinger, M.D., MSc, FRCS 
Professor of Surgery, Head, Division of 
Hepatobiliary/Pancreatic Surgical Oncology Prgm 
Robert Gryfe, M.D., PhD, Zane Cohen, M.D. 
Zane Cohen, Centre for Digestive Diseases 
Univ. Health Network and Mount Sinai Hospital 
200 Elizabeth St, 10EN, Room 206, Toronto 
Ontario, M5G2C4 Canada  
Prof. Evelien Dekker, M.D., PhD 
Academic Medical Centre 
Dept. of Gastroenterology and Hepatology,  
C2-115 
PO Box 22700 
Amsterdam, 1100 DE, The Netherlands 
Prof. Dr. Med Christian Strassburg 
Dr. Robert Hüenburg 
Department of Hepato-Gastroenterology 
University of Bonn Hospital, Bldg. 334, 2nd floor 
Sigmund Freud Str 25 
Bonn, 53127 Germany  
Antoni Castells, M.D. 
Institute De Malalties Digestives 
Hospital Clinic, Villarroel 170 
Barcelona, Catalonia, 08036 Spain  
Anil Rustgi, M.D. 
University of Pennsylvania 
Perelman School of Medicine 
3400 Civic Center Blvd, 4 S Pavilion 
Philadelphia, PA 19104 USA 
Samir Gupta, M.D. 
University of California San Diego 
Clinical and Translational Research Institute 
9500 Gilman Dr. MC 0990 
La Jolla, CA 92037 USA 
Fiona Lalloo, M.D. 
Manchester Centre For Genomic Medicine 
Central Manchester University  
Saint Mary’s Hospital- Oxford Road 
Manchester, M13 9WL United Kingdom 
Giovanna da Silva, M.D. 
Cleveland Clinic Florida 
2950 Cleveland Clinic Blvd. 
Weston, FL 33331 USA 
Professor Eric Van Cutsem, M.D., Ph.D. 
Leuven Cancer Institute 
University Hospitals Leuven 
3000 Leuven, Belgium 
Dr. Jennifer Weiss, M.D. 
University of Wisconsin-Madison 
Division of Gastroenterology and Hepatology 
UWM Centennial Building 
1686 Highland Avenue 
Madison, WI 53792 USA
William Grady, M.D. 
Fred Hutchinson Cancer Research Center 
/University of Washington 
1100 Fairview Avenue N., D4-100 
Seattle, WA 98109 USA 
Field Willingham, M.D. 
Emory University 
Division of Digestive Diseases 
1365 E. Clifton Rd. NE 
Building B, Suite 1200 
Atlanta, GA 30322 USA 
Molly Cone, M.D. 
Vanderbilt-Ingram Cancer Center 
1211 21st Avenue South 
Medical Arts Building, Room 711 
Nashville, TN 37212 USA 
 
 
 
 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
9 
 
Study Schema 
MAJOR ELIGIBILITY CRITERIA 
1. Diagnosis of Familial Adenomatous Polyposis (FAP) with confirmed APC mutation AND age ≥ 18 
years. 
2. If prior colorectal surgery, at least 3 years since colectomy/proctocolectomy with ileo-rectal 
anastomosis (IRA) or pouch. 
Disease at One or More of These Sites 
1. Intact colon (pre-colectomy) 2. Rectal/Pouch Polyposis 
3. Duodenal Polyposis 
Stratification 
Stratification based on FAP-related time to first event prognosis. 
1. best (i.e., longest projected time to first FAP-related event) – rectal/pouch polyposis 
2. intermediate – duodenal polyposis 
3. worst – pre-colectomy 
If a subject has two or more of these disease sites, the stratum for randomization will be 
according to the most severe prognosis stratum as defined above. 
Randomization 
A total of 150 subjects, drugs are taken once daily. 
 
 
 
 
Randomized subjects will receive 24 months of treatment and complete their final assessment or come off-
study for an FAP-related event or for other reasons (for example, safety issues, non-compliance, withdrew 
consent, lost to follow-up).  
Subjects completing 24 months of treatment without an FAP-related event may continue on treatment for 
up to 48 months based on their randomization date as follows: 
1. If randomized between November 2015 and April 2016 eligible for up to 36 months of treatment 
2. If randomized between May 2015 and October 2015 eligible for up to 42 months of treatment 
3. If randomized between July 2014 and April 2015 eligible for up to 48 months of treatment 
or until one of the following occurs: 
1. Subject has an FAP-related event or comes off study for other reasons 
2. Trial end-date of April 30, 2019 has been reached 
3. 90 FAP-related events have occurred 
4. Less than 90 FAP-related events have accrued prior to April 30, 2019 and an earlier trial end-date 
has been set by the Sponsor and reviewed by the DMC 
5. An earlier trial end date prior to April 30, 2019 has been recommended by the DMC for safety 
reason and approved by the Sponsor 
 
CPP-1X (750 mg) 
CPP-1X (750 mg) 
Placebo (CPP-1X) 
 
+ 
 
 
+ 
 
 
+ 
 
Sulindac (150 mg) 
Placebo (Sulindac) 
Sulindac (150 mg) 


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2. 
BACKGROUND INFORMATION 
 
Natural History, Current Surgical and Endoscopic Treatment 
Familial Adenomatous Polyposis (FAP) is a syndrome caused by mutations in the Adenomatous 
Polyposis Coli (APC) tumor suppressor gene and propagated by an autosomal dominant mode of 
inheritance. Details of this syndrome can be found at OMIM ®, (Online Mendelian Inheritance in 
Man), http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175100, which is an authoritative 
listing of human genes and genetic phenotypes. This database is available to users’ courtesy of 
NCBI, the National Center for Biotechnology Information.  
FAP is caused by mutations/deletions in the APC gene, which is located on chromosome 5q21-
q22.  Gardner syndrome is a variant of FAP in which desmoid tumors, osteomas, and other 
neoplasms occur together with multiple adenomas of the colon and rectum 
(http://www.cancer.gov/cancertopics/pdq/genetics/colorectal/HealthProfessional/page4/AllPages). 
Most FAP patients will have hundreds to thousands of colorectal adenomas, and without 
prophylactic surgery develop colorectal cancer before the age of 40.  Prophylactic surgery may 
involve total abdominal colectomy with ileal-rectal anastomoses (IRA), accompanied by frequent 
rectal surveillance with polypectomy and cautery/laser ablation as needed.  Patients with 
extensive rectal involvement undergo total proctocolectomy with ileal pouch-anal reconstruction.  
Despite removing the main at-risk organ, many patients develop duodenal neoplasia (bulky 
adenomas/cancer) and require additional localized or Whipple radical surgery.  The Spigelman 
classification (Stage 3 or 4)1 can accurately predict those with adenomas that are most likely to 
progress to cancer.  Bulow and colleagues2 reviewed duodenal polyposis issues in FAP patients.  
Gastric antral adenomas may occur and rarely are symptomatic or progress to cancer.  
Despite total proctocolectomy with ileal pouch reconstruction, approximately 50% of patients will 
develop adenomatous lesions in the neo-rectum.3-6  There are case reports of cancer developing in 
the pouches. All patients who have a residual rectum after total colectomy require frequent 
surveillance, polypectomies and ablations for continuing rectal polyposis. 
Desmoids are “benign tumors” (myofibroblastic) and cause significant morbidity and mortality in 
some patients.  They are not associated with any specific FAP genotype but are more common if 
the APC mutation is distal to codon 1444; the major clinical risk factors are family history and 
prior colectomy.  Women are at greater risk. Growth of these lesions, particularly when they 
involve the root of the mesentery, can lead to extensive surgery, often resulting in resection of 
ileal pouches and permanent ileostomy.  Current treatment involves surgery, radiation, NSAIDS 
and anti-estrogens.  None of these approaches have major impact on the growth of these lesions.7-
9 Although an important site of disease and morbidity for FAP patients, this protocol will focus on 
intestinal polyposis only. 
Vasen and colleagues10 provide evidence-based guidelines for the evaluation and management of 
FAP patients and provides detailed natural history data. 
After prophylactic colectomy, all FAP patients undergo regular surveillance intervention, with 
proctoscopy and upper GI endoscopy every 6-12 months.  Surgical intervention may be required 
for progressive FAP related disease (defined in protocol).  We believe that disease control with 
our combination regimen will delay the occurrence of clinically meaningful events. 
 
Pharmacologic Clinical Trials in FAP Patients 
In the general population, certain types of colorectal polyps have increased risk of progression to 
colorectal cancer.  High risk polyps (polyps with villous histology, size ≥1 cm, high grade 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
11 
dysplasia, or multiple adenomas defined as 3 or more) have become the focus of colorectal 
tumorigenesis research due to the higher rate of malignant potential for these.11-15  The biology of 
common colorectal cancer is similar to the FAP phenotype.  Wallace and Lynch16 summarized the 
current status of chemoprevention in FAP patients.  The key drugs/drug combinations are 
described below. 
 
Sulindac Alone 
Labayle and colleagues17 studied 10 FAP patients with IRA in a randomized placebo controlled 
double blind trial of sulindac 300 mg a day for 4 month intervals.  In rectal assessment of polyp 
counts, there was a statistically significant reduction with sulindac compared to placebo (despite 
the small number of evaluable patients assessed). 
Nugent18 evaluated sulindac at 200 mg twice a day in 24 patients with duodenal neoplasia and in 
this group 12 had an IRA and the rectum was also evaluated.  This was a placebo controlled 
randomized trial.  Benefit was demonstrated in the rectum, but treatment was not statistically 
beneficial in the duodenum. 
Giardello and his group19 performed a randomized double blind trial in non-operated FAP patients 
or those who had an IRA.  Sulindac at 150 mg twice a day was the treatment regimen.  Rectal 
polyp numbers decreased 56% in the treated group. 
Tonelli et al.,20 studied 15 FAP patients after IRA.  This non-randomized trial used sulindac     
100 mg twice a day.  A benefit was seen after 6 months, but not long-term. 
Cruz-Correa21 studied 12 patients post IRA for rectal polyp control with 150 mg of sulindac twice 
a day.  A major reduction in polyp numbers was demonstrated, but with a 50% incidence of 
gastrointestinal erosions. 
Giardiello and colleagues22 utilized sulindac in 41 non-operated FAP patients, mean age of 13.  
By the end of the study all but 3 of the 21 subjects randomized to the sulindac arm were receiving 
150 mg of sulindac daily twice a day.  Treatment with sulindac for a four-year period was well 
tolerated.  Few adverse events were reported and 93% were grade 1 or grade 2 and included 
leukopenia, photosensitivity, rash, urticaria, diarrhea, vomiting, bleeding, hyperbilirubinemia, 
blurred vision, abdominal pain, and influenza like syndrome.  One subject was withdrawn 
because of possible drug-induced neutropenia.  The incidence of any adverse event did not differ 
significantly between the sulindac group and the placebo group.  There was no demonstrable 
difference in the adenoma formation compared to placebo. 
 
Celecoxib Alone 
Although FDA approved celecoxib for the treatment of FAP patients in 1999, Pfizer withdrew the 
agent’s registration.  Of note, this agent did not become a usual part of standard care for these 
patients.  This is partly due to concerns for patient safety resulting from colorectal adenoma 
prevention studies reported in 2006.23,24  These studies identified a small but finite risk of serious 
cardiovascular events associated with celecoxib treatment. 
Albeit the one most prominent study was performed at MD Anderson, Houston, TX and St. 
Mark’s Hospital, London.25,26  Patients were randomized to placebo control, celecoxib 100 mg 
twice daily, and celecoxib 400 mg twice daily.  In the Steinbach report,25 6 months of celecoxib, 
400 mg twice daily showed a 28% change from baseline in the mean number of rectal polyps, the 
lower dose of the drug (100 mg twice daily) showed an 11.9% change in the mean number of 
polyps compared to baseline.  Similar data were found in the duodenal cohort.  Polyp reduction 
with small baseline tumor burden was only 14.5%, but 31% in more involved baseline duodenal 
adenomatosis.  Again, effect was noted only in the high dose celecoxib patients.  Sixty-eight 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
12 
percent (68%) of patients in the placebo group, 56% of patients in the 100 mg twice daily group, 
and 57% of patients in the 400 mg twice daily group reported one or more adverse events of grade 
2 or higher (NCI CTC, Ver. 3.0).  The most common events were diarrhea and abdominal pain. 
 
NSAIDs Plus Eflornithine Combination 
This research program was activated in 2002, as a randomized Phase II study (ClinicalTrials.gov 
NCT00033371) comparing the effectiveness of celecoxib +/- eflornithine in FAP.  Accrual was 
discontinued after approximately 111 patients were entered.27,28_ENREF_26 
The stated purpose of this study was to “compare the effectiveness of celecoxib with or without 
eflornithine in preventing colorectal cancer in patients who have familial adenomatous 
polyposis”. The outcome measures involved changes in polyp numbers, polyp burden, and 
plaque-like duodenal polyps after 6 months of treatment.  This was a two-arm trial: 
1. Oral celecoxib (400 mg) twice daily with oral eflornithine (500 mg/m2), once daily, vs. 
2. Oral celecoxib twice daily and oral placebo once daily 
The major conclusions from that study were: 
• Addition of eflornithine, at an average daily dose of 750 mg (three 250 mg tablets) to 
celecoxib did not significantly reduce raw adenoma count according to primary endpoint 
measure (polyps in reference cluster in still color photos) compared to celecoxib alone. 
• At least borderline significance of the combination was achieved by secondary measures 
(counts in photos, weighted by diameter, and by video of larger segments of colorectum). 
• No deleterious ototoxicity due to eflornithine was detected. 
• No significant treatment-related adverse events were noted in either arm of the trial. 
• Finding of greater effect on diameter-weighted burden suggests these agents may have 
greater effect at level of adenoma promotion than initiation. 
• Based on findings from another trial, use of a web-based quantitative tool for capturing 
diameter-weighted adenoma counts from videos of total colon or rectum may be more 
informative than approaches to adenoma quantification to date. 
 
Eflornithine Alone 
There are extensive preclinical studies in mouse models of FAP.  These mouse models express a 
mutant form of the mouse homolog of the human adenomatous polyposis (APC) gene.  When 
these mouse models of FAP are treated with eflornithine alone, the agent causes a dose-dependent 
decrease in the number of both intestinal and colonic polyps.29-31 
There have been no clinical trials in FAP patients using eflornithine alone although other clinical 
trials of eflornithine have shown suppressed tumor growth in multiple tumor types.  As indicated 
above, the Lynch trial provides the first evidence of effect of eflornithine, at an average daily dose 
of 750 mg in patients with FAP.28  There was no eflornithine alone arm in that trial, so the data 
only addresses eflornithine in combination with celecoxib.  However, in that trial there was 
evidence for both safety of eflornithine at 750 mg/day in this patient population (no difference 
between NSAID alone and the combination arm) and efficacy (statistically significant effect of 
combination versus NSAID alone arm) for both total polyp volume and global polyp burden 
measures. 
The major evidence for benefit of eflornithine derives from prospective, randomized, placebo-
controlled clinical trials of eflornithine alone in patients with elevated risk for developing certain 
forms of cancer.  In one trial of 81 men with a family history of prostate cancer, oral eflornithine 
alone (500 mg per day for one year) reduced prostate polyamine contents, prostate volumes and 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
13 
prostate specific antigen (PSA) doubling times in men, compared to these same parameters in 
men taking placebo tablets.32  In a second study, 291 people with prior non-melanoma skin 
cancers were treated with eflornithine alone (500 mg/m2 per day for 4-5 years).  In that study, the 
treatment with eflornithine was associated with a highly statistically significant reduction in 
metachronous basal cell skin cancers.33  Toxicities were rare in both of these studies, and 
consisted of infrequent clinically non-significant ototoxicity (meaning that the ototoxicity was not 
apparent to the patient and was only detectable by quantitative audiology testing).  A recent report 
of this eflornithine-related toxicity was reported in detail for a clinical trial evaluating the 
combination of eflornithine and sulindac.34  Clinical studies of eflornithine monotherapy have 
also been conducted with trial endpoints consisting of tissue polyamine contents.  These markers 
are dependent on ornithine decarboxylase (ODC), the eflornithine target protein.  Doses, such as 
those proposed by the Sponsor, have been shown to reduce rectal mucosal tissue polyamine 
contents in a randomized placebo-controlled clinical trial.35  This marker study is especially 
relevant to patients with familial adenomatous polyposis (FAP), where the target tissues include 
intestinal and colonic mucosa. 
These clinical trial results are corroborated by clinical translational studies that are based on 
molecular epidemiology investigations.  Examples of this type of evidence include studies 
replicated by three independent groups in humans showing that a polymorphism affecting the 
expression of ODC, the eflornithine target protein, is highly associated with metachronous colon 
adenomas36,37 and sporadic breast cancer38  In addition, two independent groups have reported 
that this same polymorphism is associated with prostate cancer39 and colon cancer survival.40 
 
Sulindac and Eflornithine; Colorectal Polyp Chemoprevention 
Meyskens and colleagues41 performed a Phase III double-blind trial involving resected sporadic 
adenoma patients treated for three (3) years with eflornithine (500 mg once a day) plus sulindac 
(150 mg once a day) compared to placebo/placebo that demonstrated a marked reduction (70%) 
of metachronous adenomas overall, 92% efficacy against advanced adenomas, and 95% efficacy 
in decreasing the risk of developing multiple adenomas compared to placebo.  Additionally, this 
combination regimen was generally well-tolerated. 
 
Biology Of Eflornithine 
Ornithine decarboxylase (ODC) is a transcriptional target of the MYC oncoprotein and MYC 
transcription is suppressed by the APC gene product.42,43  ODC enzyme activity and polyamine 
contents are elevated in the apparently normal colonic mucosa of genotypic FAP patients, 
compared to FAP normal family members.44  These mechanistic and translational studies in 
humans indicate that ODC enzyme activity is up-regulated in the intestinal and colonic mucosa of 
patients with FAP. 
Eflornithine, also known as DFMO, is an enzyme-activated, irreversible inhibitor of ODC, an 
essential enzyme in the polyamine synthesis pathway.45  Studies in animal models of FAP 
indicate that eflornithine alone is effective in reducing the number of intestinal29 and colonic30 
tumors.  Eflornithine works in combination with the non-steroidal anti-inflammatory drug 
(NSAID) sulindac to further reduce tissue polyamine contents, as sulindac activates polyamine 
export mechanisms.46  Combination treatment with eflornithine and sulindac dramatically reduce 
the incidence of metachronous colorectal adenomas in patients with prior sporadic adenomas.41  
The majority of sporadic colorectal adenomas have mutations in APC or another gene in the 
WNT signaling pathway.  In addition, combinations of eflornithine and NSAIDS have been 
shown to reduce the number of advanced adenomas by more than 90% in mouse models of 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
14 
FAP.31  These results provide strong rationale that patients with FAP should respond to this 
therapy. 
 
Rationale for Eflornithine Dose 
Prior pharmacokinetic (PK) studies had documented linearity of serum eflornithine levels with 
oral doses as low as 100 mg/m2/day.47  Dose-de-escalation studies identified oral daily doses of 
eflornithine, which irreversibly inhibits an essential enzyme in polyamine synthesis pathway, in 
the range of 200-400 mg/m2/day as a dose range that effectively reduced colorectal tissue 
polyamine contents.35  Oral doses in this range achieve serum concentrations that inhibit ornithine 
decarboxylase enzyme activity and polyamine synthesis in cell culture models.48  Based on these 
findings, a Phase III clinical trial of eflornithine combined with the non-steroidal anti-
inflammatory drug (NSAID) sulindac was conducted to evaluate the effect of this combination on 
the incidence of metachronous colorectal adenomas in patients with prior sporadic (non-genetic) 
colorectal polys.41  Based on an average adult body surface area of 1.6 m2,49 a dose of 500 mg 
oral daily dose of eflornithine was selected.  That study found that the combination therapy 
reduced total metachronous colorectal adenomas by 70%, and advanced/multiple metachronous 
colorectal adenomas by more than 90% while also reducing colorectal polyamine levels.41,50  No 
clinically significant toxicities were found to be statistically significant in that study.  Clinically 
non-significant ototoxicities were identified in less than 10% of patients, using quantitative 
audiology methods.34 
Recently, a clinical trial of eflornithine in combination with another NSAID for prevention of 
polyps in FAP patients has been reported.  Lynch et al.27,28 _ENREF_26have reported results of a 
trial using 500 mg/m2/day eflornithine, rounded to the nearest 250 mg as 250 mg tablets were 
used in this study, combined with 400 mg BID celecoxib.  After correcting for body surface area, 
the average eflornithine dosage was three (3) 250 mg eflornithine tablets PO daily. While the 
effect of the combination was not different from celecoxib alone for the primary endpoint 
(duodenal and colorectal polyp number), the Lynch et al. study provided evidence for 
effectiveness of the combination versus celecoxib alone (statistically significant reductions in the 
secondary endpoints of polyp volume and global polyp burden).  No differences in toxicities, 
including ototoxicities, were observed between treatment arms in this study.  Another study in 
non-FAP patients but relevant to potential safety issues of the higher eflornithine dose has also 
been reported. Bailey and colleagues treated 291 patients with prior non-melanoma skin cancers 
with 500 mg/m2/day eflornithine for 4-5 years.33  One patient was reported to have subclinical 
ototoxicity in that study. Long-term follow-up of these patients found no increase in adverse 
events in the treatment group compared to placebo.33 
CPP FAP-310 will evaluate the eflornithine-sulindac combination in patients with FAP.  These 
patients are at elevated risk for intestinal and colorectal polyposis and other events related to the 
fact that they harbor germline mutations in the adenomatous polyposis coli (APC) tumor 
suppressor gene.  These genotypic FAP patients express higher levels of the eflornithine target 
gene, ornithine decarboxylase (ODC) and polyamine contents in apparently normal rectal mucosa 
than do non-genotypic familial controls.44  These levels are higher than those reported for patients 
with sporadic risk of colorectal cancer.51 
This study will use three (3) 250 mg eflornithine tablets daily in CPP FAP-310.  This is based on 
both safety and efficacy considerations.  Both the Lynch study (in FAP patients) and the Bailey 
study and others (in non-FAP patients) indicate safety of this eflornithine dose.28,33_ENREF_33  
The Lynch study provides evidence for efficacy of the higher eflornithine dose in FAP patients.28 
 


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Rationale for Sulindac Dose 
The dose of sulindac (daily oral dose of 150 mg) for this study was selected on knowledge of its 
physiology and evidence from preclinical and clinical studies. 
Experimental findings in human cell and mouse models indicate that sulindac and other NSAIDS 
activate polyamine catabolism and export.43  Thus, NSAID complement inhibitors of polyamine 
synthesis, like eflornithine, to reduce tissue polyamines.  Cell culture data demonstrated that 
sulindac metabolites reduce cell survival in vitro in a dose dependent manner at doses above 
150µM for 24 hour exposure times.52 
Eflornithine-sulindac combinations are potent inhibitors of intestinal carcinogenesis in mouse 
models,31 Figure 1. 
 
Figure 1 - Eflornithine-Sulindac Combinations Mouse Model 
 
Ignatenko, Nutrition & Cancer 2008 
 
A detailed review of the clinical pharmacokinetic of sulindac has been written53 and discusses 
long-term twice daily administration which results in accumulation of sulindac in the plasma, 
with the most common side effects being gastrointestinal and include pain, dyspepsia, nausea and 
gastrointestinal cramps. 
Clinical studies demonstrate that a range of orally administered sulindac can cause regression of 
colorectal adenomas.  In the review by Keller and Giardiello,54 sulindac doses from 100 – 300 mg 
administered once or twice daily have been shown to cause regression of colorectal adenomas in 
patients with Familial Adenomatous Polyposis (FAP).  Sulindac side effects noted in most of 
these studies were minimal although at the 300 mg/day of sulindac there may be an increase in 
cardiovascular risk in older high risk patients. 
The studies summarized in the Keller and Giardiello review provides the clinical data to support 
the use of low doses of sulindac are effective in reducing colorectal adenoma burden in FAP 
patients20,21,55,56,57,58 and that standard doses of sulindac (300-400 mg) are associated with 
significant toxicities.  Therefore, a low dose of sulindac (150 mg) once per day was selected to be 
combined with eflornithine for treatment of patients with Familial Adenomatous Polyposis that 
are at high risk of developing rectal/intestinal cancer. 
Sulindac used off label is often the choice of clinicians treating FAP patients today.59  A 
commonly used sulindac dose in progressive rectal polyposis is 150 mg twice a day; after a few 


IND 103,678 
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CPP FAP-310 Ver. 5.2, 17January2019 
 
16 
months and demonstration of regression, dosage may be reduced to 150 – 200 mg daily (Burt, 
personal communication) or to 100 mg or lower.55  There is no direct comparison between 
sulindac dosages.  It is possible that the lower dose may be just as effective but requires a longer 
time to regression. 
 
Summary of Known and Potential Risks 
 
Cardiac Risk 
A recent pooled-analysis of cardiovascular events in six clinical trials involving non-arthritis 
patients using celecoxib or placebo demonstrates that celecoxib is indeed associated with a dose-
dependent increased risk of cardiovascular events60 – high dose, long duration.  In this analysis, 
three baseline cardiovascular risk categories were proposed: low, moderate, and high, using 
clinical information obtained from routine medical assessment.  It was not known if these baseline 
cardiovascular risk assessments were associated with adverse cardiovascular events observed in 
the Phase III adenoma prevention trial of eflornithine plus sulindac (16 cardiovascular events 
occurred in this arm) compared with placebo (9 cardiovascular events occurred in the placebo 
arm).  Therefore, members of the UC-Irvine group61 performed detailed toxicity analysis of data 
from the Phase III eflornithine and sulindac versus placebo colorectal adenoma prevention trial, 
with a particular focus on baseline cardiovascular risk assessment.  Cardiovascular toxicity 
outcomes were then reported with and without exclusion of high-risk patients from the analysis. 
In the original sample of 184 placebo and 191 eflornithine/sulindac patients, respectively, 
baseline cardiovascular risk scores were evenly distributed (low: 27% vs. 30%, moderate: 34% 
vs. 29%, high: 39% vs. 41%).  A greater number of patients with high cardiovascular risk at 
baseline experienced events in the eflornithine/sulindac arm (n=9) compared to placebo (n=3). 
When all patients with high baseline cardiovascular risk were excluded from the analysis, the 
number of cardiovascular events between the treatment (n=7) and placebo (n=6) arm was 
similar.61  These results suggest a possible interaction between eflornithine/sulindac treatment and 
baseline cardiovascular risk score on cardiovascular events. 
 
Ototoxicity Risk 
In the Meyskens eflornithine/sulindac Phase III randomized placebo-controlled colon adenoma 
prevention trial41, no significant differences in hearing loss were noted compared to placebo; 
however, minor differences in hearing loss attributed to eflornithine plus sulindac combination 
were observed in detailed longitudinal analyses.34 
Temporary hearing loss is a known toxicity of treatment with eflornithine, thus a comprehensive 
approach was developed to analyze serial air conduction audiograms.  The generalized estimating 
equation method estimated the mean difference between treatment arms with regard to change in 
air conduction pure tone thresholds while accounting for within-subject correlation due to 
repeated measurements at frequencies.  Based on 290 subjects, there was an average difference of 
0.50 dB between subjects treated with eflornithine plus sulindac compared with those treated with 
placebo (95% confidence interval, −0.64 to 1.63 dB; P = 0.39), adjusted for baseline values, age, 
and frequencies.  In the normal speech range of 500 to 3,000 Hz, an estimated difference of 0.99 
dB (−0.17 to 2.14 dB; P = 0.09) was detected.  Dose intensity did not add information to models. 
There were 14 of 151 (9.3%) in the sulindac/eflornithine group and 4 of 139 (2.9%) in the placebo 
group who experienced at least 15 dB hearing reduction from baseline in 2 or more consecutive 
frequencies across the entire range tested (P = 0.02).  Follow-up air conduction done at least 6 
months after end of treatment showed an adjusted mean difference in hearing thresholds of 1.08 
dB (−0.81 to 2.96 dB; P = 0.26) between treatment arms.  There was no significant difference in 
the proportion of subjects in the sulindac plus eflornithine group who experienced clinically 
significant hearing loss compared with the placebo group.  The estimated attributable risk of 


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CPP FAP-310 Ver. 5.2, 17January2019 
 
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ototoxicity from exposure to the drug is 8.4% (95% confidence interval, −2.0% to 18.8%; P = 
0.12).  However, there is only a <2 dB difference in mean threshold for patients treated with 
combination compared with those treated elsewhere (other trials) with placebo. 
The eflornithine dose used in the Meyskens 2008 trial of patients with sporadic risk of colorectal 
cancer was 500 mgs orally per day for three years in combination with 150 mg daily sulindac.41 
No difference in ototoxicity was observed between NSAID alone and combination eflornithine 
NSAID arms in the Lynch trial of FAP patients, using an eflornithine dose of 750 mgs oral 
daily.27,28  Bailey and colleagues have recently updated their study of patients with prior non-
melanoma skin cancer that were treated with 500 mg/m2 (also rounded to the nearest 250 mg as 
they used eflornithine tablets) for 4-5 years.62  The Bailey study demonstrated a signiﬁcant (P < 
0.05) increase in uniformly transient audiometric (but not clinically detectable) hearing loss in 
participants on eflornithine.33  The follow-up study did not report any clinically significant 
differences in hearing as compared to the placebo group.62 
 
Sulindac Black Box Warning 
Sulindac like other NSAIDS carries a black box warning to consumers that it may cause increased 
risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke which can be 
fatal and an increased risk of serious gastrointestinal adverse events including bleeding, 
ulceration, and perforation of the stomach and intestines which can be fatal.  Refer to the Sulindac 
product insert (Actavis, formerly Watson Laboratories, Inc.)63 and the recent FDA Drug Safety 
Communication64 for further details.  The sulindac dose in this trial is one-half the recommended 
anti-inflammatory dose. 
3. 
TRIAL OBJECTIVES AND PURPOSE 
 
Rationale 
FAP is an orphan disease with multiple major unmet medical needs.  The current standard of 
practice involves prophylactic colectomy or proctocolectomy, followed by proctoscopic 
intervention with surgical polypectomies and/or laser/cautery ablation every 6 – 12 months for the 
rest of their lives.  Many patients have extensive polyposis at a young age and require surgery 
prior to entering college.  Following prophylactic colon surgery, follow-up intervention by 
proctoscopy and upper GI endoscopy occurs every 6 – 12 months and subsequent surgical 
interventions are generally performed at experienced centers of excellence, requiring frequent, 
inconvenient and expensive travel.  The serial interventions are unpleasant, require dietary 
restriction and enemas.  During surgical procedures, some patients require general anesthesia and 
all patients require sedation.  Surgical procedures for large or multiple adenomas may involve 
snare cautery polypectomy or trans-anal excision and carry risk of bowel perforation and or 
subsequent bleeding.  The greater the frequency and extent of the surgical procedures, the greater 
the morbidity and associated costs.  Such interventions frequently result in reduced compliance 
with medical and surgical recommendations, with subsequent increased likelihood of the 
development of an interval cancer.  In addition, repeated cautery ablations lead to scarring and 
impaired bowel function over the years. 
A major goal of this program is to defer or obviate the need for additional surgical interventions 
in patients with familial adenomatous polyposis.  In patients treated with total abdominal 
colectomy with ileo-rectal anastomoses, the addition of sulindac combined with eflornithine has 
the potential to defer or eliminate the need for a complete proctectomy by polyp control which 
may result in less frequent and less extensive endoscopic or surgical interventions. 
Prophylactic proctocolectomy does not “cure” patients with this genetic syndrome. FAP related 
disease remains a major problem in the residual rectum, pouch, anal transition zone, duodenum 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
18 
and desmoid formation; both can lead to major morbidity and mortality.  Surgical intervention is 
marginally effective, and there are no approved pharmacotherapeutic agents. 
Fifty percent (50%) of patients following total proctocolectomy with ileal pouch anal 
reconstruction develop adenomas in the pouch and require the same extensive follow-up 
evaluations and surgical treatments.  Almost all FAP patients are at risk for progressive duodenal 
adenomatous polyposis which can lead to extensive and frequent surgical endoscopic procedures 
and/or major surgical resections.  Duodenal polyposis is a major cause of morbidity, mortality, 
patient inconvenience and health care costs in FAP patients.  Ninety percent (90%) of patients 
with FAP develop duodenal polyposis2 for which there is no approved pharmacologic agent to 
control this disease.  Five (5) to 10% of patients have Spigelman Stage 4 on screening endoscopy; 
one-third of these patients develop cancer.  Of greater concern from the Bulow analysis is that 
52% of patients with duodenal polyposis who start with Stage 1, 2 or 3 will progress to Stage 4; 
the standard of care for Stage 4 is to consider some type of radical surgical intervention.  The 
complexity of managing such patients is well described in the definitive review of FAP 
management guidelines by Vasen and colleagues.10  The marginal benefit of endoscopic 
management of the duodenum is reviewed and tabulated (Table 4) in the paper by Brosens and 
colleagues.65  The data clearly demonstrate the need and potential efficacy of the pharmacologic 
control of duodenal polyposis; using the well-established Spigelman staging system as an 
objective indicator of polyp burden, along with pre-malignant histology.  The main determinant of 
Stage 4 is the presence of villous adenoma or high grade dysplasia on staging biopsies – objective 
measures of pre-cancerous risk.  
Increasing the time to clinically meaningful endpoints relevant to standard of care by increasing 
the time to important FAP-related events (FAP-related surgery, duodenal polyposis, cancer and 
death) are key factors in regard to the morbidity and mortality of this genetic disease.  FAP 
related surgical or clinical events in the rectum or pouch include surgery related to large or high 
risk adenomas or cancer; for FAP disease in the duodenum it includes surgery for enlarging or 
high risk adenomas. 
After IRA surgery, pharmacologic control may minimize the need for additional rectal surgery 
(surgical snare excisions of polyps greater than 5 mm; surgical trans-anal excision of rectal 
polyps; proctectomy) and/or minimize development of pre-cancerous adenoma (dysplastic polyps, 
villous adenoma) and cancer.  After pouch surgery it may minimize need for additional surgery 
(surgical snare excision of polyps greater than 5 mm, surgical trans-anal excision of rectal polyps, 
pouch resection with ileostomy) and/or minimize development of pre-cancerous adenomas and 
cancer. 
In FAP patients with duodenal polyposis, pharmacologic control may suppress development of 
further polyposis, slow or prevent progression to Spigelman Stage 3 and 4 disease, minimize 
progression to dysplastic polyps or villous adenomas, minimize polyposis involving the Ampulla 
of Vater, minimize development of cancer or reduce the need for procedures such as snare 
polypectomy, submucosal excisions, trans-duodenal excisions, duodenectomy, Whipple 
(pancreatic duodenectomy) or related procedures. 
Pharmacologic control in FAP patients has major implications for clinical benefit to reduce the 
morbidity of the disease and thereby improve the current standard of care.  The use of low dose 
sulindac and CPP-1X may prolong the time to occurrence of clinically important FAP-related 
disease events (FAP related events include surgical procedures and progressive advanced 
intestinal polyposis). 
 


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In addition to the above, the combination drug regimen may provide additional clinical benefit by,  
• Deferring the initial prophylactic colectomy to a more “convenient time” such as after 
graduation from school or after childbirth. 
• Increasing the use of colectomy with ileal-rectal reconstruction rather than total 
proctocolectomy which results in improved quality of life in regard to bowel function and 
reduces the risk of loss of fertility in women. 
• Reducing the risk of progressive rectal/pouch polyposis that requires surgical intervention. 
• Reducing the risk of rectal stump/pouch-related post polypectomy scarring with loss of 
bowel function (absence of compliant rectal reservoir). 
• Deferring or obviate the need for pouch removal with need for permanent ileostomy 
stoma. 
• Deferring or obviate the need for surgical intervention for advanced duodenal polyposis 
with associated morbidity and mortality. 
• Improving health-related quality of life (HRQoL). 
 
 
Rationale for Treatment Duration Extension up to 48 Months 
The initial statistical analysis plan used detailed event rate projections based on an extensive 
review of the published literature (Refer to Appendix E) and determined that a sample size of 150 
randomized subjects would be required for the primary endpoint analysis.  Because of logistical 
reasons, subject accrual was completed in April 2016 with 171 patients randomized.   
In February 2016, a blinded data review was done to project a more realistic estimate of FAP-
related event rates at the completion of the trial with a maximum of 24 months of treatment.  
Based on this analysis, it was considered unlikely we would reach the projected 90 events before 
the end of the study.  To reduce the risk of a false-negative trial (because of inadequate events 
after two years of study treatment in 171 randomized subjects), several mitigation options were 
explored.  The protocol was amended to extend treatment duration to a maximum of 36 months. 
Over 90% of subjects who reached 24 months without an FAP-related event consented to the trial 
extension. 
As of June 2017, there have been 53 FAP-related primary endpoint events.  Under the current 
event rates and with an estimated trial end-date of April 2018, projections once again do not 
indicate a high likelihood of 90 events.  Various statistical analyses, using Weibull methodology, 
indicate that under current hazard rate assumptions to maintain power > 85%, an additional trial 
extension may be required.  This protocol amendment offers all active subjects a longer-term 
blinded treatment until study completion at or before April 2019. This means, based on the date of 
randomization, a treatment extension of up to 36, 42 or 48 months.  The study will complete for 
reasons defined in Section 4.2. 
There have been five safety data monitoring committee meetings for CPP FAP-310 study, the 
most recent June 2017.  To date, the DMC has not identified any safety issues and there have 
been no recommended protocol modifications due to safety.  Additionally, for CPP FAP-310, the 
Medical Monitor performs a monthly blinded review of all adverse events to evaluate for events 
not commonly associated with drug exposure or to look for an increase in events above what is 
typical for the population under study. 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
20 
At the time of the amendment for the treatment extension, there have been twenty-six (26) serious 
adverse events (SAEs) that have been reported from the CPP FAP-310.  Two events were 
classified as SUSARs; however, no subject treatment arm assignments were unblinded.  
Twenty-one (21) of the twenty-six (26) SAEs were classified as not related to study treatment by 
the study investigators.  There were eleven (11) gastrointestinal events. These included five (5) 
small bowel/intestinal obstructions.  This type of event is not uncommon in the FAP population, 
particularly those with multiple surgeries.  There was one (1) gastrointestinal events of ileus and 
one (1) ileal stricture.  The subject with ileus had additional episodes prior to taking the study 
drugs.  Ileus and ileal stricture are expected events in the FAP and post colon surgery patient 
populations.  There was also one (1) event of rectal bleeding that was from a post-polypectomy 
ulceration.  Bleeding is a common complication from an endoscopic excision and there was also 
one (1) procedural complication that involved a post-polypectomy bleed.   
There was one (1) event of pancreatitis in a subject with a prior history of pancreatitis and one (1) 
subject with acute pancreatitis.  The subject with pancreatitis was hospitalized for six weeks and 
the event was a life-threatening, grade 4 serious adverse event.  In the case of acute pancreatitis, 
the investigator indicated that the likely cause was ampullary adenomatous disease.  FAP patients 
are at a higher risk of pancreatitis than the general population66.  Pancreatitis is a rare, but 
identified risk of sulindac.  The Investigator’s Brochure, Sulindac package Insert and published 
reports indicate that pancreatitis is associated with the use of sulindac.67 
One (1) subject experienced grade 3 constipation which quickly resolved with evacuation and 
pain management. Although constipation is a common side effect of both eflornithine and 
sulindac as documented in the Investigator’s Brochure, the investigator evaluated as not related 
due to the timing and rapid resolution of the event. 
There was one (1) event in the nervous system disorders category that was a seasonal migraine in 
a subject had a history of this type of event.  For neoplasms, there was one (1) diagnosis of lung 
adenocarcinoma with a brain lesion, unrelated to treatment.  There was also one (1) event of 
chronic myeloid leukemia, unrelated to treatment. In addition to the post-polypectomy bleed 
described above, there were three other (3) events in the injury/complications category.  There 
was one (1) wound complication related to cellulitis of an incarcerated umbilical surgical scar. 
This was unrelated to study treatment and related to multiple prior surgeries. One (1) event of 
seroma complication post-desmoid surgery was unrelated to treatment and is a known 
complication of abdominal surgery.  The one (1) event of anastomotic stricture was a 
hospitalization for the treatment of a pre-existing anal stenosis and was unrelated to treatment.  
One subject had perforated knee bursitis, likely infectious in origin, that was classified as 
unrelated to study medication.  One (1) subject with pre-existing COPD experienced an 
exacerbation that required medication and oxygen therapy, but was not related to treatment.  The 
subject with acute pancreatitis described above also experienced grade 3 hyperglycemia and was 
diagnosed with type 2 diabetes.  This event was unlikely to be related to treatment, but is reported 
to be a very rare complication of sulindac and is listed in the Investigator’s Brochure.  
The remaining five (5) events were classified as being possibly (4) or probably (1) related to 
treatment.  One (1) event of worsening of depression was listed as possibly related to treatment.  
Depression is covered in the Reference Safety Information as a known side effect of sulindac and 
with the side effect of emotional lability for eflornithine.  For vascular disorders, there was one 
(1) thromboembolic event (DVT without pulmonary embolism) listed as possibly related to 
treatment.  This is a known risk of sulindac and is listed in the Reference Safety Information in 
the Investigator’s Brochure.  One (1) subject experienced severe nausea (grade 3) approximately 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
21 
4 months after study treatment began.  This was possibly related to treatment; nausea is listed as a 
complication of both eflornithine and sulindac. 
There were two (2) events that were classified as SUSARS.  One (1) subject experience psychosis 
and paranoia, grade 3.  This began 6-8 weeks prior to the month 24 end of treatment visit and 
progressed to the point of paranoid psychosis resulting in hospitalization and treatment with anti-
psychotic, anxiolytic and insomnia medications.  The investigator assessed this event as possibly 
related.  Eflornithine has a known side effect of emotional lability and sulindac has an uncommon 
side effect of psychic disturbances, including acute psychosis, both listed in the Reference Safety 
Information.  After discharge, the subject completed the study.  The second SUSAR was a 
spontaneous abortion.  The subject had a positive pregnancy test and stopped study medication 
upon confirmation.  Approximately 2 months after discontinuation, the subject lost the fetus due 
to a suspected placental abruption.  The subject had a history of miscarriage and the event was 
classified as possibly related.  The Sponsor determined that the SAE of spontaneous abortion was 
not related to the study medication.  Eflornithine is known to be embryotoxic in animal studies 
and is listed as a safety risk in the Investigator’s Brochure.  
The constituents for this combination therapy, eflornithine and sulindac, are considered as having 
well-established medicinal use within the meaning of Annex I to Directive 2001/83.  Both active 
substances have been authorized in medicinal products for various therapeutic indications for 
doses, duration and frequency exceeding that which is used in the CPP FAP-310 Phase III clinical 
study.  Randomized clinical trials of eflornithine and sulindac alone or in combination indicate 
that these agents have minimal toxicities when used for treatment periods of 3 or more years in 
patients with risk of cancer.  The minimal toxicities observed to date in CPP FAP-310 for 
treatment of FAP patients with eflornithine and sulindac for up to 3 years supports the extension 
of the treatment time in CPP FAP-310 from 3 to up to 4 years at a dose level of 750 mg/day 
eflornithine and 150 mg/day sulindac. 
This protocol amendment may extend the trial by up to 12 months, and offers subjects (based on 
their randomization date) treatment up to 48 months. The end of study will not be beyond April 
30, 2019. Actual duration of treatment for each subject is based on the occurrence of an FAP-
related event, censoring for standard reasons unrelated to FAP-related endpoint indicators, or the 
final end of study date. In the absence of an FAP-related event, subjects will receive study 
treatment for 24 to 48 months. The final decision concerning the trial end-date if prior to April 30, 
2019, will be based on accrued FAP-related primary endpoints, number of subjects still active on 
trial, FAP event projections, and additional safety reviews. Assuming continued acceptable safety 
profile, this approach will minimize the risk of a false negative trial. 
 
Purpose 
This randomized, double-blind, phase III trial will compare the efficacy, safety and 
pharmacokinetics of the CPP-1X/sulindac combination versus CPP-1X and sulindac as single 
agents with up to a 48-month maximum treatment period in patients with Familial Adenomatous 
Polyposis (FAP). 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
22 
4. 
INVESTIGATIONAL PLAN 
 
Study Population 
• Diagnosis of phenotypic classical FAP, age ≥18 years, male and female gender.  Must be 
genotyped, with an APC mutation.  Refer to Section 6.1 for details. 
• Meets eligibility criteria for at least one FAP related disease group defined in Section 6.1. 
• If prior colorectal surgery, at least three years since colectomy with ileal-rectal 
anastomosis (IRA) or total proctocolectomy with ileal pouch-anal reconstruction (pouch). 
• Absence of major cardiac risk factors as defined in Section 6.2. 
• Absence of clinically significant hearing loss requiring a hearing aid. 
• Adequate laboratory studies (hematology, chemistry, and urinalysis) at study entry. 
 
Treatment 
• Experimental arm: 750 mg CPP-1X, and 150 mg sulindac 
• Comparator arms:  
1. CPP-1X placebo with sulindac (150 mg) 
2. CPP-1X (750 mg) with sulindac placebo 
• Treatment is administered as four tablets taken once daily with food (same time of day, 
preferably in the morning), for up to 48 months. 
• Randomized subjects will receive 24 months of treatment and complete their final 
assessment or come off-study for an FAP-related event or for other reasons (for example, 
safety issues, non-compliance, withdrew consent, lost to follow-up).  
• Subjects completing 24 months of treatment without an FAP-related event can continue on 
treatment for up to 48 months based on their randomization date as follows: 
1. If randomized between November 2015 and April 2016 eligible for up to 36 
months of treatment 
2. If randomized between May 2015 and October 2015 eligible for up to 42 months 
of treatment 
3. If randomized between July 2014 and April 2015 eligible for up to 48 months of 
treatment 
or until one of the following occurs: 
1. Subject has an FAP-related event or comes off study for other reasons 
2. Trial end-date of April 30, 2019 has been reached 
3. 90 FAP-related events have occurred 
4. Less than 90 FAP-related events have accrued prior to April 30, 2019 and an 
earlier trial end-date has been set by the Sponsor and reviewed by the DMC 
5. An earlier trial end date prior to April 30, 2019 has been recommended by the 
DMC for safety reason and approved by the Sponsor 
 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
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Randomization 
At least 150 eligible patients will be enrolled in this study.  Subjects will be randomized to one of 
three treatment groups in equal proportions (i.e., 1:1:1 randomization): 1) CPP-1X plus sulindac 
2) CPP-1X - placebo plus sulindac, 3) CPP-1X plus sulindac placebo. 
A stratified randomization procedure will be used with stratification based on FAP-related time-
to-first-event prognosis.  The event prognosis groups are represented by 1) best (i.e., longest 
projected time to first FAP-related event) - rectal/pouch polyposis, 2) intermediate - duodenal 
polyposis, and 3) worst - pre-colectomy.  If a subject has two or more of these disease sites, the 
most severe prognosis stratum will be assigned for randomization (e.g. worst > intermediate > 
best).  Since an individual may have more than one disease site involved, the trial will assess time 
to any defined FAP-related event in the subject as a whole. In order to minimize potential 
treatment arm imbalance a centralized randomization process will be used to balance among 
treatment groups within prognostic strata. 
 
Primary Outcome 
The primary objective of this trial is to determine whether the combination of CPP-1X plus 
sulindac is superior to either treatment individually, in delaying the time from the date of 
randomization to the date of the first occurrence of any FAP-related event in the subject as a 
whole.  This includes: 1) FAP related excisional intervention involving the colon, rectum, pouch, 
duodenum and/or 2) clinically important events which includes progression to more advanced 
duodenal polyposis (Stage 2, 3 or 4), cancer or death.  Section 8.2.14 provides complete detail. 
 
Secondary Outcomes 
Secondary Efficacy Analyses: 
Any improvement observed by the investigator during upper gastrointestinal (UGI) and lower 
gastrointestinal (LGI) visualization (i.e. endoscopy and colonoscopy) at the 6 and 12-month study 
visits will be described using the variables UGI Observed Improvement (UGIOI), and LGI 
Observed Improvement (LGIOI).  Each patient will have one pair of UGIOI and LGIOI outcomes 
(refer to Protocol Section 12.0 and the Statistical Analysis Plan for more detail). 
Other Secondary Outcomes in this Study Include the Following: 
To explore how study treatment group relates to other efficacy outcomes, genotype, phenotype, 
disease locations and endoscopic findings, additional analyses are planned (refer to the Statistical 
Analysis Plan for more details).   
The UGIOI and LGIOI outcomes will be tabulated and summarized using the month 6 visit 
scores, alone.  Similarly, the UGIOI and LGIOI outcomes will tabulated and summarized across 
all study visits. 
As both part of the primary analysis, and further explored in these additional analyses, median 
time to event for each treatment group will be determined.  This will be explored for each of the 
study populations (i.e. ITT, per protocol, and others), study disease stratum groups, and in the 
disease site subgroups. 
Pharmacokinetic data (plasma concentrations measured at patient visits) will be used to estimate 
population pharmacokinetic parameters for the CPP-1X (eflornithine), sulindac, and CPP-1X 
(eflornithine) + sulindac treatment groups (i.e., for each analyte for those patients on combination 
treatment). 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
24 
The subcategories of FAP events will be explored by disease stratum groups, and by disease site 
subgroups.  
The presence or absence of ODC polymorphisms, including the single nucleotide polymorphisms 
(SNPS) rs2302615 and rs2302616 and their relation to treatment group and outcome will be 
tested with the likelihood ratio test. 
The excretion of 5 urinary polyamines (diacetylspermine, n1-acetylspermidine, n8-
acetylspermidine, decarboxylated SAM, and putrescine) will be assessed in relation to treatment 
group and outcome, using the single point concentration data gathered from the urine samples 
harvested at each study visit. 
Patient reported health related quality of life measures will be evaluated using HRQoL.  
Tissue and dietary polyamine levels, as collected at patient study visits will be analyzed together 
with the results of the dietary questionnaires and related to treatment group and study outcomes. 
Safety outcome data and analyses are described in detail in the Statistical Analysis Plan. 
 
Population Pharmacokinetics for CPP-1X/Sulindac 
All subjects consented, enrolled, and randomized in this study will have pharmacokinetic samples 
drawn at their scheduled 3-month visit.  All subjects will have samples drawn on the same 
schedule regardless of treatment arm assigned.  The samples will be obtained before first morning 
dose, then four additional samples over the following eight hours. 
 
Polyamine Analysis 
At each colonoscopy/proctoscopy while on study treatment, a sample of normal rectal mucosa 
and a random urine sample will be obtained to assess tissue and urine polyamine levels.  Sample 
handling and processing procedures will be provided in the study manual, are described here 
briefly. 
Biospecimen collection: Normal (tumor-free) rectal mucosal biopsies will be obtained during 
endoscopy procedures.  Biopsy samples will be placed in separate standard cryotube tubes and 
stored in a -70 – 800C freezer.  Random urine samples (15 mL minimum) will be collected and 
stored in a -70 – 800C freezer. 
Polyamine content: Polyamine analysis will be performed as described previously.35  Briefly, 
frozen tissue samples will be homogenized and extracted in 0.2 N perchloric acid.  Urine samples 
will be adjusted to 0.2 N perchloric acid.  Polyamine (spermidine, spermine, and putrescine) 
content will be measured using reverse-phase, ion-paired high performance liquid 
chromatography.  Protein contents will be determined using the bicinchoninic acid protein assay 
(Thermo Fisher Scientific, Rockford, IL).  The spermidine-to-spermine ratio (Spd:Spm) will be 
assessed in our analyses to minimize the influence of assay variability.35,68 
Dietary polyamines: Data will be collected using the Fred Hutchinson Cancer Center food 
frequency questionnaire and will be analyzed using a polyamine database.  Average daily 
consumption of putrescine, spermidine, and spermine will be calculated.69  
 
Pharmacogenetic and Genetic Analysis 
A peripheral blood sample will be collected from enrolled subjects at baseline for subsequent 
correlative genomic studies relevant to this disease and in the event treatment-related adverse 
events are discovered during the trial. Sample handling and processing procedures, which will be 
provided in the study manual, are described here briefly. 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
25 
DNA extraction and genotyping. DNA will be extracted from peripheral blood samples using the 
QIAGEN QIAamp DNA Midi or Mini Kits (Qiagen), following the manufacturer's instructions. 
Genotyping of the ODC1 (National Center for Biotechnology Information SNP database ID 
rs2302615) +316 SNP will be conducted using a PCR amplification of the targeted region and bi-
directional cycle sequencing of purified target amplicon using PCR/Sanger sequencing primers.  
The sequencing reaction will be analysed on an Applied Biosystems 3730 Genetic Analyzer. The 
PCR amplicon will be sequenced in both forward and reverse directions to confirm the SNP. 
 
Quality of Life 
Assessment of Health-Related Quality of Life (HRQoL) is to better understand and quantify the 
impact of each treatment arm on FAP-related physical and emotional symptoms as well as FAP-
related surgical sequelae.  Specifically, postponing surgery because of reduction of polyps could 
lead to both symptomatic relief as well as reduced stress and worry about cancer, future surgery 
and/or suffering of FAP-related medical and surgical symptoms.  As such, several well-accepted 
and previously published questionnaires have been selected for use in the CPP FAP-310 trial. 
These include the EORTC core questionnaire, QLQ-C30,70 the GI-specific sub-module, QLQ-
CR29,71 and the EQ-5D health utilities index.72,73  These instruments have all been previously 
used in gastrointestinal/colorectal clinical trials and have been validated and translated to ensure 
appropriate cultural/linguistic adaptation suitable for a multi-center, international clinical trial. 
Also being used is a modified version of the Cancer Worry Scale.74 
 
 
 




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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
27 
≥15 dB hearing loss at two adjacent frequencies (p=0.07).  The observed audiometric 
abnormalities were usually reversible; 19% and 18% of eflornithine and placebo subjects had 
persistent abnormal audiograms 6 months after stopping study drug.33  
Infrequent side effects:  Hearing loss/change by audiometry testing has been reported in 8.4% of 
patients on high dose eflornithine.  Rash and alopecia have been reported in 3% of patients.  
Anorexia and abdominal pain have been reported in 2% of patients treated with eflornithine. 
Rare but serious side effects include dizziness (1%), headaches (2%), and seizures (8%) have 
been reported in patients on intravenous eflornithine.  Myelosuppression (including leukopenia, 
[37%], anemia [55%], and thrombocytopenia [14%]) has been reported at high intravenous doses, 
but does not usually occur at the low dose (750 mg) utilized in this study.33 
Pregnancy and Lactation:  Pregnancy Category C. It is unknown if eflornithine crosses the 
placenta.  Case reports in humans along with animal studies (mice, rats) indicate potential for 
fetotoxicity.  Experiments in rodents indicate that eflornithine blocks yolk sac formation and 
trophoblast differentiation, affecting processes such as vasculogenesis and steroidgenesis.75  The 
World Health Organization has not determined a breast-feeding rating for eflornithine due to 
insufficient data.  The Thompson lactation rating is that infant risk cannot be ruled out.  No 
studies investigating the safety of lactation after eflornithine administration have been conducted, 
nor are there data to determine drug levels in breast milk after drug administration.  
5.1.2. 
CPP-1X (Eflornithine) Pharmacokinetics 
The dose of CPP-1X (daily oral dose of 750 mg for an adult) for CPP-310 was selected based 
upon its known pharmacology and evidence from clinical studies.  
Time to peak concentration for oral eflornithine is 4-6 hours.   
Absorption: for the oral solution is 54-58% and is unaffected by feeding status.   
Distribution: no protein binding sites, crosses blood-brain barrier, volume of distribution is 0.3-
0.35 liters/kg. 
Metabolism: urinary recovery of unchanged drug as eflornithine is 86% and essentially not 
metabolized. 
Excretion: renal excretion. Elimination half-life: 3-3.5 hours but once daily oral dosing of 500-
750 mg is sufficient to maintain efficacy as indicated in several clinical trials. 
Eflornithine pharmacokinetic references include, Abeloff, et al., 1984,76 Haegele et al., 1981,77 
Meyskens, et al., 1998,35 and Meyskens et al., 2008.41 
5.2. 
Sulindac 
Sulindac is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-
fluoro-2-methyl-1- [[p- (methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid.  It is not a 
salicylate, pyrazolone or propionic acid derivative.  Sulindac, a yellow crystalline compound, is a 
weak organic acid practically insoluble in water below pH 4.5, but very soluble as the sodium salt 
or in buffers of pH 6 or higher.  
  Sulindac 
tablets (USP) 150 mg tablets are round yellow tablets imprinted DAN and 5661 and are supplied 
in bottles of 100.  Dispense in a well-closed container with child-resistant closure.  
 
  
Sulindac is marketed in the US for relief of signs and symptoms of the following conditions:  
osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder 
(bursitis/tendinitis), and acute gouty arthritis. 




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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
29 
Pregnancy and Lactation:  Pregnancy Category C. Sulindac crosses the placenta.  There have been 
no reports of congenital abnormalities caused by maternal use of sulindac.  However, sulindac 
should be avoided in late pregnancy because of the effects of prostaglandin inhibition (closure of 
the ductus arteriousus) on the fetal cardiovascular system.  It is not known whether this drug is 
excreted in human milk; however, it is secreted in the milk of lactating rats.  Because many drugs 
are excreted in human milk and because of the potential for serious adverse reactions in nursing 
infants from sulindac, a decision should be made whether to discontinue nursing or discontinue 
the drug, taking into account the importance of the drug to the mother.  Refer to the Sulindac 
product insert (Actavis, formerly Watson Laboratories, Inc.)78 for additional information. 
 
Sulindac Pharmacokinetics 
Refer to the Sulindac product insert (Actavis, formerly Watson Laboratories, Inc.)78 for additional 
information. 
Absorption:  90% bioavailability; sulindac must be metabolized to the sulfide metabolite before it 
is pharmacologically active. 
Distribution: Sulindac and its sulfone and sulfide metabolites are 93.1, 95.4 and 97.9% bound to 
plasma proteins.  Sulindac penetrates the blood-brain barrier and placental barriers. 
Metabolism: Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation 
relative to the sulfide metabolite in animals. 
Kinetics:  Tmax for sulindac (150 mg tablet) is 3.9 ± 2.3 hours, and 5.85±4.5 hours for the sulfone 
metabolite and 6.2 ± 3.1 hours for the sulfide metabolite. 
Elimination: Approximately 50% of the administered dose of sulindac is excreted in the urine 
with the conjugated sulfone metabolite accounting for the major portion.  Less than 1% of the 
administered dose of sulindac appears in the urine as the sulfide metabolite.  Approximately 25% 
is found in the feces, primarily as the sulfone and sulfide metabolites.  The mean effective half-
life (T1/2) for sulindac is 7.8 hours and 16.4 hours for the active sulfide metabolite. 
 
 
 


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30 
6. 
SUBJECT RECRUITMENT, INCLUSION AND EXCLUSION CRITERIA 
Subjects (male and female), ≥ 18 years will be recruited who meet the inclusion criteria below.  
Women and minorities will be represented according to their distribution in the Investigator’s 
clinical population. 
 
Patient Characteristics for Eligibility, Inclusion Criteria 
1. Diagnosis of phenotypic classical FAP with disease involvement of the duodenum and/or 
colon/rectum/pouch. 
a) 
Genotype: APC mutation (with or without family history) required  
b) 
Classical FAP Phenotype: 100’s to 1,000’s of colorectal adenomatous polyps, usually 
appearing in teenage years 
2. UGI endoscopy/LGI endoscopy (proctoscopy/colonoscopy) performed within 30 days of 
randomization.  
3. Patients with an intact colon/rectum and prophylactic surgery is being considered as a 
stratification site. 
4. Rectal/pouch polyposis as a stratification site as follows: 
4.a  At least three years since colectomy with IRA/proctocolectomy with pouch, and 
demonstrating polyposis as defined by Stage 1, 2, 3, of the proposed InSiGHT 2011 
Staging System (Appendix B) and summarized as follows: 
Stage 1:  10-25 polyps, all < 5 mm 
Stage 2:  10-25 polyps, at least one > 1 cm 
Stage 3:  >25 polyps amenable to complete removal, or any incompletely removed sessile 
polyp, or any prior evidence of high grade dysplasia, even if completely 
removed. [Note: For staging purposes only.] 
4.b  For all subjects, any rectal/pouch polyps > 5 mm must be excised at “baseline”. 
5. Duodenal polyposis as a stratification site; one or more of the following: 
5.a  Current Spigelman Stage 3 or 4. (Refer to Appendix A for Modified Spigelman Score 
and Classification table). 
5.b  Prior surgical endoscopic intervention within the past six months for Spigelman Stage 3 
or 4 that may have been down staged to Spigelman 1 or 2. 
6. Hematopoietic Status (within 30 days prior to randomization): 
a) 
No significant hematologic abnormalities 
b) WBC at least 3,000/mm3  
c) 
Platelet count at least 100,000/mm3 
d) Hemoglobin at least 10.0 g/dL 
e) 
No history of clinical coagulopathy 
 


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CPP FAP-310 Ver. 5.2, 17January2019 
 
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7. Hepatic Status (within 30 days prior to randomization): 
a) 
Bilirubin no greater than 1.5 times ULN 
b) AST and ALT no greater than 1.5 times ULN 
c) 
Alkaline phosphatase no greater than 1.5 times ULN 
8. Renal Status (within 30 days prior to randomization): 
a) 
Creatinine no greater than 1.5 times ULN 
9. Hearing: 
a) 
No clinically significant hearing loss, defined in Section 6.2, number 9. 
10. If female, neither pregnant nor lactating.  
11. Negative pregnancy test if female of child-bearing potential.  Fertile patients must use 
effective contraception*.  Confirmation of postmenopausal status unless surgically sterile**. 
12. Absence of gross blood in stool; red blood on toilet paper only acceptable.  
13. No discrete gastric or duodenal ulcer greater than 5 mm within the past year except 
Helicobacter pylori-related peptic ulcer disease treated with antibiotics. 
14. No invasive malignancy within the past 5 years except resected non-melanomatous skin 
cancer, papillary thyroid cancer, or precancerous cervical dysplasia. 
15. No other significant medical or psychiatric problems that would preclude study participation 
or interfere with capacity to give informed consent. 
16. Use of 81 to 100 mg daily aspirin or up to 700 mg aspirin not more than once a week are 
eligible. 
17. No concurrent warfarin, fluconazole, lithium, Pradaxa® or other direct thrombin inhibitors, 
Plavix®, cyclosporine, other NSAIDs (such as ibuprofen, aspirin in excess of 700 mg weekly, 
diflunisal), diuretics (furosemide and thiazides), DMSO, methotrexate, probenecid, 
propoxyphene hydrochloride, Tylenol® (acetaminophen) preparations containing aspirin or 
cytotoxic chemotherapy drugs. 
18. Willingness to forego concurrent use of supplements containing omega-3 fatty acids, oral 
corticosteroids, non-steroidal anti-inflammatory drugs or other FAP directed drug therapy. 
19. Able to provide written informed consent and follow protocol requirements. 
*Fertile male or female, effective contraception methods include the established use of oral, injected or implanted 
hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS), barrier 
methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository, male sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate), or true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject.  Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception.  Contraceptives should be used during the study and for at least 2 weeks 
after study treatment.  
Male subjects (including men who have had vasectomies) whose partners are pregnant should use condoms while 
the partner is pregnant. If the partner is still pregnant when the subject goes off study, the subject should continue 
condom uses for at least 2 weeks afterwards. 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
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32 
**Postmenopausal status may be confirmed by any of the following: a) ≥ 12 months spontaneous amenorrhea; b) 6 
months spontaneous amenorrhea with serum FSA levels > 30 IU/L79,80; c) ≥ 6 weeks postsurgical bilateral 
oophorectomy; d) ≥ 6 weeks postsurgical hysterectomy. 
 
Exclusion Criteria 
1. Prior pelvic irradiation. 
2. Patients receiving oral corticosteroids within 30 days of enrollment. 
3. Treatment with other investigational agents in the prior 4 weeks. 
4. Use of other non-steroidal anti-inflammatory drugs (such as ibuprofen) exceeding 4 days 
per month, in the prior 6 weeks. 
5. Regular use of aspirin in excess of 700 mg per week. 
6. Treatment with other FAP directed drug therapy (including sulindac or celecoxib, fish oil) 
within 12 weeks of study enrollment. 
7. Hypersensitivity to cyclooxygenase-2 inhibitors, sulfonamides, NSAIDs, or salicylates; 
NSAID associated symptoms of gastritis. 
8. Patients must not have cardiovascular disease risk factors as defined below.  
• Uncontrolled high blood pressure (systolic blood pressure > 150 mm Hg; 
• Unstable angina;  
• History of documented myocardial infarction or cerebrovascular accident; 
• New York Heart Association Class III or IV heart failure (Refer to Appendix C); 
• Known uncontrolled hyperlipidemia defined as LDL-C ≥ 190 mg/dL or triglycerides ≥ 
500 mg/dL. 
9. Patients with significant hearing loss are not eligible for study participation as defined 
below. 
• Hearing loss that affects everyday life and/or for which a hearing aid is required. 
10. Intact colon/rectum or retained rectum or ileal pouch:  
a) 
cancer on biopsy 
b) high grade dysplasia found on polyp biopsy where the polyp is not completely 
removed 
c) 
a large polyp (>1 cm) not completely removed. 
11. Duodenal cancer on biopsy. 
12. Intra-abdominal desmoid disease, stage III or IV (staging criteria in Appendix D).9,81 
13. Inability to provide informed consent. 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
33 
 
Replacements and Screen Failures 
Randomized subjects who discontinue early for any reason will NOT be replaced and will not be 
permitted to reenter the study. 
Previously screened subjects may be rescreened for enrollment in the study with prior approval 
from the Medical Monitor.  Subjects who are rescreened 30 days after signing the informed 
consent will need to be re-consented and have all screening procedures repeated to determined 
eligibility. 
Any screen failed subject based on history, physical exam or laboratory values or endoscopy 
procedures will need to have a screen failure case report form completed by the Investigator or 
study coordinator and available for review by the study Sponsor. 
 
7. 
RANDOMIZATION AND STRATIFICATION 
Subjects eligible for this trial will be randomized into one of three treatment groups 1:1:1 (CPP-
1X plus sulindac: CPP-1X placebo plus sulindac: CPP-1X plus sulindac placebo) and stratified by 
FAP-related event prognosis using an interactive web-based system as described below.  Subjects 
will be randomized no more than 5 working days prior to their scheduled start date of treatment. 
A stratified randomization procedure will be used with stratification based on FAP-related time-
to-first-event prognosis.  The event prognosis groups are represented by 1) best (i.e., longest 
projected time to first FAP-related event) - rectal/pouch polyposis, 2) intermediate - duodenal 
polyposis and 3) worst - pre-colectomy.  If a subject has two or more of these disease sites, the 
most severe prognosis stratum will be assigned for randomization (e.g. worst > intermediate > 
best).  Since an individual may have more than one disease site involved, the trial will assess the 
time from the date of randomization to the date of the first occurrence of any FAP-related event in 
the subject as a whole.  In order to minimize potential treatment arm imbalance a centralized 
randomization process will be used to balance among treatment groups within prognostic strata. 
 
 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
34 
8. 
SPECIFIC TREATMENT PLAN AND SUBJECT MANAGEMENT 
 
Subject Assessments and Treatment Schedule 
The clinical study schedule/schema (Table 3) provides the schedule for screening, on-study visits and follow-up. 
Table 3 - FAP Study Schedule (Initial 24 Months of Treatment) 
 
Screening 
/Baseline 
Mo. 
0-1-2 
Mo. 
 3 
Mo.  
4-5 
Mo. 
 6 
Mo.  
7 -8 
Mo.  
9 
Mo.  
10-11 
Mo.  
12 
Mo. 
13-14 
Mo. 
15 
Mo. 
16-17 
Mo.  
18 
Mo. 
19-20 
Mo. 
21 
Mo. 
22-23 
24 mo. 
/EOT 
FU 30 days 
Off-Study  
FU Mo. 2-6  
Off Study 
Procedures 
 
 
(± 1 wk) 
(± 2 wks) 
(± 1 wk) 
(± 2 wks) 
(± 1 wk) 
(± 2 wks) 
(± 1 wk) 
± 2 wks21 
(± 1 wk) 
Informed Consent 
X 
 
 
 
 
X26
Polyposis History1 
X 
 
 
 
 
Medical History24 
X 
 
X 
 
X
X
 
X
X
X14
GI Symptoms 
X 
 
X 
 
X
X
 
X
X
X14
Surgical History 
X 
 
 
 
 
X14
X19
Concomitant 
Medications 
X 
X13 
X 
X13 
X 
X13 
X13 
X13 
X 
X13 
X13 
X13 
X 
X13 
X13 
X13 
X 
X14 
 
Drug Compliance 
Review 
 
X13 
X 
X13 
X 
X13 
X13 
X13 
X 
X13 
X13 
X13 
X 
X13 
X13 
X13 
X 
 
 
Adverse Events 
 
X13 
X 
X13 
X
X13
X13
X13
X
X13
X13
X13 
X
X13
X13
X13
X
X14
Chemistry Panel2 
X 
 
X 
 
X
X
 
X
X
CBC3 
X 
 
X 
 
X
X
 
X
X
Urinalysis25 
X 
 
X 
 
X
X
 
X
X
Vital Signs4 
X 
 
X 
 
X
X
 
X
X
Physical Exam/Review 
of Systems5 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Audiometry6 
X 
 
 
 
X
 
X
EKG22 
X 
 
X23 
 
X
X
 
X
X
Serum Preg. Test7 
X 
 
X 
 
X
X7
X
X7
 
X
X7
X
Dispense Medications8 
 
X8 
X 
 
X 
 
X8 
 
X 
 
X8 
 
X 
 
X8 
 
 
 
 
Subject Diary9 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Food Frequency 
Questionnaire15 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
LGI Endoscopy10 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Normal Mucosa 
Biopsy11 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
UGI Endoscopy12 
X 
 
 
 
X
X
 
X
X
Pharmacokinetics 
Blood Samples 
 
 
X16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomic Blood 
Sample 
X17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Polyamine Urine 
Samples18 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
HRQoL surveys 20 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
35 
FAP Study Schedule Footnotes (Table 3) 
Note: Shaded columns in subject schedule (Table 3) are protocol required in person visits. 
1. 
Polyposis history: Family history, age onset, physician or self-prescribed NSAIDs for polyp control, frequency and extent of post-colectomy interventions; specific 
findings during the past two endoscopies. 
2. 
Chemistry panel includes – electrolytes (Na, K, CL, CO2), liver function tests (AST, ALT, Alkaline phosphatase, bilirubin), BUN/urea, creatinine. 
3. 
CBC panel includes – hemoglobin, hematocrit, WBC, platelet count, automated differential. 
4. 
Vital signs – temperature, blood pressure, pulse, respirations. 
5. 
Physical Exam/Review of body systems (includes body system assessment - HEENT, hepatic, renal, genitourinary, reproductive, hematologic/immunologic, 
endocrine/metabolic, musculoskeletal, neurologic [i.e., grossly normal, walk into office, speech normal, no tremors, alert and oriented], dermatologic, cardiovascular, 
respiratory, gastrointestinal) – including height (baseline only), weight, vital signs. 
6. 
Audiometry will need to be done using air conduction methodology (250, 500, 1000, 2000, 4000 and 8000 Hz). 
7. 
Women of child-bearing bearing potential with no prior hysterectomy and pre-menopausal must use an effective contraception method and will have a serum pregnancy 
(HCG) done every 3 months while on study treatment (see Section 6.1, #11). 
8. 
Medications and subject diaries will be dispensed to the subject every 3 months (month 0, 3, 6, 9, 12, 15, 18, and 21) in person or by special arrangements. 
9. 
Subjects are to record in their 3-month diaries: medication use, presence of symptoms, and a self-assessment of presence of gross blood or melena. 
10. 
Lower GI (LGI) endoscopy (proctoscopy or colonoscopy) will be done on all randomized subjects that have an intact colon or rectum/pouch. 
11. 
During the LGI procedure, normal mucosal biopsy for polyamine analysis will be obtained at; screening/baseline, 6, 12, 18, and 24 months/EOT. For subjects with 
permanent ileostomy, endoscopy not required; normal mucosal biopsies are performed on the visible ileostomy stoma.  
12. 
On-study Upper GI (UGI) endoscopy will be done on all randomized subjects that have a duodenum. 
13. 
Monthly (± 7 days) phone/email contact by the study coordinator to follow-up on medication/drug compliance review, concomitant medications, and adverse events. 
14. 
The follow-up will be done as phone call to the subject to review medical history, surgical history for any FAP-related surgical events, concomitant medications and 
adverse events. 
15. 
A food frequency recall questionnaire will be administered at the screening/baseline, 12 and 24 month/EOT visits. US and Canada sites only. 
16. 
A peripheral blood sample (5 mL, lithium heparin) will be collected at each of the following time points:  pre-dose and 1, 2, 4 and 8 hours post dose. 
17. 
A peripheral blood sample (10 mL, EDTA) will be collected at screening/baseline for pharmacogenomic analysis. 
18. 
A random urine sample (15 mL minimum) will be collected at the screening/baseline, 6, 12, 18 and 24 month/EOT visits for polyamine analysis. 
19. 
The follow-up will be done monthly as phone call to review endoscopic excisional procedures/surgical history for any FAP-related surgical events. 
20. 
HRQoL surveys will include EORTC QLQ-C30 and QLQ-CR29, EQ-5D health utility index assessment, and modified Cancer Worry Scale. They will be collected at 
screening/baseline, 3, 6, 12, 18, and 24 month/EOT visits. 
21. 
EOT visit will occur within 2 weeks off study treatment for any cause including completion of treatment at 24 months. 
22. 
Subject needs to be in the supine position for 10 minutes prior to the EKG, including EKGs collected during PK sampling.  
23. 
2-EKGs will be done on the day PK samples are collected: 1) before pre-dose sample and prior to dose, and 2) before the 4 hr PK sample is obtained.   
24. 
Medical history includes – standard review of major systems, with particular attention to cardiovascular, cerebrovascular, peripheral vascular, gastrointestinal and 
hearing issues. Interaction with outside physicians should be documented. 
25. 
Urinalysis panel includes – color, clarity/appearance, specific gravity, pH, protein, glucose, ketones and blood. 
26. 
Subjects completing the initial 24 month treatment without an FAP-related event and participating in the extension study must be consented at this visit.  Go to Table 4, 
for month 24 additional extension procedures. For those subjects not participating in the extension study, this will be the end of treatment visit. 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
36 
Table 4 - FAP Study Schedule (Treatment Extension to a Maximum of 48 Months) 
 
 
Mo. 
 2421 
Mo. 
25, 26 
Mo. 
27 
Mo. 
28, 29 
Mo. 
30 
Mo. 
31, 32 
Mo. 
33 
Mo. 
34, 35 
M 
36 
Mo. 
37-38 
Mo. 
39 
Mo. 
40-41 
Mo. 
42 
Mo. 
43-44 
Mo. 
45 
Mo. 
46-47 
Mo. 
48/EOT 
FU 30 
days 
Off-
Study 
Procedures 
 
(± 1 wk) 
(± 2 wks) 
(± 1 wk) 
(± 2 wks) 
± 1 wk 
(± 2 wks) 
 
(± 1 wk) 
 
(± 2 wks17) 
± 1 wk 
Informed Consent 
X 
 
 
 
 
Medical History19 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X13 
GI Symptoms 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X13 
Surgical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
Concomitant Medications 
 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X 
X13 
Drug Compliance Review 
 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X 
 
Adverse Events 
 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X 
X12 
X12 
X12 
X 
X13 
Chemistry Panel1 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
CBC2 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Urinalysis20 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Vital Signs3 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Physical Exam4 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Audiometry5 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
EKG18 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Serum Preg. Test6 
 
 
X6 
 
X 
 
X6 
 
X 
 
X6 
 
X 
 
X6 
 
X 
 
Dispense Medications7 
X 
 
X7 
 
X 
 
X7 
 
X 
 
X7 
 
X 
 
X7 
 
 
 
Subject Diary8 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Food Frequency 
Questionnaire14 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
LGI Endoscopy9 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Normal Mucosa Biopsy10 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
UGI Endoscopy11 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Polyamine Urine Samples15 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
HRQoL surveys 16 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
37 
FAP Study Schedule Treatment Extension Footnotes (Table 4) 
Note: Shaded columns in subject schedule (Table 4) are protocol required in person visits. 
1. Chemistry panel includes – electrolytes (Na, K, CL, CO2), liver function tests (AST, ALT, Alkaline phosphatase, bilirubin), BUN, creatinine. 
2. CBC panel includes – hemoglobin, hematocrit, WBC, platelet count, automated differential. 
3. Vital signs – temperature, blood pressure, pulse, respirations. 
4. Physical Exam/Review of body systems (includes body system assessment - HEENT, hepatic, renal, genitourinary, reproductive, hematologic/immunologic, 
endocrine/metabolic, musculoskeletal, neurologic [i.e., grossly normal, walk into office, speech normal, no tremors, alert and oriented], dermatologic, cardiovascular, 
respiratory, gastrointestinal) – including height (baseline only), weight, vital signs. 
5. Audiometry will need to be done using air conduction methodology (250, 500, 1000, 2000, 4000 and 8000 Hz). 
6. Women of child-bearing bearing potential with no prior hysterectomy and pre-menopausal must use an effective contraception method and will have a serum pregnancy 
(HCG) done every 3 months while on study treatment (see Section 6.1, #11). 
7. Medications and subject diaries will be dispensed to the subject every 3 months (month 24, 27, 30,33, 36, 39, 42, and 45) in person or by special arrangements. 
8. Subjects are to record in their 3-month diaries: medication use, presence of symptoms, and a self-assessment of presence of gross blood or melena. 
9. Lower GI (LGI) endoscopy (proctoscopy or colonoscopy) will be done on all randomized subjects that have an intact colon or rectum/pouch. 
10. During the LGI procedure, normal mucosal biopsy for polyamine analysis will be obtained at months 30, 36, 42 and 48/EOT visits. For subjects with permanent 
ileostomy, endoscopy not required; normal mucosal biopsies are performed on the visible ileostomy stoma.  
11. On-study Upper GI (UGI) endoscopy will be done on all randomized subjects that have a duodenum. 
12. Monthly (± 7 days) phone/email contact by the study coordinator to follow-up on medication/drug compliance review, concomitant medications, and adverse events. 
13. The follow-up will be done as phone call to the subject to review medical history, surgical history for any FAP-related surgical events, concomitant medications and 
adverse events. 
14. A food frequency recall questionnaire will be administered at month 36 and 48/EOT visit. US and Canada sites only. 
15. A random urine sample (15 mL minimum) will be collected at months 24, 30, 36, 42 and 48/EOT visits for polyamine analysis. 
16. HRQoL surveys will include EORTC QLQ-C30 and QLQ-CR29, EQ-5D health utility index assessment, and modified Cancer Worry Scale. They will be collected at 
months 30, 36, 42 and 48/EOT visits. 
17. EOT visit will occur within 2 weeks off study treatment for any cause including completion of treatment at 48 months. 
18. Subject needs to be in the supine position for 10 minutes prior to the EKG.  
19. Medical history includes – standard review of major systems, with particular attention to cardiovascular, cerebrovascular, peripheral vascular, gastrointestinal and hearing 
issues. Interaction with outside physicians should be documented. 
20. Urinalysis panel includes – color, clarity/appearance, specific gravity, pH, protein, glucose, ketones and blood. 
21. These procedures are in addition to those listed for Month 24 on the initial treatment schedule (Table 3). 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
38 
 
Patient Accrual Logistics 
 
Initial Visit – Determining Potential Eligibility 
Based on general medical and polyposis history, prior surgery, cardiac risk assessment and 
clinical hearing loss, current aspirin and NSAID use - patients will be determined to be 
potentially eligible for this trial.  After appropriate discussions, written informed consent will be 
obtained. 
 
Subsequent Screening for Eligibility 
If the patient has not already been genotyped for FAP, genetic analysis will be performed to 
confirm the presence of an APC mutation.  
Lower GI Endoscopy:  Patients will be evaluated via colonoscopy, flexible or rigid procto-
sigmoidoscopy during the screening phase.  Biopsies, ablations, and snare excisions at baseline 
are performed per the clinician’s standard of care.  If considered eligible based on inclusion 
criteria, a grossly normal mucosa biopsy will be obtained for baseline polyamine measurement.  
Still and video documentation of the colon (vide infra) or the residual rectum or entire pouch will 
also be obtained for archiving.  Polyp size will be determined by visual comparison with biopsy 
forceps that can measure 5.0 – 5.5 mm in the fully open position.  Procedural details are provided 
in the Investigator Manual.  All randomized patients with an intact colon or rectum/pouch will 
have baseline and on-study lower GI endoscopy procedures as part of this trial. 
Upper GI Endoscopy:  The duodenum will be evaluated by forward-viewing and/or side-viewing 
gastroscopes (with still and video documentation with closed and open biopsy forceps near 
mucosa).  Procedural details are provided in the Investigator Manual.  All randomized patients 
with a duodenum will have baseline and on-study UGI endoscopy as part of this trial. Subjects 
stratified to the duodenal group must have duodenal biopsies of all polyps 1 cm or larger to 
determine HGD and histology required for determining Stage 3 or 4 Spigelman status.  
A physical exam/review of body systems, height, weight and vital signs will be performed. 
Baseline blood and urine tests within 30 days of randomization: Per eligibility criteria – CBC, 
chemistry profile, urinalysis, and a sample for pharmacogenomic and genetic analysis. 
In order to ascertain how many patients with clinical FAP have baseline hearing deficits, patients 
meeting all the criteria for this trial will undergo air conduction audiometry.  Results will not be 
relevant to eligibility. 
 
Final Eligibility and Potential Screen Failures 
If the patient has signed the informed consent, and all eligibility criteria are met, the subject will 
be randomized.  Screening UGI, LGI and rectal/pouch images will be submitted to the central 
imaging laboratory for central collection and archiving.  Quality of life questionnaires (EORTC 
QLQ-C30, EORTC QLQ-CR29, EQ-5D, and the modified Cancer Worry Scale) will be provided 
to the subject to complete to obtain baseline values.  A food frequency questionnaire will be 
provided to the subject to complete for baseline values at North American (United States and 
Canada) sites only. 
The patient may be a screen failure based on history, physical exam, genetic assessment, or other 
laboratory values.  A screen failure case report form will need to be completed by the 
Investigator or study coordinator and available for review by the study Sponsor.  
 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
39 
 
Drug Administration 
After confirming eligibility, the patient will be randomized to one of the three treatment arms 
(Table 5).  Randomization should be performed within 5 working days prior to the initiation of 
treatment.  Specific procedures for randomization will be included in the study manual. 
Table 5 - Study Medication Schedule1 
AGENT and DOSE 
ROUTE 
RX INTERVAL 
CPP-1X 750 mg & Sulindac 150 mg 
Oral 
Daily for up to 48 
months 
OR 
 
CPP-1X placebo & Sulindac 150 mg 
Oral 
Daily for up to 48 
months 
OR 
 
CPP-1X 750 mg & Sulindac placebo 
Oral 
Daily for up to 48 
months 
1The medications are to be taken at approximately the same time daily with food. 
* Each CPP-1X tablet = 250 mg;  ** Each sulindac tablet = 150 mg 
The study medication and subject diaries will be dispensed to the subject at the initial treatment 
visit and at 3 month intervals thereafter in person or by special arrangement.  Subjects will be 
instructed to take their medication with food at approximately the same time each day, preferably 
in the morning.  The subject will be instructed to record dosing compliance on a weekly basis in 
the subject diary. 
Based on published data utilized to project event rates, subjects will receive treatment for up to 
48 months.  However, interim analyses prescribed by the Data Monitoring Committee charter 
may result in earlier stopping based on futility or toxicity.  
 
Initial 24-Month Treatment Intervention Assessments 
Refer to Section 8.1, Table 3 and Table 4 for subject assessments and the treatment schedule for 
screening, on-study, end of treatment and follow-up visits. 
During the initial 24-month drug intervention, subjects will be followed monthly by phone or in 
person visits interview for assessment of possible toxicities and medication compliance.  A diary 
of compliance and symptoms will be maintained by subjects and reviewed during the next office 
visit.  At each interval assessment visit (month 3, 6, 12, 18, and 24), until the subject completes 
24 months of treatment or the subject comes off study treatment additional drug supplies and 
subject diaries will be provided. 
At months 1, 2, 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23 (+ 1 week), a follow-up visit via 
phone contact will be performed to assess for side effects, other medications, to remind subjects 
to complete their diary and to continue to take their study medications. 
At the 3-month visit (+ 1 week), subjects will have a physical exam/review of body systems 
(including weight and vital signs), blood and urine samples obtained for laboratory tests (CBC, 
chemistry panel, urinalysis), pharmacokinetics (PK), and EKGs (before the pre-dose sample, 
prior to drug administration and before the 4-hour PK sample collection.  Subject needs to be in 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
40 
the supine position for 10 minutes prior to the EKG).  Women of child bearing potential will also 
have a serum pregnancy test performed.  Concomitant medications, adverse events and 
medication compliance will also be reviewed.  Quality of life questionnaires (EORTC QLQ-C30, 
EORTC QLQ-CR29, EQ-5D, and the modified Cancer Worry Scale) will be provided to the 
subject to complete. 
At the 6-month and 18-month visits (+ 2 weeks), subjects will have a physical exam/review of 
body systems (including weight and vital signs), blood samples obtained for laboratory tests 
(CBC, chemistry panel, urinalysis), a random urine sample will be obtained for polyamine 
determination, EKG (Subject needs to be in the supine position for 10 minutes prior to the EKG) 
and their first on study treatment upper and lower endoscopy procedures with image and video 
documentation will be obtained.  A normal rectal/pouch mucosal biopsy for polyamine 
determination will be obtained during the colonoscopy/proctoscopy procedure.  Women of child 
bearing potential will also have a serum pregnancy test performed. Concomitant medications, 
adverse events and medication compliance will also be reviewed. Quality of life questionnaires 
(EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D, and the modified Cancer Worry Scale) will 
be provided to the subject to complete. Study drug and diaries will be dispensed. 
At the 9-month, 15-month and 21-month visits (+ 1 week), subjects will have drug and diary 
dispensing. Women of child bearing potential will also have a serum pregnancy test performed.  
Concomitant medications, adverse events and medication compliance will also be reviewed. 
At the 12-month and 24-month visits (+ 2 weeks), subjects will have a physical exam/review of 
body systems (including, weight and vital signs), blood samples obtained for laboratory tests 
(CBC, chemistry panel, urinalysis), a random urine sample will be obtained for polyamine 
determination, audiometry testing, EKG (Subject needs to be in the supine position for 10 
minutes prior to the EKG) and their second set of on study treatment endoscopy procedures with 
image and video documentation will be obtained. A normal mucosal biopsy for polyamine 
determination will be obtained during the colonoscopy/proctoscopy procedure.  Women of child 
bearing potential will also have a serum pregnancy test performed. Concomitant medications, 
adverse events and medication compliance will also be reviewed. Quality of life questionnaires 
(EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D, and the modified Cancer Worry Scale) will 
be provided to the subject to complete.  A food frequency questionnaire will be provided to the 
subject to complete at North American (United States and Canada) sites only. Study drug and 
diaries will be dispensed at 12-month and if the subject continues on the treatment extension at 
24-month. 
Subjects completing the initial 24 months of study treatment, without an FAP related event, and 
have completed the 24 month visit procedures as outlined below may be eligible to participate in 
the 24 month treatment extension (See Section 8.2.10).  For those subjects that do not go on to 
the treatment extension, this will be the end of treatment visit.  It must be documented in the 
subject’s medical record why the subject declined participation in the treatment extension if they 
met the requirements for participation, see Section 8.2.10. 
 
Initial 24 Month Treatment Intervention Early Termination (+ 2 weeks) 
Within 2 weeks off final study pill treatment for any cause, all subjects will have a follow-up 
history and physical exam/review of body systems (including, weight and vital signs), along with 
toxicity assessment.  Repeat blood laboratory tests (CBC, chemistry panel, and urinalysis), a 
random urine sample will be obtained for polyamine determination, EKG (Subject needs to be in 
the supine position for 10 minutes prior to the EKG) and audiometry will be performed.  Women 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
41 
of child bearing potential will also have a serum pregnancy test performed.  Concomitant 
medications, adverse events and medication compliance will also be reviewed.  Quality of life 
questionnaires (EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D and the modified Cancer 
Worry Scale) will be provided to the subject to complete.  A food frequency questionnaire will 
be provided to the subject to complete at North American (United States and Canada) sites only.  
Repeat upper and lower endoscopies with image and video documentation will be obtained at the 
Month 24/EOT visit or if the subject has completed at least 3 months of treatment from the 
previous on-study upper and lower endoscopy procedures (including baseline).  A normal 
mucosal biopsy sample for polyamine determination will be obtained during the 
colonoscopy/proctoscopy procedure. 
If the subject has an unscheduled upper/lower endoscopy for any reason, these procedures should 
be captured with image and video documentation including the collection of a normal mucosal 
biopsy, if possible.  A random urine sample should be obtained for polyamine determination, if 
possible. 
Subjects will be formally taken off-study treatment and complete the End of Treatment (EOT) 
assessments if there is a cumulative delay/suspension of study medication for any reason of: 
 
> 90 days from randomization to month 36 
 
> 105 days from randomization to month 42 
 
> 120 days from randomization to month 48 
A temporary suspension from taking study medication as stated above (for example, due to a 
non-FAP disease related surgery or procedure), will be documented as a treatment delay and the 
subject will continue on study, on their original schedule. 
 Initial 24 Month Treatment Intervention Follow-Up (30-days post end of treatment 
visit +/- 1 week) Off Study 
Thirty-days (30) after completion of the end of study evaluations, subjects will be contacted by 
phone for a clinical update in regard to symptoms and interval medical history.  Concomitant 
medications and adverse events will also be reviewed.  The subject will provide a clinical update 
and procedure date for any FAP-related surgical event or major endoscopic excisional event that 
has occurred since the last contact. These include partial colectomy, colectomy with IRA, total 
procto-colectomy, proctectomy, pouch resection, sub-mucosal resection, trans-duodenal 
excision, ampullectomy, duodenectomy, or Whipple procedure. 
An FAP-related event at any disease site (colon/rectum/pouch, duodenum) will lead to 
discontinuation of the study treatment but follow-up of the subject will continue until the end of 
the 30 day follow-up period. 
 Initial 24 Month Treatment Intervention Follow-Up (Months 2-6, each month +/- 1 
week) Off Study 
For the next 5 months after the 30 day follow-up, if the subject went off study treatment for 
disease progression indicating the need for an any FAP-related surgical event or major 
endoscopic excisional event, and the surgical/endoscopic event had not yet occurred at the time 
of the 30 days post end of treatment visit, subjects will be contacted by phone to obtain the 
procedure date of any FAP-related surgical event or major endoscopic excisional event that has 
occurred since the last contact.  These include partial colectomy, colectomy with IRA, total 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
42 
procto-colectomy, proctectomy, pouch resection, sub-mucosal resection, trans-duodenal 
excision, ampullectomy, duodenectomy, or Whipple procedure. 
 
Treatment Extension Intervention (Months 25 - 48) 
Subjects completing the initial 24 months of study treatment, without an FAP related event, and 
have completed all the 24 month visit procedures as outlined in Section 8.2.6 and Table 3 and 
Table 4 may be eligible to participate in the treatment extension.  
In order to participate, a subject must meet the following requirements: 
1. 
Subject has completed 24 months of treatment without an FAP related event. 
2. 
Subject has completed all the month 24 visit procedures. 
3. 
Subject is no more than 14 days beyond the 24 month or 36 month visit. 
4. 
Subject has signed the informed consent for treatment extension. 
Once the above requirements are met, the subject will have drug and diary dispensed. 
At months 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, 41, 43, 44, 46, and 47 (+ 1 week), a follow-
up visit via phone contact to assess for side effects, other medications, to remind subjects to 
complete their diary and to continue to take their study medications. 
At the 27-month, 33-month, 39-month and 45-month visits (+ 1 week), subjects will have drug 
and diary dispensing. Women of child bearing potential will also have a serum pregnancy test 
performed.  Concomitant medications, adverse events and medication compliance will also be 
reviewed. 
At the 30-month and 42-month visits (+ 2 weeks), subjects will have a physical exam/review of 
body systems (including weight and vital signs), blood samples obtained for laboratory tests 
(CBC, chemistry panel, urinalysis), a random urine sample will be obtained for polyamine 
determination, EKG (Subject needs to be in the supine position for 10 minutes prior to the EKG) 
and their first on study treatment upper and lower endoscopy procedures.  A normal rectal/pouch 
mucosal biopsy for polyamine determination will be obtained during the 
colonoscopy/proctoscopy procedure.  Women of child bearing potential will also have a serum 
pregnancy test performed. Concomitant medications, adverse events and medication compliance 
will also be reviewed. Quality of life questionnaires (EORTC QLQ-C30, EORTC QLQ-CR29, 
EQ-5D, and the modified Cancer Worry Scale) will be provided to the subject to complete. 
At the 36-month, and 48-month visits (+ 2 weeks), subjects will have a physical exam/review of 
body systems (including, weight and vital signs), blood samples obtained for laboratory tests 
(CBC, chemistry panel, urinalysis), a random urine sample will be obtained for polyamine 
determination, audiometry testing, EKG (Subject needs to be in the supine position for 10 
minutes prior to the EKG) and their second set of on study treatment endoscopy procedures. A 
normal mucosal biopsy for polyamine determination will be obtained during the 
colonoscopy/proctoscopy procedure.  Study drug and diaries will be dispensed at 36-month if 
eligible to continue. Women of child bearing potential will also have a serum pregnancy test 
performed. Concomitant medications, adverse events and medication compliance will also be 
reviewed. Quality of life questionnaires (EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D, and 
the modified Cancer Worry Scale) will be provided to the subject to complete.  A food frequency 
questionnaire will be provided to the subject to complete at North American (United States and 
Canada) sites only. 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
43 
 Treatment Extension - End of Treatment/Early Termination (+/- 2 weeks) 
Within 2 weeks of final study pill treatment for any cause, all subjects will have a follow-up 
history and physical exam/review of body systems (including, weight and vital signs), along with 
toxicity assessment.  Repeat blood laboratory tests (CBC, chemistry panel, and urinalysis), EKG 
(Subject needs to be in the supine position for 10 minutes prior to the EKG) and audiometry will 
be performed. Women of child bearing potential will also have a serum pregnancy test 
performed. Concomitant medications, adverse events and medication compliance will also be 
reviewed. Quality of life questionnaires (EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D and 
the modified Cancer Worry Scale) will be provided to the subject to complete.  A food frequency 
questionnaire will be provided to the subject to complete at North American (United States and 
Canada) sites only.  
Repeat upper and lower endoscopies with image and video documentation will be obtained at the 
end of treatment visit if the subject has completed at least 3 months of treatment from the 
previous on-study upper and lower endoscopy procedures (including month-24). A normal 
mucosal biopsy will be obtained during the colonoscopy/proctoscopy procedure and a urine 
sample will be collected for polyamine determination. 
If the subject has an unscheduled upper/lower endoscopy for any reason, these procedures should 
be captured with image and video documentation including the collection of a normal mucosal 
biopsy, if possible.  A random urine sample should be obtained for polyamine determination, if 
possible. 
 Treatment Extension Follow-Up (30-days post end of treatment visit +/- 1 week) 
Off Study 
Thirty-days (30) after completion of the treatment extension evaluations, subjects will be 
contacted by phone for a clinical update in regard to symptoms and interval medical history.  
Concomitant medications and adverse events will also be reviewed. The subject will provide a 
clinical update and procedure date for any FAP-related surgical event or major endoscopic 
excisional event that has occurred since the last contact. These include partial colectomy, 
colectomy with IRA, total procto-colectomy, proctectomy, pouch resection, sub-mucosal 
resection, trans-duodenal excision, ampullectomy, duodenectomy, or Whipple procedure. 
An FAP-related event at any disease site (colon/rectum/pouch, duodenum) will lead to 
discontinuation of the study treatment but follow-up of the subject will continue until the end of 
the 30 day follow-up period. 
 Termination of Treatment Extension Procedures 
Subjects on the treatment extension can continue on treatment for up to 48 months based on their 
date of randomization as follows: 
1. If randomized between November 2015 and April 2016 eligible for up to 36 months 
2. If randomized between May 2015 and October 2015 eligible for up to 42 months 
3. If randomized between July 2014 and April 2015 eligible for up to 48 months 
or until one of the following occurs: 
1. Subject has an FAP-related event or comes off study for other reasons 
2. Trial end-date of April 30, 2019 has been reached 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
44 
3. 90 FAP-related events have occurred 
4. Less than 90 FAP-related events have accrued prior to April 30, 2019 and an earlier trial 
end-date has been set by the Sponsor and reviewed by the DMC 
5. An earlier trial end date prior to April 30, 2019 has been recommended by the DMC for 
safety reason and approved by the Sponsor. 
 Treatment Compliance 
Subjects will be formally taken off-study treatment and complete the End of Treatment (EOT) 
assessments if there is a cumulative delay/suspension of study medication for any reason of: 
 
> 90 days from randomization to month 36 
 
> 105 days from randomization to month 42 
 
> 120 days from randomization to month 48 
 Definition of FAP-Related Events or Serious and Unexpected Toxicity 
The time from the date of randomization to the date of the first occurrence of any FAP-related 
event at any disease site (colon/rectum/pouch, duodenum) will lead to discontinuation of the 
study treatment.  Follow-up of the subject for FAP-related events will continue, per protocol, 
until the end of the 30 day post-treatment. 
FAP-related primary events by disease site are as follows: 
1. Pre-operative, intact colon: 
a) 
Disease progression^ indicating need for colectomy with IRA or total procto-
colectomy  
 
2. Rectum or pouch events include one or more of the following: 
a) 
Excisional intervention by surgical snare or trans-anal excision to remove any 
polyp ≥ 10 mm in size (per pathology report) and/or pathologic evidence of high 
grade dysplasia.* 
b) Disease progression^ indicating need for proctectomy 
c) 
Disease progression^ indicating need for pouch resection 
d) Development of cancer in rectum or pouch 
e) 
Death 
 
3. Duodenal disease includes the following: 
a) 
Progression in Spigelman Stage to more advanced stage (Stage 2, 3 or 4), refer to 
Appendix A 
b) Disease progression indicating need for excisional intervention (sub-mucosal 
resection, trans-duodenal excision, ampullectomy, duodenectomy, Whipple 
procedure) 
c) 
Development of cancer 
d) Death 
 
Note, excisional intervention may include open surgery, trans-anal surgery or endoscopic 
excisions/snare but does not include cautery ablations or hot biopsy. 
*For those subjects stratified to the duodenal group, all concurrent rectal pouch polyps > 5 mm 
must have been removed at baseline for this event to apply. 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
45 
^Disease progression is based on endoscopic evaluations compared to baseline demonstrating a 
clinically significant increase in number and/or size of polyps (~25% increase in disease burden), 
presence of a large sessile or ulcerated adenoma not amenable to removal, high grade dysplasia 
in any adenoma, or in-situ or invasive cancer. 
Discontinuation from study treatment due to a potential treatment related serious adverse event 
may include the following:  
• Gastrointestinal hemorrhage, ≥ grade 3 
• Tinnitus ≥ grade 2, or clinical hearing impairment ≥ grade 3 
• Cardiovascular events include cardiac arrest, cardiac-chest pain, myocardial 
infarction, thromboembolic event, phlebitis (deep or superficial), and spontaneous 
abdominal wall or retroperitoneal hematoma at least 10 cm in maximum dimension.  
• Grade ≥ 3 Cardiac ischemia/infarction or cerebrovascular ischemia, whether related 
to study drug or not. 
Adverse events and serious adverse events must be recorded carefully and completely on the 
case report forms and SAE report forms.  Adverse event reporting and grading will be done 
using the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 
If a subject comes off study treatment for any of the above listed FAP or SAE events, the subject 
will need to complete all tests, procedures and assessments required at the Final Intervention/End 
of Treatment visit, including 30-day follow-up. 
All subjects who go off study treatment due to an FAP-related event, toxicity, or intercurrent 
illness, or who withdraw consent for further treatment will be followed for at least 30 days from 
their last dose of study medication.  
 
Study Blinding Information and Criteria for Protocol Treatment Removal 
 
Blinding and Unblinding 
Treatment will be provided in a double blind manner such that neither the subject, Investigator, 
clinic staff nor the Sponsor will know which combination is being administered.  Randomization 
numbers will be assigned based on information obtained from an interactive web-based response 
system. 
Subject treatment will be unblinded in emergency situations by the study Investigator if it is in 
the best interest of the trial subject in order to provide medical care to the subject and includes 
medical decisions such as whether to start or stop treatment or institute alternative treatment if 
required.  Specifically, we expect that unblinding of an individual study subject’s treatment 
assignment may occur if in the opinion of the Investigator that the identification of the study 
medication is necessary to protect the welfare of the subject. The study drug may be discontinued 
without unblinding the participant. 
If the blind is prematurely broken for a subject, it is the responsibility of the Investigator to 
promptly document and explain any unblinding to Cancer Prevention Pharmaceuticals within 24 
hours of the blind being broken. 
Unblinding of subject treatment is done via the IWRS by the Investigator.  If the Investigator is 
unable to access IWRS, the Drug Safety Group at Chiltern should be contacted at 1-919-468-
2288 (US) and 001-919-468-2288 (EU) for a subject’s treatment code. 
 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
46 
 
Protocol Treatment Withdrawal (Off-Study Treatment) 
Participants will be withdrawn from protocol treatment under the following circumstances: 
1. 
Evidence of an FAP-related event as defined in Section 8.2.14.  
2. 
Clinical reduction in hearing acumen requiring use of a hearing aid. 
3. 
Grade ≥ 3 cardiac ischemia/infarction or cerebrovascular ischemia, whether related to 
study drug or not. 
4. 
Pregnancy while on treatment, see Section 11.8. 
5. 
Intercurrent illness which would, in the judgment of the treating physician, affect 
assessments of clinical status to a significant degree and/or require discontinuation of 
drugs.  Participants will not discontinue study drugs for other medical events which are 
not considered to be treatment related.  This determination will be made by the treating 
physician.  
6. 
Cumulative delay of study intervention for any reason as follow: 
• > 90 days from randomization to month 36 
• > 105 days from randomization to month 42 or 
• > 120 days from randomization to month 48 
The first day of study treatment initiation is the randomization date regardless of study 
visit and/or procedure delays. 
7. 
Completion of treatment intervention. 
8. 
At the request of the Sponsor in situations such as protocol violations or concerns about 
the subject’s safety. 
9. 
The subject is lost to follow-up. 
10. The subject may withdraw from the study-treatment at any time for any reason. 
11. Subject death. 
 
Protocol Withdrawal (Off-Study) 
1. 
The subject may withdraw from the study at any time for any reason. 
9. 
DISEASE ASSESSMENT AND SAMPLE COLLECTION 
 
Baseline Endoscopy 
A. 
Colon, Rectal, Pouch Assessment 
Colonoscopy or flexible sigmoidoscopy will be used to assess the colon, rectum or the neo-rectum 
(ileal pouch) and video images captured for archiving and subsequent review.  The last images 
will be retroflexed pictures of the distal rectum or pouch at the anorectal ring.  One pass will be 
performed.  Further details will be provided in the Imaging Manual. 
Rectal/Neorectal Pouch 
The entire residual rectum or pouch will be video-captured three times by: 
 Advancing flexible scope to ileo-rectal anastomosis or proximal pouch.  After 
advancement, the scope will be “twirled” to visualize all walls of the bowel as it is 
withdrawn. 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
47 
 Retroflexed views of the distal rectum will be obtained at each visualization. 
 Images of the bowel will be obtained using biopsy forceps in the fully open position 
placed near the mucosa. 
Rectal/Neorectal Pouch Enumeration and Measurement 
 Number of polyps in the rectum or pouch 
 Endoscopic estimation of polyp size will be determined by visual comparison to a biopsy 
forceps that can measure, 5.0 - 5.5mm in the fully open position. 
o Number of polyps between 5 – 10 mm 
o Number of polyps > 10 mm 
 All rectal/pouch polyps > 5 mm in diameter must be excised at baseline if the subject will 
be stratified to the rectum/pouch group.  For details concerning subjects stratified to the 
rectal/pouch polyposis group (with or without involvement of the duodenum) please see 
Section 6.1, #4.  For details concerning subjects stratified to the duodenal polyposis group 
(with or without involvement of rectum/pouch at stratification) please see Section 8.2.14.  
Smaller polyps may be ablated per the treating institutions standard of care and three additional 
sets of video images will then be obtained as “baseline”.  
B. 
Duodenal Assessment 
Duodenal assessment will use a forward and/or side-viewing endoscope with video images 
captured for subsequent review.  The Spigelman classification (Appendix A) at screening will be 
utilized to stage the initial extent of disease and assess subject eligibility.  A side-viewing scope 
may be used to improve assessment of the ampulla of Vater/papilla.  Ampullary biopsies (with 
histology) and snare excisions will be performed per the protocol, Investigator Manual, and the 
institution’s standard of care and the results of these procedures will be used as the subject’s 
baseline Spigelman classification.  Further details will be provided in the Imaging Manual. 
The screening stage will be the initial Spigelman Stage (extent of polyposis combined with 
histology) and the baseline Spigelman Stage will be the post-snare intervention. 
 
Follow-up Endoscopies 
At six month intervals (+/- two weeks) – per Section 8.1, subjects will undergo repeat upper and 
lower endoscopy.  At any interval assessment, if any subject requires an excisional intervention 
(as defined in Section 8.2.14), or has duodenal Spigelman stage progression (Stage 2, 3 or 4), the 
subject will be considered to have an FAP-related event and will come off study treatment.  
 
Imaging Submission 
All de-identified images will be captured on DVD or flash drive, de-identified, and forwarded to 
a central imaging laboratory for archiving.  All data will be de-identified in regard to subject, site 
and treatment but subject study ID number will be available for baseline and subsequent 
comparison as appropriate.  Post-hoc global assessment by blinded reviewers not involved in this 
trial will perform the assessment - using a 5 point scale - much less, somewhat less, none or 
minor changes, somewhat worse, much worse.  This process will be defined in detail and 
included in the imaging manual for still and video endoscopy image submission. 
 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
48 
 
Population Pharmacokinetic Sampling  
All subjects will have blood samples obtained for pharmacokinetic studies.  Pharmacokinetic 
sampling will occur once at the scheduled 3-month visit.  Samples may be collected within ± 1 
weeks of this visit.  These visits start in the morning, to allow for subjects to hold their morning 
study medication dose, and for samples to be taken during standard working hours. 
The subject will be contacted by a study coordinator at least three (3) days prior to the scheduled 
visit to remind the subject to not take their morning dose of study medication on the day of the 
planned visit. 
On the morning of the visit, upon subject arrival, it will be verified that the subject did not take 
their morning dose of study medication.  Those subjects that mistakenly took their morning dose 
will be sent home and rescheduled within the next week.   
Prior to the pre-dose blood sample collection, a resting EKG will be obtained (subject needs to 
be in the supine position for 10 minutes prior to the EKG).  After the EKG was obtained, a pre-
dose blood sample (5 mL, lithium heparin vacutainer tube) will be collected.   
The subject will then take their study medications in the usual manner.  The subject may then 
leave the clinic and have their typical breakfast.  Subjects will be asked to note the time breakfast 
was finished, as that will be recorded. 
Table 6 – Pharmacokinetic Sample Number, Sampling Times and EKG collection 
Sample 
Number 
Target Time 
No Earlier Than 
No Later Than 
 
EKG – Prior to pre-dose sample collection and drug administration 
1 
Pre-dose* 
NA
NA
2 
1 hour post dose
45 minutes
75 minutes 
3 
2 hours post dose
90 minutes
150 minutes 
 
EKG – Prior to 4 hour sample collection 
4 
4 hours post dose*
3 hours
5 hours 
5 
8 hours post dose
6 hours
10 hours 
*EKGs need to be done 1) before the pre-dose sample and before drug administration 
and 2) before the 4 hour samples are collected. 
Post dose blood samples will be collected (5 mL each) at 1, 2, 4, and 8 hours following the 
morning dose of study medication (see Table 5).  Deviations around these sample times should 
be no more than ± 15 minutes, ± 30 minutes, ± 60 minutes (1 hour), ± 120 minutes (2 hours), 
respectively, keeping in mind that the fourth and fifth samples must be at least one hour apart.   
At the 4 hour time point and prior to the 4 hour blood sample collection, a resting EKG will be 
obtained (subject needs to be in the supine position for 10 minutes prior to the EKG).  After the 
EKG is obtained, the 4 hour time point blood sample (5 mL, lithium heparin vacutainer tube) 
will be collected. 
On the pharmacokinetic sampling case report form page, study coordinators will record the time 
of the pre-dose blood sample and the time breakfast was finished.  Also, the relative ideal blood 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
49 
sampling times (relative to dose time), and the actual blood sampling times will be recorded.  
Missed samples or samples collected outside of the time windows will still be stored and 
analyzed.  Collected blood samples will be processed, stored, and shipped to a central laboratory 
according to procedures provided in the study manual. 
Plasma concentration data from this trial will be pooled with data from other clinical trials, when 
available, for analysis.  For each drug, a database will be constructed that includes the nominal 
and recorded dosing history, plasma analyte concentrations, demographic (body size, age, race, 
gender) data, laboratory data (hepatic and renal function), medical history (colonic resection), 
and clinical trial identifier.  These data will be analyzed using methods appropriate for sparse 
data (mixed-effects modeling using NONMEM). 
 
Polyamine Sample Collection (Normal Mucosa Biopsy, Random Urine Sample) 
Subject tissue samples will undergo a baseline polyamine assay (examination of grossly normal 
rectal mucosal cup forcep biopsy and random urine sample - minimum 15 mL) pre-treatment, as 
a component of the screening process, and at each endoscopy/proctoscopy evaluation.  Collected 
tissue and urine samples will be processed, stored, and shipped to a central laboratory according 
to procedures provided in the study manual. 
For subjects who have signed the Optional Research Use of Biospecimens portion of the 
informed consent, left over urine or tissue samples may be used for exploratory assessment of 
levels of expression of RNA, proteins, or other molecules, such as polyamines, in the polyamine 
synthesis pathway, the APC signaling pathway, and other related pathways.  Analysis may 
include mutation status for genes involved in the polyamine synthesis pathway, APC pathway, or 
other FAP related pathways. 
 
Pharmacogenomic and Genetic Testing Sample Collection 
Subjects will have 10 mL of peripheral blood collected in an EDTA vacutainer tube during their 
baseline/screening visit for subsequent correlative science research.  Collected blood samples 
will be processed and shipped to a central laboratory according to procedures provided in the 
study manual. 
For subjects who have signed the Optional Research Use of Biospecimens portion of the 
informed consent, left over blood samples may be used for exploratory assessment of levels of 
expression of RNA, proteins, or other molecules, such as polyamines, in the polyamine synthesis 
pathway, the APC signaling pathway, and other related pathways.  Analysis may include 
mutation status for genes involved in the polyamine synthesis pathway, APC pathway, or other 
FAP related pathways. 
 
 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
50 
10. 
QUALITY OF LIFE AND DIETARY ASSESSMENTS 
 Assessment of Quality of Life and Subject Preferences 
For this study, we plan to use four (4) instruments to measure HRQoL and subject preferences or 
utilities.  These instruments include the EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D, and a 
modified Cancer Worry Scale. 
• The EORTC QLQ-C30 is a self-administered quality of life questionnaire70 with multi-
dimensional scales.  It consists of both multi-item scales and single item measures, 
including five functioning domains, a global quality of life domain, three symptom 
domains and six single items.  
• The EORTC QLQ-CR29 gastrointestinal / colorectal sub-module71 is composed of 4 
functional and 18 symptom related sub-scales.  The 4 functional scales include body 
image, weight, anxiety and sexual function.  The symptom related scales include single 
item and multi-item questions concerning stool frequency, bleeding and mucous 
discharge, stool leakage, abdominal bloating, flatulence, embarrassment and site-specific 
pain among others. 
• The EuroQol EQ-5D is a standardized instrument for use as a measure of health outcome 
and is applicable to a wide range of health conditions and treatments.72,73  It provides a 
simple descriptive profile and a single index value for health status. 
• The Cancer Worry Scale74 is a brief psychometric instrument that was designed to assess 
both the frequency of worrying about “getting cancer some day” and measuring the 
impact of worry on mood and performing daily activities.  This scale was originally 
developed by Caryn Lerman and her colleagues to study breast cancer and has been 
modified for use in this FAP trial.  
The validity and reliability of both the QLQ-C30 and the QLQ-CR29 questionnaires have been 
studied by the EORTC Study Group on Quality of Life and both instruments will be scored 
according to the EORTC Scoring Manual and analyzed accordingly. 
HRQoL measures will be obtained at baseline, month 3, at every interim endoscopy visit, and at 
end of treatment.  For each single item or multi-item sub-scale, a linear transformation will be 
applied to standardize raw scores to range between 0 and 100.  HRQoL secondary endpoints will 
include all single item or multi-item sub-scales from both the EORTC QLQ-C30 and QLQ-CR29 
and subjects will be considered as deteriorated (or improved) for a given single item or multi-
item sub-scale if their change score from baseline was 10 points or more on the standardized 
scale. 
In addition to the HRQoL assessment, subject preferences (or utilities) will also be assessed.  
Data will be collected at baseline, month 3, at every interim endoscopy visit, and at end of 
treatment and preference weights among the treatment arms will be determined using the 
EuroQol EQ-5D assessment of individual health states.72,73  Quality-adjusted survival among the 
three treatment arms will be generated by multiplying the utility value by the amount of time 
spent in a specified health state.  
The modified version of the Cancer Worry Scale will also be administered at baseline, month 3, 
at every interim endoscopy visit, and at end of treatment and it will be scored according to the 
guidance provided by Lerman et al.74 


IND 103,678 
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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
51 
 Dietary Assessment 
The Food Frequency Questionnaire (FFQ) is the most common dietary assessment tool used in 
large epidemiologic studies of diet and health.  The self-administered FFQ booklet asks 
participants to report the frequency of consumption and portion size of approximately 125 line 
items over a defined period of time (e.g. the last month; the last three months).  Each line item is 
defined by a series of foods or beverages.  Additional questions on food purchasing and 
preparation methods enable the analysis software to further refine nutrient calculations.  The 
FFQ was developed by the Nutrition Assessment Shared Resource (NASR) of the Fred 
Hutchinson Cancer Research Center.  NASR periodically updates its standard FFQ to reflect 
U.S. food consumption patterns and major changes in the market place.82,83  Data from the FFQ 
will be analyzed using a polyamine database69 and will calculate the average daily levels of 
putrescine, spermidine, and spermine in the diet.  Dietary assessments via the FFQ will be 
obtained at baseline, months 12, 24, 36 and 48/end of treatment for subjects at North American 
(U.S. and Canada) sites only.  The results of the FFQ will be used to corroborate results from 
another recent trial84 that indicate consumption of a diet high in polyamines is associated with 
reduced treatment efficacy.  The results of this trial along with the earlier findings of Zell et al40 
could lead to dietary restrictions in combination with the combined eflornithine-sulindac therapy. 
11. 
ASSESSMENT OF SAFETY 
 Cardiac Risk 
All subjects will undergo a baseline medical history evaluation and EKG for cardiovascular 
disease risk assessment.  Subjects with cardiovascular risk factors as defined in Section 6.2 are 
not eligible for study participation.  On-study cardiac risk assessments, for each subject, will take 
place throughout the study via ongoing adverse event assessments and periodic EKG evaluations 
at baseline, and months 3, 6, 12, 18, 24, 30, 36, 42 and 48/end of treatment.  
 Ototoxicity Risk 
All subjects will undergo air conduction audiometry for hearing impairment as part of the 
screening process and at months 12, 24, 36 and 48/end of treatment.  Subject diaries will indicate 
the presence of symptoms and will instruct the subject to contact the treating doctor for 
assessment. These data will not be used to exclude subjects from this study.  
At months 3, 6, 12, 18, 24, 30, 36, 42 and 48/end of treatment, the subject will undergo a clinical 
assessment for ototoxicity adverse events symptoms by the research nurse or other medically 
qualified individual. 
 Gastrointestinal Risk 
Subject’s diaries will indicate presence of symptoms and will instruct the subject to contact the 
treating doctor for assessment.  Stool will be self-assessed by subjects to determine if gross blood 
or melena is present.  If so, treating doctor will be contacted and the subject assessed.  Subject 
will perform stool assessments, which will be recorded in their diary. 
At months 3, 6, 12, 18, 24, 30, 36, 42 and 48/end of treatment, the subject will undergo a clinical 
assessment for gastrointestinal adverse events symptoms by the research nurse or other medically 
qualified individual. 
 
 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
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 Safety Parameters 
Subjects will be followed for safety from the start of treatment through 30 days after treatment 
discontinuation.  Serious adverse events will be followed until resolved or returned to baseline, 
even if longer than 30 days from the subject’s off study treatment or off study date.   
Adverse events and serious adverse events must be recorded carefully and completely on the 
case report forms and SAE report forms.  Adverse event reporting and grading will be done 
using the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf).   
Serious adverse events must be reported to the Institutional Review Board (IRB)/Independent 
Ethics Review Committee (IEC)/Research Ethics Board (REB) by the Investigator and to 
regulatory authorities (FDA, National Health Authorities) by the Sponsor, according to 
established policy and regulatory requirements.  Adverse events will also be coded to an organ 
system class.  Summaries of safety data will be completed for the study population. 
 Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related (FDA definition) and is defined by the EU and 
Canadian regulations as any untoward medical occurrence in a subject or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, without any judgment about causality.  An adverse event can 
arise from any use of the drug and from any route of administration, formulation, or dose, 
including overdose. 
An adverse reaction means any adverse event caused by the drug.  Adverse reactions are a subset 
of all suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. 
An adverse event does not include: pre-existing disease, conditions, or laboratory abnormalities 
present at the start of the study that do not worsen in frequency or intensity; situations where an 
untoward medical occurrence has not occurred (e.g., hospitalizations for cosmetic or elective 
surgery or social/convenience admissions); the disease being studied or signs or symptoms 
associated with the disease unless more severe than expected for the subject’s condition. 
For the FDA, an unexpected adverse event is an event that is not listed in the Investigator’s 
Brochure (IB) at the specificity or severity observed or is mentioned in the IB as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but not 
mentioned as occurring with the drug(s) under investigation. 
The Reference Safety Information (RSI) is located in the IB Ver. CPP-201-IB08 and subsequent 
versions, which is to be used for the purposes of determining expectedness and SAE/SUSAR 
reporting. 
 
 


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 Serious Adverse Events 
A serious adverse event determined by the opinion of the Investigator or Sponsors is defined as 
1. Death; 
2. A life-threatening event (places the subject at immediate risk of death); 
3. Requires in subject hospitalization or prolongs hospitalization; 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
5. Congenital anomaly/birth defect; 
6. Important medical events (IMEs) may be considered serious when, based on medical 
judgment, they may jeopardize the subject and require intervention to prevent one of the 
above serious outcomes. 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
serious form, might have caused death. 
 Reporting of AEs, SAEs, Serious and Unexpected Adverse Experiences 
Subject Reporting of an Adverse Event 
Subjects will be instructed to contact the Investigator or Research Nurse to report any symptom.  
The Investigator will question each subject regarding symptoms at the time of each physical 
examination/review of body systems.  All adverse experiences, including duration and severity 
will be captured in the Case Report Forms provided by the Sponsor. 
All adverse events are to be documented from the day the subject receives his/her first study 
treatment through 30 days after the subject’s off study treatment date (date of last dose). 
Reporting Serious Adverse Events (SAEs) to Sponsor 
Serious Adverse Events are to be documented and reported to the Sponsor from the day the 
subject receives his/her first treatment through 30 days after the subject’s off study treatment 
date.  SAE follow-up needs to continue until the event is resolved or returned to baseline. Serious 
Adverse Events occurring to a subject after the 30-day off study treatment date should be 
reported to the Sponsor only if the SAE could be attributed to study treatment. 
An Investigator shall report to the Sponsor via telephone, fax or e-mail, any Serious Adverse 
Event regardless of causality, within 24 hours of receipt of information. 
Reporting to the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Research Ethics Board (REB) 
SAE’s must be reported to the IRB/IEC/REB by the Investigator according to each institution’s 
policy and procedures. 
Reporting to Regulatory Authorities and Participating Investigators 
The Sponsor will notify appropriate regulatory authorities by fax, telephone or in writing of any 
unexpected fatal or life-threatening suspected adverse reaction associated with the use of the 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
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study drug as soon as possible, but in no event later than 7 calendar days after initial receipt of 
the information. 
The Sponsor shall notify appropriate regulatory authorities and all participating Investigators in 
writing via IND safety reports/CIOMS reports of any serious and unexpected adverse experience 
associated with the use of the drug; and such reports shall be made as soon as possible but in no 
event later than 7 or 15 calendar days after the Sponsor’s initial receipt of the information, 
depending on the reporting requirements. 
The Sponsor will submit IND safety reports/CIOMS reports to FDA, Heath Canada, EMA, and 
National Competent Authorities as required, and all participating Investigators no later than 7 or 
15 calendar days after the Sponsor determines that the suspected adverse reaction or other 
information qualifies for expedited reporting based on country specific regulatory requirements.  
If any regulatory authority requests any additional data or information, the Sponsor will submit it 
as soon as possible, but no later than 15 calendar days after receiving the request. 
The Sponsor will report all adverse experiences to the U.S. FDA in Annual Reports to the IND, 
and to all applicable regulatory authorities annually as required, in addition to the final report of 
the clinical trial. 
 Reporting of Pregnancy 
If following initiation of study treatment, it is discovered that: 
• A female subject is pregnant or may have become pregnant at the time of investigational 
drug exposure, the investigational drug will be immediately discontinued until further 
assessment. If it is determined that study drug should be permanently discontinued, all study 
required procedures for study discontinuation and follow-up must be completed unless 
contraindicated by the pregnancy.   
• For male subjects, if their partner is pregnant or may have become pregnant, the male subject 
must agree to the use of a barrier birth control method as stated in section 6.1 #11 [Male 
subjects (including men who have had vasectomies) whose partners are pregnant should use 
condoms while the partner is pregnant. If the partner is still pregnant when the subject goes 
off study, the subject should continue condom uses for at least 2 weeks afterwards].  If he 
does not agree to the above, he will be terminated from the study and all study required 
procedures for study discontinuation and follow-up must be completed. 
The Investigator must notify the Medical Monitor within 24 hours of learning of the pregnancy 
and record the pregnancy on the Pregnancy Reporting Form and submit it to Cancer Prevention 
Pharmaceuticals via fax or email.  
The Investigator must report using the Pregnancy Reporting Form, follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome.  Generally, 
infants should be followed for a minimum of 6-8 weeks but additional follow up is not needed 
when a newborn is healthy. 
Pregnancy itself is not considered an AE or SAE but any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE and reported 
as described in Sections 11.4 - 11.8. 
 Concomitant Medications 
All concomitant medications and medications taken within 30 days before the first study drug 
administration until the subject’s off study treatment date, and concomitant medications for AEs 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
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55 
recorded within the 30-days post-EOT, will be coded to therapeutic drug classes and generic 
names using, for example, the WHO Drug classification dictionary. 
Subjects are to be instructed to not take the following medications or supplements while on study 
treatment: oral corticosteroids (such as prednisone), NSAIDS (such as ibuprofen, celecoxib, 
aspirin in excess of 700 mg weekly), diflunisal, supplements containing omega-3-fatty acids 
(such as fish oil), anticoagulants (such as warfarin, Pradaxa®, Eliquis®, Plavix®, and other direct 
thrombin inhibitors), fluconazole, lithium, furosemide and thiazides, DMSO, methotrexate, 
probenecid, propoxyphene hydrochloride, Tylenol® (acetaminophen) preparations containing 
aspirin or cytotoxic chemotherapy drugs. 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
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12. 
STATISTICAL CONSIDERATIONS 
The Statistical Analysis Plan (SAP) will focus on analysis of the primary and secondary 
endpoints, in order to assess the extent to which the combination of CPP-1X 750 mg daily + 150 
mg sulindac is more effective than each agent alone in delaying the time from the date of 
randomization to the date of the first occurrence of any FAP-related event in Familial 
Adenomatous Polyposis (FAP) patients.  Eligible patients who have given informed consent will 
enter the study with the intent to participate for the full treatment period.  Accrual is expected to 
take 12-24 months.  Eligible patients who have given informed consent will enter the treatment 
extension phase with the intent to participate for the full study extension treatment period of up 
to an additional 24 months. 
The Statistical Analyses Plan will include method descriptions and will pre-specify the statistical 
approaches to be used, primary and secondary study endpoints, data handling conventions and 
randomization processes.  
At least 150 eligible patients will be enrolled in this study, with at least 50 per treatment group.  
Patients will be randomized to one of three treatment groups within the prognostic strata defined 
in Section 4.3 in equal proportions (i.e., 1:1:1 randomization): 1) CPP-1X plus sulindac, 2) CPP-
1X placebo plus sulindac, 3) CPP-1X plus sulindac placebo.   
The study is double blinded, so neither subjects nor Investigator nor Sponsor will be aware of 
treatment assignment. 
For the primary efficacy analyses, we will use the intent-to-treat (ITT) population defined as all 
subjects that have been randomized to one of the three study arms.  Subjects will be analyzed in 
the group to which they were randomized, whether or not they received their assigned treatment, 
any treatment whatsoever, or completed their treatment course and follow-up.  The safety 
outcome will be analyzed using all subjects in the ITT population who received at least one dose 
of study drug (safety population).  
 Primary Efficacy Objective and Analysis 
The primary objective of this trial is to determine whether the combination of CPP-1X + sulindac 
is superior to either single-agent treatment individually in delaying the time from the date of 
randomization to the date of the first occurrence of any FAP-related event.  Section 8.2.14 
provides complete detail on FAP-related events. 
Thus the primary objective contains two treatment comparisons:  
1. CPP-1X placebo + sulindac active vs. CPP-1X active + sulindac active,  
and 
2. CPP-1X active + sulindac placebo vs. CPP-1X active + sulindac active 
These two treatment comparisons will be performed sequentially as described below. 
The combination of CPP-1X active + sulindac active is specified as the reference treatment 
group because it is common to both comparisons.  In addition, because the purpose of the 
combination treatment is to delay the time from randomization to FAP-related disease 
progression compared to single-agent treatments, formulating the hypothesis tests in this manner 
will allow a positive rather than a negative Z-score for the test statistic to be interpreted as 
supportive of this purpose. 
Each comparison will be performed at the 2-sided 0.05 level of statistical significance. 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
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As explained in the Statistical Analysis Plan, the decision to seek regulatory approval based upon 
the results of the primary objective will be taken sequentially. 
CPP will sequentially perform the two primary comparisons as part of the primary analysis, each 
at the 2-sided p = 0.05 level.  All information concerning these comparisons will be clearly 
provided to both Agencies.  The single treatment comparison requested by FDA will be 
available, as will the two comparisons requested by EMA, both at the requested level of alpha.  
This approach fulfills the differing requirements for the primary comparison as asked for by each 
Agency.  
We note that this approach is both a fixed-sequence and gatekeeping approach.  It is fixed-
sequence in that the comparison of combination with single-agent Sulindac takes place before 
the comparison of combination with single-agent Eflornithine and the first serves as a gatekeeper 
for the second (i.e., no declaration of significance in the second comparison will be made if the 
first comparison is not significant at the 0.05 level).  Therefore, the type I error in the sequential 
testing is well controlled.  In addition, because both tests must be significant for EMA approval, 
the type I error of the second test in the sequence is less than 0.05. 
The analytic method for the primary analysis will be a time-to-event analysis using the stratified 
log-rank test.  The stratified Cox proportional hazards regression models will be used for 
secondary assessments.85  Graphical analyses (log-minus-log plots) will be used to check the 
assumption of constant hazard ratios.  For the primary analysis, two stratified log-rank tests will 
be performed with treatment coded as a binary value (i.e., 0 or 1). Time to event curves will be 
displayed using the method of Kaplan and Meier86.  Additional analyses involving the overall 3-
treatment group comparison and use of additional study populations or the two pairwise 
treatment comparisons, will be performed as supplemental analyses. 
If an FAP-related event occurs, that patient will be said to have an observed or uncensored event 
and will be considered a treatment failure.  If a subject withdraws, that subject will be treated as 
a censored observation as of the last recorded clinic visit (endoscopic disease assessment). 
If a subject has not progressed or is not known to have died at the date of analysis cut-off, time to 
first FAP-related event will be censored at the date of the last adequate endoscopy procedures 
before the cut-off date.  Similarly, if a subject discontinues study participation due to toxicity and 
begins receiving other therapy, the time to FAP event will be censored at the date of the last 
adequate endoscopy procedure.   
Prior to the primary analysis, balance will be assessed between the three arms in terms of key 
potential confounders measured at the baseline visit.  If any of these variables is found 
significantly out of balance across the three groups using a 2 degree of freedom test of 
homogeneity at the 0.01 level of significance, it will be incorporated into -a sensitivity analysis 
using a stratified Cox model including that term in addition to the treatment arm.  The primary 
result for the trial will be the unadjusted stratified log-rank test.  The covariate-adjusted score test 
(adjusted stratified log-rank test) will serve only as a secondary analysis to aide in the 
interpretation of the primary result. 
 Secondary Efficacy Outcome and Analysis 
Any improvement observed by the investigator during upper gastrointestinal (UGI) and lower 
gastrointestinal (LGI) visualization (i.e. endoscopy and colonoscopy) at the 6 and 12-month 
study visits will be described using the variables UGI Observed Improvement (UGIOI), and LGI 


IND 103,678 
Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
58 
Observed Improvement (LGIOI).  Each patient will have one pair of UGIOI and LGIOI 
outcomes (refer to the Statistical Analysis Plan for more detail). 
UGIOI and LGIOI are binary outcomes derived from numerical determinations (henceforth, 
“investigator change scores” or more briefly, “scores”) assigned by the investigator during each 
procedure, using a scale (–2, –1, 0, +1, +2) which corresponds, respectively, to the investigator’s 
overall qualitative assessment of: much worse, worse, no change, improved, much improved.  At 
the month 6 procedures the investigator scores UGI and LGI findings as changes from baseline.  
At the month 12 procedures, the UGI and LGI findings are scored relative to the month 6 
procedures. 
The UGIOI (and respectively, the LGIOI) secondary endpoint independently summarizes the 
corresponding 6- and 12-month investigator change scores according to whether or not there was 
any positive improvement at either month 6 (compared to baseline) or at month 12 (compared to 
baseline or month 6), under the condition that there be no worsening at either timepoint 
(compared to the preceding timepoint).  Refer to the Statistical Analysis Plan for further details 
on the planned analysis.  
 Other Secondary Outcomes 
Other secondary outcomes will include the following: 
To explore how study treatment group relates to other efficacy outcomes, genotype, phenotype, 
disease locations and endoscopic findings, additional analyses are planned.  These analyses will 
be performed in the ITT group, the Per Protocol Group, and other defined subgroups (see 
protocol Section 12.5, Populations for Analysis and the Statistical Analysis Plan) wherever 
possible and will all be clearly noted as such. 
The UGIOI and LGIOI outcomes will be tabulated and summarized using the month 6 visit 
scores, alone.  Similarly, the UGIOI and LGIOI outcomes will tabulated and summarized across 
all study visits. 
As both part of the primary analysis, and further explored in these additional analyses, median 
time to event for each treatment group will be determined. This will be explored for each of the 
study populations (i.e. ITT, per protocol, and others), study disease stratum groups, and in the 
Disease Site subgroups (refer to the Statistical Analysis Plan for more details). 
Pharmacokinetic data (plasma concentrations measured at patient visits) will be used to estimate 
population pharmacokinetic parameters for the CPP-1X (eflornithine), sulindac, and CPP-1X 
(eflornithine) + sulindac treatment groups (i.e., for each analyte for those patients on 
combination treatment). 
The subcategories of FAP events will be explored by disease stratum groups, and by Disease Site 
subgroups (refer to the Statistical Analysis Plan). 
The presence or absence of ODC polymorphisms, including the single nucleotide polymorphisms 
(SNPS) rs2302615 and rs2302616 and their relation to treatment group and outcome will be 
tested with the likelihood ratio test. 
The excretion of 5 urinary polyamines (diacetylspermine, n1-acetylspermidine, n8-
acetylspermidine, decarboxylated SAM, and putrescine) will be assessed in relation to treatment 
group and outcome, using the single point concentration data gathered from the urine samples 
harvested at each study visit. 


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Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
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Patient reported health related quality of life measures will be evaluated using HRQoL (refer to 
Statistical Analysis Plan for more details). 
Tissue and dietary polyamine levels, as collected at patient study visits will be analyzed together 
with the results of the dietary questionnaires and related to treatment group and study outcomes. 
Safety outcome data and analyses are described in detail in the Statistical Analysis Plan. 
 Sample Size Determination 
The primary endpoint of this trial, time to meaningful clinical events in an orphan disease 
population, is novel and to date there are no published trials to draw upon that have incorporated 
the exact FAP-related endpoint of this trial.  Available data from primary literature sources 
include clinical studies where polyps were counted over a fixed time period, in different FAP 
populations (see Appendix E for tabulated listing).   
From these data a reasonable range of event frequencies was estimated to produce the sample 
size and power calculations incorporated into this trial.  These time-to-event estimates were 
reviewed by key FAP opinion leaders prior to finalization of the study design.  The following 
reflects the possible range of FAP events it was thought plausible to observe. 
 Power Calculation Assumptions 
1) The level of statistical significance is set at 0.05, using a 2-sided stratified log-rank test for 
time-to-first FAP-related event in continuous time, for each of the two between-group 
comparisons (i.e. single agent sulindac vs. CPP-1X plus sulindac and single agent CPP-1X vs. 
CPP-1X plus sulindac).  The only covariates in the log-rank test will be the treatment groups; 
2) A doubling of the two-year event-free proportion from either of the single agent treatment 
arms to the combination treatment group;  
3) Power of at least 85% to detect the above-mentioned treatment effect comparing either of the 
two single treatment arms to the combination arm; 
4) The two single-agent treatment groups have approximately the same event rate. 
The following calculations are based on our review of limited single-agent data for eflornithine 
and sulindac, where FAP clinical trial primary endpoints involved polyp counting.  Extrapolating 
these data to two-year event-free proportions implies a single overall two-year event-free 
proportion of at least 60% to 70% for the combination treatment group and 30% in each single 
agent treatment group.   
 Hazard Rates 
Because the power of time-to-event analyses depends on the total number of observed primary 
endpoints (“events”) and the hazard ratio in a given two-arm comparison of a single-agent versus 
combination therapy, we translate the above doubling of two-year event-free proportions into 
hazard ratios under a simplifying assumption of exponentially distributed time-to-event.   
Furthermore, the stratified log-rank test is an optimal test (locally most powerful) under the 
assumption that the ratio of the two groups’ hazard functions remains constant over time (the 
proportional hazards assumption).  Note that the much stronger assumption, that the individual 
hazard functions themselves remain constant over time, would be dubious in this trial.  
Therefore, irrespective of how the two-year event-free proportions are translated into hazard 
ratios, it is the latter which forms the design alternative parameter for the trial. 
Under the exponential assumption, the hazard ratio (HR) comparing one treatment arm to 


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Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
60 
another is given by the natural logarithm of the two-year event-free proportion for the first arm 
divided by the natural logarithm of the two-year event-free proportion for the other arm.  Thus if 
the combination arm is assumed to have a two-year event-free proportion of 60%, which is 
double that of the 30% two-year event-free proportions assumed for the single-agent arms, the 
HR is {log(0.60) / log(0.30)} = 0.4243.  This is the design alternative hazard ratio for this trial 
as it represents the minimum clinically meaningful treatment effect desired for the combination 
therapy compared to either single-agent therapy.  Insofar as the combination therapy may have a 
two-year event-free proportion of at least 60%, and may prove to be perhaps 70% or greater, the 
design alternative HR of 0.4243 is conservative; the true (albeit unknown) HR is thought 
possibly to range from 0.4243 down to 0.30 = {log(0.70) / log(0.30)}. 
Given that the primary hypotheses are stated in terms of comparing either single-agent arm to the 
combination arm, we note that the equivalent design alternative hazard ratio becomes  
{log(0.30) / log(0.60)} = 1/0.4243 = 2.357. 
For the anticipated range of hazard ratios, 25 to 49 events would be needed for each two-group 
comparison at the 2-sided 0.05 level to achieve 85% power87,88   Assuming two-year event 
proportions of 70% in either of the two single-agent groups and 30% to 40% in the combination 
arm with 50 patients per arm, the expected number of patients with an FAP-related event in 
either of the two single-agent groups would be 35 and 15 - 20 in the combination arm.  The study 
design expectation is to have 50 - 55 patients with a FAP-related event in each two arm 
comparison, achieving at least 85% power under the design alternative.  The standard deviation 
around the expectation of 55 events is 4.74, so observing the required number of 49 events or 
more would be highly likely (the probability is about 91%).  If the total number of events in 
either comparison were only 43, there will still be 80% power to declare a significant treatment 
difference under the design alternative of 0.4243. 
As the two-year event proportion in the combination arm decreases from 40% with a 
corresponding decrease in the hazard ratio, the likelihood of observing the required number of 
events to maintain 85% power actually increases.  For example, at the lower expectation of 50 
events arising from an assumed two-year event proportion of 30% in the combination arm, the 
standard deviation of the total number of events in a two-arm comparison decreases to 4.58 and 
the probability that the observed number of events will exceed the 25 required to achieve 85% at 
a HR of 0.30 is virtually certain. 
 Populations for Analysis 
 Intent-to-Treat (ITT) Population  
The intent-to-treat population includes all patients that have been randomized to one of the three 
study arms (CPP-1X plus sulindac, CPP-1X placebo plus sulindac, CPP-1X plus sulindac 
placebo).  Patients will be analyzed in the group to which they were randomized, whether or not 
they received any treatment or completed their treatment and follow-up. 
 Safety Population 
The safety population is defined as all ITT patients who received at least one dose of study 
medication.  Patients who do not receive any study treatment (CPP-1X or sulindac or their 
combination) are excluded from this population.  Patients will be analyzed in the treatment group 
for which actual treatment was initially received. 
 
 


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61 
 Per Protocol Population 
The per-protocol population is defined as the subset of the ITT population that fulfill all protocol 
eligibility, intervention, and outcome assessments. 
 Other Populations 
Within the entire study patient population there will be subsets who did not receive the full 
course of per protocol treatment.  The major indicators for premature withdrawal are delineated 
below.  The patient diary and pill count will define the extent of treatment compliance during the 
study. 
For exploratory and sensitivity analyses the following subsets will be included in secondary 
analyses: 
• Subject withdrawn for personal reasons 
• Treatment discontinued because of disease symptoms 
• Treatment discontinued because of patient symptoms 
• Compliance <80% treatments taken 
• Treatment discontinued because of intercurrent medical or surgical illness. 
 Other Statistical Methods  
 Demographic and Baseline Characteristics 
Patients in the three populations (ITT, Safety, Per Protocol) will be summarized for demographic 
and baseline characteristics in a descriptive fashion.  Namely, categorical and continuous-valued 
data will be displayed using standard summary statistics (e.g., frequency tables, n, means, 
medians, standard deviations, and ranges).  Data will be presented per group and overall.   
Demographic features summarized will include age, gender, race, institution at which each 
patient registered, and country among other features.  Baseline characteristics will include 
laboratory values and disease-related characteristics, as well as any other relevant values.  
Categorical data will be compared among groups using chi-squared methods, while continuous-
valued data will be compared using standard nonparametric methods (e.g., the Kruskal-Wallis 
test).89  Significance will be defined at the 0.05 level, unless otherwise noted.  Thus p-values less 
than or equal to 0.05 will be declared significant. 
 Patient Disposition and Treatment Summaries 
Subjects will be assigned for analysis to the treatment group to which they were randomized, 
regardless of whether the patients received any treatment. 
Subject disposition and treatment will be summarized for ITT and safety populations defined 
previously.  Subject disposition will be consistent with the CONSORT criteria,90 and will include 
per treatment group enumeration of all patients randomized, the number deemed ineligible, the 
number of FAP-related events, and the number of study drop outs.  These will be further 
described in subgroups such as drop outs due to adverse events, serious adverse events, 
administrative withdrawals for non-compliance, withdrawals of consent for continued follow-up, 
withdrawals for other reasons, and the number lost to follow-up.  Additional summaries will 
include reasons for patients discontinuing treatment and/or modifying treatment dosages.  A 
listing of screened and ineligible patients along with the reason for each also will be summarized. 
 
 


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Cancer Prevention Pharmaceuticals, Inc. 
FAP – CPP-1X (Eflornithine HCl/Sulindac) 
CPP FAP-310 Ver. 5.2, 17January2019 
 
62 
 Categorical or Continuous-Valued Secondary Outcome and Safety Data 
For categorical data, comparisons will be made between treatment groups using standard chi-
square techniques as the primary approach.  In particular, Cochran-Mantel Haenszel one degree 
of freedom test will be used to reflect the stratified randomization.  Exact p-values and 95% 
confidence intervals by the point probability method will be reported91. 
For continuous endpoints, standard analysis of covariance (ANCOVA) methods will be used as 
the primary approach to compare treatment groups at end of treatment with the following 
covariates: baseline value, binary indicator variables for the two highest-risk stratification levels 
used in the randomization (using the lowest-risk, i.e., rectum/pouch polyposis, group as the 
reference stratum), and a binary treatment indicator (1=combination treatment, 0=single 
treatment). 
For ordered categorical data, a Kruskal-Wallis nonparametric test for ordered categorical 
response will be used to compare treatment groups.89 
Treatment-emergent adverse events will be enumerated and analyzed according to the incidence, 
intensity, type of adverse events, and clinically significant changes in the patient’s physical 
examination findings, vital signs and clinical laboratory results.  Safety variables will be 
tabulated and presented for all patients in the safety and per-protocol populations as defined 
previously.  
Adverse events will be graded and coded using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE, Version 4.03).  Treatment-emergent events will be tabulated, where 
treatment-emergent is defined as any adverse event that occurs after administration of the first 
dose of study drug and through 30 days after the last dose of study drug, or any event that is 
present at baseline and continues after the first dose of study treatment but worsens in intensity.  
Events that are considered related to treatment (possibly, probably or definitely drug-related) 
also will be tabulated separately.  Tables that enumerate adverse events by severity will also be 
provided.  Deaths, serious adverse events and events resulting in study discontinuation will be 
tabulated in data listings including additional relevant information on each patient.  Tables will 
be presented both overall (all arms combined), by each treatment group separately, and by cell. 
Where appropriate, statistical comparisons between treatment arms will be provided using the 
above-mentioned methods for analysis of categorical data. 
 Subgroup Analyses 
Subgroups will be analyzed in the spirit of exploratory analyses including but not limited to the 
various study populations and separately within each disease-prognosis stratum. 
 Health Related Quality of Life (HRQoL) 
For this study four (4) instruments to measure HRQoL and patient preferences or utilities will be 
administered to subjects at baseline and months 3, 6, 12, 18, 24, 30 36, 42 and 48/end of 
treatment.  These instruments include the EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D, and 
a modified Cancer Worry Scale. 
The validity and reliability of both the QLQ-C30 and the QLQ-CR29 questionnaires have been 
studied by the EORTC Study Group on Quality of Life and both instruments will be scored 
according to the EORTC Scoring Manual and analyzed accordingly.  For each single item or 
multi-item sub-scale, a linear transformation will be applied to standardize raw scores to range 
between 0 and 100.  HRQoL secondary endpoints will include all single item or multi-item sub-
scales from both the EORTC QLQ-C30 and QLQ-CR29 and patients will be considered as 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
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deteriorated (or improved) for a given single item or multi-item sub-scale if their change score 
from baseline was 10 points or more on the standardized scale.   
Patient preferences (or utilities) will also be assessed using the EuroQoL EQ-5D.  Preference 
weights among the treatment arms will be determined using the EuroQol EQ-5D assessment of 
individual health states.72,73  Quality-adjusted survival among the three treatment arms will be 
generated by multiplying the utility value by the amount of time spent in a specified health state.  
The modified version of the Cancer Worry Scale will also be administered and it will be scored 
according to the guidance provided by Lerman et al74. 
HRQoL data will be obtained while patients are receiving treatment.  At the time of an FAP-
related event (primary outcome), additional long-term clinical follow-up and QoL data will not 
be obtained as part of this trial.  Hence, HRQoL trends comparing the nine subsets will be 
obtained, but comparative longitudinal analyses defining the impact of an FAP-related event on 
QoL will not be feasible until subsequent long-term studies are performed. 
 Dietary Assessment 
The FFQ was developed by the Nutrition Assessment Shared Resource (NASR) of the Fred 
Hutchinson Cancer Research Center. NASR periodically updates its standard FFQ to reflect U.S. 
food consumption patterns and major changes in the market place.82,83  Data from the FFQ will 
be analyzed using a polyamine database69 and will calculate the average daily levels of 
putrescine, spermidine, and spermine in the diet.  Dietary assessments via the FFQ will be 
obtained at baseline, months 12, 24, 36, 42 (only if end of treatment) and 48/end of treatment for 
subjects at North American (U.S. and Canada) sites only. 
 General Procedures for Handling of Missing Data 
Every reasonable effort will be made to continue follow-up of all study participants, including 
those who discontinue randomized therapy, to prevent data loss.  It is recognized that missing 
values represent a potential source of bias in a clinical trial and so every effort will be undertaken 
to fulfill all the requirements of the protocol concerning the collection and management of data. 
For the primary time to event analysis, the only possible patient outcome is an observed FAP-
related event, or a censored observation.  Participants who are lost to follow-up for reasons 
deemed unrelated to their health status will be censored at the time their status is last known, 
based upon data collected at the last recorded clinic visit.  For patients who may have missed a 
study visit, every effort will be made to obtain endoscopic results at their close-out visit and 
those endoscopy results will be used for the primary analysis.   
Secondary analysis data include the presence of a specific genetic mutation, and urinary 
metabolite concentrations (See Section 12.2). The main analysis of the secondary objectives will 
include collected data only, without imputing or weighting data to compensate for missing data.  
For sensitivity analyses involving secondary endpoints with missing data, we will use the last 
observation carried forward (LOCF) method to complete the missing data.  Any sensitivity 
analysis that incorporates LOCF will be clearly noted.  Sensitivity analyses of these data will be 
performed to explore study results more fully, in a manner consistent with ICH Guidance “E9 
Statistical Principles for Clinical Trials (February, 1998)”. 
All available efficacy and safety data will be included in data listings and tabulations.  Data that 
are potentially spurious or erroneous or appear as outliers will be examined using standard data 
management operating procedures, prior to database lock and statistical analysis. 


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 Interim Monitoring and the Data Monitoring Committee 
A Data Monitoring Committee (DMC) will oversee the performance and safety conduct of this 
study.  The DMC will consist of at least three members (two MDs and one statistician as voting 
members) who will receive confidential reports on a periodic basis.  The DMC will be 
responsible for decisions regarding possible termination of the study for either futility or safety 
reasons. 
A detailed DMC Charter will be produced separately by the DMC membership.  It is anticipated 
that any reviews of study data will be performed in a blinded manner, looking at pooled data (all 
treatment groups combined into one group) to assess mission-critical parameters such as overall 
recruitment and event rates.  Any pre-specified interim analyses will be conducted in a blinded 
manner.  Of course, patient safety issues take precedence over bias-protection and control of type 
I error, and so the DMC will have the privilege of breaking the blind on a need-to-know basis if 
safety issues of concern arise in order to consider risk-benefit issues.  Details concerning DMC 
responsibilities and duties may be submitted as a stand-alone document to the FDA and EMA, 
including items such as specification of early termination rules and other matters as the DMC 
deems to be important and relevant to the ethical conduct of this study.  
CPP will inform the DMC that there will be two study evaluations for the DMC to consider 
during the trial, one interim look for sample size reassessment and one look for futility. 
The method for reassessment of sample size is based upon the FDA Guidance, “Adaptive Design 
Clinical Trials for Drugs and Biologics (February 2010)”.  There will be no hypothesis testing.  
The DMC will assess the observed trial event rate based on pooled data only.  They will make a 
recommendation to the Sponsor on whether the pooled event rate is sufficient to preserve the 
integrity of the trial, and if not, to recommend a revised sample size.  For this assessment the 
study statistician will, if possible, estimate the overall observed event rate and 90% confidence 
interval.  This assessment will be performed using data from a single time point, when 
enrollment is approximately 95% complete.  If this type of assessment is not possible, then as 
assessment will be performed taking into consideration the total number of subjects randomized, 
total number of events, total number of dropouts, and cumulative study safety data. 
Prespecified Interim Efficacy and Futility Analysis 
A pre-specified interim efficacy and futility analysis will be conducted in a blinded manner.  The 
assessment will be performed after a total of 45 primary endpoints have occurred, which 
represents 50% of expected maximum trial information, or as soon thereafter as possible.  Refer 
to the Statistical Analysis Plan for more details. 
The analysis will be performed for each of the two treatment comparisons contained in the 
primary objective:  
1. CPP-1X placebo + sulindac active vs. CPP-1X active + sulindac active,  
and 
2. CPP-1X active + sulindac placebo vs. CPP-1X active + sulindac active  
The efficacy analysis will use a modified Haybittle-Peto stopping rule based on the stratified log-
rank Z-score.  If that Z-score equals or exceeds 3.2905 in absolute value, for either two-arm 
comparison, the difference between treatment arms would be declared statistically significant at 
the two-tailed 0.001 level of significance.  In that case it may be reasonable for the DMC to 
initiate a conversation about stopping the trial on ethical grounds.  Assuming this is not the case 


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and the trial continues to its planned end, the Z-score criterion for declaring significance at the 
5% level at the end of the trial will be increased in magnitude to plus or minus 1.962 in order to 
preserve the overall type I error rate for the trial at 0.05. 
For the futility analysis, the DMC will be provided with the numerical value of the stratified log-
rank Z-score.  The futility analysis uses a one-sided futility stopping criterion of Z = −0.50. That 
is, if the Z-score is less than or equal to −0.50, an investigation will be initiated to consider 
stopping the trial for futility or discontinuing one of the single-agent treatment arms.  The futility 
stopping criterion of Z = −0.50 is consistent with a conditional power of less than 20%.  That is, 
assuming between 44 and 60 FAP-related events have occurred by trial end in either of the two-
arm comparisons (where between 52 and 55 are expected), if the log-rank critical ratio Z-score 
were equal to −0.5 (or less) when one-half the expected total number of events had been 
observed (namely, 45 across all three arms), then under the design alternative hazard ratio of 
2.3569, there would be no more than a 20% chance of declaring a significant benefit of the 
combination therapy compared to the single agent therapy if the trial were to continue to the 
planned end. In that case, it would be reasonable for the DMC to consider stopping or altering 
the trial on grounds of futility.  The DMC will also be provided with the conditional power of the 
observed Z-score for each two-arm comparison. 
Any numerical values generated from the futility analysis (such as Z-score, conditional power, 
etc.) must be treated as confidential by the DMC and Independent Statistician at the CRO.  If the 
DMC recommendation is to continue the study as planned, such numerical values will not be 
forwarded or conveyed in any manner to the Steering Committee, Sponsor, or any other parties. 
 Pharmacokinetic Analysis for Eflornithine and Sulindac 
The text that follows applies to each of the two compounds, eflornithine and sulindac.  Separate 
analyses will be performed for each drug. 
To perform the population pharmacokinetic analysis, a dataset will be constructed as follows: 
1. All subjects with at least one sample will be included in the analysis.  Actual sample time 
will be used in the analysis. 
2. Dosing history will be assembled based on CRF data.  Dosing records will assume 100% 
compliance, except as documented in the CRF. 
3. The dataset will be constructed using a script in R (www.R-project.org).  All steps will be 
documented.  All decisions regarding handling of aberrant data will be documented. 
4. Covariate data (age, extent of prior colectomy, body size, gender, race, laboratory values, 
etc.) will be included in the dataset.  The dataset will be constructed using values 
obtained temporal to the time of sampling. 
The pharmacokinetic analysis will be performed using NONMEM (version 7.1 or greater).  
Graphics will be created using PLT Tools (version 3.0 or greater) using R (version 2.11 or 
greater).  Initially, linear compartmental models will be applied to the data.  The choice between 
1-, 2-, and 3-compartment models will be based on the graphics and the minimum value of the 
objective function.  If graphics suggest nonlinearity in pharmacokinetics with respect to dose 
and/or concentration, nonlinear models will be evaluated. 
Once the optimal structural and error model has been determined, covariate effects will be 
assessed using a variety of tools including graphics of post hoc parameter estimates vs. 
covariates, a general linear model of parameters as a function of covariates, or an automated 


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FAP – CPP-1X (Eflornithine HCl/Sulindac) 
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66 
covariate search (PLT Tools).  Covariates will be incorporated into the model if they are 
physiologically appropriate, achieve statistical significance (generally requiring a P value < 0.01 
in this exploratory environment), and improve the graphics. 
Once a final model is determined, the model will undergo validation.  The strength of covariate 
effects will be determined using likelihood profiles.  Confidence intervals for parameter 
estimates will be determined using bootstrap techniques.  If appropriate, a visual predictive 
check will be performed. 
All NONMEM outputs and graphics will be provided with the population pharmacokinetic 
report.  Results will be summarized detailing the process of model building.  The report will 
include key graphics demonstrating the fit of the model to the data and covariate effects. 
 
13. 
STUDY MANAGEMENT AND REPORTING PROCEDURES  
 Data Monitoring  
A Data Monitoring Committee (DMC) will oversee the performance and safety conduct.  The 
DMC will consist of at least three members (two MDs and one statistician as voting members) 
who will receive confidential reports on a periodic basis.  The DMC will be responsible for 
decisions regarding possible termination of the study for either futility or safety reasons, refer to 
Section 11, Assessment of Safety and Section 12.8, Interim Monitoring and the Data Monitoring 
Committee. 
 Patient Tablet Dispensing Record 
Three (3) month supplies of study drug(s) are issued in person or by special arrangement.  
Subjects will keep a written diary concerning their compliance in taking the four tablets daily. 
The drugs are to be taken at approximately the same time each day with food, preferably in the 
morning.  If the dose is missed, the tablets may be taken with mid-day or evening meals.  If an 
entire day is missed, this should be indicated in the weekly dose accountability in the medication 
diary, but double-dosing the following day is not allowed.  If the subject vomits within an hour 
after taking the tablets, the subject will record a missed dose in the diary. If the subject vomits 
more than 1 hour after taking the tablets, no dose was missed.  In either case, no additional 
tablets are to be taken until the scheduled dose the next day.  Any unused medication must be 
returned at the subject’s next scheduled visit and an accounting of the medication will be 
performed and recorded by the research nurse or other qualified individual. 
 Investigator Documentation 
The Investigator will provide the Sponsor with a fully executed FDA form 1572 including the 
Investigator’s dated curriculum vitae.  A current curriculum vitae is also required for each sub-
Investigator listed on the FDA Form 1572.  A current dated curriculum vitae is defined as 
updated within 2 years. 
The Investigator will indicate on the FDA Form 1572 the name and location of the clinical 
laboratory which will be used for subject evaluation.  The laboratory’s certification, certification 
number and date of certification and the laboratory normal values will be provided.  Any changes 
in the clinical laboratory or laboratory values will be provided promptly to the Sponsor who will 
report it to the FDA. 


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The Investigators and Sub-Investigators must provide CPP with an FDA Form 3454 certifying 
the absence of financial interests and arrangements, or Form 3455 disclosing such financial 
interests and arrangements and any steps taken to minimize bias. 
 Protocol Amendments 
All amendments to the study protocol must be submitted to the IRB/IEC/REB for written 
approval.  The approval letter, signed by the IRB/IEC/REB Chairperson, must refer specifically 
to the Investigator, the protocol number and protocol title, the protocol amendment number and 
the date of the protocol amendment.  A copy of the approval letter and revised informed consent 
document (if appropriate) must be sent to CPP.  A protocol amendment may be implemented 
only after it has been approved by the IRB/IEC/REB and submitted to the FDA and other 
regulatory agencies as appropriate.  In the case of a protocol change intended to eliminate an 
apparent immediate hazard to subjects, the change may be implemented immediately, but the 
change must then be documented in a protocol amendment and approved as described above. 
 Access to Source Data and Documents 
Monitors and/or auditors of CPP or representatives of the Sponsor must be allowed to visit and 
monitor all study site locations periodically to assess the data, quality and study integrity.  The 
monitors and/or auditors will review study records (typically CRFs) and directly compare them 
with the source documents and discuss the conduct of the study with the Investigator and verify 
that the investigational site is compliant and continues to be acceptable.  In addition, the site may 
be audited by government inspectors who must be allowed access to CRFs, source documents 
and other study files.  The site must promptly notify CPP of any inspections scheduled by 
regulatory authorities, and also forward copies of the inspection reports to CPP. 
 Investigational Agent Records and Accountability 
It is the Investigator’s responsibility to ensure that accountability records of drug use and 
disposition are maintained at the study site and that the drug is maintained in a secure location 
under storage conditions prescribed by the Sponsor.  The site pharmacist or appointed 
investigational agent monitor will be the individual completing the records or logs for 
accountability and drug dispensing at each site.  The site pharmacist must comply with all 
applicable regulations and guidelines.  The logs should include the amount of drug received; 
amount currently on site, drug lot or batch numbers; amount dispensed to each study subject with 
appropriate subject study identification numbers; non-study disposition (wastage, broken), 
amount returned to site and Sponsor, amount destroyed at study if requested.  CPP will provide 
forms to assist with drug inventory if the site does not have an established procedure that meets 
the requirements.  Drug inventory records will be inspected by the Sponsor’s study monitors 
during the period of study treatment.  Audits will be done to verify drug accountability.  If a site 
has been determined to be non-compliant with drug accountability corrective action will be 
initiated. 
At the completion or termination of the study, all unused investigational agent will be returned to 
the repository unless authorized in writing to be destroyed at the site.  If the drug is to be 
destroyed on site, appropriate policies and procedures at the site must be in place for proper 
disposal of chemotherapeutic agents.  These procedures will be reviewed by Sponsor’s study 
monitors prior to providing written authorization for on-site drug destruction.  The unused study 
drug can only be destroyed after being inspected and reconciled by the Sponsor’s study monitor.   
 


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 Data Handling and Record Retention 
Following the completion and closure of the clinical study, in accordance with applicable 
regulatory requirements, the Investigator will maintain a copy of all study records in a safe and 
secure location.  Completed original CRFs, which are dated and signed by the investigator, and 
any resolved query reports will be retained by the Sponsor.  A copy of each completed CRF and 
signed resolved query report must be retained at the investigational site.  The Investigator will 
retain a copy of all study records in a secure location for a minimum period of 2 years after 
licensure for marketing of drug or 15 years from the close of the trial or until receipt of 
notification by Sponsor that clinical development of this treatment has been terminated. 
 Protocol Deviations 
The Investigator is not permitted to alter or deviate from the protocol without a written waiver 
from the Sponsor.  This waiver should also be reported by the Investigator to his/her 
IRB/IEC/REB.  An immediate and unapproved deviation is permitted if immediate subject safety 
concerns mandate a deviation. 
 Study Termination 
The Sponsor may terminate the study at any time.  If the study is terminated, the Sponsor will 
promptly notify the Investigator to enter no further subjects on the study and remove current 
subjects from the study.  The Sponsor will also inform regulatory authorities of the action. 
1. The study will also be terminated when the objectives have been fully met and all of the 
designated data collected. 
2. The Sponsor reserves the right to terminate an Investigator’s participation in this clinical 
trial for refusal of the Investigator and/or site to comply with any requirements stated in 
this clinical protocol. 
 Use of Data and Publication 
All data and results and intellectual property rights in the data and results that are derived from 
the study will be property of CPP.  CPP may utilize the results and data in variety of ways 
including submission to regulatory authorities or to other investigators under disclosure.  Data 
from any individual center must not be published or presented until the complete multicenter 
study has been published or presented in full.  Subsequently, an investigator may use the data 
derived from the clinical study for scientific purposes but must discuss any publication with the 
Sponsor prior to submission or release of any data.  The Sponsor is aware of the rights of an 
Investigator to publish the results when the study is completed, and the Investigator must provide 
a draft of the abstract or manuscript to the Sponsor within 30 to 60 days prior to submission of 
the abstract or manuscript.  The Sponsor will provide a timely review and response to the 
Investigator.  In the event of a difference of opinion between the Investigator and Sponsor, all 
efforts will be put forth to find a solution that is agreeable to both the Sponsor and Investigator.  
However, the final decision for submission/dissemination of results rests solely with the 
Investigator. 
 
 
 


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14. 
HUMAN SUBJECTS 
The study will not be initiated until a protocol has been filed to the IND or approved by the 
appropriate regulatory authorities and the informed consent documents have been fully reviewed 
and approved by each participating institution’s IRB/IEC/REB.  The approval and associated 
documents will be provided to the Sponsor.  All relevant regulations of the regulatory authorities 
will be followed. 
 Ethical Conduct 
The study will be conducted in compliance with the regulations from the FDA, Health Canada, 
local competent authorities, and the EMA, including Protection of Human Volunteers (21 CFR 
50), Institutional Review Boards (21 CFR 56), Good Clinical Practice guidelines (ICH), and 
Obligations of Clinical Investigators (21 CFR 312), Food and Drug Regulations (C.R.C., C.870), 
C.05.001 - Division 5, Drugs For Clinical Trials Involving Human Subjects, Regulation (EU) 
No.1235/2010, Directive 2010/84/EU, Directive 2001/20/EC (The Clinical Trials Directive), 
Commission Directive 2005/28/EC (The GCP Directive), and any other applicable country 
specific regulations. 
The protocol will be reviewed and approved by each institution’s IRB/IEC/REB, and as 
applicable, any country or regional IRB/IEC/REB.  Written documentation of the IRB/IEC/REB 
approval of the protocol and informed consent must be provided by the Investigator to the 
Sponsor prior to study initiation.  Serious adverse events regardless of causality will be reported 
to the Sponsor and to the IRB/IEC/REB, and the Investigator will keep the IRB/IEC/REB 
informed as to the progress of the study. 
 Informed Consent 
The Investigator or his designee will explain the nature of the study and will inform the subject 
that participation is voluntary and that they can withdraw at any time.  Written informed consent 
and required authorization to use private information will be obtained and documented from each 
subject prior to entry into the study. 
The consent form generated by the Investigator must be approved by the IRB/IEC/REB and be 
acceptable to Cancer Prevention Pharmaceuticals.  Each subject’s signed informed consent form 
must be kept on file by the Investigator for possible inspection by regulatory authorities and or 
Cancer Prevention Pharmaceuticals personnel or representatives of Cancer Prevention 
Pharmaceuticals. 
 Confidentiality 
The Investigator and his staff shall maintain the confidentiality of all subject records.  Subject 
data will be made available upon request to monitors from CPP Corporation (study Sponsor), 
regulatory authorities, the Institutional Review Board, Independent Ethics Committee, or 
Research Ethics Board, and to other government agencies that have responsibility for clinical 
research activities. 
Data that is released by the Investigator to the Sponsor, regulatory authorities, or the 
IRB/IEC/REB will not be directly traceable to the subject.  In the event that a publication of this 
research incorporates a subject’s medical data, the data will not identify the subject. 


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15. 
LISTING OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse event 
ALT 
Alanine Amino Transferase
a.m. 
Morning 
APC 
Adenomatous Polyposis Coli-tumor suppressor gene
AST 
Aspartate Amino Transferase
BID 
Twice a day 
0C 
Degrees centigrade
CBC 
Complete blood cell count
CFR 
Code Federal Regulations
CIOMS 
Council for International Organizations of Medical Sciences
cm 
Centimeters 
COX 
Cyclooxygenase 
CPP 
Cancer Prevention Pharmaceuticals
CPP-1X 
Eflornithine, DFMO, difluoromethylorthine
CRC 
colorectal cancer 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events
dB 
Decibels 
DFMO 
Eflornithine, CPP-1X, difluoromethylorthine
dL 
deciliter 
DMC 
Data Monitoring Committee
DMSO 
Dimethylsulfoxide
DNA 
Deoxyribonucleic Acid
EDTA 
Ethylene Diamine Tetra Acetic Acid
EFS 
Event free survival
EKG 
Electrocardiogram
EORTC 
European Organization for Research and Treatment of Cancer
EOT 
End of Treatment
EU 
Europe 
FAP 
Familial Adenomatous polyposis
FDA 
Food and Drug Administration
FFQ 
Food Frequency Questionnaire
GCP 
Good Clinical Practices
GI 
Gastrointestinal 
HCG 
Human Chorionic Gonadotropin
HDPE 
High density polyethlylene
HEENT 
Head, Ear, Eyes, Nose, Throat
HGD 
High grade dysplasia
HRQoL 
Health-Related Quality of Life
IB 
Investigator’s Brochure
ICH 
International Committee on Harmonization
IME 
Important medical event


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Abbreviation 
Description 
IND 
Investigational New Drug Application
InSiGHT 
International Society for Gastrointestinal Hereditary Tumours
IRA 
Ileal-rectal anastomosis
IRB/IEC/REB 
Institutional Review Board/Independent Ethics Committee/Research Ethics Board
ITT 
Intent-to treat 
IUD, IUS 
Intrauterine device, Intrauterine system
LGI 
Lower gastrointestinal
LGIOI 
LGI Observed Improvement
LOCF 
Last observation carried forward
mg 
milligrams 
mL 
milliliters 
mm 
millimeters 
MST 
Mountain Standard Time
N 
Normal 
NCBI 
National Center for Biotechnology information
NCI 
National Cancer Institute
NSAIDS 
Nonsteroidal anti-inflammatory drugs
NASR 
Nutrition Assessment Shared Resource
ODC 
Ornithine decarboxylase
OMIM 
Online Mendelian Inheritance in Man
PCR 
Polymerase Chain Reaction
PK 
Pharmacokinetics
PO 
By mouth, orally 
PSA 
Prostate specific antigen
QLQ  
Quality of Life Questionnaire 
QoL  
Quality of Life  
RNA 
Ribonucleic acid 
RSI 
Reference Safety Information
RX 
Treatment 
SAE 
Serious Adverse Event
SAP 
Statistical Analysis Plan
SNP 
Single nucleotide polymorphism
Spd:Spm 
Spermidine to spermine ratio
SWOG 
Southwest Oncology Group
TEN 
Toxic epidermal necrosis
UGI 
Upper gastrointestinal
UGIOI 
UGI Observed Improvement
ULN 
Upper limit of normal
US 
United States 
T1/2 
Half-life 
WBC 
White Blood Cell
WHO 
World Health Organization
 


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16. 
REFERENCES 
 
1. 
Spigelman AD, Williams CB, Talbot IC, et al: Upper gastrointestinal cancer in 
patients with familial adenomatous polyposis. Lancet:783-785, 1989 
 
2. 
Bulow S, Bjork J, Christensen IJ, et al: Duodenal adenomatosis in familial 
adenomatous polyposis. Gut 53:381-6, 2004 
 
3. 
Wu JS, McGannon EA, Church JM: Incidence of neoplastic polyps in the ileal 
pouch of patients with familial adenomatous polyposis after restorative proctocolectomy. Dis 
Colon Rectum 41:552-6; discussion 556-7, 1998 
 
4. 
Tekkis PP, Fazio VW, Lavery IC, et al: Evaluation of the learning curve in ileal 
pouch-anal anastomosis surgery. Ann Surg 241:262-8, 2005 
 
5. 
Tajika M, Nakamura T, Nakahara O, et al: Prevalence of adenomas and 
carcinomas in the ileal pouch after proctocolectomy in patients with familial adenomatous 
polyposis. J Gastrointest Surg 13:1266-73, 2009 
 
6. 
Groves CJ, Beveridge l G, Swain DJ, et al: Prevalence and morphology of pouch 
and ileal adenomas in familial adenomatous polyposis. Dis Colon Rectum 48:816-23, 2005 
 
7. 
Sturt NJ, Clark SK: Current ideas in desmoid tumours. Fam Cancer 5:275-85; 
discussion 287-8, 2006 
 
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Sinha A, Tekkis PP, Neale KF, et al: Risk factors predicting intra-abdominal 
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APPENDIX A SPIGELMAN’S SCORE AND STAGE_ENREF_92 
Modified Spigelman’s Score and Classification (Saurin, 2004)92 
 
Score 
Factor 
1 Point 
2 Points 
3 Points 
No. of polyps 
1-4 
5-20 
> 20 
Polyp size, mm 
1-4 
5-10 
> 10 
Histology 
Tubulous 
Tubulovillous 
Villous 
Dysplasia 
Low grade 
— 
High grade* 
NOTE:  Classification as follows based on score scale. 
Stage 0: 
no polyps 
Stage 1: 
1 to 4 points 
Stage 2: 
5 to 6 points 
Stage 3: 
7 to 8 points 
Stage 4: 
9 to 12 points 
*High-grade dysplasia would be assigned to any epithelium showing nuclear stratification all the 
way to the tops of the cells and loss of mucin production. It can encompass intraepithelial 
carcinoma if the cells are pleomorphic or even cribiformed in architecture but still all located above 
the basement membrane. 
Comment: All adenomas in the duodenum demonstrate at least low grade dysplasia; if intermediate 
grade use low grade for points. 
Vienna Classification of Gastrointestinal Epithelial Neoplasia (Schlemper et al., 2000)93 
Category 1 
Negative for neoplasia/dysplasia
Category 2 
Indefinite for neoplasia/dysplasia
Category 3 
Non-invasive low grade neoplasia (low grade adenoma/dysplasia) 
Category 4 
Non-invasive high grade neoplasia 
4.1 
High grade adenoma/dysplasia 
4.2 
Non-invasive carcinoma (carcinoma in situ)a 
4.3 
Suspicion of invasive carcinoma
Category 5 
Invasive neoplasia 
5.1 
Intramucosal carcinomab 
5.2 
Submucosal carcinoma or beyond
a Non-invasive indicated absence of evident invasion. 
b Intramucosal indicated invasion into the lamina propria or muscularis mucosae. 
 


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APPENDIX B 
InSiGHT RECTUM/POUCH ASSESSMENT AND STAGE94 
 
_ENREF_95 
 
Patients who cannot be allotted a particular stage (e.g., patients with mix polyposis) contact 
Cancer Prevention Pharmaceuticals for assistance with staging assignment. 
Stage 
Polyp Description 
Recommended 
Intervention 
Comment 
0 
0-10 polyps, all <5mm 
Repeat FS in 1 years 
 
1 
10-25 polyps 
most <5mm, none >1cm 
Ablate polyps; repeat 
sigmoidoscopy in 1 year 
Chemopreventive 
may be considered 
2 
10-25 polyps, any >1cm, 
amenable to complete removal  
Repeat sigmoidoscopy 6 
months 
Polypectomy preferred 
Removal of large 
polyps clearly 
necessary 
Chemopreventive 
valuable 
3 
> 25 polyps amenable to 
complete removal, or any 
incompletely removed sessile 
polyp, or any prior evidence of 
HGD, even if completely 
excised 
Repeat sigmoidoscopy 3-6 
months; consider 
proctectomy 
Large polyps must 
be removed; 
second opinion on 
polyp management 
helpful 
4 
>25 polyps not amenable to 
complete removal, or any 
incompletely excised sessile 
polyp showing HGD; any 
invasive cancer 
Proctectomy/pouch 
revision +/- ileostomy 
clearly indicated within 3 
months 
Any decision to 
delay surgery must 
be highly 
individualized and 
based on 
compelling 
circumstances 


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APPENDIX C 
NEW YORK HEART ASSOCIATION CLASSIFICATION TABLE 
NYHA Classification - The Stages of Heart Failure 
In order to determine the best course of therapy, physicians often assess the stage of heart failure 
according to the New York Heart Association (NYHA) functional classification system.  This 
system relates symptoms to everyday activities and the patient's quality of life. 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of 
breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or 
dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but 
less than ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity 
is undertaken, discomfort is increased. 
 


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APPENDIX D 
Desmoid Staging System9 
 
Stage 
Description 
I 
Asymptomatic, <10 cm maximum diameter, and not 
growing* 
II 
Mildly symptomatic, <10 cm maximum diameter, and not 
growing 
III 
Moderately symptomatic or bowel/ureteric obstruction, or 10 
to 20 cm, or slowly growing
IV 
Severely symptomatic, or >20 cm, or rapidly growing 
 
Mildly symptomatic = sensation of mass, pain, but no restrictions;  
Moderately symptomatic = sensation of mass, pain; restrictive but not hospitalized;  
Severely symptomatic = sensation of mass, pain; restrictive and hospitalized. 
* Stage I may also include larger, stable, asymptomatic desmoids 
 
_ENREF_95 
 


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APPENDIX E 
Event Rate Summary Table 
Familial Adenomatous Polyposis (FAP) Review:  Evidence-Based Projected Event Rates at 2 Years 
Rectum (after IRA) and Pouch (after Ileal-Pouch Anal Reconstruction)
Key References 
Comments 
Event/Rate
Bertagnolli, et al., N Eng J Med, 2006 
Bulow, et al., Dis Colon Rectum, 2008 
Church, et al., Surg Onc Clin N Am, 2009 
Church, et al., Dis colon Rectum, 2005 
Groves, et al., Dis Colon Rectum, 2005 
Huang, et al., Church, Familial Cancer, 2011 
Nieuwenhuis, et al., Dis Colon Rectum, 2009 
Tonelli, et al., J Surg Onc, 2000 
Vasen, The Lancet, 1996 
West, et al., Gut, 2010 
 
 
• 80% of patients develop adenomas within the pouch body. 
• 71% ↓of adenomas after 4-6 mo. Sulindac (300-400mg/day)-
analysis combined randomized studies. 
• Incidence of pouch adenomas is time-dependent with 42% of 
patients at 7 yrs from pouch construction. 
• Median time from pouch construction to diagnosis pouch 
adenomas, 4.7 yrs (0.5-12 yrs). 
• Celecoxib treated patients, median time to first polypectomy 
post IRA was 18.69 months; 90.9% (30 patients) had a post IRA 
rectal polypectomy. 
• Celecoxib treated patients, post IPAA, 3 of 24 pts (12.5%) had 
post IPAA polypectomy, 21 censored.  25th and 50th percentiles 
of time to first polypectomy in IPAA patients was 169.9 months 
• 80% of patients develop adenomas within the pouch body. 
• Celecoxib treated patients, median time to first polypectomy post IRA was 18.69 
months; 90.9% (30 patients) had a post IRA rectal polypectomy. 
 
 
 
Duodenal Disease 
Key References 
Comments 
Event/Rate
• Recurrence rate of adenoma development is > 
50% after endoscopic treatment and treatment is 
associated with 17% complication rate 
(perforation, hemorrhage, pancreatitis) 
• Rate of progression between Spigelman stages 
variable, 4 – 11 yrs 
 
• 95-100% of all FAP patients develop duodenal adenomas 
• 10-25% of patients have Stage III/IV 
• 36% of Spigelman Stg IV develop cancer 
• Endoscopic resection/ablation - local recurrence rate 72.5% with 
mean follow-up interval of 12.8 months.  Surgical resection-
30% mean follow-up of 44 months, Definitive resection 47 pts 
with recurrence rate of 9%.  Surgical morbidity-48%. 
• Patients down staged from Spigelman stage IV demonstrate 
increased rate of disease progression back to severe disease.
 
Pre-Colectomy 
 
Comments 
Event/Rate
 
• Diagnosis with recommendation to proceed with prophylactic 
colectomy or proctocolectomy. 
 
 
Summary Projected 2 year Event Rate: Excisional 
intervention and/or high risk adenoma – 40-60% 
Summary Projected 2 Year Event Rate: Excisional 
intervention, cancer – 90% 
Summary Projected 2 Year Event Rate: Excisional 
intervention, cancer – 50% 

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FAP – CPP-1X (Eflornithine HCl)/Sulindac 
SAP Final Ver. 5.2, January 25, 2019  
 
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STATISTICAL ANALYSIS PLAN 
 
 
 
A DOUBLE-BLIND, RANDOMIZED, PHASE III TRIAL OF THE SAFETY 
AND EFFICACY OF CPP-1X/SULINDAC COMPARED WITH CPP-1X, 
SULINDAC AS SINGLE AGENTS IN PATIENTS WITH FAMILIAL 
ADENOMATOUS POLYPOSIS (FAP) 
 
Protocol Number:  
 
CPP FAP-310 
 
Statistical Analysis Plan 
 
Version: 
 
 
Ver. 5.2, January 25, 2019 
 
NCT Number: 01483144 
 
 
Sponsor: 
Cancer Prevention Pharmaceuticals, Inc. 
1760 E. River Road, Suite 250  
Tucson, AZ 85718  
Phone: 520-908-7774  
Fax: 520-232-2191 
 


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STATISTICAL ANALYSIS PLAN (SAP) SIGNATURE SHEET 
 
The undersigned have reviewed the format and content of this Statistical Analysis Plan (SAP) for 
Cancer Prevention Pharmaceuticals, Inc. study CPP FAP-310 titled “A DOUBLE-BLIND, 
RANDOMIZED, PHASE III TRIAL OF THE SAFETY AND EFFICACY OF CPP-1X/SULINDAC 
COMPARED WITH CPP-1X, SULINDAC AS SINGLE AGENTS IN PATIENTS WITH FAMILIAL 
ADENOMATOUS POLYPOSIS (FAP)” and have approved this SAP as finalized. 
 
 
____________________________________ 
 
_______________________ 
Bruce Levin, Ph.D. 
 
 
 
 
 
Date 
Statistician 
 
 
____________________________________ 
 
_______________________ 
Robert B. MacArthur, Pharm.D., M.S. 
 
 
Date 
Clinical Affairs and Development 
 
 
____________________________________ 
 
_______________________ 
Alfred M. Cohen, M.D. 
 
 
 
 
Date 
Chief Medical Officer 


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Table of Contents 
STATISTICAL ANALYSIS PLAN (SAP) SIGNATURE SHEET ............................................... 2 
1. 
LIST OF ABBREVIATIONS ............................................................................................. 5 
2. 
INTRODUCTION .............................................................................................................. 6 
3. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 6 
3.1 
Overview of Study ............................................................................................................. 6 
3.2 
Study Objectives ................................................................................................................ 7 
3.2.1 
Primary Analysis ....................................................................................................... 8 
3.2.2 
Regulatory Review of Primary Outcome Compliance ............................................. 8 
3.2.3 
Secondary Efficacy Analyses ................................................................................... 9 
3.2.4 
Other Secondary Outcomes .................................................................................... 10 
4. 
POPULATIONS FOR ANALYSIS .................................................................................. 12 
4.1 
Intent-to-Treat (ITT) Population ..................................................................................... 12 
4.2 
Safety Population ............................................................................................................ 13 
4.3 
Per Protocol Population ................................................................................................... 13 
4.4 
Other Populations ............................................................................................................ 13 
5. 
DETERMINATION OF SAMPLE SIZE AND STATISTICAL METHODS ................. 13 
5.1 
Determination of Sample Size ......................................................................................... 13 
5.2 
Power Calculation Assumptions ..................................................................................... 13 
5.3 
Hazard Rates .................................................................................................................... 14 
5.4 
Data Monitoring Committee (DMC) ............................................................................... 15 
5.4.1 
DMC General Information ...................................................................................... 15 
5.4.2 
Prespecified Interim Efficacy and Futility Analysis ............................................... 15 
5.5 
Statistical Methods .......................................................................................................... 18 
5.5.1 
Demographic and Baseline Characteristics ............................................................ 18 
5.5.2 
Patient Disposition and Treatment Summaries ....................................................... 19 
5.5.3 
Analytic Methods for Time-to-Event Data ............................................................. 19 
5.5.4 
Analytic Methods for Categorical or Continuous-Valued Secondary Outcome and 
Safety Data ............................................................................................................. 20 
5.5.5 
Assessment of Toxicities ........................................................................................ 20 
5.5.6 
General Procedures for Handling Missing Data ..................................................... 21 
5.5.7 
Subgroup Analyses ................................................................................................. 21 
5.6 
Health Related Quality of Life (HRQoL) Statistical Methods ........................................ 21 
5.7 
Dietary Assessment ......................................................................................................... 22 
6. 
RANDOMIZATION ALGORITHM AND STRATIFICATION FACTORS ................. 23 
7. 
OTHER ISSUES AND FURTHER DETAILS ................................................................ 23 
7.1 
Statistical Software Used in Data Analysis ..................................................................... 23 
7.2 
Draft Tables, Listings and Figures .................................................................................. 23 


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7.3 
Details of Calculating the Stratified Log-rank Z-Score .................................................. 23 
7.4   Details of Calculating Conditional Power ....................................................................... 24 
8. 
REFERENCES ................................................................................................................. 25 
 
 
LIST OF TABLES 
Table 3.1 
Projected Event Free Rate by Disease Site .............................................................. 7 
Table 3.2 
Overall Event Free Proportions After Two Years of Follow-up* ............................ 7 
Table 3.3  
Disease Site Subgroups .......................................................................................... 10 
Table 5.1 
Interim Futility Analysis Details ............................................................................ 17 
Table 5.2 
Conditional Power at the Futility Boundary as a Function of Number of FAP Events 
at the Time of Futility Analysis, Using Futility Criterion Z = −0.5 ......................... 18 
 
LIST OF FIGURES 
Figure 5.1 
Schematic Diagram for Efficacy, Futility, and Terminal Analyses ....................... 18 
 
 
 


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1. LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event
ANCOVA 
Analysis of covariance
CPP 
Cancer Prevention Pharmaceuticals, Inc.
CPP-1X 
Eflornithine, DFMO, Difluoromethylornithine
CRO 
Contract Research Organization
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC/DSMB 
Data Monitoring Committee/Data Safety Monitoring Board 
EDC 
Electronic Data Capture System
EFS 
Event-Free Survival
EMA 
European Medicines Agency
EORTC 
European Organisation for Research and Treatment of Cancer 
FAP 
Familial Adenomatous Polyposis
FDA 
Food and Drug Administration
FFQ 
Food Frequency Questionnaire
HRQoL 
Health Related Quality of Life
ICH 
International Conference on Harmonization
ITT 
Intent-To-Treat
LGI 
Lower Gastrointestinal
LGIOI 
LGI Observed Improvement
LOCF 
Last Observation Carried Forward
NASR 
Nutrition Assessment Shared Resource (Fred Hutchinson Cancer 
Research Center)
NCI 
National Cancer Institute
ODC 
Ornithine Decarboxylase
QLQ 
Quality of Life Questionnaire
SAM 
S-Adenosyl Methionine
SAE 
Serious Adverse Event
SAP 
Statistical Analysis Plan
SAS 
Statistical Analysis System
UGI 
Upper Gastrointestinal
UGIOI 
UGI Observed Improvement
Z-score 
The value of the critical ratio (score statistic divided by its 
standard error) based on the stratified log-rank statistic. 
 
 


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2. INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the proposed statistical analysis of the Cancer 
Prevention Pharmaceuticals, Inc. (CPP) study CPP FAP-310 entitled: “A DOUBLE-BLIND, 
RANDOMIZED, PHASE III TRIAL OF THE SAFETY AND EFFICACY OF CPP-1X/SULINDAC 
COMPARED WITH CPP-1X, SULINDAC AS SINGLE AGENTS IN PATIENTS WITH FAMILIAL 
ADENOMATOUS POLYPOSIS (FAP)”. 
The purpose of this document is to apply sound analytic principles through description and pre-
specification of the statistical approaches and data handling conventions for key analyses and the 
randomization processes. 
This plan will focus on analysis of the primary and secondary endpoints, intended to assess the 
extent to which the combination treatment (CPP-1X 750 mg daily + sulindac 150 mg daily) is 
more effective than each of the two single agent treatments alone (CPP-1X 750 mg daily + 
placebo, and sulindac 150 mg daily + placebo) in delaying the time from the date of 
randomization to the date of the first occurrence of any FAP-related event in FAP patients.  
Sample size and total FAP-related events will be discussed, along with study population 
definitions.  In addition, we will summarize our approach regarding the analysis of safety data, 
pharmacokinetic data, and patient reported quality of life data.  The composition, charter, and 
initial tasks of the Data Monitoring Committee (DMC) will be described, along with planned 
interim analyses. 
3. STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Overview of Study 
This is a randomized, double-blind, phase III trial in patients with FAP to evaluate the safety and 
efficacy of the combination product 750 mg CPP-1X + 150 mg sulindac versus each of the two 
single-agent products: 1) 750 mg CPP-1X; and 2) 150 mg sulindac.  The primary study 
comparisons will be made between the combination product and each single agent product, 
separately. 
Eligible patients who have given informed consent will enter the study with the intent to 
participate for the full treatment period of 24 months.  Based on a subject’s date of 
randomization, patients will be offered continued preparticipation in blinded treatment for up to a 
total of 36, 42 or 48 months of treatment if they have completed the initial 24 months of 
treatment without an FAP event until one of the following occurs: 1) subject has an FAP event or 
comes off study for other reasons, 2) all randomized subjects have reached a minimum of 24, 36, 
42 or 48 months of treatment.  
A stratified randomization procedure will be used based on FAP-related time-to-first-event 
prognosis.  The event prognosis groups are represented by 1) best (i.e., longest projected time to 
first FAP-related event) - rectal/pouch polyposis, 2) intermediate - duodenal polyposis, and 3) 
worst - pre-colectomy.  If a subject has two or more of these disease sites, the most severe 
prognosis stratum will be assigned for randomization (e.g. worst > intermediate > best).  Since 
an individual may have more than one disease site involved, the trial will assess time to any 
defined FAP-related event in the patient as a whole.  In order to minimize potential treatment 
arm imbalance a centralized randomization process will be used to balance treatment groups 
within disease prognostic strata. 


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The stratification is predicated on the following projected event rates for the disease site specific 
eligibility criteria (rectal/pouch polyposis, duodenal polyposis, pre-colectomy) which are 
provided in the clinical study protocol (Appendix E) and summarized in Table 3.1. 
Table 3.1 
Projected Event Free Rate by Disease Site  
Disease Site 
Projected 2-year Event Free Rate Without Treatment
Rectum/Pouch Polyposis 
Excisional intervention and/or high risk adenoma – 40 - 60% 
Duodenal Polyposis 
Excisional intervention, Spigelman stage progression, cancer – 50%
Pre-colectomy 
Colectomy, proctocolectomy – 10%
 
The stratified randomization will be reflected in stratified analyses for the primary and secondary 
endpoints.  For design purposes only, however, the following simplified assumptions were made: 
an overall event free proportion of 30% in the single agent treatment group and 60% in the 
combination treatment group after 24 months of study treatment.  This is described further in 
Table 3.2 below.  See Section 5.1 for sample size and power calculations. 
Table 3.2 
Overall Event Free Proportions After Two Years of Follow-up* 
Treatment 
S(t) 
t (months)
Median Time to Event (months) 
Combination 
0.6 
24 
32.566
Single Agent 
0.3 
24 
13.817
*These proportions are assumed for design purposes only.  The median times to event are based on the 
assumption of an exponential time-to-event function S(t) in each group. 
 
At least 150 eligible patients will be enrolled in this study, with at least 50 per treatment group.  
Patients will be randomized to one of three treatment groups within the prognostic strata defined 
above in equal proportions (i.e., 1:1:1 randomization): 1) CPP-1X plus sulindac, 2) CPP-1X 
placebo plus sulindac, 3) CPP-1X plus sulindac placebo.  The study is double blinded, so neither 
patients nor Investigator nor Sponsor will be aware of treatment assignment. 
The grading of adverse events will be based on the current version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE Version 4.03). 
Refer to the CPP FAP-310 protocol for the details of the treatment and study schedule, and 
description of study procedures and tests. 
3.2 
Study Objectives 
The primary study analysis will be performed using the intent-to-treat (ITT) population which is 
defined in Section 4.1.  Statistical methods for the primary analysis are described in Sections 5.1 
and 5.5.3. 
The primary objective of this trial is to determine whether the combination of CPP-1X + sulindac 
is superior to either single-agent treatment individually in delaying time from the date of 
randomization to the date to the first occurrence of any FAP-related event. 
Thus the primary objective contains two treatment comparisons:  
1. CPP-1X placebo + sulindac active vs. CPP-1X active + sulindac active,  
and 
2. CPP-1X active + sulindac placebo vs. CPP-1X active + sulindac active  


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These two treatment comparisons will be performed sequentially, as described below. 
The combination of CPP-1X active + sulindac active is specified as the reference treatment 
group because it is common to both comparisons.  In addition, because the purpose of the 
combination treatment is to delay the time from randomization to FAP-related disease 
progression compared to single-agent treatments, formulating the hypothesis tests in this manner 
will allow a positive rather than a negative Z-score for the test statistic to be interpreted as 
supportive of this purpose. 
Each comparison will be performed at the 2-sided 0.05 level of statistical significance. 
As explained in Section 3.2.1 below, the decision to seek regulatory approval based upon the 
results of the primary objective will be taken sequentially. 
3.2.1 Primary Analysis 
The primary analysis will be a time-to-event analysis using the stratified log-rank test. Graphical 
analyses (log-minus-log plots) will be used to check the assumption of constant hazard ratios 
with the COX model.  See Section 7.3 below for further details of the calculation of the stratified 
log-rank statistic. The strata are the patient’s sites of disease involvement at baseline, which is 
determined prior to randomization, and are:  Rectal/pouch polyposis, Duodenal polyposis, and 
Pre-colectomy.   
For the primary analysis, two stratified log-rank tests will be performed with treatment coded as 
a binary value (i.e., 0 or 1). Time to event curves will be displayed using the method of Kaplan 
and Meier[8].  Additional analyses involving the overall 3-treatment group comparison and use 
of additional study populations (see Section 4.) for the two pairwise treatment comparisons, will 
be performed as supplemental analyses. Refer to section 5.5.3 for further details. 
3.2.2 Regulatory Review of Primary Outcome Compliance 
CPP has received advice from both the FDA and the EMA concerning the test method and 
criteria (Sections 3.2 and 5.) to be used when analyzing the primary study outcome, including the 
value of alpha. 
The US Food and Drug Administration (FDA) noted that the comparison of single agent CPP-1X 
vs. combination treatment will not provide information about the treatment effect of CPP-1X (i.e. 
eflornithine), and therefore this result will not be included in the product label.  Therefore, the 
primary analysis of import to FDA is the comparison of single agent sulindac vs. combination 
treatment. 
The European Medicines Agency (EMA) noted that for the three arm trial design the superiority 
of the combination treatment must be tested against both mono-components.  The combination 
treatment must be shown to be superior to both mono-components, or else the results will be 
considered inconclusive.  As a consequence, consistent with EMA/SAWP commentary, alpha 
does not need to be adjusted for multiplicity and two separate 5% two-sided tests will suffice. 
To harmonize the advice provided by these two Agencies, CPP will sequentially perform the two 
primary comparisons as part of the primary analysis, each at the 2-sided p = 0.05 level.  All 
information concerning these comparisons will be clearly provided to both Agencies.  The single 
treatment comparison requested by FDA will be available, as will the two comparisons requested 
by EMA, both at the requested level of alpha.  This approach fulfills the differing requirements 
for the primary comparison as asked for by each Agency.  


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We note that this approach is both a fixed-sequence and gatekeeping approach.  It is fixed-
sequence in that the comparison of combination with single-agent Sulindac takes place before 
the comparison of combination with single-agent Eflornithine and the first serves as a gatekeeper 
for the second (i.e., no declaration of significance in the second comparison will be made if the 
first comparison is not significant at the 0.05 level).  Therefore, the type I error in the sequential 
testing is well controlled.  In addition, because both tests must be significant for EMA approval, 
the type I error of the second test in the sequence is less than 0.05. 
3.2.3 Secondary Efficacy Analyses 
Any improvement observed by the investigator during upper gastrointestinal (UGI) and lower 
gastrointestinal (LGI) visualization (i.e. endoscopy and colonoscopy) at the 6 and 12-month 
study visits will be described using the variables UGI Observed Improvement (UGIOI), and LGI 
Observed Improvement (LGIOI).  Each patient will have one pair of UGIOI and LGIOI 
outcomes. 
UGIOI and LGIOI are binary outcomes derived from numerical determinations (henceforth, 
“investigator change scores” or more briefly, “scores”) assigned by the investigator during each 
procedure, using a scale (–2, –1, 0, +1, +2) which corresponds, respectively, to the investigator’s 
overall qualitative assessment of: much worse, worse, no change, improved, much improved.  At 
the month 6 procedures the investigator scores UGI and LGI findings as changes from baseline.  
At the month 12 procedures, the UGI and LGI findings are scored relative to the month 6 
procedures. 
The UGIOI (and respectively, the LGIOI) secondary endpoint independently summarizes the 
corresponding 6- and 12-month investigator change scores according to whether or not there was 
any positive improvement at either month 6 (compared to baseline) or at month 12 (compared to 
baseline or month 6), under the condition that there be no worsening at either timepoint 
(compared to the preceding timepoint).  Here are the specific possibilities (where “Improvement” 
stands for either the UGIOI or LGIOI secondary endpoint): 
• If the 6-month score is –2 or –1, Improvement=NO irrespective of the 12-month score. 
 
• 
If the 6-month score is 0, then Improvement=YES if and only if the 12-month score is +1 
or +2.  Otherwise Improvement=NO. 
 
• 
If the 6-month score is +1 or +2, then Improvement=YES if and only if the 12-month 
score is greater than or equal to 0.  Otherwise Improvement=NO. 
Any patient who drops out of the study before the month 12 assessment will be considered 
Improvement=NO. 
These binary UGIOI and LGIOI secondary efficacy endpoints will be compared in a manner 
analogous to the primary analysis, using the same two primary treatment comparisons (1: CPP-
1X placebo + sulindac active vs. CPP-1X active + sulindac active; and 2: CPP-1X active + 
sulindac placebo vs. CPP-1X active + sulindac active), and conditioning on the three disease site 
strata (Rectum/Pouch Polyposis, Duodenal Polyposis, Pre-colectomy).  The null hypothesis of no 
association between treatment group and Improvement endpoints will be tested using the exact 
Mantel-Haenszel procedure for combining the evidence contained in the fourfold tables 
(Treatment=Single agent vs. Combination cross-classified by Improvement=YES vs. NO) across 
the three strata.  For each of the two treatment comparisons, exact Mantel-Haenszel p-values will 
be calculated for both the UGI and LGI assessments (using the point-probability method based 


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on the convolution of three independent central hypergeometric distributions; see [1]).   
The overall type I error for the secondary efficacy analysis will be controlled using the Hochberg 
step-up method for multiple comparisons[2].  This analysis will be performed in the ITT 
population.  The primary analysis will serve as a gatekeeper to control the overall type I error 
rate at 0.05 for both primary and secondary analyses.  That is, significance for the secondary 
efficacy analysis will be declared only if the primary p-value is 0.05 or less, when the p-values 
are tested sequentially per the Hochberg method[2].  
Further analyses of the secondary endpoints may be conducted to evaluate and provide additional 
evidence to support its validity and confirm its clinical relevance. 
3.2.4 Other Secondary Outcomes 
To explore how study treatment group relates to other efficacy outcomes, genotype, phenotype, 
disease locations and endoscopic findings, additional analyses are planned.  These analyses will 
be performed in the ITT group, the Per Protocol Group, and other defined subgroups (see Section 
4 Populations for Analysis) wherever possible and will all be clearly noted as such. 
The UGIOI and LGIOI outcomes will be tabulated and summarized using the month 6 visit 
scores, alone.  Similarly, the UGIOI and LGIOI outcomes will tabulated and summarized across 
all study visits. 
As both part of the primary analysis, and further explored in these additional analyses, median 
time to event for each treatment group will be determined. This will be explored for each of the 
study populations (i.e. ITT, per protocol, and others), study disease stratum groups, and in the 
Disease Site subgroups (see below). 
Pharmacokinetic data (plasma concentrations measured at patient visits) will be used to estimate 
population pharmacokinetic parameters for the CPP-1X (eflornithine), sulindac, and CPP-1X 
(eflornithine) + sulindac treatment groups (i.e. for each analyte for those patients on combination 
treatment). 
The subcategories of FAP events will be explored by disease stratum groups, and by Disease Site 
subgroups (see below).  The subcategories of FAP events include: 
Table 3.3  
Disease Site Subgroups 
No Group 
Description 
1 
Disease Progression Indicating Need 
for Colectomy with IRA or Total 
Procto-Colectomy 
Applies only to subjects with FAP surgical 
status of precolectomy (field name: 
DIAGSXST, code 1) 
2 
Excisional intervention by surgical 
snare or trans-anal excision to remove 
any polyp >=10mm in size (per 
pathology report) and/or pathologic 
evidence of high grade dysplasia 
Excisional intervention does not apply to 
subjects with FAP surgical status of colectomy 
with ileostomy (field name: DIAGSXST, code 
4) or subjects with FAP surgical status of 
precolectomy (field name: DIAGSXST, code 
1). For all remaining subjects, all >5 mm polyps 
must have been removed at baseline 
also 


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No Group 
Description 
High grade dysplasia does not apply to subjects 
with FAP surgical status of colectomy with 
ileostomy (field name: DIAGSXST, code 4) 
3 
Disease Progression Indicating Need 
for Proctectomy 
Does not apply to subjects with FAP surgical 
status of proctocolectomy with ileal pouch 
anastomosis (IPAA) (field name: DIAGSXST, 
code 3) or FAP surgical status of colectomy 
with ileostomy (field name: DIAGSXST, code 
4) 
4 
Disease Progression Indicating Need 
for Pouch resection 
Does not apply to subjects with FAP surgical 
status of precolectomy (field name: 
DIAGSXST, code 1). or FAP surgical status of 
colectomy with ileostomy (field name: 
DIAGSXST, code 4) or FAP surgical status of 
colectomy with ileorectal anastomosis (IRA) 
(field name: DIAGSXST, code 2) 
5 
Development of cancer in rectum or 
pouch 
Does not apply to subjects with FAP surgical 
status of colectomy with ileostomy (field name: 
DIAGSXST, code 4) 
6 
Progression in Spigelman Stage to 
more advanced stage (Stage 2, 3, 4) 
Does not apply to subjects without duodenum 
(determined by abdominal surgical procedure of 
duodenectomy, duodenohemipancreatomy, or 
Whipple procedure (field name SXPROC) and 
screening/baseline upper GI endoscopy not 
done (field name UGIND, Boolean data type) 
7 
Disease Progression indicating need 
for excisional intervention (sub-
mucosal resection, trans-duodenal 
excision, duodenectomy, 
ampullectomy, Whipple procedure) 
Does not apply to subjects without duodenum 
(determined by abdominal surgical procedure of 
duodenectomy, duodenohemipancreatomy, or 
Whipple procedure (field name SXPROC) and 
screening/baseline upper GI endoscopy not 
done (field name UGIND, Boolean data type) 
8 
Development of cancer in duodenum 
Does not apply to subjects without duodenum 
(determined by abdominal surgical procedure of 
duodenectomy, duodenohemipancreatomy, or 
Whipple procedure (field name SXPROC) and 
screening/baseline upper GI endoscopy not 
done (field name UGIND, Boolean data type) 
9 
Spigelman stage (no progression) 
 
Does not apply to subjects without duodenum 
(determined by abdominal surgical procedure of 
duodenectomy, duodenohemipancreatomy, or 
Whipple procedure (field name SXPROC) and 


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No Group 
Description 
screening/baseline upper GI endoscopy not 
done (field name UGIND, Boolean data type) 
10 
>= 10 mm polyp in rectum pouch 
 
Does not apply to subjects with FAP surgical 
status of colectomy with ileostomy (field name: 
DIAGSXST, code 4) or subjects with FAP 
surgical status of precolectomy (field name: 
DIAGSXST, code 1). For all remaining 
subjects, all >5 mm polyps must have been 
removed at baseline. 
11 
High grade dysplasia (rectum-pouch) 
 
Does not apply to subjects with FAP surgical 
status of colectomy with ileostomy (field name: 
DIAGSXST, code 4) 
 
These subcategories will be analyzed within the assigned disease strata (i.e. assigned at time of 
randomization).  Separately, they will be analyzed by Disease Site, according to the concept of 
“the patient as a whole” meaning that all known disease sites will be considered because patients 
more often than not have more than one diseased organ system.  For example, a patient 
randomized to treatment in the Duodenal Polyposis stratum who is also known to have colonic 
polyps will appear in the analyses for both Disease Site subgroups (Duodenal and Colonic).  The 
total number of patients in the Duodenal Disease Site subgroup will include, for example, all 
patients randomized in the Duodenal Polyposis stratum + all other patients with known duodenal 
disease (irrespective of whether they have rectal/pouch disease).  A similar approach will be 
taken for the Rectum/Pouch Polyposis group and Pre-colectomy strata. 
The presence or absence of ODC polymorphisms, including the single nucleotide polymorphisms 
(SNPS) rs2302615 and rs2302616 and their relation to treatment group and outcome will be 
tested with the likelihood ratio test. 
The excretion of 5 urinary polyamines (diacetylspermine, n1-acetylspermidine, n8-
acetylspermidine, decarboxylated SAM, and putrescine) will be assessed in relation to treatment 
group and outcome, using the single point concentration data gathered from the urine samples 
harvested at each study visit. 
Patient reported health related quality of life measures will be evaluated using HRQoL (see 
Section 5.6 Health Related Quality of Life (HRQoL) Statistical Methods for more details). 
Tissue and dietary polyamine levels, as collected at patient study visits will be analyzed together 
with the results of the dietary questionnaires (see Section 5.7 Dietary Assessment) and related to 
treatment group and study outcomes. 
Safety outcome data and analyses are described in Section 5.5.5 Assessment of Toxicities. 
4. POPULATIONS FOR ANALYSIS 
4.1 
Intent-to-Treat (ITT) Population 
The intent-to-treat population includes all patients that have been randomized to one of the three 
study arms.  Patients will be analyzed in the group to which they were randomized, whether or 


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not they received their assigned treatment, any treatment whatsoever, or completed their 
treatment course and follow-up. 
4.2 
Safety Population 
The safety population is defined as all ITT patients who received at least one dose of study 
medication.  Patients who do not receive any study treatment (CPP-1X or sulindac or their 
combination) are excluded from this population.  Patients will be analyzed in the treatment group 
according to which actual treatment was initially received. 
4.3 
Per Protocol Population 
The per-protocol population is defined as the subset of the ITT population that fulfill all protocol 
eligibility, intervention, and outcome assessments. 
4.4 
Other Populations 
Within the entire study patient population there will be subsets who did not receive the full 
course of per protocol treatment.  The major indicators for premature withdrawal are delineated 
below.  The patient diary and pill count will define the extent of treatment compliance during the 
study. 
For exploratory and sensitivity analyses the following subsets will be included in secondary 
analyses: 
 Patients withdrawn for personal reasons 
 Treatment discontinued because of disease symptoms 
 Treatment discontinued because of patient symptoms 
 Compliance <80% treatments taken 
 Treatment discontinued because of intercurrent medical or surgical illness. 
5. DETERMINATION OF SAMPLE SIZE AND STATISTICAL METHODS 
5.1 
Determination of Sample Size 
The primary endpoint of this trial, time to meaningful clinical events in an orphan disease 
population, is novel and to date there are no published trials to draw upon that have incorporated 
the exact FAP-related endpoint of this trial.  Available data from primary literature sources 
include clinical studies where polyps were counted over a fixed time period, in different FAP 
populations (see protocol for tabulated listing).   
From these data a reasonable range of event frequencies was estimated to produce the sample 
size and power calculations incorporated into this trial.  These time-to-event estimates were 
reviewed by key FAP opinion leaders prior to finalization of the study design.  The following 
reflects the possible range of FAP events it was thought plausible to observe. 
5.2 
Power Calculation Assumptions  
1) The level of statistical significance is set at 0.05, using a 2-sided stratified log-rank test for 
time-to-first FAP-related event in continuous time, for each of the two between-group 
comparisons (i.e. single agent sulindac vs. CPP-1X plus sulindac and single agent CPP-1X vs. 
CPP-1X plus sulindac).  The only covariates in the log-rank test will be the treatment groups 
(see section 7.3 for details); 
2) A doubling of the two-year event-free proportion from either of the single agent treatment 
arms to the combination treatment group;  


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3) Power of at least 85% to detect the above-mentioned treatment effect comparing either of the 
two single treatment arms to the combination arm; 
4) The two single-agent treatment groups have approximately the same event rate. 
The following calculations are based on our review of limited single-agent data for eflornithine 
and sulindac, where FAP clinical trial primary endpoints involved polyp counting.  Extrapolating 
these data to two-year event-free proportions implies a single overall two-year event-free 
proportion of at least 60% to 70% for the combination treatment group and 30% in each single 
agent treatment group.  This is described further in Table 3.2. 
5.3 
Hazard Rates 
Because the power of time-to-event analyses depends on the total number of observed primary 
endpoints (“events”) and the hazard ratio in a given two-arm comparison of a single-agent versus 
combination therapy, we translate the above doubling of two-year event-free proportions into 
hazard ratios under a simplifying assumption of exponentially distributed time-to-event.  Note 
that the primary analysis described below, in Section 7.3, does not rely on such an assumption 
and provides a statistically valid test of the null hypothesis even if hazard rates are not constant.  
Furthermore, the stratified log-rank test is an optimal test (locally most powerful) under the 
assumption that the ratio of the two groups’ hazard functions remains constant over time (the 
proportional hazards assumption).  Note that the much stronger assumption, that the individual 
hazard functions themselves remain constant over time, would be dubious in this trial.  
Therefore, irrespective of how the two-year event-free proportions are translated into hazard 
ratios, it is the latter which forms the design alternative parameter for the trial. 
Under the exponential assumption, the hazard ratio (HR) comparing one treatment arm to 
another is given by the natural logarithm of the two-year event-free proportion for the first arm 
divided by the natural logarithm of the two-year event-free proportion for the other arm.  Thus if 
the combination arm is assumed to have a two-year event-free proportion of 60%, which is 
double that of the 30% two-year event-free proportions assumed for the single-agent arms, the 
HR is {log(0.60) / log(0.30)} = 0.4243.  This is the design alternative hazard ratio for this trial 
as it represents the minimum clinically meaningful treatment effect desired for the combination 
therapy compared to either single-agent therapy.  Insofar as the combination therapy may have a 
two-year event-free proportion of at least 60%, and may prove to be perhaps 70% or greater, the 
design alternative HR of 0.4243 is conservative; the true (albeit unknown) HR is thought 
possibly to range from 0.4243 down to 0.30 = {log(0.70) / log(0.30)} (see discussion below). 
Given that the primary hypotheses are stated in terms of comparing either single-agent arm to the 
combination arm, we note that the equivalent design alternative hazard ratio becomes  
{log(0.30) / log(0.60)} = 1/0.4243 = 2.357. 
For the anticipated range of hazard ratios, 25 to 49 events would be needed for each two-group 
comparison at the 2-sided 0.05 level to achieve 85% power [3, 4].  Assuming two-year event 
proportions of 70% in either of the two single-agent groups and 30% to 40% in the combination 
arm with 50 patients per arm, the expected number of patients with an FAP-related event in 
either of the two single-agent groups would be 35 and 15 - 20 in the combination arm.  The study 
design expectation is to have 50 - 55 patients with a FAP-related event in each two arm 
comparison, achieving at least 85% power under the design alternative.  The standard deviation 
around the expectation of 55 events is 4.74, so observing the required number of 49 events or 
more would be highly likely (the probability is about 91%).  If the total number of events in 
either comparison were only 43, there will still be 80% power to declare a significant treatment 


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difference under the design alternative of 0.4243.   
As the two-year event proportion in the combination arm decreases from 40% with a 
corresponding decrease in the hazard ratio, the likelihood of observing the required number of 
events to maintain 85% power actually increases.  For example, at the lower expectation of 50 
events arising from an assumed two-year event proportion of 30% in the combination arm, the 
standard deviation of the total number of events in a two-arm comparison decreases to 4.58 and 
the probability that the observed number of events will exceed the 25 required to achieve 85% at 
a HR of 0.30 is virtually certain. 
5.4 
Data Monitoring Committee (DMC)DMC General Information  
A Data Monitoring Committee (DMC) will oversee the performance and safety conduct of this 
study.  The DMC will consist of at least three members (two MDs and one statistician as voting 
members) who will receive confidential reports on a periodic basis.  The DMC will be 
responsible for decisions regarding possible termination of the study for either futility or safety 
reasons. 
A detailed DMC Charter will be produced separately by the DMC membership.  It is anticipated 
that any reviews of study data will be performed in a blinded manner, looking at pooled data (all 
treatment groups combined into one group) to assess mission-critical parameters such as overall 
recruitment and event rates.  Of course, patient safety issues take precedence over bias-protection 
and control of type I error, and so the DMC will have the privilege of breaking the blind on a 
need-to-know basis if safety issues of concern arise in order to consider risk-benefit issues.  
Details concerning DMC responsibilities and duties may be submitted as a stand-alone document 
to the FDA and EMA, including items such as specification of early termination rules and other 
matters as the DMC deems to be important and relevant to the ethical conduct of this study. 
CPP will inform the DMC that there will be two study evaluations for the DMC to consider 
during the trial, one interim look for sample size reassessment and one look for efficacy and 
futility. 
The method for reassessment of sample size is based upon the FDA Guidance, Adaptive Design 
Clinical Trials for Drugs and Biologics (February 2010).  There will be no hypothesis testing.  
The DMC will assess the observed trial event rate based on pooled data only.  They will make a 
recommendation to the sponsor on whether the pooled event rate is sufficient to preserve the 
integrity of the trial, and if not, to recommend a revised sample size.  For this assessment the 
study statistician will, if possible, estimate the overall observed event rate and 90% confidence 
interval.  This assessment will be performed using data from a single time point, when 
enrollment is approximately 95% complete.  If this type of assessment is not possible, then an 
assessment will be performed taking into consideration the total number of subjects randomized, 
total number of events, total number of dropouts, and cumulative study safety data. 
5.4.2 Prespecified Interim Efficacy and Futility Analysis 
A pre-specified interim efficacy and futility analysis will be conducted as described below.  The 
assessment will be performed after a total of 45 primary endpoints have occurred, which 
represents 50% of expected maximum trial information, or as soon thereafter as possible.  After 
reviewing the analysis results in a closed session, the DMC will provide recommendations 
regarding possible termination of the study for either futility, efficacy, or safety reasons, to the 
Sponsor Steering Committee. 
The analysis will be performed for each of the two treatment comparisons contained in the 


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primary objective:  
1. CPP-1X placebo + sulindac active vs. CPP-1X active + sulindac active, 
and 
2. CPP-1X active + sulindac placebo vs. CPP-1X active + sulindac active. 
As stated above in Section 3.2, the combination of CPP-1X active + sulindac active is specified 
as the reference treatment group because it is common to both comparisons and formulating the 
hypothesis tests in this manner will allow a positive rather than a negative Z-score for the test 
statistic to be interpreted as supportive of this purpose. 
The efficacy analysis will use a modified Haybittle-Peto stopping rule based on the stratified log-
rank Z-score.  If that Z-score equals or exceeds 3.2905 in absolute value, for either two-arm 
comparison, the difference between treatment arms would be declared statistically significant at 
the two-tailed 0.001 level of significance.  In that case it may be reasonable for the DMC to 
initiate a conversation about stopping the trial on ethical grounds.  Assuming this is not the case 
and the trial continues to its planned end, the Z-score criterion for declaring significance at the 
5% level at the end of the trial will be increased in magnitude to plus or minus 1.962 in order to 
preserve the overall type I error rate for the trial at 0.05. 
For the futility analysis, the DMC will be provided with the numerical value of the stratified log-
rank Z-score.  The futility analysis uses a one-sided futility stopping criterion of Z = −0.50. That 
is, if the Z-score is less than or equal to −0.50, an investigation will be initiated to consider 
stopping the trial for futility or discontinuing one of the single-agent treatment arms.  The futility 
stopping criterion of Z = −0.50 is consistent with a conditional power of less than 20%.  That is, 
assuming between 44 and 60 FAP-related events have occurred by trial end in either of the two-
arm comparisons (where between 52 and 55 are expected), if the log-rank critical ratio Z-score 
were equal to −0.5 (or less) when one-half the expected total number of events had been 
observed (namely, 45 across all three arms), then under the design alternative hazard ratio of 
2.3569, there would be no more than a 20% chance of declaring a significant benefit of the 
combination therapy compared to the single agent therapy if the trial were to continue to the 
planned end. In that case, it would be reasonable for the DMC to consider stopping or altering 
the trial on grounds of futility.  The DMC will also be provided with the conditional power of the 
observed Z-score for each two-arm comparison. 
The details of the efficacy and futility analysis are provided in Table 5.1 below which presents a 
schematic diagram of the procedure.  Also Table 5.2 provides more precise conditional power 
values corresponding to the futility criterion Z = −0.50 as a function of the total number of events 
in either two-arm comparison.  See Section 7.4 below for further details of the conditional power 
calculation. 
Any numerical values generated from the futility analysis (such as Z-score, conditional power, 
etc.) must be treated as confidential by the DMC and Independent Statistician at the CRO.  If the 
DMC recommendation is to continue the study as planned, such numerical values will not be 
forwarded or conveyed in any manner to the Steering Committee, sponsor, or any other parties. 
 
 
 


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Table 5.1 
Interim Futility Analysis Details 
Estimated Look Time Point 
Description 
 
When 45 primary endpoints have 
occurred, corresponding to when 
50% of maximum trial information 
has been amassed 
Efficacy criterion Z = 1.962 at terminal analysis. 
Futility criterion of Z = −0.50 or less at interim analysis. 
Type I error for exiting the upper efficacy boundary at or 
before terminal analysis = 0.024952.* 
Type I error for exiting the lower efficacy boundary at or 
before terminal analysis = 0.001928.* 
Total Type I error for end of study comparison  =  0.026936.*
Assuming 52 events at trial end in either two-arm 
comparison, power = 0.8705. 
Assuming 55 events at trial end in either two-arm 
comparison, power = 0.8881. 
 
*Assume one interim analysis at ½ information time with upper efficacy boundary at Be 
= 3.2905, lower efficacy boundary at −Be, and one-sided futility boundary  
Bf  = −0.50.  Assume upper efficacy terminal criterion C = 1.9602 and lower efficacy 
terminal criterion −C.  Then the probability of exiting the upper efficacy boundary at 
either interim or terminal analysis under the null hypothesis is given by  






e
f
B
B
e
dz
z
C
z
B
)
(
)
2
(
)
(

 
and the probability of exiting the lower efficacy boundary at either interim or terminal 
analysis under the null hypothesis is given by 







e
f
B
B
e
dz
z
C
z
B
)
(
)
2
(
)
(

, 
where 
)
(z

 is the standard normal probability density function and 
)
(z

 is the standard normal 
cumulative distribution function. 
 
 
 
 


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Figure 5.1 
Schematic Diagram for Efficacy, Futility, and Terminal Analyses 
‐4
‐3
‐2
‐1
0
1
2
3
4
0
0.5
1
Log‐rank    Z‐score
Information Fraction (1 = Total Expected Number of FAP events / 4)
Stop for futility‐‐‐‐‐>
Z = −0.5
Continue until trial end‐‐‐‐‐>
Reject Ho in favor 
of combination Tx
Reject Ho in favor 
of single agent Tx
Z = −1.962‐‐‐‐‐>
Z = +1.962‐‐‐‐‐>
Declare no 
significant difference
Z = −3.2905
Z = +3.2905
Reject Ho in favor 
of combination Tx
Reject Ho in favor 
of single agent Tx
 
 
Table 5.2 
Conditional Power at the Futility Boundary as a Function of Number of FAP 
Events at the Time of Futility Analysis, Using Futility Criterion Z = −0.5 
Total FAP events  
in either two-arm comparison 
at time of futility analysis 
Assumed number of FAP-related events  
in either two-arm comparison 
at trial conclusion 
Conditional 
power  
 
30 
60
0.177
29 
58
0.167
28 
56
0.157
27 
54
0.148
26 
52
0.138
25 
50
0.129
24 
48
0.120
23 
46
0.111
22 
44
0.103
 
5.5 
Statistical Methods 
5.5.1 
Demographic and Baseline Characteristics 
Patients in the three populations (see Section 4.) will be summarized for demographic and 
baseline characteristics in a descriptive fashion.  Namely, categorical and continuous-valued data 
will be displayed using standard summary statistics (e.g., frequency tables, n, means, medians, 


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standard deviations, and ranges).  Data will be presented per group and overall. 
Demographic features summarized will include age, gender, race, institution at which each 
patient registered, and country, among other features.  Baseline characteristics will include 
laboratory values and disease-related characteristics, as well as any other relevant values.  
Categorical data will be compared among groups using chi-squared methods, while continuous-
valued data will be compared using standard nonparametric methods (e.g., the Kruskal-Wallis 
test)[5].  Significance will be defined at the 0.05 level, unless otherwise noted.  Thus p-values 
less than or equal to 0.05 will be declared significant. 
5.5.2 
Patient Disposition and Treatment Summaries 
Subjects will be assigned for analysis to the treatment group to which they were randomized, 
regardless of whether the patients received any treatment. 
Patient disposition and treatment will be summarized for the ITT and safety populations defined 
previously (see Section 4.2).  Patient disposition will be consistent with the CONSORT 
criteria[6], and will include per treatment group enumeration of all patients randomized, the 
number deemed ineligible, the number of FAP-related events, and the number of study drop outs.  
These will be further described in subgroups such as drop outs due to adverse events, serious 
adverse events, administrative withdrawals for non-compliance for more than 90 days from 
randomization to month 36 or more than 105 days from randomization to month 42 or more than 
120 days from randomization to month 48, withdrawals of consent for continued follow-up, 
withdrawals for other reasons, and the number lost to follow-up.  Additional summaries will 
include reasons for patients discontinuing treatment and/or modifying treatment dosages.  A 
listing of screened and ineligible patients along with the reason for each also will be summarized. 
5.5.3 
Analytic Methods for Time-to-Event Data 
The analytic method for the primary analysis will be a time-to-event analysis using the stratified 
log-rank test, as previously described.  The stratified Cox proportional hazards regression models 
will be used for secondary assessments[7].  Graphical analyses (log-minus-log plots) will be used 
to check the assumption of constant hazard ratios.  See Section 7.3 below for further details of 
the calculation of the stratified log-rank statistic. 
For the primary analysis, two stratified log-rank tests will be performed with treatment coded as 
a binary value (i.e., 0 or 1). Time to event curves will be displayed using the method of Kaplan 
and Meier[8].  Additional analyses involving the overall 3-treatment group comparison, and use 
of additional study populations (see Section 4.) for the two pairwise treatment comparisons, will 
be performed as supplemental analyses. 
If an FAP-related event occurs, that patient will be said to have an observed or uncensored event 
and will be considered a treatment failure.  If a subject withdraws, that subject will be treated as 
a censored observation as of the last recorded clinic visit (endoscopic disease assessment). 
If a subject has not progressed or is not known to have died at the date of analysis cut-off, time to 
first FAP-related event will be censored at the date of the last adequate endoscopy procedures 
before the cut-off date.  Similarly, if a subject discontinues study participation due to toxicity and 
begins receiving other therapy, the time to FAP event will be censored at the date of the last 
adequate endoscopy procedure.   
If a subject has two or more missing assessments, time to first FAP-related event for the subject 
will be censored at the time of last adequate evaluation prior to the missing assessment. 


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If a subject has no baseline assessment, time to first FAP-related event for the subject will be 
censored at the date of randomization. 
See Section 5.5.6 below for further details of handling missing data.  Every effort will be made 
to minimize the occurrence of censoring and missing data. 
Prior to the primary analysis, balance will be assessed between the three arms in terms of key 
potential confounders measured at the baseline visit.  If any of these variables is found 
significantly out of balance across the three groups using a 2 degree of freedom test of 
homogeneity at the 0.01 level of significance, it will be incorporated into a sensitivity analysis 
using a stratified Cox model including that term in addition to the treatment arm.  The primary 
result for the trial will be the unadjusted stratified log-rank test.  The covariate-adjusted score test 
(adjusted stratified log-rank test) will serve only as a secondary analysis to aid in the 
interpretation of the primary result. 
5.5.4 Analytic Methods for Categorical or Continuous-Valued Secondary Outcome and 
Safety Data 
For categorical data, comparisons will be made between treatment groups using standard chi-
squared techniques as the primary approach.  In particular, the Cochran-Mantel-Haenszel one 
degree of freedom test will be used to reflect the stratified randomization.  Exact p-values and 
95% confidence intervals by the point-probability method will be reported[1]. 
For continuous endpoints, standard analysis of covariance (ANCOVA) methods will be used as 
the primary approach to compare treatment groups at end of treatment with the following 
covariates: baseline value, binary indicator variables for the two highest-risk stratification levels 
used in the randomization (using the lowest-risk, i.e., rectum/pouch polyposis, group as the 
reference stratum), and a binary treatment indicator (1=combination treatment, 0=single 
treatment). 
For ordered categorical data, a Kruskal-Wallis nonparametric test for ordered categorical 
response will be used to compare treatment groups[5]. 
5.5.5 Assessment of Toxicities 
Treatment-emergent adverse events will be enumerated and analyzed according to the incidence, 
intensity, type of adverse events, and clinically significant changes in the patient’s physical 
examination findings, vital signs and clinical laboratory results. Safety variables will be tabulated 
and presented for all patients in the safety and per-protocol populations as defined previously.  
Adverse events will be graded and coded using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE, Version 4.03).  Treatment-emergent events will be tabulated, where 
treatment-emergent is defined as any adverse event that occurs after administration of the first 
dose of study drug and through 30 days after the last dose of study drug, or any event that is 
present at baseline and continues after the first dose of study treatment but worsens in intensity.  
Events that are considered related to treatment (possibly, probably or definitely drug-related) will 
also be tabulated separately.  Tables that enumerate adverse events by severity will be provided.  
Deaths, serious adverse events and events resulting in study discontinuation will be tabulated in 
data listings including additional relevant information on each patient.  Tables will be presented 
both overall (all arms combined), by each treatment group separately, and by cell. Where 
appropriate, statistical comparisons between treatment arms will be provided using the above-
mentioned methods for analysis of categorical data. 


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5.5.6 General Procedures for Handling Missing Data 
Every reasonable effort will be made to continue follow-up of all study participants, including 
those who discontinue randomized therapy, to prevent data loss. It is recognized that missing 
values represent a potential source of bias in a clinical trial and so every effort will be undertaken 
to fulfill all the requirements of the protocol concerning the collection and management of data. 
For the primary time to event analysis, the only possible patient outcome is an observed FAP-
related event or a censored observation.  Participants who are lost to follow-up will be censored 
at the time their status is last known, based upon data collected at the last recorded clinic visit.  
For patients who may have missed a study visit, every effort will be made to obtain endoscopic 
results at their close-out visit and those endoscopy results will be used for the primary analysis 
Secondary analysis data include the presence of a specific genetic mutation, and urinary metabolite 
concentrations (see Section 3.2.3).  The main analysis of the secondary objectives will include 
collected data only, without imputing or weighting data to compensate for missing data.  For 
sensitivity analyses involving secondary endpoints with missing data, we will use the last 
observation carried forward (LOCF) method to complete the missing data.  Any sensitivity 
analysis that incorporates LOCF will be clearly noted.  Sensitivity analyses of these data will be 
performed to explore study results more fully, in a manner consistent with ICH Guidance “E9 
Statistical Principles for Clinical Trials (February, 1998)”. 
All available efficacy and safety data will be included in data listings and tabulations. Data that 
are potentially spurious or erroneous or appear as outliers will be examined using standard data 
management operating procedures, prior to database lock and statistical analysis.  These 
procedures will be fully described in the study report. 
5.5.7 
Subgroup Analyses 
Subgroups will be analyzed in the spirit of exploratory analyses including but not limited to the 
various study populations (see Section 4) and separately within each disease-prognosis stratum. 
5.6 
Health Related Quality of Life (HRQoL) Statistical Methods 
For this study four (4) instruments to measure HRQoL and patient preferences or utilities will be 
administered to subjects at baseline and at 3, 6, 12, 18, 24, 30, 36, 42 and 48 months post-
enrollment/end of treatment.  These instruments include the EORTC QLQ-C30, EORTC QLQ-
CR29, EQ-5D, and a modified Cancer Worry Scale. 
 The EORTC QLQ-C30 is a self-administered quality of life questionnaire[9] with multi-
dimensional scales. It consists of both multi-item scales and single item measures, 
including five functioning domains, a global quality of life domain, three symptom 
domains and six single items. 
 The EORTC QLQ-CR29 gastrointestinal/colorectal sub-module[10] is composed of 4 
functional and 18 symptom related sub-scales.  The 4 functional scales include body 
image, weight, anxiety and sexual function.  The symptom related scales include single 
item and multi-item questions concerning stool frequency, bleeding and mucous 
discharge, stool leakage, abdominal bloating, flatulence, embarrassment and site-specific 
pain among others. 
 The EuroQoL EQ-5D is a standardized instrument for use as a measure of health outcome 
and is applicable to a wide range of health conditions and treatments[11, 12].  It provides 
a simple descriptive profile and a single index value for health status. 


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 The Cancer Worry Scale[13] is a brief psychometric instrument that was designed to 
assess both the frequency of worrying about “getting cancer some day” and measuring 
the impact of worry on mood and performing daily activities.  This scale was originally 
developed by Caryn Lerman and her colleagues to study breast cancer and has been 
modified for use in this FAP trial. 
The validity and reliability of both the QLQ-C30 and the QLQ-CR29 questionnaires have been 
studied by the EORTC Study Group on Quality of Life and both instruments will be scored 
according to the EORTC Scoring Manual and analyzed accordingly.  For each single item or 
multi-item sub-scale, a linear transformation will be applied to standardize raw scores to range 
between 0 and 100.  HRQoL secondary endpoints will include all single item or multi-item sub-
scales from both the EORTC QLQ-C30 and QLQ-CR29 and patients will be considered as 
deteriorated (or improved) for a given single item or multi-item sub-scale if their change score 
from baseline was 10 points or more on the standardized scale.  
Patient preferences (or utilities) will also be assessed using the EuroQoL EQ-5D.  Preference 
weights among the treatment arms will be determined using the EuroQol EQ-5D assessment of 
individual health states[11, 12].  Quality-adjusted survival among the three treatment arms will 
be generated by multiplying the utility value by the amount of time spent in a specified health 
state. 
The modified version of the Cancer Worry Scale will also be administered and it will be scored 
according to the guidance provided by Lerman et al[13]. 
HRQoL data will be obtained while patients are receiving treatment. At the time of an FAP-
related event (primary outcome), additional long-term clinical follow-up and QoL data will not 
be obtained as part of this trial. Hence, HRQoL trends comparing the nine subsets will be 
obtained, but comparative longitudinal analyses defining the impact of an FAP-related event on 
QoL will not be feasible until subsequent long-term studies are performed. 
5.7 
Dietary Assessment 
The Food Frequency Questionnaire (FFQ) is the most common dietary assessment tool used in 
large epidemiologic studies of diet and health.  The self-administered FFQ booklet asks 
participants to report the frequency of consumption and portion size of approximately 125 line 
items over a defined period of time (e.g. the last month; the last three months).  Each line item is 
defined by a series of foods or beverages.  Additional questions on food purchasing and 
preparation methods enable the analysis software to further refine nutrient calculations.  The 
FFQ was developed by the Nutrition Assessment Shared Resource (NASR) of the Fred 
Hutchinson Cancer Research Center.  NASR periodically updates its standard FFQ to reflect 
U.S. food consumption patterns and major changes in the market place[14, 15].  Data from the 
FFQ will be analyzed using a polyamine database[16-18] and will calculate the average daily 
levels of putrescine, spermidine, and spermine in the diet.  Dietary assessments via the FFQ will 
be obtained at baseline, months 12, 24, 36, 42 (only if end of treatment), and 48/end of treatment 
for subjects at North American (U.S. and Canada) sites only.  Clinical study sites outside of 
North America will not be included because the foods on the North American food frequency 
questionnaire are not the same as those widely consumed in Europe and elsewhere.  
 


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6. RANDOMIZATION ALGORITHM AND STRATIFICATION FACTORS 
At least 150 eligible patients will be randomized in this study.  Patients will be randomized to 
one of three treatment groups in equal proportions (i.e., 1:1:1 randomization): 1) CPP-1X plus 
sulindac, 2) CPP-1X-placebo plus sulindac, 3) CPP-1X plus sulindac placebo. 
A stratified randomization procedure will be used with stratification based on FAP-related time-
to-first-event prognosis.  The event prognosis groups are represented by 1) best (i.e., longest 
projected time to first FAP-related event) - rectal/pouch polyposis, 2) intermediate - duodenal 
polyposis, and 3) worst - pre-colectomy.  If a subject has two or more of these disease sites, the 
most severe prognosis stratum will be assigned for randomization (e.g. worst > intermediate > 
best).  Since an individual may have more than one disease site involved, the trial will assess 
time to any defined FAP-related event in the patient as a whole.  In order to minimize potential 
treatment arm imbalance a centralized randomization process will be used to balance among 
treatment groups within prognostic strata. 
7.  OTHER ISSUES AND FURTHER DETAILS 
7.1 
Statistical Software Used in Data Analysis 
All analyses will be performed using SAS statistical analysis software version 9.1 or later.  If other 
software is used (i.e. WinNonPop for population pharmacokinetics, SAS macros for futility 
analysis, etc.), it will be clearly described in the clinical and statistical study reports. 
7.2 
Draft Tables, Listings and Figures 
The TLF (Tables, Listings, Figures) templates and shells are noted as Ver. 2.0, October 6, 2014 
(SAP Ver. 3.0 September 30, 2014) based on revision provided from Data 
Management/Statistical Group at Ockham now Chiltern.  These draft templates have been 
removed as an Appendix to the amended SAP and are available upon request. 
7.3 
Details of Calculating the Stratified Log-rank Z-Score 
Patient follow-up will be analyzed in continuous time, although it is recognized that FAP event 
detection will cluster around scheduled study visits, at months 6, 12, 18, 24, 30, 36, 42 and 48 
and event times may be tied as follow-up time is measured only to the nearest day. Censorings 
are possible at the baseline visit (month 0) for patients who dropped out of the trial before their 
first follow-up visit.  The primary test statistic will be the stratified log-rank statistic.  Each two-
arm comparison will be performed separately.  This will be implemented in SAS by specifying 
the TIES=DISCRETE option in PROC PHREG.  The single agent treatments, respectively, will 
be coded as 1 and the combination treatment will be coded as 0.  The square root of the score test 
chi-squared statistic will be calculated and the sign of the estimated log hazard ratio (+ if the 
HR>1 and − if the HR<1) will be attached.  This results in the stratified log-rank Z-score.  In 
symbols, 
2
)ˆ
(
X
sign
Zk



, where ˆ  denotes the estimated log hazard ratio coefficient for 
treatment A in the Cox model and where X2 denotes the SCORE TEST chi-squared statistic 
reported within the “Testing Global Null Hypothesis: BETA=0” table at the top of the PHREG 
results section.   
The following sample PHREG procedure could be used in SAS to derive the stratified log-rank 
Z-score: 
proc phreg data=TwoArmData; 
model time*censor(1) =  Treatment / rl ties=discrete; 


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Page 24 of 25 
strata Stratification_Factor; 
title "Stratified Cox Regression Analysis for Single Agent vs Combination"; 
run; 
quit; 
NB:  The model includes the variables time, censor, and treatment, only. 
 
7.4  
Details of Calculating Conditional Power 
Conditional power is given by the following formula[20].   













k
K
k
K
K
k
k
I
I
I
I
I
z
I
Z
)
(
power
 l
Conditiona
2
/
1


, 
where 
Zk is the value of the stratified log-rank test statistic from the observed data at interim analysis; 
z1−/2 is the critical value for a two-tailed test at =0.05, namely +1.962 adjusted for the interim 
efficacy analysis; 
IK = the information number expected at trial end = ¼ times the total expected number of events;  
Ik = the information number at futility analysis = ¼ times the observed number of events at 
interim analysis; 
θ is the log hazard ratio at the design alternative, log 2.3569 = −log 0.42428 = +0.85736; and 
)
(

 is the standard normal cumulative distribution function. 
 
Example.  Suppose at the time of interim analysis, the number of FAP-related events are as follows:  
For single-agent treatment A, 20; for single-agent treatment B, 16; and for combination treatment 
C, 9.  Then in the two-arm comparison of A versus C, there would be a total of 29 events, so the 
information number is Ik=29/4=7.25.  We assume that there will be double this number for the 
corresponding comparison at the end of the trial; thus IK = 14.5.  Suppose the Z-score at the futility 
analysis happens to just equal the futility criterion, i.e., suppose Zk = −0.50.  Then applying the 
above formula yields conditional power of  
 
1670
.0
25
.7
5.
14
)
25
.7
5.
14
(
85736
.0
5.
14
962
.1
25
.7
5.0













. 
This is the conditional power at the futility boundary.  Suppose, however, that the observed Z-
score at the futility analysis were actually +0.50 instead of −0.5.  Then the −0.5 in the first term of 
the above expression would be replaced by Zk=+0.50, and the resulting observed conditional power 
would be 0.5135, a non-futile result. 
Note that the probability of a significant negative result at the terminal analysis, given that there is 
no stopping for futility at the interim analysis, is not included in the above expression.  That is 
because practical interest for futility analysis resides only in the conditional probability of a 
significant benefit of the combination treatment.  In any case, the term which has been omitted is 
numerically negligible. 


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8. REFERENCES 
1. 
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Edition ed. 2003: New York: John Wiley & Sons.  See generally Section 2.7 and 
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2. 
Hochberg, Y.A., A Sharper Bonferroni procedure for multiple tests of significance. 
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3. 
Freedman, L.S., Tables of the number of patients required in clinical trials using the 
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4. 
Schoenfeld, D., The asymptotic properties of nonparametric tests for comparing survival 
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5. 
Lehmann, E.L., Nonparametrics: statistical methods based on ranks. 1975, San 
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6. 
Schulz, K.F., et al., CONSORT 2010 statement: updated guidelines for reporting parallel 
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7. 
Cox, D.R., Regression models and life tables. J Royal Stat Soc, 1972. Series B: p. 34182-
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8. 
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9. 
Aaronson, N.K., et al., The European Organization for Research and Treatment of 
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11. 
Brooks, R., EuroQol: the current state of play. Health Policy, 1996. 37(1): p. 53-72. 
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Drummond, M.F., et al., Methods for the Economic Evaluation of Health Care 
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13. 
Lerman, C., et al., Psychological side effects of breast cancer screening. Health Psychol, 
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14. 
Kristal, A.R., A.L. Shattuck, and A.E. Williams. Food frequency questionnaires for diet 
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15. 
Neuhouser, M.L., et al., Validity of short food frequency questionnaires used in cancer 
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16. 
Zoumas-Morse, C., et al., Development of a polyamine database for assessing dietary 
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17. 
Raj, K.P., et al., Role of dietary polyamines in a phase III clinical trial of 
difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal 
adenomas. Br J Cancer, 2013. 108(3): p. 512-8. 
18. 
Zell, J.A., et al., Associations of a polymorphism in the ornithine decarboxylase gene 
with colorectal cancer survival. Clin Cancer Res, 2009. 15(19): p. 6208-16.